GROW India Pediatric Endocrinology Protocols

GROW India
Growth & Obesity Workforce
Glucose Disorders Workshop

FromOctober
the Organizing
Why GROW India?
Secretary’s
16 2014, 9:00-10:30 PM
Growth is an integral part of
childhood that differentiates a Hotel Amar
child from an adult. The term
growth is not restricted to linear
growth alone but encompasses Course Co-ordinator
Dr Anurag Bajpai, PROTOCOLS
PEDIATRIC ENDOCRINOLOGY
holistic development of an
individual including intellectual
Pediatric Endocrinologist, Regency Hospital Kanpur
and pubertal development and
bone growth. Improving growth is
Fortis CDOC, FMRI, Gurgaon
t h e m o s t e ff e c t i v e w a y o f
improving the health of a society.
Lack of growth in short stature,

compromised reproductive Concept
potential and reduced bone mass Anurag Bajpai
Grow India would be a non governmental workforce dedicated to
adversely affecting the quality of
l i f e o f t h e i n d i v i d u a l . improving growth in children. It would work towards prevention and
Unfortunately lack of awareness early identification of growth disorders, making health care more
and access to preventive and approachable to children with growth disorders, providing suppor
therapeutic health care for to children with chronic growth disorders and developing nove
growth disorders has resulted in strategies for improving care of these children. The key players o
GROW Society
d i s a s t r o u s c o n s e q u e n c e s . would include health care professionals, school authorities, non
Excess growth in the form of
governmental organizations and media. The concept would be
obesity on other hand leads to
piloted at Kanpur with subsequent nation wide implementation.
the development of lifestyle
1
diseases like diabetes and heart
disease.
2
Table of contents
Section Page number
1.1 Growth Assessment 6
1.2 Growth chart- Which, when & how? 10
1.3 Bone age assessment 15
1.4 Management of growth failure 20
1.5 Obesity 27
2.1 Pubertal assessment 35
2.2 Precocious puberty 41
2.3 Delayed puberty 55
2.4 Hyperandrogenism 65
2.5 Turner syndrome 72
2.6 Disorders of sexual differentiation 84
2.7 Undescended testis 96
2.8 Gynecomastia 100
3.1 Sodium disorders 103
3.2 Potassium disorders 113
3.3 Metabolic acidosis 125
4.1 Hypocalcemia 129
4.2 Vitamin D deficiency 138
4.3 Refractory rickets 145
3
Section Page number
5.1 Diabetes mellitus- Classification 150
5.2 Diabetic ketoacidosis 155
5.3 Ambulatory management of type 1 DM 164
5.4 Type 1 DM- What’s new? 176
5.5 Hypoglycemia 185
6.1 Congenital hypothyroidism 203
6.2 Acquired hypothyroidism 211
6.3 Hyperthyroidism 215
6.4 Thyroid swelling 221
4
Pediatric Endocrinology Protocols
GROW Society
Web- www.grow-india.org,
Email- grow_india@yahoo.com
Growth & Obesity Workforce 5

GROW Society Pediatric Endocrinology Protocols
GROW India
Why GROW India? GROW Society Team

Growth is an integral part of Dr MM Maithani, Patron
childhood that differentiates a
child from an adult. The term Mrs Rajni Gupta, Advisor
growth alone but encompasses
Mrs Kumkum Swarup, Advisor
holistic development of an Dr Rashmi Kapoor, President
and pubertal development and Dr Rishi Shukla, Vice President
Dr Anurag Bajpai, General Secretary
Dr Yuthika Bajpai, Treasurer

Lack of growth in short stature, Dr Alok Bajpai, Executive

potential and reduced bone mass Dr Anjali Tiwari, Executive
Dr Vivek Saxena, Executive
Dr Samarth Vohra, Executive
and access to preventive and approachable to children with growth disorders, providing support
Mr Ashwani Kohli, Executive
therapeutic health care for to children with chronic growth disorders and developing novel
growth disorders has resulted in strategies for improving care of these children. The key players of
piloted at Kanpur with subsequent nation wide implementation.
the development of lifestyle GROW Society
diseases like diabetes and heart
Regency
disease. Hospital Limited, A2 Sarvodaya Nagar Kanpur, UP, 208001
Website- www.grow-india.org, Email grow_india@yahoo.com
Published by GROW Society Publications, Kanpur, 2014 (c) All rights reserved
6 Growth & Obesity Workforce

From the Editor’s Desk
Pediatric Endocrinology remains an exotic specialty dealing with rare and complicated disorders
requiring cumbersome work-up and exorbitant treatment for most pediatricians. On the contrary
Pediatric Endocrinology deals with a number of common disorders which can be worked up and
managed to a great extent with limited resources. Awareness of Pediatric Endocrinology is
mandatory for all Pediatricians for ensuring holistic evaluation of a child as growth and
development is what sets apart a child from an adult. Unfortunately lack of awareness and
training in the speciality results in missing and messing of a number of children with these
disorders. This is reflected by delayed presentation of children with growth and endocrine
disorders when not much can be done. GROW Society, growth and obesity workforce, was
formed as a non governmental workforce in Kanpur in 2013 with an aim of increasing
awareness about pediatric endocrine disorders amongst pediatricians, general physicians and lay
public. The organization has been working with schools, parents and pediatricians the three key
players involved in the management of children with pediatric endocrine disorders. Key efforts
have included development of school workshop modules for parents and teachers, formation of
patient support groups for growth hormone deficiency, celiac disease, hypothyroidism and type
1 DM and development of pediatric endocrine modules for pediatricians. The society has
developed six modules on growth, puberty, thyroid, glucose disorders, electrolyte and calcium
homeostasis that have been implemented across the country as three full day Practical Pediatric
Endocrine Course and 30 half day workshops.
The launch of GROW Society Pediatric Endocrinology Protocols forms the next logical step in
achieving the goal of the Society. The book covers almost the entire range of pediatric
endocrine disorders with special emphasis on common conditions presenting to the
pediatricians. The book is divided into six modules (corresponding to the GROW Society training
modules). They have been developed with an aim of providing practical approach for
assessment and management of the disorders. Clinical assessment has been given due
importance with an aim of minimizing investigations. The book is aimed at complimenting the
modules developed by the society and should be useful for postgraduate trainees and practicing
pediatricians.
Please let us know of your feedback that would be invaluable for us.
Anurag Bajpai, Pediatric Endocrinologist, Regency Hospital Kanpur
General Secretary, GROW Society,
Web- www.grow-india.org, www.dranuragbajpai.com
Email- dr_anuragbajpai@yahoo.com

Section 1- Growth
1.1 Growth Assessment
Careful growth assessment is the cornerstone of successful evaluation of a

child with growth disorder. The most important parameters to evaluate in a
child with growth disorder include those measuring linear growth (length,
height and growth velocity), body proportions and markers of adiposity (weight
for height and body mass index).
RECOMMENDATIONS FOR GROWTH MONITORING

The Indian academy of pediatrics task force for growth monitoring
recommends the following protocol for growth assessment.
! Birth- Weight, length, head circumference, penile length testicular descent
! Six weeks to three years
! During vaccination visits (6, 10, 14 weeks, 9 months, 15-18 months)
! Additional visit around six month coinciding with any illness
! Six monthly visits between 18 to 36 months
! Parameters- Weight, length, head circumference
! 3-8 years
! Six monthly height and weight
! BMI and stretched penile length from 6-8 years
! 8-18 years
! Annually
! Height, weight, BMI and sexual maturity rating.
ASSESSMENT OF LINEAR GROWTH

This includes cross-sectional measurement of height and longitudinal
measurement of growth velocity. Both are important as while height gives a
snapshot of growth; growth velocity gives a clue about the progress of the
child.
Cross sectional assessment

Length should be measured in children younger than two years of age and
those with height less than 80 cm. In older children measurement of height is
recommended.

Interpretation
! Growth chart- Compared to population reference
! More than 97th percentile- Growth acceleration
! 3rd- 97th percentile- Normal
! Less than 3rd percentile- Growth retardation
! Adjustment for pubertal stage crucial
Assessment of genetic potential

Cross sectional growth should always be interpreted in light of parental
expectation. This involves actual measurement of parental height as reported
heights are usually erroneous.
! Calculation of mid parental height
Mid parental height = Father height + Mother height

2
Target height (boys) = Mid parental height + 6.5 cm
Target height (girls) = Mid parental height – 6.5 cm
Target height range = Target height ± 6 cm
! Assessment
! Mark target height and range on growth chart
! Plot current height on growth chart
! Extrapolate current height percentile to final height
! Interpretation
• Height above target height range- Growth acceleration

• Height in target height range- Normal

• Height below target height range- Growth retardation
Longitudinal assessment
Longitudinal measures of growth should ideally be done over a period of at
least six months (ideally one year) given the inherent errors in height
measurement and saltatory pattern of growth.
Norms for growth velocity

Age Normal Abnormal
1-2 years 10 cm/year < 7 cm/year
6 years- puberty 5 cm/year < 4 cm/year
ASSESSMENT OF BODY PROPORTIONS

! Upper segment to lower segment ration
! Measurement
! Measure standing height
! Measure height while sitting on a stool (sitting height)
! Upper segment= Measured height on stool − height of stool
! Lower segment= Height − upper segment
! Normal range- Birth- 1.7: 1.0, decrease by 0.07/year till 10 years to
become 1.0: 1.0
! Interpretation
! Decreased- Decreased spine growth
! Increased- Decreased limb growth
! Arm span- Measure of limb growth
! Stretched arm against firm wall, perpendicular to chest
! Arm span= distance between the distal end of the two middle fingers
! Normal range
! Boys: Less than height till 12 years of age; Ht + 5.3 cm in adults
! Girls: Less than height till 14 years of age; Ht + 1.2 cm in adults
! Interpretation
! Increased- Increased limb growth
! Decreased- Decreased limb growth
! Metacarpal shortening
! Firm scale placed over closed fist joining third to fifth metacarpal
! Metacarpal shortening if scale more than 2 mm away from metacarpal

ADIPOSITY ASSESMENT
Obesity implies excessive body fat and not merely excess weight. As methods
of measuring body fat are cumbersome and expensive, clinical parameters are
used as markers of obesity.
Body mass index- Body mass index (BMI) is the most widely used parameter
to define obesity. It takes into account body weight as well as the height of the
individual. It is calculated by the formula
BMI = Weight kg/ height m2
BMI is interpreted in light of population reference.

! >95th Percentile- Obesity
! 85th - 95th Percentile- Overweight
! 5th - 85th Percentile- Normal
! <5th Percentile- Malnutrition
! < 1st percentile- Severe malnutrition
Weight for height- This parameter compares the child’s weight to the
expected weight for his/her height. This is recommended for children below
two years of age. Values above 95% are indicative of obesity while those
below 80% indicate malnutrition.
FURTHER READING
1. Lifshitz F, Botero D. Worrisome growth. In: Pediatric Endocrinology, Eds:
Lifshitz F, Marcel Dekker, 2003, New York, 4th edition. Pp 1-47.
2. Khadilkar VV, Khadilkar AV, Choudhury P, Agarwal KN, Ugra D, Shah NK.
IAP growth monitoring guidelines for children from birth to 18 years. Indian
Pediatr 2007; 44: 187-97.

1.2 Growth Charts- Which, When & How
Growth charts represent the most important diagnostic tools for evaluating a
child with growth disorder. Careful plotting of growth charts often provides
reasonably good idea for the underlying diagnosis. There is thus a need for
routine monitoring of all children using growth charts.
What are growth charts? Growth charts are percentile curves prepared from
population based studies where anthropometric measures are collected from a
large number of children in a cross sectional manner.
Types of growth charts in use: Growth charts that are most commonly used
are height, weight, BMI and head circumference charts. Many other charts
such as sitting height, subischeal length, biacromial diameter, knee height,
skin fold thickness etc are available but are mainly used for research purpose.
Most growth charts have standard 7 percentile lines viz. 3rd ,10th, 25th, 50th,
75th ,90th and 97th.
Height Charts: Height charts are used from birth to 18 years of age in both
sexes. They are very useful to monitor the growth of the baby and child over a
period of time. These charts are also known as distance charts. Age is divided
into monthly intervals. Along with distance charts height velocity charts are
also used to monitor growth velocity. These charts are particularly useful to
pick-up growth failure early as growth velocity is a more sensitive indicator of
growth failure.
Weight Charts: These charts are used from birth to 18 years in both sexes. In
infancy they are more often used than in later childhood. Weight charts are
useful to diagnose both failure to thrive as well as obesity.
BMI Charts: BMI charts which are age and sex specific are useful in
diagnosing overweight and obesity at all ages.In addition to the usual standard
7 percentile lines BMI charts have two other lines viz. 85th and 95th to
diagnose overweight and obesity respectively.
Shortcomings of growth charts: Although generally very useful growth

charts are not fool proof and they have certain short comings. Growth charts
need to be country specific and need to be regularly updated (WHO
recommends that each country needs to update its chart every decade) so
that secular trend in the growth pattern can be accommodated.

Which growth charts to use? Given the plethora of growth charts available it
is often a dilemma to choose a growth chart. Some guidelines are as below.
Height chart- Below 5 years of age WHO charts are recommended. Beyond
that the options include CDC charts, KN Aggarwal charts recommended by
IAP and Khadilkar chart of affluent children. There are subtle differences in the
measures at different ages across the charts and are important in research
setting. From a clinical stand point use of any growth chart with correction for
parental height is adequate.
BMI- The options include CDC charts, IOTF charts and Khadilkar’s charts
based on affluent Indian children. The CDC charts tend to underestimate
obesity in Indian population data. The IOTF chart have been aimed to even
out regional differences in obesity and based on back tracking of adult obesity
cut-offs. These charts are more for research purposes. In practice most
children presenting for evaluation of obesity are much above 95th percentile for
age, the cut-off for obesity for most growth charts.
HOW TO USE GROWTH CHARTS?

Growth charts have two axes. X axis has age and Y axis has the respective
parameter such as height, weight, BMI etc. Anthropometric parameters are
measured and plotted against the specific age on the x axis. If the plotted dot
falls between the 3rd and 97th percentile lines it is considered as normal. 50th
percentile is considered as average. The danger lines change from chart to
chart. In case of height chart any reading above or below 3rd or 97th percentile
is abnormal. In case of height velocity chart anything below 25th percentile for
age is considered abnormal. For interpretation of BMI, any child above the 85th
percentile is overweight and above 95th percentile is obese.
STEPS IN EVALUATING GROWTH CHART

Three key steps to look in the growth chart are.
! Current height and weight status- As reflected by percentile.

! Correction for mid parental height
! Plot MPH at the age of 18 years. This is 50%ile for the child.
! Put points 6 cm and above the mid parental height.
! Backtrack from the two range points in parallel to the other percentile
lines. This provides the target height range. Alternatively forward track
the current growth to 18 years and see if it fits in to target height range.
! Calculation of height and weight age
! Draw a line from the current height till it meets the 50th percentile line.

! Now draw a perpendicular to this point till the X axis.

! The age corresponding to this point represents the height age.
! Repeat the same exercise for weight to obtain weight age.
! Interpretation
! In children with growth failure
! Nutritional growth retardation (malnutrition, systemic illness and
malabsorption) has predominant effect on weight age which is
much lower than height age and chronological age.
! Endocrine causes (hypothyroidism, GHD) on the other hand result
in much greater compromise in height age than weight age.
• Wt age << Ht age < Bone age < Chronological age- Nutritional
• Ht age = Bone age << wt age < Chronological age- Endocrine
! Obesity
! Height age is greater than chronological age in exogenous obesity.
! Lower Ht indicates the possibility of pathological obesity.
• Chronological age < Ht age < weight age- Exogenous obesity
• Ht age < BA < chronological age < wt age- Pathological obesity
ILLUSTRATIVE CASES
Case 1- Catch down growth in an infant for Diabetic mother

Case 2- Familial short stature
Case 3- Constitutional delay of puberty and growth

Case 4- Nutritional growth retardation due to celiac disease
Case 5- Short stature due to growth hormone deficiency

1.3 Bone age assessment
Bone age assessment forms an important aspect of growth assessment.

Importantly bone age has diagnostic as well as prognostic value in a child with
growth failure.
INDICATIONS
! Assessment of growth failure
! Diagnostic role
! Severe delay- Endocrine etiology (Hypothyroidism, GHD)
! Mild delay- Constitutional delay of puberty, systemic diseases
! Normal- Turner syndrome, skeletal dysplasia
! Prognostic role- Prediction of adult height
! Confirmation of fetal hypothyroidism- Absent knee epiphysis
! Consideration of GnRH analog treatment in precocious puberty
! Bone age 2 years greater than chronological age
! Height SDS for bone age less than -2
! Assessment of obesity
! Delayed bone age suggests endocrine etiology
! Advances bone age is suggestive of constitutional obesity
SITE
! Infants- Knee AP
! Childhood and adolescence- Left hand AP (non dominant hand)
! For epiphyseal closure- Knee and shoulder AP
TECHNIQUES FOR BONE AGE ASSESSMENT

Assessment of bone age involves comparison of skeletal maturity to
population standards. The most widely used bone age tools include Greulych-
Pyle atlas and Tanner Whitehouse methods. These methods are cumbersome
and difficult to implement in routine pediatric practice. Given the complexities
of GP atlas and TW2 methods a simplified figure has been constructed to
provide a quick idea of bone age. Skeletal maturation progresses from
proximal to distal direction while fusion happens in the reverse fashion from
distal to proximal. Thus the site to be assessed should be based on age of the
child. Carpal bones are of importance in the first two years of life beyond
which distal bones assume significance. Comparison of size of epiphyses to
metaphysis of proximal and distal interphalengeal joints is most important clue
to bone age between 6-12 years. The size of epiphysis is lower than

metaphysis till 6-10 years of age and become similar to metaphysis by around
12 years of age Capping of metaphysis indicates near fusion of epiphyses.
Age group Region of interest
Infancy Capitate and hamate
Early childhood Metacarpal and phalanges
Pre puberty Compare ephiphyses to metaphysis
Early Puberty Ephiphsis size
Late puberty Fusion of phalanges

Infancy Capitate and hamate
Early childhood Metacarpal and phalanges
Pre puberty Pediatric

Compare Endocrinology
ephiphyses Protocols
to metaphysis
Early Puberty Ephiphsis size
Late puberty Fusion of phalanges
Infancy (Focus on Capitate and Hamate)

Early Childhood- Metacarpal and phalanges
Pre puberty- Compare ephiphysis to metaphysis

Early puberty- Epiphyseal Size
Late Puberty- Fusion of Phalangeal epiphysis

1.4 Management of growth failure
Management of growth failure involves comprehensive assessment and timely

initiation of growth promoting interventions. Given the limited duration of
growth the process should be expedited in children presenting at an older age.
INDICATIONS FOR EVALUATION

Extensive evaluation
2. Short Stature is reserved for children with height below 1st percentile .
In children with milder growth failure (height between 1st to 3rd percentile )
evaluation should be done if growth velocity is compromised. Children with
2.1 Criteria
slow growth rateless
•Height resulting in crossing
than 3rd percentile twodeviation
or −2 standard percentile lines between the age of
score (SDS)
•Growth velocity less than 25th percentile or −1 SDS
two years and puberty need to be evaluated even if height is in normal range.
2.2 Etiology
ETIOLOGY
Short stature
Physiological Pathological
Constitutional delay
Familial short stature
Secondary growth failure

Primary growth failure
Skeletal dysplasia
Achondroplasia
Hypochondroplasia
Dysmorphic syndromes
Turner syndrome
Down syndrome
Silver Russell syndrome
Prader willi syndrome
Intrauterine growth retardation
Systemic diseases Endocrine diseases

Malnutrition- PEM, zinc deficiency Growth hormone deficiency (GHD)
Cardiac- Congenital heart disease, RHD Growth hormone insensitivity (GHIS)
GIT- Celiac disease, crohns disease Hypothyroidism
Liver- Chronic liver disease Cushing syndrome
Kidney- Renal failure, renal tubular acidosis Type 1 Diabetes mellitus
Respiratory- Cystic fibrosis, bronchial asthma Rickets
Infections- AIDS, tuberculosis Pseudohypoparathyroidism

EVALUATION
! History
! Age of onset
! Prenatal- Genetic syndromes, intrauterine infections
! Infancy- Congenital growth hormone deficiency, hypothyroidism
! Early childhood- Malabsorption (celiac disease), RTA
! Late childhood- Acquired GHD, hypothyroidism, systemic diseases
! Perinatal history
! Birth weight, length, head circumference (IUGR)
! Mode of delivery (breech delivery associated with GHD)
! Jaundice (intrauterine infection, hypothyroidism, hypopituitarism)
! Hypoglycemia, micropenis (hypopituitarism)
! Lymphedema (turner syndrome)
! Feeding difficulty, hypotonia (Prader willi syndrome)
! Puberty
! Delayed- Hypothyroidism, hypopituitarism, CDPG, celiac disease
! Advanced- Hypothyroidism (girls), untreated precocious puberty
! Family history (familial short stature, GHD, GHIS, skeletal dysplasia)
! Onset and progression of puberty in parents (constitutional delay)
! History suggestive of urinary tract infection, tuberculosis, HIV infection
! Features of steatorrhea (cystic fibrosis, malabsorption)
! Features of liver disease, renal failure, cardiac disease, hypothyroidism
! History of exposure to steroids, radiotherapy, chemotherapy
! Developmental delay- PHP, hypothyroidism, genetic syndrome
! Examination
! Upper segment to lower segment ratio
! Increased- Achondroplasia, turner syndrome
! Decreased- Spondylo-ephiphyseal dysplasia
! Arm span- Decreased in achondroplasia and hypochondroplasia
! Metacarpal shortening- Turner syndrome, pseudohypoparathyroidism
! Pubertal status (delayed in CDGP, hypopituitarism, turner syndrome)
! Diagnostic clues, features of common disorders

Table 1.41 Clues to etiology of short stature

Clue Etiology
Mid line defect (cleft lip, palate) Hypopituitarism
Micropenis Hypopituitarism, prader willi syndrome
Blindness (optic dysplasia) Hypopituitarism
Single central incisor Hypopituitarism
Rickets Renal failure, malabsorption, RTA
Pallor Renal failure, malabsorption
Malnutrition Protein energy malnutrition, malabsorption
Metacarpal shortening Turner syndrome, pseudohypoparathyroidism
Cardiac murmur Turner syndrome, CHD, intra-uterine infection
Deafness Turner syndrome, intra-uterine infection
Tetany Pseudohypoparathyroidism (PHP)
Mental retardation Hypothyroidism, genetic syndromes, PHP
Table 1.42 Comparison of familial short stature and CDPG
Feature Constitutional delay Familial short stature

Weight Decreased Normal
Growth velocity Normal Normal
Skeletal maturation Retarded Normal
Family history
Short stature No Yes
Delayed puberty Yes Variable
Puberty Delayed Normal or early
Final height Low normal Compromised

Figure 1- Eight-year-old girl with disproportionate short stature. She had large
head, bowing of legs and short limbs. X ray of the lumbar spine showed
cuboid lumbar vertebrae confirming achondroplasia.
Figure 2 Six-year-old girl with severe growth retardation (height SDS −7) and
rickets. Investigations showed severe hyperchloremic acidosis and
nephrocalcinosis suggesting distal renal tubular acidosis

Figure 3 Six-year-old boy with severe growth retardation (height SDS- −3.4),
central obesity, micropenis and cryptorochidism. Peak GH after clonidine
stimulation test were 0.4 ng/ml confirming growth hormone deficiency.
APPROACH

MANAGEMENT
Nutritional therapy
! Correct iron deficiency (3 mg/kg/day iron for three months)
! Zinc supplementation (10 mg/day for 3-6 months)
Specific treatment
! Hypothyroidism- Thyroxin supplementation
! Celiac disease- Gluten free diet
! Constitutional delay of puberty and growth
! Androgens after bone age is greater than 12 year
! Testosterone 50 mg once a month intramuscularly for 6 months
! Experimental therapy
! Delay of epiphyseal fusion- GnRH agonist, aromatase inhibitors
! Limb lengthening (Ilizarov technique)- Skeletal dysplasia
Growth Hormone Therapy

Condition Indication Dose Gain Status
GHD All 25-50 µg/kg/day 2-3 Recommended
Turner Ht < 5th percentile 50-100 µg/kg/day 1-2 Recommended
Renal failure Growth retardation 50-100 µg/kg/day 1-2 Recommended
SGA No catch up ** 50-200 µg/kg/day 2-3 Recommended
PW syndrome Growth failure 25-50 µg/kg/day 2-3 Recommended
ISS Growth failure*** 50-100 µg/kg/day 0.5-1 Experimental
*- In height SDS, **- by four years of age, ***-Height SDS < −2.5, GVSDS < −1
! Growth hormone deficiency
! Exclude or treat ACTH and TSH deficiency
! Minimum period of two years after treatment for malignancy
! Treatment- Growth hormone- 25-50 µg/kg/day
! Increase in growth velocity to 8-12 cm/year during first year
! Growth velocity of 6-8 cm/year during subsequent years
! Overall improvement in height by 2-3 SDS
! Turner Syndrome
! Indications
! Height less than fifth percentile
! No need of GH provocation test
! Dose- 50-100 µg/kg/day

! Concomitant treatment
! Oxandrolone (non aromatizable androgen)
! Pubertal induction after 13 years or five years after GH
! Chronic renal insufficiency (CRF)

! Indication- Growth retardation on renal replacement program
! Prerequisite- Correct metabolic acidosis, anemia, hyperparathyroidism
! Dose- 50 µg/kg/day
! Expected benefit- Increase in height by 1.0- 1.5 SDS
Small for gestational age (SGA)

! Indications
! Birth weight less than −2 SDS
! Height less than −2.5 SDS by four years of age
! Growth velocity less than 0 SDS
! Dose- 50-200 µg/kg/day
! Prader willi syndrome

! Indications- Growth failure
! Pre-requisite- Exclude obstructive sleep apnea (risk of death)
! Dose- 25-50µg/kg/day
! Follow-up- Height SDS, BMI SDS, glucose tolerance
! Response- Improvement in growth, body composition, obesity
! Idiopathic short stature

! Indication- Height SDS < −2.5 and growth velocity SDS < −1
! Dose– 50-100 µg/kg/day (for at least six months)
! Expected benefit- 5-6 cm
FURTHER READING
1. Growth hormone research society. Consensus guidelines for the diagnosis
and treatment of growth hormone (GH) deficiency in childhood and
adolescence: summary statement of the GH Research Society. GH
Research Society. J Clin Endorinol Metab 2000; 85; 3990-3993.
2. Bajpai A, Menon PS. Growth hormone therapy. Indian J Pediatr 2005; 72;
139-144.
3. Rosenfeld GR, Cohen P. Disorders of growth hormone/insulin like growth
factor and action. In: Pediatric Endocrinology Eds: Sperling MA. WB
Saunders 2002, Philadelphia, 2nd Edn. Pp 211-288

1.5 Obesity
Childhood obesity has emerged as a global epidemic with doubling of

prevalence over the last two decades. Studies from different parts of India
have shown a prevalence of overweight and obesity from 15-28%. Moreover
most obese children become obese adults. Timely evaluation and
management of childhood obesity is therefore crucial.
What is Obesity?
The term obesity implies excessive body fat and not merely excess body
weight. Thus body weight alone is not a reliable marker of obesity. The gold
standard for diagnosis of obesity is increased body fat measured by bio
impedance or dual energy enhanced X Ray absorbidometry (DEXA). In
practice surrogate markers of adiposity using a combination of height and
weight are used.
Body mass index: Body mass index (BMI) should be used for diagnosing
obesity after the age of two years. BMI takes into account the weight and
height of the individual.
BMI = Weight (kg) ÷ height (m)2
BMI correlates well with body fat and complications in children. The use of
BMI may however incorrectly diagnose obesity in muscular individuals while
underestimating adiposity in sedentary children with reduced muscle mass.
BMI cutoffs for diagnosing obesity have been developed using statistical
distribution (CDC charts) or extrapolating from adult cutoffs (International
obesity task force). Indians have greater risk of metabolic syndrome compared
to their western counterparts for the same BMI. BMI varies with age, ethnicity
and gender, age and gender specific local charts should thus be used to
interpret BMI. Body mass index between 85th-95th percentile for age indicate
overweight while that above 95th percentile suggest obesity. BMI greater than
99th percentile (120% of 95% percentile) implicate severe obesity. As the aim
of assessing BMI is to identify individuals at risk for metabolic complications
lower BMI cutoffs have been recommended for Indian adults (23 kg/m2 for
overweight and 28 kg/m2 for obesity). The applicability of lower cutoffs in
Indian children needs to be studied.
Weight for height: Weight for height should be used in children younger than
two years of age. Weight for height more than 120% suggests obesity.

Waist circumference: Waist circumference is a marker of abdominal obesity,

a predictor of metabolic syndrome. Levels higher than 95th percentile for age
and gender are abnormal.
What causes obesity?

In most children obesity is not due to a disease but related to life style factors
(constitutional obesity) while pathological causes account for less than 1%
cases (Table 1). It is important to identify pointers to pathological obesity to
avoid unnecessary work-up in children with constitutional obesity.
Constitutional obesity- Constitutional obesity results from an imbalance

between energy intake and expenditure. It is caused by a combination of
genetic and environmental factors. Family history is common. Both low and
high birth weight is associated with increased risk of obesity later in life.
Dietary habits associated with childhood obesity include missing meals
(especially breakfast), higher portion size, snacking, frequent eating out and
watching television while eating. Breast-feeding in infancy has protective
effect. Lack of activity and increased inactivity are associated with obesity.
Endocrine causes: Endocrine diseases are rare but treatable causes of

childhood obesity. They should be considered in the presence of clinical
pointers, growth failure and delayed puberty. Cushing syndrome presents with
central obesity, high blood pressure, growth failure and violaceous striae.
Hypothyroidism is a rare cause of isolated obesity and is usually associated
with growth failure and developmental delay. In GH deficiency and
pseudohypoparathyroidism, growth retardation and hypocalcemia are
dominant clinical features.
Dysmorphic syndromes- Obesity is often a manifestation of dysmorphic
syndromes. Many of these syndromes are associated with hypogonadism or
hypotonia (Prader Willi, Carpenter and Laurence Moon Biedl Bardet
syndromes).
Hypothalamic obesity- Hypothalamic obesity is caused by increased appetite
due to CNS insult by surgery, radiation, tumors and trauma. These disorders
are associated with excessive appetite, signs and symptoms of CNS
involvement and other hypothalamic-pituitary defects.
Monogenic obesity: Single gene defects are a very rare cause of obesity.
They should be suspected in children with early onset obesity, rapid weight
gain and strong family history. Inefficient leptin action (deficiency or resistance)
results in uncontrolled appetite and obesity. Abnormalities in mineralocorticoid
receptor and proconvertase have also been associated with obesity. MC4

receptor defects are the commonest monogenic form of obesity and are
associated with growth acceleration.
Drugs- Commonly used drugs associated with obesity include corticosteroids,
antipsychotics (olanzipine, resperidone), anti depressants (paroxitene) and
anti epileptics (valproate, lamotrigine).
Why bother about obesity?
Category Complications
Metabolic Insulin resistance, type 2 DM, metabolic syndrome,

hyperandrogensim
Cardiovascular Hypertension, dyslipidemia, atherosclerosis
Gastrointestinal Non alcoholic fatty liver disease, gall stones,

gastroesophageal reflux
Skeletal Blounts disease, slipped capital femoral epiphysis,

fractures
Respiratory Obstructive sleep apnea, hypoventilation syndrome
Neurological Benign intracranial hypertension
How to evaluate a child with obesity?
Evaluation of an obese child involves careful clinical assessment followed by

focused investigations. The key questions in a child with obesity include the
cause of obesity and it’s effects.
What is the cause of obesity?

Most children with obesity do not require investigations for the cause of
obesity. It is important to identify the children who need work-up by clinical
examination.

Differentiating constitutional from pathological obesity
Feature Constitutional Pathological
Pattern Generalized Central
Growth rate Accelerated Retarded
Skeletal maturation Advanced Retarded
Dysmorphic features Absent May be present
Endocrine features Absent May be present
Clinical evaluation- The clinical evaluation should include detailed history and
examination. Pathological obesity should be considered in children with early
onset of obesity, rapid weight gain, growth failure, dysmorphism,
developmental delay and pubertal delay. Pointers to specific disorders should
be evaluated (table 4, 5). Detailed dietary history including duration of breast
feeding, age at weaning, meal pattern, calorie intake, snacking, consumption
of junk food and features of feeding disorders should be evaluated. Duration of
activity and inactivity should be looked into. Family history of consanguinity,
type 2 DM, ischemic heart disease and dyslipidemia should be inquired. Drug
history should assess intake of steroids, valproate and antipsychotic drugs.
History of CNS infection, trauma, radiation, tumor or surgery indicates
hypothalamic obesity. Examination should include assessment of growth
parameters, pubertal status and clues to diagnosis. Pubertal assessment may
be challenging in obese children. Obese boys frequently present with
concerns of small penile size. This is usually due to penis buried in the
suprapubic pad. Stretched penile length should be measured after pressing
the suprapubic pad of fat to ascertain the actual size of penis.
Investigations- No workup is required in children with normal growth, facies,

development and pubertal development. Thyroid profile and evaluation for
cushing syndrome should be done in the presence of growth failure and/or
characteristic clinical features. The effects of obesity on endocrine functions
should be considered while assessing endocrine functions. Mildly elevated
TSH levels with normal free T4 are common in obese children. This is not the
cause of obesity and should not be treated unless TSH is persistently
elevated. Cortisol levels may be mildly elevated in obese children and should

not be mistakenly diagnosed as cushing syndrome. Genetic testing for Prader

Willi syndrome should be done in the presence of facial features, history of
infantile hypotonia and growth failure. Monogenic causes of obesity should be
considered only in the presence of clinical features or pointers to diagnosis.
Clues to diagnosis to cause of obesity
Disorder Features
Delayed puberty Bardet Biedl, Prader Willi syndrome
Retinitis pigmentosa, polydactyly Alstrom, Bardet Beidl syndrome
Short hand and feet Prader Willi syndrome
Buffalo hump, stria Cushing syndrome
Short fourth metacarpal Pseudohypoparathyroidism, turner
Developmental delay Prader Willi, hypothyroidism, PHP
What are the complications of obesity?

When to evaluate? Assessment of complications of obesity should be done in
children with BMI above 95th percentile and those with BMI of 85-95th
percentile and family history of type 2 DM, hypertension, polycystic ovarian
disease or anathosis nigricans.
Clinical evaluation- History should inquire about symptoms of complications

of obesity like headache, vomiting (benign intracranial hypertension), day time
somnolence, respiratory distress, snoring (obstructive sleep apnea),
abdominal pain (fatty liver, gall stone disease), acne, hirsuitism, menstrual
irregularity (polycystic ovarian syndrome), pain in hip and knee (slipped capital
femoral epiphyses) or abnormal gait (Blount’s disease). Examination should
include measurement of blood pressure, acanthosis nigricans, hepatomegaly,
cardiac examination, and pedal edema (obstructive sleep apnea and cor
pulmonale) and range of movement of knee and hip (slipped capital femoral
epiphyses).
Investigations- Investigations should include a baseline oral glucose

tolerance test using fasting and 2 hours after 1.75 gm/kg glucose (maximum of

75 gm) blood sugar levels, lipid profile and liver function tests. Age appropriate
cutoffs should be used for these investigations (table 6). These tests should be
repeated every three years if normal. Fasting insulin has limited role and is not
routinely required. Mildly elevated liver transaminases are common in obese
children; persistent elevation beyond twice the upper limit indicates non
alcoholic steatohepatitis. Children with elevated transaminases should
undergo ultrasound abdomen and work-up for other causes of hepatic
dysfunction (hepatitis B and C, wilson disease and autoimmune hepatitis).
Sleep studies may be required in the presence of snoring, day time
somnolence or lethargy.
Cutoffs for investigations for assessment of obesity complications
Investigation Normal Borderline Abnormal
Blood sugar
Fasting < 100 mg/dL 100-125 mg/dL > 126 mg/dL
2 hours after < 140 mg/dL 140-199 mg/dL > 200 mg/dL
glucose
Total cholesterol < 170 mg/dL 170-199 mg/dL > 200 mg/dL
LDL cholesterol <110 mg/dL 110-129 mg/dL > 130 mg/dL
Triglyceride < 90 mg/dL 90-129 mg/dL > 139 mg/dL
HDL cholesterol >45 mg/dL 40-45 Mg/dL <40 mg/dL
AST <40 IU/L 40-80 IU/L >80 IU/L
How to manage a child with obesity?

The management of childhood obesity is a big challenge. It requires a
multidiscplinary approach involving physician, nutritionists and physical
trainers. The goal is to bring body mass index to the normal range for age and
gender. Excessive and rapid weight loss adversely effects the growth of the
child and should be avoided. In most cases weight stabilisation is the initial
aim. Weight loss should not exceed 1 kilogram every month in most children.
The child and parents should be counselled that their is no quick fix solution of
obesity and the child would need to adhere to the modified life style through
out the life. Key focus is on changing the life style of the child with use of
drugs and surgery in the rarest of the rare cases.

Life style measures

The cornerstone to management is lifestyle measures. The whole family
should be encouraged to follow a healthy life style as a unit as focusing on the
child alone is often counter productive.
Nutritional therapy- The child should be advised to stick to regular meals.

Skipping of breakfasts and snacking in between meals should be discouraged.
The caloric intake should be reduced by 20%. Overzealous restriction and fad
diets is not recommended. Food pyramid and traffic light approach for diet
may be used to highlight healthy eating pattern. Special emphasis should be
laid on fixed portion size, decreased junk food consumption, avoiding
television viewing while eating and increased fruit consumption.
Physical activity- Periods of inactivity should be reduced along with increase

physical activity. Screen time, time spend on watching television, computer
and mobile devices, should be restricted to less than one hour a day. Increase
in routine activities like house hold chores and walking to school should be
encouraged. A plan of enjoyable activity like dancing, sports and running
should made to ensure a minimum of 30 minutes daily. Weight bearing
exercises and over regimented schedule should be avoided.
Specific management
Specific treatment should be initiated in children with hypothyroidism, growth
hormone deficiency and cushing syndrome. Children with mildly elevated TSH
level do not need treatment. Obese children with Prader Willi Syndrome and
growth failure may benefit from growth hormone therapy. Octretotide is
effective in hypothalamic obesity while the use of leptin is reserved for leptin
deficiency.
Treatment of complications
Complications should be treated early to avoid long term adverse effects.
Metformin is indicated in children with insulin resistance and type 2 DM, non
alcoholic fatty liver disease and polycystic ovarian disease. Statins are the
drug of choice for children with persistent dyslipidemia. Treatment of non
alchololic fatty liver disease includes the use of metformin, vitamin E and
pioglitazone. Girls with polycystic ovarian syndrome benefit from life style
modifications, metformin, oral contraceptives and antiandrogens.
Medroxyprogesterone acetate is beneficial in children with obesity
hypoventialtion syndrome while continuous positive airway pressure may be
used in obstructive sleep apnea.

Medical treatment for obesity

Drugs for treatment of obesity have faced a number of problems in the past
due to the adverse effects. Orlistat is the only drug cleared for use in children
with obesity. The drug inhibits gastric lipase resulting in reduced absroption of
fat with modest weight loss. The major side effects include abdominal pain,
bloating, steatorrhea and leakage of oil. The medicine should be combined
with fat soluble vitamins. Newer agents in the pipe line include MC4 receptor
modulators, GLP1 analogs and endo-cannabinoid agonists.
Surgical management
Bariatric surgery should be considered only in severe obesity when other
measures have failed. The intervention should be done after achievement of
final height due to potential adverse growth effects. Bariatric surgery is a major
surgical undertaking and should be viewed as a potentially life saving
procedure and not just a cosmetic procedure. The patients need to adhere to
strict dietary restriction for life. Laparoscopic adjustable banding is the
recommended procedure in children. Malabsorptive procedures and gastric
sleeve should not be done in children.
Further reading
1. Alemzadeh R, Rising R, Cedillo M, Lifshitz F. Obesity in children. In:

Pediatric Endocrinology, Eds: Lifshitz F, Marcel Dekker, 2003, New York,
4th edition Pp 823-858.
2. Muglia LJ. Majzoub JA. Gungor N, Arslanian AA. Nutritional disorders. In:
Pediatric Endocrinology Eds: Sperling MA. WB Saunders 2002,
Philadelphia, 2nd Edn. Pp 671-688.
3. Freemark F. Metabolic consequences of obesity and their management. In:
Clinical Pediatric Endocrinology, Eds Brook CGD, Clayton PE, Brown RS,
Blackwell publishing, 2005, London, 5th Edition. Pp 419-435.
4. Speiser PW, Rudolf MCJ, Anhalt H et al on behalf of the obesity
consensus working group. Consensus statement: Childhood obesity. J Clin
Endocrinol Metab 2005; 90: 1871-1887.
5. Barlow SE, Expert Committee. Expert committee recommendations
regarding the prevention, assessment, and treatment of child and
adolescent overweight and obesity: summary report. Pediatrics 2007; 120
Suppl 4:S164.

Resource book Pediatric Endocrinology Protocols
Section 2- Puberty
2.1 Pubertal assessment
Assessment of pubertal status is essential in evaluating a child with

growth disorder. This is done using the standard method described by
Tanner and Whitehouse and involves staging of axillary hair, pubic hair,
genital staging and testicular volume is boys and axillary hair, pubic
hair, breast staging and achievement of menarche. When pubertal
staging is known it becomes easier to interpret the growth chart as
pubertal growth accounts for over 20% of adult height.
AGE LIMITS
Gender Age of onset Criteria
Precocious Delayed
Girl
Breast development 8-13 years Before 8 years After 14 years
Pubarche 10-12 years Before 8 years After 14 years
Menarche 12-15 years Before 9 years After 16 years
Boys
Testicular enlargement 9-14 years Before 9 years After 14 years
* LWPES recommendations- Precocious puberty if thelarche occurs
before 7 years in white girls and 6.5 years in African American girls
PATTERN OF PUBERTAL DEVELOPMENT IN GIRLS

Age at onset: The usual age at onset of puberty in girls is around 10
years (range 8–13 years) and duration is around three years (range 2–
5 years). Skeletal maturation is an important determinant of pubertal
development as bone age correlates better with menarche compared
to chronological age. Recently there has been an observation of an
earlier onset of thelarche with relatively little change in that of
menarche.
External physical changes: Enlargement of breast (thelarche) is the

first pubertal event in girls closely followed by the development of pubic
hair (pubarche) and onset of menstrual cycles (menarche).
Differentiation of lipomastia and true thelarche may be difficult in obese
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GROW Society Pediatric Endocrinology Protcols
girls. This can be done by approximating thumb and index finger

around the nipple area. In girls with true thelarche an area of
resistance would be encountered between the thumb and finger while
no resistance is noted in lipomastia. Breast development may remain
unilateral initially or may be asymmetrical during the first year of
thelarche. Although pubarche usually occurs within six months of
thelarche, it may precede thelarche in 10% of girls. Pubic hair growth
is independent of estrogen production and mediated by adrenal
androgens. Early pubarche in the absence of breast development
indicates adrenarche or androgen excess due to adrenal or ovarian
causes. On the contrary sparse pubic hair in a girl with normal breast
development and primary amennorhea indicates androgen insensitivity
syndrome. Menarche is usually attained within two years of thelarche.
Menarche within one year of thelarche is suggestive of
hyperestrogenic state due to ovarian cyst secondary to
hypothyroidism, functional ovarian cyst or McCune Albright Syndrome.
Stage Breast Pubic hair

I No breast tissue Same as abdominal hair
II Breast bud, enlargement of areola M i n i m a l l y p i g m e n t e d ,
mainly labia
III Further enlargement of breast and Darker and coarser hair in
areola mons
IV Secondary mound formed by Adult type, less distribution
papilla and areola
V Adult contour with projection of Adult feminine distribution
papilla alone
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Anatomical changes: Puberty is associated with increase in vaginal

length and appearance of estrogenic changes in vaginal mucosa.
Inspection of vaginal mucosa helps in assessing the pubertal status of
a girl. Red glistening vaginal mucosa suggests lack of estrogen
exposure and prepubertal state, while pink mucosa with mucus
production is indicative of pubertal state and estrogenic effect. The first
radiological sign of puberty is the increase in the utero-cervical ratio
resulting in change in the shape of uterus from a tubular to a pear
shaped structure. This is followed by an increase in uterine length and
endometrial thickness. Endometrial thickness greater than 5 mm
suggests imminent menarche. Puberty is associated with increase in
ovarian volume and development of multiple ovarian follicles giving the
appearance of multicystic ovary. This ‘multicystic ovary’ can be readily
differentiated from ‘polycystic ovarian syndrome’ by the presence of
small (less than 8 mm) and centrally located cysts.
Table 2.11- Pubertal assessment on pelvic ultrasound

Feature Prepubertal Pubertal
Uterine shape Tubular Pear shaped
Uterine to cervical ratio Less than 1 More than 1
Endometrial thickness Less than 5 mm More than 5 mm
Ovarian follicles Absent Multiple, central
Growth spurt: Pubertal growth in girls occurs in early puberty (Tanner

II and III) with a peak growth velocity of 8–10 cm a year. The extent of
growth after puberty may be influenced by the timing of menarche.
Thus while most girls grow by 4-6 cm after menarche; post menarchal
growth may be 10 cm in girls with early menarche. The usual growth
from thelarche and menarche is around 20 cm and 6 cm respectively.
PUBERTAL DEVELOPMENT IN BOYS

Age at onset: In boys puberty starts at the age of 11.5 years (normal
range 9 years to 14 years). Spermarche occurs during mid-puberty and
is achieved in most boys by 14 years.
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Physical changes: Gonadal growth with an increase in testicular

volume is the first pubertal
development in boys. Testicular
volume is compared to the
numbered beads provided in the
prader orchidometer. Testicular
volume greater than 4 ml indicates
pubertal onset. If an orchidometer is
not available, testicular diameter
should be measured with the sum of
longitudinal and transverse length.
Diameter greater than 2 centimeters
is suggestive of pubertal
development. Testicular growth is
followed by penile enlargement and
pubarche. Stretched penile length is
measured after retracting the
prepuce and stretching the penis to
the point of resistance. The distance between pubic symphysis and the
tip of penis is measured using a transparent firm scale. The scrotal
skin initially reddens, develops rugosities, and later becomes
hyperpigmented. Pubic hair appears shortly after genital development
has begun.
Growth spurt: Pubertal growth spurt in boys occurs later than that in
girls (Tanner stage III and IV) and is associated with higher peak
growth velocity (10–12 cm/year).
Table 2.12- Tanner staging for boys

Stage Genital Test volume Pubic hair
I Prepubertal < 4 ml Same as abdominal hair
II Early penile growth, thins 4-10 ml Fine pubic hair at base
and red scrotal of penis
appearance
III Increase in penile length, 10-15 ml Increase in number,
scrotal growth darkening
IV Increased penile length 15-20 ml Spread around thigh.
and width, pigmented Less than adult
scrotum distribution
V Adult size > 20 ml Adult male distribution
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Table 2.13- Comparison of pubertal development in boys and girls
Feature Girls Boys

Onset 10-12 years 12-14 year
First sign Breast development Testicular enlargement
Growth spurt Early (Tanner I and II) Late (Tanner III and IV)
Sexual maturity Menarche 14 years Spermarche 15 years
Pattern of pubertal progression observed in girls and boys.
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Endocrine assessment
Gonadotropin secretion is characterized by pulsatile release of the
hormones making estimations of single sample unreliable. There levels
should therefore be measured in a pooled sample taken at 0, 15 and
30 minutes apart. LH is a better indicator of pubertal status compared
to FSH as it shows greater increase during puberty. Basal LH more
than 0.6 IU/L and LH to FSH ratio more than 1 is suggestive of
gonadotropin dependent precocious puberty. Recently basal LH levels
greater than 0.1 IU/L were shown to have sensitivity of 94% and
specificity of 88% for CPP. GnRH stimulation test is required if
baseline gonadotropin levels are inconclusive. Pubertal LH levels ( 5
U/L) and LH to FSH ratio more than 0.9 are diagnostic of central
precocious puberty. The difficulties in procuring GnRH has led to the
development of GnRH agonist test in the assessment of pubertal
disorders. Recently the test has been found to have good diagnostic
accuracy with the use of single sample after administration of GnRH
agonist Triptorelin (100 µg subcutaneously).
FURTHER READING
1. B a j p a i A , M e n o n P S N . P u b e r t y - P h y s i o l o g y a n d
Neuroendrocrinology. Pediatric Endocrine Disorders. Eds:
Desai M, Bhatia V, Menon PSN. Orient Longman, Second
Edition, 2007.
2. Grover S, Bajpai A. Puberty. WHO Encyclopaedia of public
health. Elseiver, In Press.
3. Menon PSN and Bajpai A. 2006. Pubertal disorders. In
Textbook of Adolescent Medicine 1st edition, Ed S Bhave,
84-94. New Delhi: Jaypee Brothers Medical Publishers Pvt Ltd.
4. Dattani MT and Hindmarsh PC. 2005. Normal and abnormal
puberty. In Clinical Pediatric Endocrinology 5th edition, Eds C
Brook, P Clayton and R Brown, 183-210. Oxford: Blackwell
Publishing.
42 Grow Society
2.2 Precocious puberty
Precocious puberty in Girls

CRITERIA
Category Criteria
Premature thelarche Breast stage II before 8 years of age
Premature Pubarche Pubic hair stage II before 8 years of age
Premature menarche Menarche before 10 years of age
Discordant puberty Menarche within 1 year of thelarche
ETIOLOGY
Precocious puberty
Incomplete variants Complete precocious puberty

Premature thelarche
Premature adrenarche
Premature menarche
Gonadotropin dependent
Gonadotropin independent Idiopathic
Estrogenic ovarian cyst Organic
Estrogenic ovarian tumor Brain tumor
Estrogenic adrenal tumor Hypothalamic hamartoma
McCune Albright syndrome Glioma
Primary hypothyroidism Congenital anomaly
Hydrocephalous
Arachanoid cyst
Cerebral dysgenesis
Neurological insult
Infection
Trauma
Surgery
Radiation
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EVALUATION
History
• Onset
• Early childhood- Hypothalamic hamartoma, MAS
• Late childhood- Idiopathic central puberty
• Course
• Minimal progression- Slowly progressive variant
• Gradual progression- Idiopathic precocious puberty
• Rapid progression- Organic pathology
• Fluctuant- McCune Albright Syndrome
• Pattern
• Isolated breast development
• Isolated thelarche
• Evolving precocious puberty
• Isolated pubic hair development
• Premature adrenarche
• Non classical CAH
• Isolated vaginal bleeding
• Local cause- Infection, trauma, tumor
• Withdrawal bleed- Hypothyroidism, ovarian cyst
• Family history of early puberty (idiopathic puberty)

• Features of raised ICP, focal neurological deficits, seizures
• Neurological insult (radiation, trauma, surgery, infections)
• Uncontrollable laughter episodes (gelastic epilepsy)
• Exposure to steroids, estrogen
• Features of hirsuitism, virilization in girls isolated pubarche
• Features of hypothyroidism
• Examination
• Growth parameters
• Café-au-lait spots, bony deformities, rickets (McCune Albright)
• Neurological examination including fundus examination
• Abdominal examination for ovarian or adrenal mass
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Figure 1- This eight-year-old girl presented with breast development for

one year and two episodes of vaginal bleeding three months later. She
had short stature (height SDS- -2.5), retarded bone age (6 years). TSH
levels were and extremely elevated (> 100 mU/ml). Treatment with
thyroxine resulted in reversal of pubertal changes within three months.
Figure 2 This six-year-old girl presented with breast development for

six months. She had no pubic hair development or vaginal bleeding.
Investigations showed advanced bone age (8.5 years) and pubertal
gonadotropin levels (LH 1.9 mU/L, FSH 2.1 mU/L). She was started on
GnRH analog treatment.
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Investigations
Complete puberty
I GnRH dependent vs independent puberty
• Baseline gonadotropin
• LH more important than FSH
• Gonadotropin dependent LH > 0.6 mU/L (LH < 0.1 suggests
prepubertal levels)
• Stimulated gonadotropin levels- GnRH agonist test
• Inj Triprorelin 100 µg subcutaneously
• LH and FSH at 0,120 and 240 minutes
• GnRH dependent peak LH > 5 mU/L
II- Evaluation of GnRH dependent puberty

• Imaging for hypothalamic pituitary region
• Mandatory in girls younger than 6 years of age
• Should be performed in all if feasible
III Evaluation of GnRH independent precocious puberty

• Thyroid function tests
• Ultrasound for ovarian and adrenal pathology
• Bone scan for fibrous dysplasia (MAS)
Isolated precocious puberty

Isolated thelarche
Feature Isolated thelarche Atypical precocity
Onset Usually before 2 years Usually after 2 years
Growth Normal Accelerated
Course Non progressive Progressive
Gonadotropin High FSH, normal LH High LH and FSH
Bone age Normal Advanced
Pelvic ultrasound Pre pubertal Pubertal changes
Treatment None required GnRH analog
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Isolated pubarche- Measure DHEAS and testosterone

DHEAS Testosterone Probable Diagnosis
Mildly elevated Low Premature pubarche
Elevated Mildly elevated CAH (measure 17OHP)
Significantly elevated Elevated Adrenal tumor
Normal Significantly elevated Ovarian tumor
Isolated vaginal bleeding

• Vaginal examination
• Exclude sexual abuse, infection
• Ultrasound (uterus, endometrial thickness and ovarian cysts)
• Endocrine work-up if evidence of puberty present
Approach
Initial assessment involves confirming the presence and extent of
pubertal development. Bone age is important in evaluation of girls with
early breast development. Retarded bone age in this setting is
suggestive of hypothyroidism while normal bone age indicates slowly
progressive variant of puberty. Basal and/or GnRH stimulated
gonadotropin levels should be performed in girls with advanced bone
age. Pubertal gonadotropin levels (elevated LH and LH to FSH ratio)
are diagnostic of central precocious puberty and should be followed by
neuroimaging (preferably MRI) Neuroimaging may be avoided girls
older than six years of age with slowly progressive puberty and no
neurological features. Normal basal and GnRH stimulated
gonadotropin levels are suggestive of gonadotropin independent
precocious puberty. These girls should undergo ovarian and adrenal
imaging to identify the source of estrogen production. Normal adrenal
and ovarian imaging in a girl with peripheral precocious puberty should
prompt evaluation for McCune Albright syndrome (skeletal survey,
bone scan and features of endocrinopathies). DHEAS levels should be
done in girls with isolated pubarche. Mildly elevated levels are
suggestive of premature adrenarche while very high levels should
prompt evaluation for congenital adrenal hyperplasia and adrenal
tumor (17 OHP and adrenal ultrasound). Endocrine etiology is unlikely
in girls with isolated vaginal bleeding. Endocrine work-up should be
done only after common causes like foreign body; trauma, infection
and sexual abuse have been excluded.
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Precocious puberty
Extent of pubertal
Complete/ Isolated pubarche Isolated menarche

Thelarche DHEAS Local examination
Pelvic ultrasound
Retarded Normal Advanced

Exclude hypothyroidism Slowly progressive variant Basal LH, FSH
Low LH Elevated LH
GnRH stimulation test
Pre-pubertal Pubertal
Gonadotropin independent Gonadotropin dependent

Ultrasound adrenal and ovary MRI head
Bone scan for fibrous dysplasia
MANAGEMENT
Gonadotropin Dependent
Indications
• Age of onset less than 6 years
• Age of onset between 6-8 years with rapid progression
• Bone age 2 years more than chronological age
• Height SDS for bone age less than −2
• Predicted Ht SDS > −2 SDS < target ht SDS
• Concern about early menarche
Options
Medroxyprogesterone acetate- Oral, im depot
o No effect on auxological outcome
o May be considered in intellectual disability
Cyperoterone acetate- 100 mg/day, minimal effect on height
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GnRH analog
Preparation Dose Preparation Frequency
Triptorelin 50 µg/kg 3.75 mg Monthly
Leuprolein 50-300 µg/kg 3.75 mg Monthly
Leuprolide depot 150-450 µg/kg 11.25 mg Three monthly
Gosorelin - 10.8 mg Three monthly
Expected response
o Initial flare up for one to two months
o May cause withdrawal bleeding
o Decrease in growth velocity to normal levels
o Regression in pubertal changes and uterine size
o Stabilization of bone age
o No effect on pubarche
Discontinuation of treatment
o Chronological age of 10 years
o Bone age of 12 years
o Predicted height in the target height range
Gonadotropin independent
Hypothyroidism- Thyroid hormone replacement
Ovarian cyst
• No treatment from endocrine point of view
• Thyroid function tests
• McCune Albright syndrome with recurrent cysts
McCune Albright Syndrome

• Tamoxifen- 15 mg daily
• Aromatase inhibitor- Anastrazole, letrozole
• Concomitant treatment
• GnRH analog in girls with secondary CPP
• Bisphosphonate for fibrous dysplasia
• Octreotide for GH excess
• Anti thyroid drugs for hyperthyroidism
Estrogenic adrenal or ovarian tumors- Surgery
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36. Precocious
Precocious Puberty
puberty in boys
in boys
36.1 Criteria-
CRITERIA- Onset
Onset ofofpubertal
pubertal changes
changesbefore the age
before of 9age
the years
of 9.5 years
•Testicular volume more than
•Testicular volume more than 4 ml4 ml
••Pubic
Pubichair stage
hair II or II
stage more
or more
•Penile enlargement
•Penile enlargement
36.2 Etiology
ETIOLOGY
Precocious puberty
Gonadotropin independent
Idiopathic
Organic
Brain tumor
Endogenous Exogenous Hypothalamic hamartomas
Testosterone cream Glioma
Congenital anomaly
Hydrocephalous
Testicular source Adrenal source Arachnoid cyst
CAH Cerebral dysgenesis
21 OH deficiency CNS insult
11 OH deficiency Infection
Head Trauma
Autonomous Apparent LH excess

Testicular tumor McCune Albright Syndrome
Testotoxicosis/ GIPP
CAH- Congenital adrenal hyperplasia, HCG- Human chorionic gonadotropin

* Gonadotropin Independent Precocious Puberty (Activating LH receptor mutation)
Important causes (In order of importance)

Gonadotropin dependent (60%) Gonadotropin independent (40%)
Idiopathic (40-50%) Congenital adrenal hyperplasia
CNS tumor Adrenal tumor
CNS insult HCG producing tumor
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Table 1 Gonadotropin dependent and independent puberty
Feature Gn dependent Gn independent

Testicular volume Enlarged Pre pubertal (less than 4 ml)
Gonadotropin
Basal Usually high Low
Stimulated Elevated Low
Etiology Idiopathic Congenital adrenal hyperplasia
CNS tumor Adrenal or testicular tumor
CNS insult HCG producing tumor
Treatment GnRH analog Specific treatment, anti-androgen
Confirmation of diagnosis
•Tanner staging
•Testicular volume (Orchidometer)
•Stretched penile length
•Bone age (Advanced bone age indicates precocious puberty)
EVALUATION
History
• Onset
• Infancy- Hypothalamic hamartomas, adrenal tumor
• Early childhood- Hypothalamic hamartoma, testotoxicosis
• Late childhood- CNS tumor, CAH, HCG tumor
• Progression
• Rapid- Organic CNS pathology, adrenal tumor
• Gradual- CAH, idiopathic precocious puberty
• Family history of early puberty, consanguinity, sibling death

• Features of raised intracranial tension, focal deficits, seizures
• CNS insult (radiotherapy, trauma, surgery, infections, birth
asphyxia)
• Gelastic seizures (laughter spells)- Hypothalamic hamartoma
• Pigmentation (congenital adrenal hyperplasia)
• Possibility of exogenous testosterone exposure
Examination
• Growth parameters
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• Testicular size
• Pubertal- Gonadotropin dependent puberty
• Pubertal but not commensurate with pubertal stage- HCG
secreting tumor, testotoxicosis
• Pre pubertal- Gonadotropin independent
• Unilateral enlargement- Testicular tumor, adrenal rests in long
standing CAH
• Pigmentation (congenital adrenal hyperplasia)

• Blood pressure (hypertension in 11 hydroxylase deficiency)
• Abdominal examination (adrenal mass)
• Café-au-lait spots, bony deformities, rickets (McCune Albright)
Figure 3 Seven-year-old boy presented with increased penile length

(12 cm) and prepubertal testicular volume (2 ml). Investigations
showed elevated basal 17OHP levels (5000 ng/ml, 160 nmol/L)
confirming the diagnosis of simple virlizing 21 hydroxylase deficiency.
Abdominal CT scan showed bilateral enlarged adrenals.
52 Grow Society
Figure 4 Four-year-old boy presented with increased penile size for

three months. On examination, he had increased penile size (8 cm)
with pubertal testicular development (testicular volume 10 ml).
Baseline gonadotropin levels were elevated (LH 3.2 mU/L, FSH 2.8
mU/L). MRI showed hypothalamic hamartoma.
Figure 5 Six-year-old boy with precocious puberty and mild increase in

testicualr volume (6 ml). Investigations showed low basal and GnRH
stimulated gonadotropin levels (peak LH 0.1 mU/L), normal adrenal
ultrasound and 17OHP levels. Urine HCG test was strongly positive
and blood HCG levels were highly elevated (15000 IU/ml). Head CT
scan showed intraventricular mass lesion suggestive of germinoma.
INVESTIGATIONS
! Gonadotropin dependent vs independent puberty
! Baseline gonadotropin levels - LH and FSH (pooled samples)
! Interpretation- Gonadotropin dependent if LH > 0.7 mU/L
! GnRH agonist test
! Indication- Low basal gonadotropin
! LH, FSH at 0, 120 and 240 minutes after 0.1 mg triptorelin
! GnRH dependent puberty if peak LH more than 5 mU/L
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Evaluation of GnRH dependent puberty- MRI/ CT Head
Evaluation of GnRH independent precocious puberty

• Initial
• Adrenal imaging (high resolution ultrasound)
• 17 hydroxyprogesterone (17OHP)
• If indicated
• ACTH stimulation test- Borderline 17OHP levels
• HCG levels- Gonadotropin independent precocious puberty
with normal 17OHP and adrenal imaging
APPROACH
Precocious puberty
Assess extent, testicular size
Baseline LH, FSH
Pre pubertal LH
GnRH stimulation test Pubertal LH
Pre-pubertal Pubertal
Adrenal imaging
Normal Mass lesion
MRI head
ACTH test Adrenal tumor
Normal 17OHP High 17OHP

HCG levels CAH
Normal High
LH receptor study HCG tumor
CT head, chest and abdomen
Initial assessment of a boy with precocious puberty should be directed

towards confirmation of the diagnosis and evaluating the extent of
pubertal development. Testicular size is the most important part of
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examination of a boy with precocious puberty. Pubertal testicular

volume (more than 4 ml) commensurate with pubertal stage indicates
gonadotropin dependent puberty while pre pubertal testicular volume
(less than 4 ml) is suggestive of gonadotropin independent precocious
puberty. Prolonged untreated precocious puberty may however trigger
the hypothalamic-pituitary axis resulting in pubertal testicular volume.
Mild testicular enlargement may occur in apparent LH excess states
like HCG secreting germ cell tumors or testotoxicosis. Effects of LH on
testicular growth are restricted to the leydig cell compartment with no
effect on sertoli cells, the major contributor to testicular volume. Leydig
cell hyperplasia in apparent LH excess states, thus results in slight
enlargement of testicular size that is not commensurate with the stage
of pubertal development. Unilateral testicular enlargement in a boy with
precocious puberty should raise the possibility of testicular tumor;
prolonged untreated congenital adrenal hyperplasia may however
result in nodular testis due to testicular adrenal rests. Baseline
gonadotropins should be performed in all boys with precocious puberty
and are usually able to differentiate gonadotropin dependent and
independent puberty. GnRH stimulation test should be done in the
unlikely event of low LH levels with pubertal testicular volume. All boys
with central precocious puberty should undergo neuroimaging
(preferable MRI) as organic etiology is much more common than in
girls. Pituitary function tests should be done if organic pathology is
identified. Boys with gonadotropin independent precocious puberty
should undergo adrenal imaging and estimation of 17OHP levels to
identify adrenal tumor and congenital adrenal hyperplasia. HCG levels
should be performed if these investigations are normal. CT scan of
chest, abdomen and brain should be done to localize the HCG
secreting tumor in boys with high HCG levels. Normal adrenal imaging,
17OHP and HCG levels in the setting of gonadotropin independent
precocious puberty point to the diagnosis of testotoxicosis.
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MANAGEMENT
• Gonadotropin dependent precocious puberty- GnRH analog
• Indication- All
• Duration- Age of 12 years, bone age of 14 years, predicted
height in the target height range
• Expected effect
• Regression in pubertal development
• Increase in predicted final height by 10-15 cm
• Gonadotropin independent precocious puberty

• Congenital adrenal hyperplasia
• 21 hydroxylase deficiency
• Hydrocortisone- 10-15 mg/m2/day
• Fludrocortisone- 0.1 mg/day
• 11 beta OHD deficiency- Hydrocortisone 10-15 mg/m2/day
• Adrenal tumor- Surgery
• HCG secreting tumor- Surgery
• Testotoxicosis
• Antiandrogen- Flutamide
• Aromatase inhibitor- Anastrazole, letrozole
Further reading
1. Grover S, Bajpai A. Puberty. International Encyclopaedia of
public health. Elseiver, In Press.
2. Bajpai A, Menon PSN. Precocious puberty. Pediatric Endocrine
Disorders. Eds: Desai M, Bhatia V, Menon PSN. Orient
Longman, Second Edition, 2007.
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2.3 Delayed puberty
CRITERIA
No pubertal development by 15 years of age
Inability to complete development within five years of onset
ETIOLOGY
Delayed puberty
Constitutional delay of puberty
Hypothalamic-pituitary dysfunction Ovarian dysfunction

Hypogonadotropic hypogonadism Hypergonadotropic hypogonadism
Reversible Irreversible Congenital Acquired

Malnutrition Gonadal dysgenesis Radiation
Anorexia nervosa Turner syndrome Chemotherapy
Hyperprolactinemia Pure gonadal dysgenesis Torsion
Systemic disease Enzyme defect Infection
StAR, 3 βHSD Autoimmune
17OHase, 17 βHSD
Aromatase
Gonadotropin resistance
Congenital Acquired PHP
Radiation FSH receptor resistance
CNS tumor
Neurosurgery
Infection
Isolated defect Hypopituitarism

Kallmann syndrome Septo-optic dysplasia
CHARGE syndrome Holoprosencephaly
Prader Willi syndrome PROP1 mutation
GPR54 mutation
LH gene deletion
GnRH receptor defect
Leptin deficiency
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EVALUATION
History
• Pattern
• No initiation of pubertal development- Hypogonadotrophic
hypogonadism, steroidogenic defect, classical turner syndrome
• Failure to progress after normal initial development- Mosaic
turner syndrome, acquired ovarian, autoimmune ovarian failure
• Features of chronic systemic illness
• Family history of delayed puberty (constitutional delay)
• CNS insult (radiation, trauma, surgery, infections, asphyxia)
• Features of hypopituitarism, neurological involvement
• Abnormal smell sensation (Kallmann syndrome)
• Deafness (Turner, CHARGE syndrome, PHP)
• Developmental delay (Prader willi syndrome, CHARGE)
• Tetany (Hypoparathyrodism, pseudohypoparathyroidism)
• Alopecia, Vitiligo, candidiasis, adrenal insufficiency (APS)
Examination
• Short stature- Turner, Hypopituitarism, celiac disease
• Body mass index
• Low- Malnutrition or anorexia nervosa
• Obesity PHP, prader willi, leptin deficiency
• Features of Turner Syndrome
• Smell sensation
• Galactorrhea (hyperprolactinemia)
• Midline defects (hypopituitarism)
• Abdominal examination (adrenal mass)
• Dysmorphism suggestive of CHARGE, PW syndromes
• Pigmentation (steroidogenic defects)
• Vitiligo, alopecia (Autoimmune polyendocrinopathy)
• BP(hypertension in 17 beta hydroxylase deficiency)
Investigations
• Initial
• Bone age
• SGPT, creatinine, complete blood examination
• FSH- After bone age more than 12 years
• FSH > 2 mU/L- Hypogonadotropic
• FSH > 10 mU/L- Hypergonadotropic
• FSH 2-10 mU/L- Intermediate
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• Evaluation of hypogonadotrophic hypogonadism

• Reversible causes- Prolactin, Thyroid profile, Celiac serology
• No reversible cause identified- MRI head
• Evaluation of hypergonadotropic hypogonadism

• Karyotype- At least 50 metaphase plates in view of mosaicism
• Evaluation for normal karyotype- Ultrasound pelvis for
ovaries, screening for APS
APPROACH
Initial evaluation should be directed towards identifying nutritional and

systemic disorders. This should be followed by bone age, pelvic
ultrasound and gonadotropin levels. Basal gonadotropin levels are
usually sufficient to discriminate hypo- and hypergonadotropic
hypogonadism; GnRH stimulation test should be done if they are
inconclusive. Reversible causes like hyperprolactinemia and
hypothyroidism should be excluded in girls with low gonadotropin
levels. Neuroimaging and anterior pituitary evaluation is required in
girls with permanent HH. Karyotype should be done in girls with
hypergonadotropic hypogonadism. Girls with no overt ovarian insult
and normal karyotype should be evaluated for steroidogenic defects,
autoimmune disorders and PHP (serum calcium and phosphate PHP).
Delayed puberty
Exclude systemic illness, nutritional disorder
Gonadotropin levels
Low FSH
Prolactin levels High FSH
Exclude ovarian insult
Karyotype
High HH
Hyperprolactinemia Smell sensation Normal
Thyroid profile CNS imaging Ultrasound pelvis
CNS imaging Pituitary functions Autoimmune evaluation
Steroidogenic precursors
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MANAGEMENT
•Specific measures
! Malnutrition- Nutritional rehabilitation
! Hyperprolactinemia- Dopamine agonist
! Hypopituitarism- Hormone replacement
•Non Specific measure
Pubertal induction- Bone age more than 13 years
o Estrogen
! Synthetic- Ethinyl estradiol
! Conjugated estrogen- Premarin
! Start at 10-20% of adult dose
! Increase by 20% of adult dose every six months
! Achieve target adult dose in two years
o Progesterone- Withdrawal bleeding, Endo thickness > 5 mm
! Preparation- Medroxyprogesterone, norethisterone
! Dose- 10 mg OD for 10 days a month (day 11-21)
o Switch to oral contraceptives after adult dose achieved
Table 1- Guidelines for estrogen replacement in girls

Dose Ethinyl estradiol Premarin Topical
Initial dose 2 µg/day 0.3 mg/day 25 µg patch
Increment every 6 mo 2-5 µg/day 0.3 mg/day 25 µg patch
Adult dose 20 µg/day 1.25 mg/day 100 µg patch
Strength 20 µg 1.25 mg 50, 100 µg
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Delayed Puberty in Boys

CRITERIA- Lack of pubertal development by 14 years of age
ETIOLOGY
Delayed puberty
Constitutional delay of puberty
Hypothalamic-pituitary dysfunction Testicular dysfunction

Hypogonadotropic hypogonadism Hypergonadotropic hypogonadism
Congenital Acquired Congenital Acquired

Radiation Klinefelter Infection
Brain tumor, trauma Gonadal dysgenesis Radiation
Neurosurgery Enzyme defect Chemotherapy
Infection StAR, 3 βHSD Trauma
17 βOHase, βHSD
5 α reductase
Isolated defect Hypopituitarism
Androgen resistance
Kallmann syndrome Malformation
Partial AIS
Prader Willi syndrome PROP1
GPR54 mutation
LH gene deletion
FSH gene deletion
GnRH receptor defect
Leptin deficiency
EVALUATION
History
• Extent
• No adrenarche- CDPG, steroidogenic defects
• Adrenarche present- Isolated HH
• Progression
• No initial development- Congenital cause, HH
• Initial development followed by arrest- Klinefelter
• Delayed puberty in family (constitutional delay in puberty)
• Mother- Age at menarche
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• Father- Onset of shaving, continuing growth in college

• Neurological features- Seizures, focal deficit, raised ICP
• CNS insult- Radiation, trauma, surgery, infections, asphyxia
• Features of hypopituitarism
• Testicular insult- Trauma, torsion, mumps, radiation, chemotherapy
• Developmental delay (prader willi syndrome, CHARGE)
Examination
• Growth
• Short stature- Hypopituitarism, prader willi syndrome
• Tall stature- Klinefelter syndrome
• Testicular size
• Enlarged- Hypothyroidism, fragile X syndrome
• Atrophic- Radiation, Klinefelter, PW syndrome
• Obesity- Leptin deficiency, prader willi syndrome

• Midline defects (CNS malformation)
• Pigmentation (steroidogenic defects), gynecomastia (Klinefelter)
• Klinefelter syndrome- Tall stature, atrophic testis, low upper
segment to lower segment ratio
• Smell sensation (Kallmann syndrome)
• Dysmorphism- CHARGE, prader willi syndromes
Table 2 Pointers to diagnosis of delayed puberty in boys
Pointer Etiology
Growth failure, midline defects Hypopituitarism, celiac
Tall stature, eunuchoid habitus Klinefelter syndrome, isolated HH
Adrenal insufficiency Adrenal hypoplasia, StAR, 3β-HSD)
Abnormal smell sensation Kallmann syndrome
Obesity PW, LMMBB syndromes
Polydactyly LMBB, Smith-Lemli-Optiz
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Investigations
Initial Investigations
• Bone age
• Marked delay- Constitutional delay, hypopituitarism
• Normal, mild delay- Klinefelter, isolated HH
• Screening investigations- SGPT, creatinine, CBC
• Gonadotropin levels- After bone age of 12 years

• FSH < 2 mU/L- Hypogonadotropic
• FSH more than 10 mU/L- Hypergonadotropic
• FSH 2-10 mU/L- Intermediate
• Constitutional delay versus permanent HH

• Clinical
• Family history (suggestive of constitutional delay)
• Abnormal smell (Kallmann syndrome)
• Adrenarche (indicative of permanent delay)
• Follow-up after testosterone (gold standard)
• Spontaneous production (constitutional delay)
• Continuing deficiency (permanent HH)
• Investigations
• DHEAS- Elevated levels suggestive of permanent HH
• Early morning testosterone- > 20 ng/dL impending puberty
• GnRH agonist test
• No response- Permanent HH
• Increase in Gn levels- Constitutional delay
• HCG stimulation- Injection HCG 4000 IU/m2 intramuscularly

• Interpretation- Testosterone levels
• > 300 ng/dL- Constitutional delay
• < 300 ng/dL- Permanent HH
•
• Permanent hypogonadotropic hypogonadism- MRI head
• Hypergonadotropic hypogonadism
• Testicular insult- Infection, trauma, torsion, radiation
• Karyotype- No obvious testicular insult
• Gonadal biopsy- High FSH with normal karyotype
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Constitutional delay versus permanent HH

Features Constitutional delay Permanent HH
Family history Common Rare
Adrenarche Usually absent May be present
DHEAS Usually low Low/ high
Bone age Marked delay Mild delay
Morning testosterone May be elevated Low
GnRH agonist test Positive response No response
HCG test Increase in testosterone No response
Follow-up Spontaneous puberty No puberty
APPROACH
Initial evaluation should include work-up for systemic diseases, bone

age and gonadotropin levels. The main thrust of evaluation of boys
with low gonadotropin levels is to differentiate constitutional delay of
puberty and growth (CDPG) from permanent hypogonadotrophic
hypogonadism (HH). Follow-up for pubertal features is the gold
standard for diagnosis but requires prolonged observation. Short
course of testosterone (100 mg testosterone ester per month for 3-6
months) helps in reducing the period of follow-up. Morning
testosterone levels greater than 20 ng/dL (0.7 nmol/L) are suggestive
of CDPG while pubertal DHEAS indicate permanent HH. Positive
response to HCG or GnRH stimulation test suggests CDPG. Boys with
permanent HH should undergo neuroimaging). Boys with
hypergonadotropic hypogonadism should be evaluated for testicular
insult (trauma, torsion, radiation exposure, alkylating agent treatment)
and Klinefelter syndrome (karyotype). Further evaluation is directed by
baseline testosterone levels.
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Delayed puberty
Screening investigations
Gonadotropin
Low
High
Clinical follow-up
Exclude testicular insult
GnRH/ HCG test
Karyotype
Normal
Response No response
Testosterone
CDPG Permanent HH
MRI head
Low High
HCG test DHT
Testicular biopsy
Low High/ normal

5 α Reductase defect Partial AIS
MANAGEMENT
Testosterone preparations
Preparation Route FrequencyDose
Initial Adult
Testosterone ester* Intramuscular 3-4 weekly 100 mg 300 mg
Testosterone pellets SC Implant 3 monthly 300 mg 900 mg
Testo undeconate Oral Daily 5 mg 10 mg
IM depot 3 monthly 500 mg 1000 mg
Non- Specific measures
• Constitutional delay of puberty and growth
• Indications- Bone age more than 13 years
• Injection testosterone ester 100 mg monthly for 3 doses
• Repeat course for three months if no improvement
• Testosterone one month after last dose of testosterone
• Less than 300 ng/ml-Permanent HH
• More than 300 ng/ml- CDGP, follow-up
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Hypogonadotropic hypogonadism
Testosterone ester 100 mg im monthly for 3 doses
Clinical response
No response Clinical improvement

Repeat course for 3 months
Stop testosterone
Testosterone levels 1 month later
> 300 ng/dL (10 nmol/L) < 300 ng/dL (10 nmol/L)
Constitutional delay Likely permanent HH
No further treatment Continue testosterone
• Permanent HH
• Pubertal induction
• Inj testosterone ester 100 mg monthly for six doses
• Increase testosterone to 100 mg/week as
• Three weekly injection of 300 mg
• Testosterone pellets three to six monthly
• Testo undeconate depot- 1000 mg every 3 months
• Hypergonadotropic hypogonadism
• After a bone age of 13 years
• Initial dose- 100 mg testosterone ester monthly
• Adult dose- 100 mg weekly
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GROW Society ! 67
2.4 Hyperandrogenism
Hyperandrogenism
POINTERS TO DIAGNOSIS
•Dr Yuthika
Hirsuitism-
Bajpai, Sexual hairs in male distribution (face, chin, back,
chest,medial
Consultant Reproductive part of thigh,
Medicine, buttocks)
Regency Hospital Limited, Kanpur
•POINTERS
Acne-TOPre pubertal, requiring medical treatment
DIAGNOSIS
• Alopecia-
•Hirsuitism-Diffuse,
Growth of rapidly progressive
sexual hairs in male distribution (face, chin, back, chest, medial
part of thigh, buttocks)
• Menstrual irregularity-
•Acne- Pre pubertal, Amenorrhea,
requiring medical treatment polymenrorrhea
•Alopecia- Diffuse, rapidly progressive
•Menstrual irregularity- Amenorrhea, polymenrorrhea, menorrhagia
ETIOLOGY
Etiology
Hyperandrogenism
Exogenous Endogenous
Phenytoin
Diazoxide
Steroids
Cyclosporine
Ovarian Source
Adrenal source
Functional Structural Functional Structural

CAH Adenoma PCOS Arrehenoblastoma
21OHD, 3βHSD, 11OHD Carcinoma Secondary Villous cord tumor
Glucocorticoid resistance Hyperprolactinemia
FAH Hypothyroidism
Important
CAH- Congenitalcauses
adrenal in order of
hyperplasia, prevalence
PCOS- Polycystic Ovarian Syndrome, OHD- Hydroxylase
deficiency, HSD- Hydroxysteroid dehydrogenase deficiency
Table• 1 Differentiation
PCOS of hirsuitism and virilization
•
Feature
Hypothyroidism
Hirsuitism Virilization
• Hyperprolactenemia
Sites affected Skin, sebaceous gland Muscle, vocal chord, clitoris
• Drug Hair
Features
induced
growth, acne, menstrual Clitoromegaly, male habitus,
• Non classical
irregularity CAH muscularity, voice change
Etiology P C O S , n o n c l a s s i c a l C A H , Ovarian or adrenal tumor
functional hyperandrogenism
Course Slowly progressive Rapidly progressive
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Table 1 Differentiation of hirsuitism and virilization

Feature Hirsuitism Virilization
Sites Skin, sebaceous gland Muscle, vocal chord, clitoris
Features Hair growth, acne, menstrual Clitoromegaly, muscularity,
irregularity voice change
Etiology PCOS, non classical CAH, Ovarian or adrenal tumor
functional hyperandrogenism
Course Slowly progressive Rapidly progressive
Table 2 Diagnostic criteria of PCOS

Category Criteria
Clinical* Hyperandrogenism- Hirsuitism, acne, alopecia
Menstrual irregularity- Amenorrhea, polymenrorrhea
Investigations High androgen levels (DHEAS), high LH levels
Imaging** Multiple ovarian cysts (2-10)
Peripherally located
Increased ovarian volume (> 10.8 cc in adolescents)
Two out of 3 considered positive, * Present in 5% of general
population, **- Present in 20% of general population
Practical issues in adolescents

•Menstrual cycles usually irregular for two years after menarche
•Acne and hirsuitism common in normal girls
•Multicystic ovaries common finding
•Androgen levels usually higher around puberty
•Diagnosis should be revisited in adulthood
EVALUATION
History
• Onset
• Prepubertal- CAH, adrenal tumor
• Pubertal- Polycystic ovarian syndrome
• Progression
• Gradual- Polycystic ovarian syndrome, CAH
• Rapid- Adrenal or ovarian androgen producing tumor
• Family history of consanguinity, infertility, hirsuitism (CAH)
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• History of waxing and depilation, menstrual history

• Birth weight (low birth weight is a risk factor for PCOS)
• History of premature pubarche (CAH, risk factor for PCOS)
• Exposure to phenytoin, diazoxide, steroids, cyclosporine
Examination
• Identify physiological variants
• Hypertrichosis- Increase in non sexual hair
• Non inflammatory acne during late puberty
• Extent
• Hirsuitism alone- PCOS, CAH
• Hirsuitism with menstrual irregularity- PCOS, CAH
• Hirsuitism and Virilization- Androgenic tumor
• Obesity, acanthosis nigricans (polycystic ovarian syndrome)
• Cushing syndrome (round facies, striae, pigmentation)
• Hypertension (cushing, PCOS, 11 beta OHD)
• Galactorhhea (hyperprolactinemia)
• Abdominal examination (adrenal or ovarian lump)
• Pigmentation- Cushing disease, CAH
Investigations
Confirmation of hyperandrogenism
• DHEAS (Dehydroandrostenidione sulfate)
• Adrenal androgen production (99% by adrenal)
• Prolonged half life and high secretion
• Normal levels- 100-200 ng/dL (2-5 nmol/L)
• High levels (>700 ng/dL) suggestive of adrenal etiology
• Testosterone
• Marker of adrenal or ovarian androgen production
• Normal levels- 0.3-3 nmol/L
• Post-pubertal girl with hyperandrogenism
• 80-150 ng/dL- PCOS, non-classic CAH
• > 150 ng/dL- Androgenic adrenal or ovarian tumor
Identification of source of androgen- DHEAS and testosterone
DHEAS Testosterone Interpretation
High Normal Mild adrenal cause
High High Significant adrenal cause
Normal High Ovarian cause
Normal Normal Measure free testosterone
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Identification of etiology
• Adrenal source (DHEAS > 700 ng/dL)
• Adrenal imaging- Tumor, adrenal hyperplasia
• Dexamethasone suppression test
• Indications- High DHEAS, normal imaging
• Protocol- Dexa 0.5 mg 6 hourly for 8 doses
• Normal response
• Cortisol less than 50 nmol/L (1.4 µg/dL)
• DHEAS less than 50 nmol/L (1.2 ng/dL)
• Testosterone less than 1 nmol/L (30 ng/dL)
Cortisol Androgen response Interpretation

Suppressed Suppressed CAH, functional
Suppressed Not suppressed PCOS, ovarian tumor
Not suppressed Not suppressed Adrenal tumor, cushing
• 17OHP- Normal adrenal imaging

• < 200 ng/dl- 21OHD excluded
• 200- 800 ng/ml- ACTH stimulation test
• >800 ng/ml- 21OHD
• ACTH stimulation test
• Urine free cortisol (features of cushing syndrome)
• Ovarian source
• Imaging- Polycystic ovarian syndrome, ovarian tumor
• Work-up for PCOS- Glucose tolerance test
APPROACH
Features of hyperandrogenism like acne, hirsuitism and menstrual
irregularity are common in pubertal girls emphasizing the need for
careful patient selection. Hirsuitism should be differentiated from
hypertrichosis, generalized increase in body hair. Rapidly progressive
virilization (clitoromegaly, change in voice and increased muscularity)
is characteristic of androgen producing ovarian and adrenal tumor.
DHEAS and testosterone levels should be assessed in girls with
hyperandrogenism. Extremely high testosterone levels (more than 10
nmol/L, 300 ng/dL) should prompt evaluation for androgen producing
tumors. High testosterone with normal DHEAS levels indicates ovarian
hyperandrogenism and should be followed-up with ovarian imaging.
High DHEAS levels are pathognomic of adrenal pathology and should
prompt adrenal ultrasound and 17OHP to identify adrenal tumor and
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CAH. Dexamethasone suppression test should be done if adrenal

imaging and 17OHP levels are normal to differentiate functional
adrenal hyperandrogenism (suppressed DHEAS levels) from
autonomous production (no suppression). Normal testosterone and
DHEAS levels in a girl with hyperandrogenism suggests mild ovarian
hyperandrogenism (PCOS or functional ovarian hyperandrogenism)
which can be confirmed with estimation of free androgen index or
androstenidione levels.
Hyperandrogenism
Confirm diagnosis, assess for virilization
Absent Present
DHEAS Adrenal and ovarian imaging
17OHP levels
High- Adrenal cause Normal- Ovarian cause

Adrenal ultrasound, 17OHP Likely PCOS
Serum prolactin levels Ovarian imaging
Normal
Dexamethasone test
Suppressed Non- suppressed

FAH Autonomous source
Initial evaluation should include confirming the diagnosis of hyperandrogenism. Features of

hyperandrogenism like acne, hirsuitism and menstrual irregularity are common in pubertal girls
MANAGEMENT
emphasizing the need for careful patient selection. Hirsuitism should be differentiated from
Non specificgeneralized increase in body hair. Rapidly progressive virilization (clitoromegaly,
hypertrichosis,
• change in voice and increased muscularity) is characteristic of androgen producing ovarian and
Hirsuitism/
adrenal tumor. DHEAS Acne and testosterone levels should be assessed in girls with
• Lag of 6-12
hyperandrogenism. months
Extremely highin response
testosterone to medical
levels (more than treatment
10 nmol/L, 300 ng/dL) should
promptCosmetic
evaluation formeasures
androgen producing tumors. High testosterone with normal DHEAS levels
• should be considered during this time
indicates ovarian hyperandrogenism and should be followed-up with ovarian imaging. High DHEAS
levels are pathognomic of adrenal pathology and should prompt adrenal ultrasound and 17OHP
Specific measures
levels to identify adrenal tumor and congenital adrenal hyperplasia. Dexamethasone suppression
test should be done if adrenal imaging and 17OHP levels are normal to differentiate functional
• adrenal
Anti hyperandrogenism
androgens- (suppressed
Spironolactone (50-100
DHEAS levels) mg twiceproduction
from autonomous a day), (no
cyperoterone
suppression). (25-50 mg/day),
Normal testosterone and DHEAScombine with
levels in a girl with OCPs- Teratogenic
hyperandrogenism suggests
mild ovarian hyperandrogenism (PCOS or functional ovarian hyperandrogenism) which can be
effect, menstrual irregularity
confirmed with estimation of free androgen index or androstenidione levels.
• 5 Alpha reductase inhibitors- Finastride- 5 mg BD
• MANAGEMENT
Polycystic ovarian syndrome- According to presenting features
Non specific
• Obesity, insulin
! Hirsuitism/ Acne resistance- Life style measures, metformin
• Hirsuitism,
" Practical acne-
points Anti-androgen
♦ Lag of 6-12 months in response to medical treatment
♦ Cosmetic measures should be considered during this time
" Specific measures
♦ Anti androgens
" Agents
! Spironolactone- 50-100 mg twice a day
! Cyperoterone- 25-50 mg/day
" Adverse effects- Menstrual irregularity, hyperkalemia
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" Combine with oral contraceptive pills
! Teratogenic effect
! Cause menstrual irregularity
♦ 5 Alpha reductase inhibitors
• Menstrual irregularity- Oral contraceptive pill

• Increased SHBG levels (estradiol effect)
• Inhibition of LH secretion (progesterone effect)
• Options
• Drosperinone estradiol combination (yasmin)
• Low androgenic effect
• Less weight gain (anti mineralocorticoid effect)
• Estradiol cyperoterone combination (Diane)
• Antiandrogenic effect of cyperoterone
• More effective
• Conventional pill- Higher weight gain, slower response
Table Oral contraceptives in management of PCOS

Combination Estrogen Progesterone Features
Microgynova EE 20-50 µg Levonoresterol 100 µg Higher weight gain
Economical
Diane EE 35 µg Cyperoterone 2 mg Anti androgenic
Yasmin EE 30 µg Drosperinone 3 mg Less weight gain
Antiandrogenic
• Congenital adrenal hyperplasia- Dexa 0.25 mg/m2/day night
• Adrenal/ ovarian tumor- Surgery
APPROACH TO MANAGEMENT
Mild hyperandrogenic symptoms and menstrual irregularity are
common in adolescent girls. Treatment should therefore be reserved
for girls with severe hirsuitism, acne or menstrual irregularity. Life style
measures and metformin should be initiated in girls with clinical
(obesity, acanthosis nigricans) or laboratory features of insulin
resistance (glucose intolerance or high fasting insulin levels). Lack of
response to these measures should prompt treatment according to
clinical features. Girl with predominant acne or hirsuitism with normal
menstrual cycles should be started on antiandrogens like cyperoterone
or spironolactone. Cosmetic measures should be advised during the
lag phase (6-12 months) of response to these drugs. Lack of response
to these agents or subsequent development of menstrual irregularity is
an indication for starting oral contraceptives. Antiandrogen containing
oral contraceptives (diane or yasmin) are preferred in these girls. Oral
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contraceptives should be considered in girls presenting with menstrual

irregularity.
APPROACH
Adolescent with PCOS
Assess for insulin resistance
Present Absent
Life style measures, metformin
Improvement No improvement
Continue for 1 year
Assess presenting complaint
Menstrual irregularity Acne/ hirsuitism

Oral contraceptives Antiandrogen
No improvement in 12 months Improvement

Consider oral contraceptives Continue for 2 years
Mild hyperandrogenic symptoms and menstrual irregularity are common in adolescent girls.
Treatment should therefore be reserved for girls with severe hirsuitism, acne or menstrual
irregularity. Life style measures and metformin should be initiated in girls with clinical (obesity,
acanthosis nigricans) or laboratory features of insulin resistance (glucose intolerance or high
fasting insulin levels). Lack of response to these measures should prompt treatment according to
clinical features. Girl with predominant acne or hirsuitism with normal menstrual cycles should be
started on antiandrogens like cyperoterone or spironolactone. Cosmetic measures should be
advised during the lag phase (6-12 months) of response to these drugs. Lack of response to these
agents or subsequent development of menstrual irregularity is an indication for starting oral
contraceptives. Antiandrogen containing oral contraceptives (diane or yasmin) are preferred in
these girls. Oral contraceptives should be considered in girls presenting with menstrual irregularity.
! Congenital adrenal hyperplasia

" Glucocorticoid preparations
♦ Hydrocortisone 10-15 mg/m2/day in three divided doses
♦ Prednisolone 2.5-3 mg/m2/day in two divided doses
♦ Dexamethasone- 0.25 mg/m2/day once at night
" Consider antiandrogens if significant hirsuitism
! Adrenal/ ovarian tumor- Surgery
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2.5 Turner syndrome
Turner syndrome, haploinsufficiency of whole or part of X

chromosome, is associated with a constellation of findings including
growth failure, pubertal delay and cardiovascular anomalies. Advances
in management have resulted in dramatic improvement in outcome in
girls with turner syndrome. Timely assessment and management in the
purview of multi specialty clinical setup is essential to achieve
favorable outcome.
EPIDEMIOLOGY
Turner syndrome is the most common chromosomal abnormality
present in three percent of all fetuses. However 99% of 45 X fetuses
are aborted in the first and second trimester accounting for 10% of all
spontaneous abortions. This results in an overall prevalence of 1 in
2500 live girls.
CLINICAL FEATURES
The diagnosis of Indian girls with turner syndrome is delayed. Even in
developed countries a mean difference of five years from the onset of
growth failure to diagnosis has been observed. Early identification is
helpful in allowing early initiation of growth promoting therapy and
evaluation for potential life threatening diseases.
ANTENATAL
Ultrasound findings indicative of turner syndrome include increased
fetal nuchal translucency and cystic hygroma. These findings are non
specific and also observed in autosomal trisomy disorders.
INFANCY
The pointer of Turner syndrome in infancy include lymphedema ( 97%
of cases) and left sided cardiac defects (coarctation of aorta and
bicuspid aortic valve).
CHILDHOOD & ADOLESCENCE

Growth failure is the commonest pointer to diagnosis of turner
syndrome (82% of all). Most girls in India however present in
adolescence with delayed puberty. Skeletal abnormalities, hearing
defect and facial features may also point to the diagnosis at this age.
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ADULTHOOD
Women with turner syndrome may present later in life with secondary
ammenorhea or infertility.
Age group Features
Intrauterine Increased neck translucency, cystic hygroma
Infancy Cystic hygroma, lymphedema, coarctaction, PAPVR
Childhood Growth failure, hearing, delayed puberty, skeletal
Adulthood Secondary amenorrhea, infertility
DIAGNOSIS
Conventionally turner syndrome has been diagnosed in the presence
of complete deletion of X chromosome but mosaic and sub-
chromosomal deletions have been increasingly identified. The
karyotype analysis should study 30 metaphase plates to identify 10%
mosaicism with 95% confidence. In patients with characteristic features
but normal karyotype, analysis from additional sites like skin is
indicated.
CRITERIA
The diagnosis of turner syndrome requires complete or partial absence
of X chromosome and characteristic clinical features in a phenotypic
female. FSH may be normal before maturation of the hypothalamic-
pituitary axis and is an unreliable marker in young girls. Elevated FSH
levels should be followed up with karyotype to identify Y cell line.
Identification of 45X cell population in boys or girls with no turner
stigmata is not diagnostic of turner syndrome. Girls with ring
chromosome and Xq isochromosome are phenotypically
indistinguishable from those with classical turner syndrome and should
be included in the purview of the disorder. Xq24 deletion with
predominant ovarian involvement and normal growth and distal Xp
deletions (with the exception of Xp22.3) with short stature and minimal
ovarian involvement should not be diagnosed as turner syndrome.
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PRENATAL DIAGNOSIS
The increased use of prenatal karyotype has resulted in identification
of a number of fetuses with 45 X and 45 X mosaic karyotype. However
in many of these cases have normal female karyotype postnatally. This
is due to fallacy of antental karyotype in identifying mosaicism. This
should be considered while counseling families with antenatal
diagnosis of turner syndrome. The likelihood of turner syndrome with
suggestive antenatal karyotype depends on the pretest probability of
the disease. It is much higher when the karyotype is done as workup
for specific ultrasound findings than when done for advanced maternal
age. A postnatal karyotype is mandatory to confirm the antenatal
findings.
KARYOTYPE-PHENOTYPE CORRELATION
The manifestations of turner syndrome depend on the extent and
distribution of the defect. It is now understood that the classic turner
syndrome represents the most severe end of the spectrum. Most girls
with turner syndrome have mosaic form or sub-chromosomal deletions
with milder clinical spectrum. Girls with deletion of short arm of X
chromosome predominantly present with growth failure while those
with long arm involvement have ovarian failure as their presenting
feature. The presence of Y line is associated with risk of gonadal
tumors. Ring chromosome arrangement is predictor of mental
subnormality.
Anomaly Association
45 X0 Classic turner syndrome
Marker chromosome Virlization
Y cell line Gonadoblastoma
Xq Ovarian failure
Xp deletion Short stature, variable pubertal failure
46 Xi (isochromosome) Pubertal delay
46 X ring Mental retardation
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DETECTION OF Y LINE
Y chromosomal material is present in 5% girls with turner syndrome
while an additional 3% have marker chromosome (a fragment of either
X or Y chromosome). The presence of Y material is associated with
12% risk for development of gonadoblastoma, which carries a risk for
malignant transformation. This highlights the need for prophylactic
gonadectomy in girls with Y cell line. The need for universal screening
for girls with turner syndrome with FISH for Y material is questionable.
Currently FISH is recommended for girls with marker chromosome or
virlization. The identification of Y material without these features has
very low risk of development of gonadal tumors.
ASSOCIATIONS
Turner syndrome is associated with a constellation of abnormalities
affecting multiple body systems (Table 3). The impact of these
associations should be assessed in the holistic perspective of the
disease and not as extrapolation of isolated manifestations in normal
individuals. This is highlighted by the natural history of aortic root
dilatation and dissection in women with turner syndrome. Women with
turner syndrome are at much higher risk of aortic dissection at the
same aortic size corrected for body size compared to non turner
women. These differences highlight the need for turner specific
recommendations for assessment and management of associations.
GROWTH FAILURE
Short stature is universal in turner syndrome. Birth size is mildly
reduced along with reduced growth velocity during infancy. Many girls
however are above the fifth percentile for normal chart till five years of
age and height compromise usually manifests after this age. This
combined with delayed and blunted pubertal growth spurt results in
final height 20 cm below target height. The inevitability of growth failure
in turner syndrome has resulted in modification of guidelines for growth
promoting therapy in these girls. Traditionally GH has been initiated
after growth failure has set in. Unfortunately significant height deficit
has occurred by this stage. Given the inevitability of growth
compromise in turner syndrome, starting GH early when the height is
in the normal range would improve the likelihood of normal adult
height. The etiology of growth failure in turner syndrome is multi
factorial. The main cause is haploinsufficiency of SHOX (short stature
homeobox gene in X), a gene located on distal part of short arm of X
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chromosome. GH and IGF1 levels are normal in turner syndrome but

elaborate studies have demonstrated mild GH and IGF1 resistance.
The role of low estradiol levels in the prepubertal age group on growth
have3 also
Table beenofsuggested.
Associations turner syndrome
System Association Intervention
Growth Growth failure GH, oxandrolone
Puberty Delayed puberty, secondary FSH at 12 years, hormone
amenorrhea, infertility replacement
Cardiovascular Coarctation of aorta, bicuspid aortic Four limb blood pressure, ECG,
valve, PAPVR, aortic dissection ECHO at baseline, MRI at 18
years, imaging every five years
Ear Otitis media, conductive and Hearing assessment, otoscopic
sensorineural hearing loss examination, hearing aid
Ophthalmological Strabismus, ptosis, color blindness Fundoscopy
Orthopedic Scoliosis, lordosis, reduced cortical Orthopedic review
density, congenital dislocation of hip
Renal Collecting duct abnormality, horse shoe Ultrasound kidney
kidney, positional abnormality
Autoimmune Hypothyroidism, celiac disease Thyroid function, TTG
Dermatological Pigmented nevi Monitoring for size
OVARIAN DYSFUNCTION
The onset of ovarian failure in turner syndrome begins in utero with
accelerated degeneration of ovarian follicles. Estradiol levels are lower
than non turner girls even in the prepubertal age group. The decline in
estradiol levels triggers increase in LH and FSH during infancy and
early childhood. The levels decrease around five years of age and
increase again with the maturation of hypothalamic-pituitary axis. FSH
levels are therefore unreliable marker of turner syndrome between
5-12 years of age. The spectrum of ovarian dysfunction in turner
syndrome ranges from delayed puberty, primary amenorhea,
GROW Society 17 ! 79
secondary amenorhea, infertility to normal reproductive outcome.

Spontaneous puberty is observed in one third girls and menarche can
happen in a few cases. Pregnancy has been reported in 2-5% women
with turner syndrome and limited to those with mosaic karyotype.
Given the likelihood of spontaneous puberty it is important to assess
ovarian functions before pubertal induction. The possibility of oocyte
retrieval and cryopreservation should be explored in girls identified at
an early age with preserved ovarian functions.
CARDIOVASCULAR ASSOCIATION
Cardiovascular abnormalities occur in around 50% of girls with turner
syndrome and is a major cause of increased morbidity and mortality.
The common abnormalities include coarctation of aorta (11%), bicuspid
aortic valve (16%) and partial anomalous pulmonary venous return.
This mandates the need for baseline echocardiography. Webbing of
neck is a strong predictor of cardiovascular abnormality. Girls with
turner syndrome are at increased risk of hypertension that should be
periodically monitored and managed. The major concern in turner
syndrome is life threatening aortic dissection that has been reported in
around 1% of cases. This represents 100 fold increased risk compared
to general population. Risk factors for aortic dissection include bicuspid
aortic valve, hypertension, elongated transverse aortic arch and aortic
dilatation. Aortic arch size is an important predictor of aortic dissection.
Women with turner syndrome are at increased risk of dissection for the
same aortic dimension corrected to body surface area compared to
general population. Therefore lower cutoffs for aortic size index ( 2 cm/
m2 body surface area) are recommended for close follow-up. These
individuals should be put on beta blockers to lower the risk of
dissection. Increased aortic dimension is a contraindication for
pregnancy and competitive sports. Other cardiac abnormalities include
prolongation of QRS complex, hypertension and dyslipidemia.
UROLOGOCIAL ABNORMALITIES
Urological anomalies occur in 30-40% girls with turner syndrome. They
include collecting system malformation, horse shoe kidney and
positional abnormalities. All girls with turner syndrome should undergo
renal ultrasound at diagnosis. The risk of development of renal
complications is minimal if initial ultrasound is normal.
OPHTHALMOLOGICAL
The ocular manifestations of turner syndrome include strabismus,
ptosis, epicanthic folds and refractory errors. They predispose them at
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risk for amblyopia and need to be regularly monitored by pediatric

opthalmologists. The prevalence of red green color blindness is
increased and similar to male population.
HEARING LOSS
Turner syndrome is associated with both conductive and sensorineural
hearing loss. This emphasizes the need for detailed otoscopic
examination and hearing assessment. Conductive hearing loss is
related to recurrent otitis media caused by abnormal ear anatomy. It is
important to identify and treat otitis media early to prevent long term
complications. Sensorineural hearing loss is particularly common
during adolescence.
DENTAL
Common dental problems in turner syndrome include dental
malocclusion and dental enamel hypoplasia. They are at increased risk
of root resorption. These abnormalities emphasizes the need for
regular dentist evaluation.
SKELETAL
Skeletal abnormalities associated with turner syndrome include short
neck, cubitus valgus, shield chest, congenital dislocation of hip,
brachymetacarpia and madelung abnormality. Scoliosis and kyphosis
is common in turner syndrome and may worsen with growth hormone
treatment. Bone mineral density corrected for body size assessed by
dual energy X Ray absorbometery is normal in adequately
estrogenized girls with turner syndrome. The cortical bone density in
girls with turner syndrome is however reduced. There is limited if any
benefit of adding bisphosphonate treatment in these girls as the drug
has limited effect on cortical bone density.
DERMATOLOGICAL
Pigmented nevi are common in girls with turner syndrome. The risk of
malignant transformation is similar to general population and not
increased with growth hormone treatment.
AUTOIMMUNE ASSOCIATIONS
Turner syndrome predisposes individuals to increased risk of
autoimmune disorders like type 1 diabetes mellitus, hypothyroidism
(24%), hyperthyroidism (2%) and celiac disease (5%). Thyroid disease
should be assessed at diagnosis and then annually due to high risk of
GROW Society ! 81
association. TTG IgA antibody should be performed at baseline and in

the presence of symptoms of celiac disease.
MANAGEMENT
Advances in management have ensured near normal outcome in girls
with turner syndrome. This requires a holistic approach using a multi-
displinary team well versed with the nuances in the management of the
disease. Timely assessment to identify associations and management
is required for the same.
GROWTH
Strategies to increase adult height in turner syndrome aim at
increasing the growth rate (growth hormone and oxandrolone) or
duration (delayed initiation of estradiol).
Growth hormone (GH)

Growth hormone has been successfully used for around three decades
in turner syndrome. Turner syndrome was the second indication after
growth hormone deficiency for which GH was approved.
Indication- Conventionally GH has been initiated after the onset of
growth failure. This resulted in inadequate catch-up growth and
compromised adult height. The inevitability of growth failure in turner
syndrome indicates the need for earlier initiation of GH. This has
resulted in a paradigm shift of using GH in turner syndrome from
“height below the fifth percentile for normal growth chart” to “growth
faltering as reflected by reduced growth velocity”. Evaluation of the
GH-IGF-1 axis is not required but may be considered if height is
significantly below the turner growth chart. Hypothyroidism and celiac
disease should be excluded before starting GH.
Dose- GH dose in turner syndrome is substantially higher than that

used in children with growth hormone deficiency (0.375 mg/kg/week,
53 microgram/kg/day versus 0.175 mg/kg/week, 25 microgram/kg/day).
Body surface area based dosing is more suited in older girls and those
with obesity. GH should be administered daily at bedtime. A dose-effect
response has been demonstrated with flattening of response at higher
doses. In a randomized controlled trial of 60 Dutch girls, GH at dose of
6 IU/m2/day (67 microgram/kg/day) resulted in 5.3 cm greater gain
compared to 4 IU/m2/day (45 microgram/kg/day). The use of 8 IU/m2/
day (90 microgram/kg/day) however did not increase final height
further.
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Growth benefit
GH increases height in turner syndrome, the extent of response is
however variable. Earlier studies suggested minimal response to 17
cm gain when compared to historical controls. There are only two
randomized controlled trials on the effect of GH in turner syndrome. In
the Canadian study GH treatment of 154 girls for 5.5 years from the
age of 7-13 years increased final height by 7.2 cm. In another trial a
gain of 0.78 SDS (5 cm) with GH treatment for 7.2 years (0.3 mg/kg/
week in three divided doses) was observed in 80 girls with turner
syndrome. Reduced response in this study may be related to the use
of lower dose and only thrice weekly GH. In the only Indian study,
Khadilkar et al, studied the effect of GH (0.3 mg/kg/week) for one year
in 16 girls. They observed an increase in growth velocity from 3.2 cm/
year to 6.7 cm/year with an increment of 2.4 cm in predicted adult
height. The overall evidence indicates an increase of 1.5 cm per
treatment year.
Factors influencing outcome

Factors influencing response to GH include age at treatment (earlier
the better), dose (higher the better), duration (longer the better) and
mid parental height (higher the better). This emphasizes the need for
earlier diagnosis and treatment in turner syndrome. Prediction models
have been developed that help predict response and determine tailor
made doses.
Non auxological benefits

GH treatment in turner syndrome reduces adiposity and improves body
compostion. Beneficial effects on quality of life were not observed in a
large French study evaluating 568 adults with turner syndrome.
Duration
GH should be continued till final height is achieved as indicated by
growth velocity less than 2 cm per year and bone age of 14 years.
Treatment should be continued till at least two years to achieve
reasonable response.
Adverse effects
GH is safe as determined by follow up of a large number of girls with
turner syndrome. In particular no effect on aortal diameter and cardiac
size, a key area of concern, has been noted. GH treatment has been
associated with increased scoliosis, otitis media, benign intracranial
hypertension and glucose intolerance. There is no evidence of
GROW Society ! 83
increased risk of colon cancer or other malignancies in girls with turner

syndrome treated with GH.
Androgen
Given the extent of growth compromise despite GH alternative growth
promoting strategies have been explored. This is particularly true when
diagnosis is delayed. Oxandronolone, a non aromatizable androgen,
was associated with mild increment in growth at a dose of 60
microgram/kg/day in initial studies at the risk of virlization and clitoral
enlargement. Subsequent studies have shown that lower dose (30
microgram/kg/day) results in equivalent growth benefits with lower
rates of virlization. In a randomized controlled trial oxandrolone at a
dose of 50 microgram/kg/day along with GH at the age of nine years
resulted in increase in final height by 4.6 cm. This was similar to
delaying pubertal induction to 14 years of age (3.8 cm). This indicates
that the use of oxandrolone in girls with delayed diagnosis may obviate
the need for delaying pubertal induction.
ESTROGEN REPLACEMENT THERAPY

Delayed or interrupted puberty is observed in over 90% of girls with
turner syndrome. Adequate hormonal therapy is essential to achieve
good long term outcome.
Timing
Earlier estradiol replacement was delayed till the age of 14 years (or at
least 4 years after starting GH) to increase final height. This increase in
adult height was offset by psycho-social problems of delayed pubertal
maturation. Early diagnosis and initiation of growth hormone therapy
now allows timely pubertal induction.
Preparation
Estradiol valerate and micronized progesterone are emerging as
physiological alternatives to conjugated equine estradiol (CEE) and
synthetic estrogen (ethinyl estradiol) and progesterone (medroxy
progesterone acetate).
Route
Transdermal route is superior to oral estrogen replacement as oral
estrogen suppresses hepatic IGF1 production. Moreover girls with
turner syndrome are at a higher risk for thrombotic effects of estradiol.
Transdermal estradiol has the advantage of lower thrombotic risk.
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Protocol
Estrogen should be started at 5-10% of adult dose (0.25 mg of
estradiol valerate, 5 microgram of ethinyl estradiol or 0.12 of CEE) at
the age of 12 years. The dose should be increased in quantums of
10-20% every six months to adult dose (2 mg of estradiol valerate,
0.625 mg of CEE and 30 microgram of ethinyl estradiol) over two
years. Progesterone (200 microgram daily of micronized progesterone
or 10 mg of medroxy progesterone acetate) is added after two years of
replacement or when withdrawal bleed occurs. This should be followed
by cyclical estrogen-progesterone replacement. Full adult dose of
estrogen should be used till the age of 30 years to mimic physiological
estradiol peak. Between 30 to 50 years the dose may be lowered to
the minimum dose required to prevent osteoporosis. After the age of
fifty years the need for estradiol replacement should be determined
based on recommendations for post menopausal women. Periodic
monitoring of endometrial thickness and breast examination is
required.
Table 4- Hormone replacement guideline in turner syndrome
Age Hormone replacement
Before 12 years Monitor for spontaneous puberty, FSH
12-13 years Start estrogen at 10-20% of adult dose (0.25 mg estradiol valerate,
0.125 mg CEE, 5 microgram ethinyl estradiol daily)
14-15 years Gradually increase estrogen by 10-20% of adult dose every six
month to achieve adult dose by 2 years (2 mg estradiol valerate,
0.625 mg CEE, 50 microgram ethinyl estradiol daily)
15 years Add progesterone after breakthrough bleeding (200 mg of
micronized progesterone on day 20-30)
15-30 years Full adult dose with estradiol valerate and micronized progesterone
(consider oral contraceptives as options)
30-50 years Use lowest possible dose to prevent osteoporosis
> 50 years Used as per indications for post menopausal women
GROW Society ! 85
CARDIOVASCULAR SYSTEM
Echocardiography, chest X Ray and ECG should be performed at of
diagnosis. Periodic assessment of blood pressure, blood sugar and
lipids is essential. Echocardiography should be repeated every five
years. Cardiac MRI provides a holistic picture about aortic root size
and should be done at the age when it is feasible to ascertain aortic
root size. MRI should be repeated periodically to monitor aortic size.
Individuals with increased root size index (more than 2 cm/m2) should
be started on beta blockers and advised to avoid pregnancy and
competitive sports.
HEARING
Hearing assessment and detailed otological examination should be
done at diagnosis. Hearing aid should be applied early to avoid long
term impact. Timely detection and treatment of otitis media is of
paramount importance.
86 Grow Society
2.6 Disorders of Sexual Differentiation

42 Disorders of Sexual Development
Criteria- Discordance
42.1 Criteria- Discordancebetween genetic,
between genetic, gonadal
gonadal and sex
and phenotypic phenotypic sex
42.2 Pointers
Pointers to diagnosis
to diagnosis
•Genital ambiguity
•Genital ambiguity
•Penoscrotal hypospadia
•Penoscrotal hypospadia
•Bilateral inguinal masses in girls
Bilateral
••Bilateral inguinal in
cryptorchidism masses
boys in girls, cryptorchidism in boys
Primary
••Primary amenorrhea
amenorrhea in normal
in girls with girls with normal
pubertal pubertal development
development
Etiology
42.3 Etiology
Disorders of Sexual Development
Gonadal dysgenesis
Undervirilization Virilization
Ovo-testicular DSD
Functional defect Structural defect Maternal Fetal

Testicular dysgenesis Hyperandrogensi
Decreased production Decreased

Adreno- testicular defect action
SLO syndrome
StAR deficiency
3 βHSD deficiency Adrenal Extra- Adrenal
17 α OHD 21 OH deficiency Aromatase deficiency
Isolated testicular defect 11 OH deficiency
3 βH S D
DSD- Disorder of Sexual Development, StAR- Steroidogenic Acute Regulatory

Protein, OHD- Hydroxylase deficiency, βHSD- Beta hydroxysteroid dehydrogenase ,
SLO- Smith Lemeli Optiz syndrome, 5 ARII- Alpha reductase II, AIS- Androgen
insensitivity syndrome

Important causes
• 21 hydroxylase (In order of importance)
deficiency
• •21
XYhydroxylase deficiency
gonadal dysgenesis
• •XY gonadal
Androgen dysgenesis
insensitivity syndrome
• Androgen insensitivity syndrome
GROW Society ! 87
Urogenital ridge
Adrenal SF1 WT1 Kidney
Bipotential gonad
SRY, SOX 9
DAX 1
Testis
Ovary
Estrogen Testosterone
Mullerian development Anti mullerian hormone
Wolfian regression Mullerian regression
5 α reductase
Wolfian development Dihydrotesotsoterone External
genital development
Figure Figure
1 Sexual
41.1 Sexualdevelopment
development and itsbegins with development
disorders. Sexual the developmentbegins with of
bipotential gonad from
the development the urogenital
of bipotential gonad from the ridge under
urogenital ridgethe
underinfluence
the influence of
of WT1
(wilms tumor
WT1 (wilms1) and tumorSF1 genes.
1) and SF1 genes.TheseThese genes
genes play play an important
an important role in therole in
the development of other organs (WT1 for kidney and
development of other organs (WT1 for kidney and SF1 for adrenals). SRY SF1 for
gene (sex
regulatory region on Y chromosome)
adrenals). SRY gene (sex regulatory region on Y chromosome)is central to the process of gonadal is
differentiation. In boys, SRY gene induces testis determining genes like SOX9 while
central inhibiting
to the anti process of gonadal differentiation. In boys,
testis gene DAX1 resulting in testicular development. Sertoli cells of
SRY gene
inducesthetestis determining
testis secrete genes
anti mullerian hormonelikefromSOX9
6 weeks while inhibiting
of gestation while leydiganti
cell testis
gene DAX1 resulting
testosterone productioninstarts
testicular
from sevendevelopment.
weeks of gestation. Sertoli cellsareof the
These agents
testis secrete
responsibleantifor mullerian
regression of hormone
mullerian duct fromand 6development
weeks ofof gestation
wolfian duct while
leydig cell testosterone production starts from seven tissue
respectively. Testosterone is converted by the 5 alpha reductase II in genital weeks
to of
the potent hormone dihydrotestosterone, that is responsible for virilization of external
gestation. These agents are responsible for regression of mullerian
genitalia resulting in labioscrotal fusion and development of penile urethra. Absence
duct and development
of SRY of wolfian
gene in girls results in activationduct respectively.
of anti testis gene DAX1 Testosterone
and ovarian is
converted by theEstrogen
development. 5 alpha reductase
produced II involved
by ovaries are in genital tissue oftomullerian
in maintenance the potent
hormone ductdihydrotestosterone,
while lack of testosterone resultsthat is responsible
in the regression for Disorders
of wolffian ducts. virilization
of of
externalsexual
genitalia
developmentresulting in labioscrotal
can therefore fusion
result from disorders and development
of gonadal development or of
function. Disordered
penile urethra. Absence gonadal
of SRYdevelopment
geneisin observed
girls with
resultsdefectsininactivation
genes involvedof anti
in the development of the bipotential gonad (WT1 and SF1), testis (SRY and SOX9
testis gene DAX1 and ovarian development. Estrogen produced by
gene deletion in males and SRY insertion in females) and ovary (DAX1 over
ovaries expression
are involvedin males).in maintenance
Disorders of mullerian
of gonadal functions duct testosterone
include impaired while lack of
testosterone results in the regression of wolffian ducts. Disorders of
88 Grow Society
Table 42.1 Embryological analogs of sexual development

sexual development can therefore result from disorders of gonadal
Embryological structure Male counterpart Female counterpart
development or function. Disordered gonadal development is observed
Mullerian
with ductin genes Mullerian
defects involvedtubercle Fallopian of
in the development tube,
theuterus, upper
bipotential
gonad (WT1 and SF1), testis (SRY and SOX9 gene deletion in males
vagina
and SRY
Wolfian insertion in Epididymis,
duct females) and vas ovary (DAX1
deferens, Wolfian over expression in
tubercle
males). Disorders of gonadal functions include impaired testosterone
production (steroidogenic seminal vesicle and action (androgen insensitivity
defects)
Genital tubercle Penile corpora
syndrome and 5 α reductase deficiency) in boys Clitoris
and increased adrenal
(congenital adrenal hyperplasia) or ovarianLabia
Labio scrotal fold Scrotal sac majora
(aromatase deficiency)
androgen production
Labio urethral fold inPenile
girls.urethra Labia minora
Table 1 Karyotype
Table 42.2 based
Karyotype based classification
classification of DSD
of disorders of sexual differentiation
Karyotype Normal genital appearance* Genital ambiguity
46 XX SRY insertion Congenital adrenal hyperplasia
Severe 21OHD Aromatase deficiency
Maternal virilization
Maternal drug intake
46 XY SRY deletion Testicular dysgenesis
SF1 defect Steroidogenic defects
Gonadal dysgenesis Partial AIS
Severe StAR defect 5ARII deficiency
Complete AIS
46 XY/XO Gonadal dysgenesis
Ovo-testicular DSD
* Discordant to genotypic sex
Table 42.3 Classification of DSD ESPE-LWPES consensus statement 2005
Category Previous name Disorders
Ovo testicular DSD True Hermaphroditism
46 XY DSD Male pseudohermaphroditism Testicular dysgenesis
Steroidogenic defects
AIS, 5 AR II deficiency
46 XX DSD Female pseudohermaphroditism CAH, XX gonadal dysgenesis
Aromatase deficiency
AIS- Androgen insensitivity syndrome, CAH- Congenital adrenal hyperplasia
Table 42.4 Gene defects associated with gonadal dysgenesis
Gene Function Gender affected Features
GROW Society ! 89
Gonadal dysgenesis Partial AIS
Severe StAR defect 5ARII deficiency
Complete AIS
46 XY/XO Gonadal dysgenesis
Ovo-testicular DSD
* Discordant to genotypic sex
Table 2 Classification
Table 42.3 Classification of of
DSDDSD ESPE-LWPES
ESPE-LWPES consensus statement 2005
WT1 Gonadal, renal development Boys Renal dysplasia
Category Previous name Disorders
Ovo testicular DSD True Hermaphroditism Denys Drash, Frasier
46 XY DSD Male pseudohermaphroditism syndromedysgenesis
Testicular
SF1 Gonadal, adrenal development Boys Adrenal failure
Steroidogenic defects
SOX9 G o n a d a l , s k e l e t a l Boys Skeletal dysplasia
AIS, 5 AR II deficiency
development Female pseudohermaphroditism CAH, XX gonadal dysgenesis
46 XX DSD
DAX1 Anti testis factor Boys Complete sex reversal
SRY Testis determining factor Both Aromatase
Complete deficiency
sex reversal
AIS- Androgen insensitivity syndrome, CAH- Congenital adrenal hyperplasia
WT1- Wilms Tumor 1 gene, SF1- Steroidogenic factor 1, SOX9- Sexual development
Table 42.4 Gene defects
on X chromosome associated
9, DAX1- withRegulatory
, SRY- Sex gonadal dysgenesis
region on Y Chromosome
Gene 3Function
Table Gender affected Features
Table 42.5Steroidogenic defects
Steroidogenic defects associated
associated with DSDwith DSD
Enzyme Features Diagnostic test
Associated with under virilization
7 D H C SLO syndrome High 7 Dehydrocholesterol
dehydrogenase
StAR Adrenal insufficiency Low DHEA, pregnenolone, 17OHP
Complete sex reversal
17 hydroxylase Hypertension Low 1 7 O H P, high
deoxicorticosterone
17 βHSD III Complete sex reversal Low testosterone, high
androstenidione
5 α reductase Virilization at puberty High testosterone to DHT ratio
Associated with virilization
21 hydroxylase Adrenal insufficiency High 17OHP
11 β hydroxylase Hypertension High Deoxycortisol
Associated with both virilization and under virilization
3 βHSD Adrenal insufficiency High 17 OH pregnenolone, DHEA
SLO- Smith-Lemeli-Optiz syndrome, 17OHP- 17 hydroxy progesterone, DHEA-
Dehydroandrostinidione, DHT- Dihydrotestosterone
42.4 Evaluation
42.41 HISTORY
•Presentation
! Genital ambiguity
" Congenital adrenal hyperplasia
" Gonadal dysgenesis
" Partial AIS
" Steroidogenic defects
! Boy with cryptorchidism- Congenital adrenal hyperplasia
90 Grow Society
Evaluation
HISTORY
Genital ambiguity- Congenital adrenal hyperplasia, gonadal
dysgenesis, partial AIS
Boy with cryptorchidism- Congenital adrenal hyperplasia
Girl with inguinal masses- complete AIS, 17 βHSD defect
Primary amenorrhea with normal pubertal development- Complete AIS
Perinatal history- Maternal virilization (virilization disorders, aromatase
deficiency), intake of steroids, progesterone
Family history- Genital ambiguity, consanguinity, sibling death
(congenital adrenal hyperplasia), infertility (complete androgen
insensitivity syndrome), delayed puberty (steroidogenic defects)
EXAMINATION
Genital examination
Exclude normal variants
Labial edema
Prominent but not enlarged clitoris
Apparent small penis embedded in suprapubic fat
Appearance of clitoromegaly in preterm girls
Labial adhesion without clitoromegaly
Appearance
Prader staging (Stage I-V)
Stage I- Clitoromegaly, no labioscrotal fusion
Stage II-III- Increasing clitoromegaly and early labial fusion
Stage IV- Increased labial fusion, single urogenital opening
Stage V- Male appearance with small penis
Asymmetry- Mixed gonadal dysgenesis, ovo testicular DSD

Extreme variation in genital appearance for same condition
Appearance is not pathognomic for underlying condition
Gonads- Palpate from inguinal canal to labioscrotal fold, Number, size,

consistency (smooth, homogenous- Testis, hetergoneous- ovo-testis)
Phallus- Stretched phallic length, breadth, amount of erectile tissue,

chordee
Labioscrotal fold
Anogenital index (> 0.5 suggests labio scrotal fusion)
Anogenital index = Anus to posterior forchutte/ Anus to clitoris
GROW Society ! 91
Rugosity, pigmentation (suggestive of virlization)
Urogenital!opening-
Labioscrotal fold
Number, site of urethral opening
" Anogenital index (> 0.5 suggests labio scrotal fusion)
Anogenital index = Anus to posterior forchutte/ Anus to clitoris
Pigmentation (congenital adrenal hyperplasia, SF1 defect)
" Rugosity, pigmentation (suggestive of virlization)
Hypertension (11 beta hydroxylase, 17 alpha hydroxylase defect)
! Urogenital opening- Number, site of urethral opening
Hemihypertrophy (WT1 gene defect)
•Pigmentation (congenital adrenal hyperplasia, SF1 defect)
Skeletal dysplasia (SOX 9 defect)
•Hypertension (11 beta hydroxylase, 17 alpha hydroxylase defect)
Polydactyly, microcephaly, mid facial narrowing (SLO syndrome)
•Hemihypertrophy (WT1 gene defect)
•Skeletal dysplasia (SOX 9 defect)
Pointers to diagnosis in DSD
•Polydactyly, microcephaly, mid facial narrowing (SLO syndrome)
Pointer Likely diagnosis
Table 42.6 Pointers to diagnosis in DSD
Pigmentation Congenial adrenal hyperplasia, SF1 defect
Genital asymmetry Mixed gonadal dysgenesis, ovo testicular
Pigmentation Congenial adrenal hyperplasia, SF1 defect
Skeletal dysplasia
Genital asymmetry Mixed SOX
gonadal9 dysgenesis,
defect ovo testicular DSD
Polydactyly, microcephaly
Skeletal dysplasia SOX 9Smith-Lemeli-Optiz
defect syndrome
Polydactyly, microcephaly Smith-Lemeli-Optiz
Hypertension syndrome defect
11 or17 hydroxylase
Hypertension 11 or17 hydroxylase defect
Hemihypertrophy WT1 mutation
Hemihypertrophy WT1 mutation
Renal failure
Renal failure Denys Denys Drash syndrome
Drash syndrome
Features of syndromic
Table 42.7 Features causes
of syndromic ofofDSD
causes DSD
Syndrome Underlying defect Features
Smith-Lemeli-Optiz 7 DHC dehydrogenase Undervirilization, sex reversal, adrenal
failure, microcephaly, polydactyly
Denys Drash WT1 mutation Undervirilization, nephrotic syndrome,
hemihypertrophy, abdominal tumors
Frasier WT1 mutation Undervirilization, renal dysplasia
Sweyer SRY Sex reversal, skeletal abnormalities
92 Grow Society
Figure 2 This two-week-old girl was referred for evaluation of

clitromegaly. There were no features of pigmentation, labioscrotal
fusion or palpable gonads. Clitoris was 0.6 cm in length. She was
diagnosed as prominent clitoris with no underlying disorder of sexual
differentiation and managed conservatively. On follow-up at the age of
six months the girl had normal genital appearance.
Figure 3 This three-week-old neonate presented with genital ambiguity.

Examination revealed Prader Stage IV genitalia, single urogenital
opening, no palpable gonads and generalized hyperpigmentation.
There was a history of death of male sibling at the age of one month.
Pelvic ultrasound confirmed the presence of uterus. Investigations
showed hyponatremia (sodium 112 mmol/L), hyperkalemia (potassium
6 mmol/L) and elevated 17OHP levels (200 nmol/L, 6000 ng/dL)
confirming the diagnosis of salt wasting 21 hydroxyalse deficiency. She
was started on hydrocortisone and fludrocortisone and underwent
genitoplasty at the age of six months
GROW Society ! 93
Figure 4 This three-month-old boy presented with small phallic size

(stretched penile length 1.5 cm), penoscrotal hypospadia and
asymteric gential appearance. Investigations were suggestive of
gonadal dysgenesis (karyotype 46 XY/XO).
Figure 5- This one-month child was referred for evaluation of genital

ambiguity. Examination showed small penile size (1.2 cm) with
penoscrotal hypospaidia. Gonads were palpable bilaterally. No
mullerian structures were identified on pelvic ultrasound. Further work-
up showed low ratio of Dihydrotestosterone to testosterone after HCG
stimulation test suggesting the diagnosis of 5 alpha reductase
deficiency. The child was reared as a boy and treated with a short
course of testosterone with increase in penile size. He underwent
correction for hypospadia at the age of 1 year.
94 Grow Society
INVESTIGATIONS
Initial investigations
Karyotype
FISH study for Y chromosome (For rapid diagnosis)
Ultrasound for mullerian structures
Electrolytes in neonates
Disease to identify CAH
classification
Disease classification
Karyotype Palpable gonads Mullerian structure Group
46 XX Absent Present Virilized female
46 XY Present/ absent Absent Undervirlized male
46 XX, XY Present Present Gonadal dysgenesis
Further!evaluation
Further evaluation
" Virilized female
Virilized female
Initial work-up♦ Initial work-up
! 17 Hydroxyprogesterone- Interpretation
" 17 Hydroxyprogesterone
• > 100 nmol/L,! 3000
Role-ng/dl- 21OHD
Diagnosis of congenital adrenal hyperplasia
• 20-100 nmol/L- 11 βOHD,
! Interpretation 3 βHSD deficiency
• < 20 nmol/L- CAH unlikely
• > 100 nmol/L, 3000 ng/dl- 21OHD
• 20-100 nmol/L- 11 βOHD, 3 βHSD deficiency
! Retrograde genitogram
• < 20 nmol/L- CAH unlikely
Role- Characterization of urogenital fusion
" Retrograde genitogramopening
Indications- Single urogenital
Procedure-! X Role-
ray Characterization
after injecting dyeof urogenital
through fusion
UG opening
! Indications- Single urogenital opening
! Further evaluation
! Procedure- X ray after injecting dye through UG opening
! Mildly elevated
♦ Further 17OHP levels (2-100 nmol/L)- 17
evaluation
hydroxypregnenolone
" Mildly elevated 17OHP (high levels
in 3(2-100
βHSD deficiency),
nmol/L)
Deoxycortisol (high in 11 βOHD), urinary steroid
! 17 hydroxypregnenolone (high in 3 βHSD profile
deficiency)
! Normal 17OHP levels- Gonadal biopsy (46 XX gonadal
! Deoxycortisol (high in 11 βOHD)
dysgenesis), aromatase gene study (aromatase deficiency)
! Urinary steroid profile
" Normal 17OHP levels
Under virilized male
Initial work-up- Serum! Gonadal biopsy (46 XX gonadal dysgenesis)
testosterone
! < 50 ng/dL- Gonadal
! Aromatasedysgenesis,
gene studysteroidogenic defects
(aromatase deficiency)
! More than 300 ng/dL- Testosterone action defects
" Under virilized male
Further work-up♦ Initial work-up- Serum testosterone
" < 50 ng/dL- Gonadal dysgenesis, steroidogenic defects
" More than 300 ng/dL- Testosterone action defects
♦ Further work-up
" Low testosterone levels
GROW Society ! 95
! Mullerian inhibitory substance (MIS)
• Principle- Marker of sertoli cell functions
• Indications- Low testosterone levels
•
! Low testosterone levels

! Mullerian inhibitory substance (MIS)- Low- Testicular
dysgenesis, normal- Steroidogenic defect, leydig cell defect
! HCG stimulation test
! Gonadal biopsy- Low MIS levels
! Work-up for associations
Renal ultrasound, urine protein (Denys Drash)
Abdominal malignancy (WT1)
Skeletal survey (SOX 9 mutation)
Approach
Initial assessment should be directed towards excluding physiological
variants like prominent (but not enlarged) clitoris, small penis
embedded in supra pubic fat and labial adhesion that may be
misdiagnosed as genital ambiguity. Special care should be taken in
preterm girls where prominent clitoris may give rise to false impression
of clitoromegaly. Initial work-up should include detailed physical
examination, serum electrolytes, karyotype and pelvic ultrasound.
Careful examination and pelvic ultrasound is sufficient to categorize
the individual into broad diagnostic groups. Demonstration of mullerian
structures in a child with no palpable gonads suggests virilization
disorder and should be followed with 17OHP levels. High 17OHP
levels (more than 100 nmol/L, 3000 ng/dL) are characteristic of classic
21 hydroxylase deficiency; milder elevation (20-100 nmol/L, 600-3000
ng/dL) should prompt evaluation for 3 βHSD and 11 β hydroxylse
deficiency. Gonadal biopsy should be done if 17OHP levels are normal
to identify gonadal dysgenesis. Maternal virilization during pregnancy
in this setting is indicative of maternal hyperandrogenism or the rare
disorder of aromatase deficiency. Absence of mullerian structures
suggests normal fetal anti mullerian hormone production and a
diagnosis of undervirilised male. Most of these individuals have
palpable gonads; disorders of defective virilization should however be
considered even if gonads are not palpable. Testosterone levels help in
differentiating disorders of testosterone production (low levels;
steroidogenic defects or testicualr dysgenesis) and action (high or
normal levels; 5 α reductase defect or androgen insensitivity
syndrome). HCG stimulation test and gonadal biopsy should be
considered if testosterone levels are low. High testosterone levels
should prompt estimation of HCG stimulated DHT to differentiate 5α
reductase deficiency (low levels) from androgen insensitivity syndrome
(high levels). Presence of gonads and mullerian is suggestive of
96 Grow Society
levels; 5 α reductase defect or androgen insensitivity syndrome). HCG stimulation

test and gonadal biopsy should be considered if testosterone levels are low. High
testosterone levels should prompt estimation of HCG stimulated DHT to differentiate
5α reductase deficiency (low levels) from androgen insensitivity syndrome (high
gonadal dysgenesis or ovotesticular DSD and should be followed-up
levels). Presence of gonads and mullerian is suggestive of gonadal dysgenesis or
with gonadal biopsy.
ovotesticular DSD and should be followed-up with gonadal biopsy.
Disorder of sexual development

Examination, karyotype, pelvic
Present Absent
Present Absent Absent Present
Gonadal dysgenesis Undervirlized male Virilized female
Low High High Normal

Steroidogenic defect Dihydrotestosterone Gonadal dysgenesis
Testicular dysgenesis Low- 5 ARII defect Aromatase defect
42.5 Management
Management
•Components
•Components
! Management of life threatening conditions
!! Management
Initiation of Specificof life threatening conditions
treatment
!! Initiation
Parental of Specific treatment
education
!! Parental
Decision abouteducation
gender of rearing
!! Decision
Surgical about
procedures gendertoof
according rearing
gender of rearing
! Surgical procedures according to gender of rearing
•Management team
•Management team
! Endocrinologist
!! Endocrinologist
Pediatric surgeon
!! Pediatric
Social worker surgeon
!! Social worker
Geneticist
! Geneticist
StepI-I-Exclude
Step Exclude life threatening
life threatening conditioncondition
!! Serum electrolytes
Serum electrolytes
!! Blood
Blood glucose
glucose
!! Initiate
Initiate hydrocortisone
hydrocortisone and fludrocortisone
and fludrocortisone if CAH diagnosed if CAH
diagnosed
GROW Society ! 97
Step II Parental education

! Considerations- Assess psychosocial impact and
avoid gender specific (like he, she) and neutral titles
(like it) and layman language (may be confusing and
derogatory)
Step III- Specific management

! Congenital adrenal hyperplasia
! 21 hydroxylase deficiency- HC and FC
! 11 hydroxylase deficiency- Hydrocortisone
! 3 βHSD deficiency- HC and fludrocortisone
! Under virilized males- Testosterone 25 mg monthly
for three doses
! SLO syndrome- Dietary modifications (high
cholesterol diet)
! 5 α reductase deficiency- Topical DHT
! XY gonadal dysgenesis- Gonadectomy
! Androgen insensitivity syndrome- Gonadectomy
Step IV Decision regarding Gender of rearing

! Considerations
! Ability to perform sexually, fertility prospects
! Feasibility of genital reconstruction
! General guidelines
Step V Surgical procedures
! Virilized girl
♦ Clitoroplasty and vaginoplasty (usually within one
year of age)
♦ Avoid clitoral resection
♦ Reassess at puberty for need for vaginoplasty
! Undervirlized boy- Testosterone (25 mg im/month for 3

doses). Plastic surgical repair for hypospadia and
chordee
98 Grow Society
2.7 Undescended testis
Epidemiology
•Prevalence- Preterm boys- 30%, term boys- 4%, one year of
age- 1%, adulthood- 0.8%
•Involvement- Unilateral (70%), bilateral (30%)
•Position- Inguinal (60%), pre scrotal (20%), abdominal (10%),
ectopic (10%)
44.3 Etiology
Etiology
Undescended testis
Unilateral Bilateral
Usually no underlying cause Idiopathic
Hypogonadism
Gonadotropin deficiency
Non-palpable Steroidogenic defects
Partial Androgen insensitivity
5 alpha reductase deficiency
Gonad present Gonad absent Growth hormone deficiency
Idiopathic Anorchia
Testicular dysgenesis Virilization disorder
Syndromes
Downs
Prader willi
Delange
Noonan
LMBB
Evaluation
Important causes (Bilateral undescended testis)
CLINICAL
• Idiopathic
Step I- Confirmation of diagnosis
• Hypogonadism
•Palpation for gonads
• Gonadal dysgenesis
•From anterior superior iliac spine to base of scrotum
44.4 Evaluation
•Examination in crossed legged and squatting position
44.41 CLINICAL
•Examination after warm compresses
Step I- Confirmation of diagnosis
• Palpation for gonads
Step II- Differentiation
• From anterior superior iliacfrom
spine toectopic and retractile testis
base of scrotum
• Examination in crossed legged and squatting position
• Examination after warm compresses
Step II- Differentiation from ectopic and retractile testis
• Scrotal sac (well formed in retractile testis)
• Cremasteric reflex (exaggerated in retractile testis)
• Hernia (indicative of undescended testis)
Step III- Evaluation for underlying cause
GROW Society ! 99
• Genital ambiguity- Disorders of sexual development (please refer
42.2)
 Testicular dysgenesis
 Steroidogenic defects
 Partial AIS
•Scrotal sac (well formed in retractile testis)

•Cremasteric reflex (exaggerated in retractile testis)
•Hernia (indicative of undescended testis)
Step III- Evaluation for underlying cause

•Genital ambiguity- Disorders of sexual development
(testicular dysgenesis, steroidogenic defects, partial
AIS, 5 alpha reductase deficiency)
• Midline defects, hypoglycemia, micropenis (MPHD)
•Dysmorphism (Noonan, De Lange, LMBB, PW syndrome)
•Obesity (Prader willi, LMBB syndrome)
•Polydactyly (LMBB syndrome)
•Pigmentation, salt wasting, non palpable testis (CAH)
Features of undescended, ectopic and retractile testis

Feature Undescended Ectopic Retractile
Pathophysiology Descent defect Path deviation Active cremasteric

Scrotum Poor size Normal Normal
Spermatic cord Long Long Normal
Hernia Common Rare Absent
Testis Dysgenetic Normal Normal
Complications Malignancy, Injury Rare
infertility
INVESTIGATIONS
Bilateral non palpable testis- Exclude 21OHD, 17OHP, Na, K
Anorchia vs abdominal testis

HCG 4000 IU/m2 and testosterone at 48 hours. Levels more than 10
nmol/L suggest abdominal testis while anorchia shows no response.
Inhibin B, AMH- Marker of sertoli cell function. Levels are high even
during pre pubertal period. Levels are undetectable in anorchia
Genital ambiguity- Karyotype, pelvic ultrasound testosterone
100 Grow Society

Localization studies
Indications
Non palpable unilateral undescended testis
Non palpable bilateral undescended testis with
Positive HCG response to testosterone
Detectable AMH levels
Studies- No role of ultrasound if testis above inguinal ring and

laparoscopy the modality of choice
Approach
Most boys with undescended testis do not have an underlying disorder.
Extensive work-up should therefore be reserved for rare boys with
special features. Investigations are required in special situations like
neonatal period (to exclude potentially life-threatening virlizing CAH),
genital ambiguity (evaluation for disorders of sexual development) and
the presence of features of hypopituitarism (pituitary function tests).
Initial evaluation should be directed towards confirming the diagnosis
of undescended testis. Careful examination in squatting position after
application of warm compresses is required to confirm the diagnosis of
undescended testis. Well development scrotal sac on the side of
absent testis is against the diagnosis of undescended testis and
suggestive of ectopic or retractile testis. No treatment is requirement in
these boys. Poorly developed scrotal sac with palpable testis is
suggestive of true undescended testis and indication for treatment.
These boys should be given a trial of HCG (250-500 IU biweekly for
five weeks). Orchidopexy should be performed if there is no response
to HCG. This should be done before the age of one year to avoid
adverse effects on testicular dysfunction. Important considerations in
boys with bilateral non-palpable testis include intra abdominal testis or
anorchia. These conditions can be differentiated by HCG stimulation
test and inhibin levels with positive response to HCG and detectable
inhibin levels indicating the presence of abdominal testis. Laparoscopy
should be done in these boys as imaging modalities have limited role
in localizing abdominal testis. No increase in testosterone to HCG and
undetectable inhibin B or antimullerian hormone levels are indicative of
anorchia. No localization studies are required in these boys.
GROW Society ! 101

 Non palpable bilateral undescended testis with
♦ Positive HCG response to testosterone
♦ Detectable AMH levels
 Studies
GROW Society  Limited role of imaging studies Pediatric Endocrinology Protcols
 No role of ultrasound if testis above inguinal ring
 Laparoscopy the modality of choice
44.4 Approach
Undescended testis
Palpable gonads
Present No
Scrotal development HCG response/ MIS
Poor Normal Absent Present

HCG trial Retractile/ Ectopic testis Anorchia Laparoscopy
No treatment
Response No response
Follow-up Orchidopexy
Most boys with undescended testis do not have an underlying disorder. Extensive
Management
work-up should therefore be reserved for rare boys with special features.
•Adverse
Investigations effectsinofspecial
are required undescended
situations liketestis
neonatal period (to exclude
•Testicular
potentially dysfunction
life-threatening virlizing –CAH),
Unlikely if before
genital one(evaluation
ambiguity year for
disorders of sexual development)
•Malignancy and the presence of features
risk- Development of seminoma. Risk 10-20 of hypopituitarism
(pituitary function
times tests).
that Initial
thanevaluation
normally should be directed
located towardsIt confirming
testis. is relatedthe to
diagnosis of undescended testis. Careful examination in squatting position after
underlying testicular abnormality. Not related to site as
application of warm compresses is required to confirm the diagnosis of undescended
testis. Wellincreased
developmentrisk forsac
scrotal contralateral
on the side ofdescended
absent testis is testis
againstand
the no
diagnosis of reduction
undescendedin risk
testisafter orchidopexy
and suggestive of ectopic or retractile testis. No
•Testicular
treatment is requirementinjury-
in theseInguinal, ectopic
boys. Poorly testis
developed scrotal sac with palpable
testis •isTorsion
suggestive of true undescended testis and indication for treatment. These boys
should•Timing-
be given a Ideally
trial of HCG (250-500
before oneIU biweekly
year of age for five weeks). Orchidopexy
should•Treatment-
be performed if there
Injection HCG- 250-500 should
is no response to HCG. This be done before
IU biweekly forthefive
age of one year to avoid adverse effects on testicular dysfunction. Important
weeks. Response is good for inguinal testis but very poor
considerations in boys with bilateral non-palpable testis include intra abdominal testis
or anorchia. with abdominal
These conditions testis
can be differentiated by HCG stimulation test and
•Surgery
! Indications
! Palpable testis- No response to HCG
! Non palpable testis
♦ Positive HCG stimulation test
♦ Detectable inhibin levels
! Procedures
! Orchidopexy
! Cord lengthening and fixation
! Orchidectomy for dysgenetic testis
102 Grow Society

2.8 Gynecomastia
40 Gynecomastia
PCriteria
40.1 Criteria
Breast tissue enlargement more than tanner stage II. Breast tissue
• Breast tissue enlargement more than tanner stage II
should • beBreast
differentiated from fat from
tissue should be differentiated in fatobese
in obeseboys.
boys. Resistance while
approximating thumb
• Resistance while and index finger
approximating thumb andin the
indexchest towards
finger in the chestnipple and
tenderness suggests
towards true
nipple and gynecomastia.
tenderness suggests true gynecomastia.
40.2 Etiology
Etiology
Gynecomastia
Puberty
Obesity
Estrogen excess HCG secreting tumor Testosterone deficiency

Germinoma Please refer 39.1
Teratoma
Endogenous Exogenous Hypogonadotropic Hypergonadotropic

Liver disease Drugs Kallmann syndrome Klinefelter syndrome
Aromatase excess Digoxin Malformation Androgen insensitivity
PZ syndrome Cimetedine Acquired defects Steroidogenic defect
Ketokonazole Testicular insult
Environmental
HCG- Human chorionic gonadotropin, PZ- Peutz Zegher syndrome

Evaluation
• Physiological (Over 90% of all cases; present in 25% of all boys)
CLINICAL
• Liver disease
Onset Peripubertal- Physiological, early- Hypogonadism
• Hypogonadism
Progression-
• Drugs Gradual- Physiological, hypogonadism; Rapid- Estrogen
or HCG producing tumor
Features of chronic liver disease, testicular or neurological insult
40.3 Evaluation
Exposure to drugs (cimetidine, digoxin), estrogen (creams, medicines)
40.31 CLINICAL
Pubertal• status-
Onset Pre pubertal- Hypogonadism, Pubertal- Physiological
Features of Klinefelter
Peripubertal- Physiological
syndrome (tall stature, eunuchoid proportions)
Early- Hypogonadism
Stigmata of chronic
• Progression liver disease
Features of Peutz Zegher
Gradual- (oralhypogonadism
Physiological, pigmentation, testicular tumor)
 Rapid- Estrogen or HCG producing tumor
GROW Society ! 103

Approach • If indicated
Extensive evaluation is not required in most boys with gynecomastia
 Gonadotropin
as most havephysiological form
Indications- Pubertal of disease. First step should be
delay
 Interpretation
directed towards differentiating gynecomastia from fatty infiltration.
♦ Low- Hypogonadotropic hypogonadism
Work-up for pubertal boys should be restricted to exclude liver disease
♦ High- Hypergonadotropic hypogonadism
and history of exposure
 Estrogen to drugs implicated in the pathogenesis of the
condition. They  should
Indicationsbe followed up six monthly for two years.
Severe and progressive
♦ Rapid gynecomastia
progression in boys with delayed puberty is
indication for evaluation
♦ Severein the form of testosterone and gonadotropin
gynecomastia
levels. Low testosterone
♦ Normal levels are levels
gonadotropin suggestive of hypogonadism that
 Workup for hyperestrogenic
should be evaluated as described in 39.4. states Estrogen levels should be
♦ Testicular ultrasound (estrogenic testicular cord tumor)
measured in boys with normal testosterone levels. High estrogen
♦ Adrenal ultrasound (estrogenic adrenal tumor)
levels should be ♦follow-ed up with evaluation for estrogen producing
Aromatase excess syndrome
testicular or adrenal
Human chorionic(adrenal
tumors and testicular ultrasound). Normal
gonadotropin
adrenal and testicular ultrasound in a boy with persistent elevation of
 Indications
estrogen indicates ♦ Rapidrare aromatase excess syndrome. Normal
progression
testosterone and ♦estrogen levels in testosterone
Normal gonadotropin, a boy with severelevels
and estradiol gynecomastia
should prompt HCG Work-up for high
levels. BoysHCG levels
with high HCG levels should undergo
localization studies♦ Testicular
for HCG examination
secreting tumors (testicular ultrasound
♦ CT scan of chest, abdomen and brain
and chest, abdomen and head CT scan).
40.4 Approach
Gynecomastia
Assess severity and pubertal status
Exclude liver disease, drugs
Pubertal, mild disease Delayed puberty, severe disease

Reassurance, follow-up
No increase Rapid increase

Follow-up till 2 years
Testosterone, LH, FSH
Low testosterone Normal testosterone

Hypogonadism (refer 39.4) Estrogen levels
Normal High
Exclude HCG tumor Hyper-estrogenic state
Testicular ultrasound
Adrenal imaging
104 Grow Society

Management
Self resolving in majority of cases by two years
Weight loss in obese children
Indications- Progressive disease, no improvement within 2 years
Treatment options
Aromatase inhibitors- Letrozole (2.5 mg/day) anastrazole (1 mg/day)
Tamoxifen 20 mg daily
Testosterone- May worsen disease as is converted to estrogen
Dihydrotestosterone- Limited studies Dose
Surgical- Laparoscopic breast tissue resection
GROW Society ! 105

Section 1II- Electrolyte disorder

3.1 Sodium Disorders
Hyponatremia
CRITERIA- Sodium < 135 mmol/L
ETIOLOGY
Increased free water Decreased sodium
Fluid overload SIADH Extra-renal loss Renal loss

Renal disease Diarrhea
Liver disease Cystic fibrosis
Cardiac failure
Hypothyroidism
Adrenal insufficiency
Salt wasting Renal disorder
Diuretic
Frusemide
Cerebral salt wasting Aldosterone defect Thiazide
Head injury Tubular necrosis
Neurosurgery Interstitial nephritis
Infection
Resistance Deficiency
PHA Generalized
CAH- StAR, 21OHD, 3βHSD
Addison disease
SF1, DAX1 defect
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Related to rapidity of onset (rate of fall more important)
• Acute- Headache, vomiting, seizures, encephalopathy
• Chronic- Somnolence, lethargy, vominting
EVALUATION
History
• Onset
• Neonatal period- Renal failure, CAH, aldosterone resistance
• Infancy- Renal failure, adrenal failure
• Early childhood- Fluid overload, renal failure, SIADH
• Late childhood- Renal failure, addison disease, SIADH
• Presentation
• Acute- Adrenal insufficiency, renal failure, CSW
• Insidious- SIADH, fluid overload
• Fluid balance
• Positive- SIADH
• Negative- Salt wasting (adrenal, cerebral or renal)
• History of gastrointestinal fluid loss

• Features of renal failure, liver disease, cardiac failure
• Risk factors for SIADH
• Exposure to diuretics
• Polyuria (adrenal insufficiency, aldosterone resistance)
• Family history of salt wasting, sibling death (CAH, PHA)
• Failure to thrive (adrenal failure, aldosterone resistance)
Examination
• Fluid status
• Over hydration (edema)- Renal failure, liver disease, CCF
• Normal- SIADH, cortisol deficiency, hypothyroidism
• Dehydration- Diarrhea, salt wasting (renal, adrenal, cerebral)
• Pigmentation (adrenal insufficiency)
• Neonatal period
• Genital ambiguity (congenital adrenal hyperplasia)
• Abdominal examination (renal mass)
• Features of cardiac failure, liver disease
GROW Society ! 107

Table 1 Pointers to diagnosis of hyponatremia

Dehydration Diarrhea, tubular necrosis, adrenal insufficiency
Pigmentation Adrenal insufficiency
Edema Cardiac, renal or hepatic disease
Genital ambiguity Congenital adrenal hyperplasia
Polyuria Tubular disorder, aldosterone defect, CSW
INVESTIGATIONS
• Initial
• Exclude psuedohyponatremia- Blood glucose, lipid, albumin
• Serum potassium
• Hyperkalemia- Renal failure, inefficient aldosterone action
• Hypokalemia- Diuretic use, tubular necrosis
• Urine sodium
• < 20 mmol/L- Diarrhea, Cardiac failure, CLD
• > 20 nmol/L- ATN, Inefficient aldosterone action, CSW, SIADH
• Renal function tests

• High urea- ARF, inefficient aldosterone action, CSW
• High urea and creatinine- Renal failure
• Further evaluation- According to fluid status

• Over hydration- Liver function tests, ECHO, serum albumin
• Normal fluid status

• Exclude hypothyroidism, adrenal insufficiency
• Consider SIADH if normal thyroid profile and cortisol
• Assess for underlying cause of SIADH
• Dehydration- According to urine sodium levels

• Less than 20 mmol/L- Extra renal loss (diarrhea, CF)
• More than 20 mmol/L- According to serum potassium
• Normal/ low- Exclude diuretics, tubular disorders
108 Grow Society

• High Potassium
Step I- Differentiate renal from adrenal cause
Feature Renal dysfunction Adrenal cause
Hydration status Edema, dehydrated* Dehydration
Blood pressure Normal or elevated Decreased
Pigmentation Absent Common
Hypoglycemia Absent May be present
Urinary sodium Variable More than 20 mmol/
L
Urea High High
Creatinine High Normal
Hematocrit Normal/ decreased Increased
Acidosis Moderate to severe Mild
Step II- Evaluation for renal cause

• Renal ultrasound
• Intravenous pyelogram
• Tubular functions
Step III- Evaluation of adrenal cause- Aldosterone levels

• Low- Aldosterone deficiency; Measure cortisol
• Low- Adrenal insufficiency
• Normal- Isolated aldosterone deficiency
• High- Pseudohypoaldosteronism
Neurological insult- Differentiate SIADH from CSW

Features SIADH Cerebral salt wasting
Urine output Decreased Increased
Fluid balance Negative Positive
Hydration Normal Dehydrated
Urinary sodium High High
Urea Normal High
Uric acid Normal or low High
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Table 2. Features of common causes of hyponatremia
Disorder Hydration Urine output Potassium Urinary sodium

Diarrhea Dehydration Decreased Low Low
Liver disease Overload Reduced Low Low
SIADH Normal Reduced Normal High
CSW Dehydration Increased Normal High
Tubulopathy Dehydration Increased Low, high High
Adrenal failure Dehydration Increased High High
APPROACH
Hyponatremia
Exclude hyperglycemia, hyperlipidemia
Hydration status
Over hydration Normal Dehydration

Liver function tests Thyroid
Cardiac evaluation profile
Hypothyroidism Normal < 20 nmol/L > 20 nmol/L

Extra renal
Diarrhea, CF
Normal, Low High

Diuretic use
CSW
High Normal
High Low
Normal Low
Adrenal failure
Please refer
110 Grow Society

MANAGEMENT
Non specific
•Principles
! Rapid correction associated with risk of central pontine myelinolysis
! Not increase by more than 0.5 mmol/L/hour, 12 mmol/L/day
! Oral route if feasible
! Rapid correction only if neurological features present
! Target sodium for acute correction 120 mmol/L
•Management- According to sodium levels
! More than 120 mmol/L- Oral salt, maintenance as 0.9% saline
! Less than 120 mmol/L- According to neurological features

! Absent- 0.9% saline (normal saline, 154 mmol/L)
! Present
♦ Rapid correction
♦ Hypertonic saline (3% sodium chloride, 0.5 mmol/ml)
♦ Dose- Correction of 2-4 hours according to the formula
3% saline ml = (120- Serum sodium) × weight × 1.2
♦ 10 ml/kg of 3% saline increases sodium by 6 mmol/L
Specific
• Gastrointestinal loss- Oral correction preferred
• Fluid overload- Treat underlying cause

o Fluid restriction- 1 L/m2/day
o Diuretics
• Cardiac failure, nephrotic syndrome- Frusemide
• Liver disease- Spironolactone
• SIADH
o Treat underlying cause- Stop incriminated drugs, treat infection
o Fluid restriction- 1 L/m2/day
o Severe disease/ nor response
! Hypertonic saline (3% saline 10 ml/kg)
! Frusemide (2 mg/kg)- Induces free water loss
• Cerebral salt wasting

o Replace fluid loss
o Salt supplementation- Parenteral normal saline, oral salt
o Refractory cases- Fludrocortisone (0.1-0.3 mg/day)
GROW Society ! 111

• Renal tubular dysfunction

• Treat underlying cause- Infection, obstruction
• Salt and water supplementation
• Self resolving
• Inefficient aldosterone action

• Adrenal insufficiency- Hydrocortisone, fludrocortisone
• Aldosterone insufficiency- Fludrocortisone, salt
• Pseudohypoaldosteronism- Salt supplementation
Hypernatremia
CRITERIA- Serum sodium more than 150 mmol/L
ETIOLOGY
Decreased free water Increased sodium
Renal loss Extra renal loss Exogenous Endogenous

Diarrhea Fluid Aldosterone excess
Sweating Salt, ORS
Breast milk
AVP defect Osmotic diuresis

Central DI Diabetes mellitus
Nephrogenic DI Mannitol
FEATURES- Related to rate of increase in sodium levels

Serum sodium Features
150-155 mmol/L Asymptomatic
155-165 mmol/L Dehydration, doughy skin, irritability
165-175 mmol/L Seizures, drowsiness
More than 175 mmol/L Seizures, coma
112 Grow Society

EVALUATION
Clinical
• Onset
Age Etiology
Neonatal period Dehydration, DI, iatrogenic
Infancy Dehydration, central or nephrogenic DI
Childhood Incorrect ORS, central DI
• Presentation
• Acute- Diarrhea, salt load
• Insidious- Diabetes insipidus
• Fluid balance
• Positive- Overload
• Negative- Diabetes insipidus
• Diarrhea, method of preparation of oral rehydration solution

• Salt load- Herbal preparation, tea
• Polyuria (diabetes insipidus, diabetes mellitus)
• Neonate– Adequacy of breast feeding (wt gain, frequency of urination)
• Increased insensible losses- Fever, high ambient temperature
• Family history of polyuria (nephrogenic DI)
• Hydration status
• Dehydration- Diarrhea, diabetes insipidus
• Normal or over hydrated- Salt load, hyperaldosteronism
• Blood pressure (elevated in hyperaldosteronism)
Investigations
• Initial
• Urine osmolality/ specific gravity
• Less than 300 mOsm/kg- Diabetes insipidus
• More than 300 mOsm/kg- Diarrhea, salt load, osmotic diuresis,
hyperaldosteronism
• Urine sodium
• Less than 20 mmol/L- DI, diarrhea, insensible water loss
• More than 20 mmol/L- Salt load, hyperaldosteronism
GROW Society ! 113

• Further evaluation
• Low urine osmolality
• Diagnostic of diabetes insipidus
• Water deprivation not required
• Vasopressin response test (please refer 11.5)
• Injection vasopressin 0.1 unit/kg subcutaneous
• Urine osmolality after 4 hours
• Increase more than 50% of baseline- Central DI
• Increase less than 50% of baseline- Nephrogenic DI
• High urine osmolality- According to urinary sodium
• Less than" 20 mmol/L-
High Likely diarrhea,
urine osmolality- osmotic
According diuresis
to urinary sodium
• More than ♦ 20 Less
mmol/L- Rule out exogenous load
than 20 mmol/L- Likely diarrhea, osmotic diuresis
♦ More than 20 mmol/L- Rule out exogenous load
APPROACH
48.5 Approach
Hypernatremia
Exclude salt load, hyperthermia
Urine osmolality*
Less than 700 mOsm/kg More than 700 mOsm/kg

Urine sodium
Diabetes insipidus
Vasopressin test
Response No response < 20 m mol/L > 20 mmol/L

Central DI Nephrogenic DI Diarrhea Salt load
Osmotic diuresis Aldosterone excess
MANAGEMENT
• DI- Diabetes insipidus * Urine specific gravity 1010 equivalent to urine osmolality of
Principles
700
• mOsm/kg
Rate of correction depends on duration and severity
• Rapid fall in sodium should be avoided
• Decrease
Initial evaluationinissodium
directedshould be less
to exclude saltthan 12inappropriately
load, mmol/L/day prepared oral
• High risk
rehydration of seizures
solution duringwater
and insensible fall of serum
losses. sodium
Neonates levels
with hypernatremia should
be assessed for adequacy of breastfeeding by evaluating weight gain pattern,
frequency of urination and level of activity. Urine osmolality (or specific gravity)
helps in differentiating DI form other conditions. Urine osmolality less than 300
mOsm/kg (or specific gravity below 1005) in the presence of hypernatremia is
diagnostic of DI. Water deprivation test is not only not required but also potentially
hazardous in these conditions. Vasopressin response test (urine osmolality 1 and 4
hour after 0.1 unit/kg vasopressin) should be done to differentiate central (increase in
114 urine osmolality) from nephrogenic DIGrow
(no increase).
Society Urine sodium levels should be
measured if urine osmolality is high. Low urine sodium levels indicate diarrhea or
insensible water losses. High serum and urinary sodium is characteristic of sodium
load. Aldosterone excess (true of apparent) may present with mild hypernatremia;
• Management
• Oral correction preferred
• Correct dehydration and sodium over 48-72 hours
• Sodium content in fluid 70-80 mmol/L
• Hemodialysis if serum sodium more than 170 mmol/L
• SPECIFIC
• Gastrointestinal loss- Depending on severity
• Mild- Oral rehydration solution
• Severe- Intravenous correction
• Steps
• Calculated level of dehydration
• Add to maintenance requirements for 48 hours
• Calculate sodium requirement and deficit for 48 hours
• Calculate free water deficit
Free water deficit = 4 × weight × (Na – 150)
• Give free water deficit as solute free fluid

• Rehydrate evenly over 48 hours
• Hourly electrolytes; 3% saline during seizures
• Salt load- Rapid fall after cessation of load, frusemide if fall slow
• Breast mild related hypernatremia
• Usually related to poor feeding and dehydration
• Encourage breast feeding with monitoring
• Diabetes insipidus
• Central- DDAVP
• Nephrogenic- Thiazide-amiloride combination
Further reading
1. Bajpai A, Kabra M, Menon PS. 21-hydroxylase deficiency: clinical
features, laboratory profile and pointers to diagnosis in Indian children.
Indian Pediatr 2004; 41:1226-1232.
2. Sharma J, Bajpai A, Kabra M. Congenital adrenal hyperplasia
presenting as hematuria and acute renal failure. Indian J Pediatr 2001;
68:1161-1162.
GROW Society ! 115

Hypokalemia
Criteria- Serum potassium less than 3.0 mmol/L
Features
Serum sodium Features
3.2 Potassium
3-3.5 mmol/L
Disorders Asymptomatic
2.5-3 mmol/L Polyuria, muscle cramp, paralytic ileus
2-2.5 mmol/L
Hypokalemia ECG changes, neck flop, muscle weakness
Less than 2 mmol/L Respiratory paralysis, cardiac arrhythmia
CRITERIA- Serum potassium less than 3.0 mmol/L
Etiology
ETIOLOGY
Intracellular shift Reduced body potassium

Metabolic alkalosis
Insulin treatment
Reduced intake Increased loss
Malnutrition
Extra renal
Gastrointestinal Renal
CSF loss
Renal dysfunction Aldosterone excess

Renal tubular acidosis
Barter syndrome
Gitelman syndrome
Diuretic use
Secondary Apparent excess True excess

Hypomagnesaemia 11 βOHD defect Hyperaldosteronism
Hypophosphatemia 17 αOHD defect GRA
11 βHSD defect
GRA- Glucocorticoid remediable aldosteronism, OHD- Hydroxylase deficiency, βHSD-

Beta hydroxysteroid dehydrogenase deficiency
Important causes
116 Grow Society
FEATURES
Serum potassium Features
3-3.5 mmol/L Asymptomatic
2.5-3 mmol/L Polyuria, muscle cramp, paralytic ileus
2-2.5 mmol/L ECG changes, neck flop, muscle weakness
Less than 2 mmol/L Respiratory paralysis, cardiac arrhythmia
• Myopathy
• Acute flaccid paralysis
• Polyuria
• Muscle cramp
• ECG changes- Prolonged PR and QRS interval, flattened ST segment ,
U wave (positive wave after T wave)
• Pointers to endocrine etiology- Early onset, failure to thrive, severe
alkalosis, hypertension
Tubular disorders associated with hypokalemia

Disorder Feature Diagnosis
Distal RTA Acidosis, rickets, renal calcification Urine- Blood CO2
Proximal RTA Acidosis HCO3 excretion
Bartter Alkalosis, failure to thrive, normal blood Genetic
pressure, renal calcification
Gitelman Alkalosis, hypocalcemia, normal urine Ca Genetic
Disorders of RASS axis associated with hypokalemic alkalosis

Disorder Defect Renin Aldosterone Diagnosis
Hyperaldosteronism Adenoma Low High Imaging
GRA CyP11AS Low High Dexa test
17 αOHD defect Enzyme Low Low DOC
11 βOHD defect Enzyme Low Low DOC
11 βHSD defect Enzyme Low Low Urine steroids
Liddle syndrome Na channel Low Low Genetic
GROW Society ! 117

EVALUATION
Clinical
• Onset
• Neonatal- Tubulopathy, aldosterone excess, low magnesium
• Infancy- Diarrhea, tubulopathy, barter syndrome, aldosterone excess
• Childhood- Diarrhea, malnutrition, diuretic use, RTA
• Presentation
• Acute- Diarrhea, diuretic use
• Insidious- Aldosterone excess, malnutrition, barter syndrome
• Failure to thrive (RTA, bartter syndrome, aldosterone excess)

• Family history (RTA, tubulopathy)
• Polyuria (RTA, aldosterone excess, bartter syndrome)
• Gastrointestinal loss (diarrhea, vomiting, nasogastric aspiration)
• Diuretic exposure (frusemide, acetazolamide, thiazide)
• Prolonged parenteral fluid (Magnesium deficiency)
• Nutritional status
• Genital ambiguity
• Virilization- 11 β hydroxylase deficiency
• Undervirlization- 17 α hydroxylase deficiency
• Blood pressure
• Hypertension- 11 βOHD, 17 αOHD, 11 βHSD defect, GRA
• Normal- Bartter syndrome, RTA, hypomagnesaemia
• Pigmentation (11 βOHD, 17 αOHD)

• Rickets (RTA, malnutrition)
Pointers to diagnosis of hypokalemia

Feature Diagnosis
Failure to thrive Nutritional, RTA, barter, aldo excess
Genital ambiguity, pigmentation 11 βOHD, 17 αOHD
Hypertension Aldosterone excess syndrome
Rickets Renal tubular acidosis, malnutrition
118 Grow Society

INVESTIGATIONS
• Initial
• Venous blood gas
Acidosis RTA, Diarrhea, acetazolamide use
Alkalosis Diuretic, aldosterone excess, bartter syndrome
• Serum sodium
• Hypernatremia- Aldosterone excess states
• Hyponatremia- Diuretic use, diarrhea
• Urinary potassium
• Less than 20 mmol/L- Extra renal loss
• More than 20 mmol/L- Renal loss, aldosterone excess
• Further evaluation
• Metabolic acidosis- Urine net charge
• Positive (impaired ammonium production)- RTA
• Negative (normal ammonium production)- Diarrhea
• RTA Classification
Feature Proximal RTA Distal RTA
Urine- blood CO2 > 10 mmol/L < 10 mmol/L
Urine pH Less than 7.5 More than 7.5
FEHCO3 More than 15% Less than 10%
Nephrocalcinosis Absent Common
• Alkalosis, high urinary sodium- According to blood pressure

• High blood pressure
• Aldosterone levels
• High- Hyperaldosteronism, GRA
• Dexamethasone suppression test
• Suppression- GRA
• No suppression- Aldosterone secreting tumor
• Low- 11 βOHD, 17 αOHD, 11 βHSD, liddle syndrome

• DOC- High in 11 βOHD, 17 αOHD
• Urinary steroid- 11 βHSD
GROW Society ! 119

• Normal blood pressure

• Magnesium levels (low in hypomagnesaemia, bartter syndrome)
• Fractional excretion of magnesium
FeMg = Urinary Magnesium × Plasma creatinine

Plasma Magnesium × Urinary creatinine
• Low- Magnesium deficiency
• High- Bartter syndrome
• Urinary calcium (hypercalciuria in bartter syndrome)

• Renal ultrasound (nephrocalcinosis in bartter syndrome)
Features of common causes of hypokalemia

Disorder Blood gas BP Urine K Aldosterone
Diarrhea Acidosis Normal Low Not needed
RTA Acidosis Normal High Not needed
GRA Alkalosis High High High
Aldo tumor Alkalosis High High High
11βHSD defect Alkalosis High High Low
11βOHD, 17 αOHD Alkalosis High High Low
Liddle syndrome Alkalosis High High Low
Bartter syndrome Alkalosis Normal High High
Low magnesium Alkalosis Normal High High
120 Grow Society

Approach
APPROACH
Hypokalemia
Exclude malnutrition, diuretic, gastrointestinal loss
Venous blood gas
Metabolic alkalosis
Metabolic acidosis Magnesium
Urine net charge
Positive Negative Low Normal

RTA Diarrhea Hypomagnesaemia Blood pressure
Normal Elevated
Bartter, Gitelman syndrome Aldosterone
High Normal
Dexamethasone suppression Urinary steroids, DOC
Positive Negative Abnormal Normal

GRA Aldosteronism CAH Liddle
Adrenal CT 11βHSD
Initial
DOC- evaluation is GRA-
Deoxycortisol, directed towards identifying
Glucocorticoid remediable gastrointestinal
aldosteronism, CAH- loss Congenital
and
diuretic use. Extensive work-up is required only
adrenal hyperplasia, βHSD- Beta hydroxysteroid dehydrogenase in the presence of severe
hypokalemia, failure to thrive, genital ambiguity, bony deformities or
hypertension.
Initial evaluationBlood gas istowards
is directed the most important
identifying investigation.
gastrointestinal lossHypokalemia is
(diarrhea, nasogastric
usually associated with alkalosis; metabolic acidosis should
aspiration, vomiting) and diuretic use (frusemide, acetazolamide, thiazide). Extensive raise the
possibility
work-up isofrequired
RTA orindiarrhea. Urine ofnetsevere
the presence charge helps in differentiating
hypokalemia, failure to thrive,RTAgenital
(positive) diarrhea (negative). Hypomagnesmia should be excluded
ambiguity, bony deformities or hypertension. Blood gas is the most important investigation. in the
setting of hypokalemic alkalosis. Hypertension and hypokalemic alkalosis
Hypokalemia is a potent stimulus of the renin-aldosterone axis resulting in alkalosis; is
suggestive of true or apparent aldosterone excess and should prompt
metabolic acidosis in a child with hypokalemia should raise the possibility of impaired acid
aldosterone levels.
excretion (distal RTA) or Low orloss
alkali normal aldosterone
(diarrhea and proximallevels
RTA). with
Urine hypokalemic
net charge helps in
alkalosis and hypertension indicates apparent mineralocorticoid
differentiating RTA (positive due to indicating impaired renal ammonium excess.
production)
Normal
diarrhea (negative due to normal urinary ammonium production). Hypomagnesmiatoshould
blood pressure in a child with hypokalemic alkalosis and failure
thrive is suggestive
be excluded in theofsetting
Bartterofand Gitelman syndromes.
hypokalemic alkalosis. Hypertension and hypokalemic
alkalosis is suggestive of true or apparent aldosterone excess and should prompt
aldosterone levels. Dexamethasone suppression test should be done if aldosterone levels
are high to differentiate GRA (suppression in aldosterone levels) from aldosterone
secreting tumor (no suppression). Low or normal aldosterone levels with hypokalemic
alkalosis and hypertension indicates apparent mineralocorticoid excess. Urinary steroid
GROW
profile Society !
and deoxycortisol levels are helpful in identifying 121 17 α
rare CAH variants (11β and
hydroxylase deficiency) and 11 βHSD deficiency. Liddle syndrome should be considered if
these investigations are normal. Therapeutic trial with hydrocortisone and spironolactone
MANAGEMENT
Non specific
• Principles
• Oral correction preferred
• ECG monitoring essential during management
• Avoid rapid correction
• Maximum concentration of potassium chloride
• Peripheral line- 60 mmol/L
• Central line- 80 mmol/L
• Do not give potassium with dextrose (intracellular migration)
• Exclude hypomagnesaemia in refractory situations
• Protocol
• Potassium 2.5-3.0 mmol/L- Oral potassium chloride- 4-6 mmol/kg/
day, potchlor (1.3 mmol/L), KCl (2 mmol/ml)
• Potassium 2.0-2.5 mmol/L- Intravenous potassium 0.3 mmol/kg/hour
• Potassium less than 2.0 mmol/L- Admit in intensive care unit,
potassium infusion 0.3-1 mmol/kg/hour
Specific
Disorder Treatment
Diarrhea Oral or intravenous potassium
RTA Bicarbonate, oral potassium
Hypomagnesaemia IM MgSO4 50 mg/kg BD for 3 days
Oral milk of magnesia 100 mg/kg/d
Aldosterone secreting tumor Surgery
GRA Hydrocortisone 10 mg/m2/day
17 α, 11 β OHD deficiency Hydrocortisone 10 mg/m2/day
11 βHSD deficiency Spironolactone 1-2 mg/kg/day
Liddle syndrome Amiloride 1-2 mg/kg/day
Bartter syndrome Indomethacin (1-2 mg/kg/day)
Potassium (3-6 mmol/kg/day)
122 Grow Society

Features
•Asymptomatic
Resource book
•ECG changes Pediatric Endocrinology Protocols
Serum potassium ECG changes
5.0-6.0 mmol/L Usually normal, tall T waves
6.0-6.5 mmol/L Tall T waves, widening of QRS interval
6.5-7.0 mmol/L
Hyperkalemia Tall T waves, narrow PR interval, wide QRS
interval
More than 7.0 mmol/L
CRITERIA- Serum potassium more Sine wave,
than cardiac
5.0 arrest
mmol/L
ETIOLOGY
Etiology
Hyperkalemia
Cellular release Extracellular shift Increased potassium

Hemolysis Metabolic acidosis
Tumor lysis
Increased intake Reduced excretion
Oral
Intravenous
Inefficient aldosterone action Renal

Renal failure
Drugs
Spironolactone
Resistance Deficiency
Amiloride
PHA
Low renin
Primary
ACE inhibitors
Indomethacin
Isolated Generalized (24.2)

Cyp11AS defect Addisons disease
CAH
PHA- Pseudohypoladosteronism, ACE- Angiotensin convertase enzyme, CAH- congenital adrenal

Pointers to endocrine
hyperplasia, etiology synthetase
Cyp11AS- Aldosterone
• Important
Early onset
causes
• Hyponatremia
• Failure to thrive, polyuria
• Pigmentation, genital ambiguity
GROW Society ! 123

POINTERS- ECG changes
Serum potassium ECG changes

5.0-6.0 mmol/L Usually normal, tall T waves
6.0-6.5 mmol/L Tall T waves, widening of QRS interval
6.5-7.0 mmol/L Tall T waves, narrow PR interval, wide QRS
> 7.0 mmol/L Sine wave, cardiac arrest
Disorders of RAAS axis associated with hyponatremia and hypokalemia

Disorder Defect Renin Aldosterone Diagnosis
Renin deficiency Acquired Low Low Renin levels
CAH 21OHD, StAR, 3βHSD High Low Metabolites
Cyp11AS Aldo synthetase High Low Steroid profile
PHA Aldosterone receptor High High Aldosterone
Gordon Chloride channel High High Genetic
EVALUATION
Clinical
Onset
Neonatal Renal failure, hemolysis, iatrogenic, CAH, PHA
Infancy Renal failure, CAH, PHA, aldosterone deficiency
Childhood Renal failure, tissue lysis, adrenal failure
• Failure to thrive (renal failure, inefficient aldosterone action)

• Family history (CAH, pseudohypoaldosteronism)
• Salt craving, polyuria (inefficient aldosterone action)
• Features of renal failure (oliguria, failure to thrive, pallor, rickets)
• Setting of hemolysis, tumor lysis, red urine (intravascular hemolysis)
• Pigmentation (adrenal insufficiency)
• Genital ambiguity (congenital adrenal hyperplasia)
Pointers to diagnosis of hyperkalemia

Feature Diagnosis
Failure to thrive Renal failure, inefficient aldosterone action
Pigmentation Adrenal insufficiency
Rickets, failure to thrive Renal failure
124 Grow Society

Investigations
Initial
• Acidosis associated with hypekalemia
• Related to shift of intracellular potassium
• 0.6 mmol/L increase in potassium for every 0.1 decrease in pH
• Not related to respiratory or organic acidosis
• Acidosis disproportionate to potassium levels- Renal failure
• Urea, creatinine (Renal failure)
• Serum sodium (low in renal failure, inefficient aldosterone action)
• Transtubular potassium gradient- Marker of renal excretion

• Role- Differentiating renal from adrenal pathology
TTKG = Urine K x Plasma Osmolality

Plasma K x Urine osmolality
• Interpretation
• Low- Renal cause
• High- Adrenal cause
Special situation
Neonate with hyponatremia- CAH versus ARF
Feature Renal failure CAH
Hydration Normal, overhydrated Dehydrated
Pigmentation Absent Common
Hypoglycemia Absent May be present
Urea High May be high
Creatinine High Normal
Hematocrit Normal or decreased Increased
• Hyponatremia with normal creatinine- Inefficient aldosterone action

• Causes- Renin deficiency, adrenal failure, Cyp 11AS deficiency,
pseudohypoaldosteronism, gordon syndrome
• Work-up- According to renin levels
• Low- Drug history, renal ultrasound
• High- According to aldosterone levels
• Low- Aldosterone deficiency; Measure cortisol levels
• Low- Adrenal insufficiency
• Normal- Isolated aldosterone deficiency
• High- Pseudohypoaldosteronism, gordon syndrome
GROW Society ! 125

♦ Low
! Hyporeninemic hypoaldosteronism
! Drug history, renal ultrasound
GROW Society ♦ High- According to aldosterone levelsPediatric Endocrinology Protcols
! Low- Aldosterone deficiency; Measure cortisol levels
" Low- Adrenal insufficiency (please refer 24.5)
" Normal- Isolated aldosterone deficiency
! High- Pseudohypoaldosteronism, gordon syndrome
Table Causes
Causes of hyponatremia
of hyponatremia andandhyperkalemia
hypokalemia
Disorder
Disorder Urea
Urea Creatinine ReninRenin Aldosterone
Creatinine Aldosterone
Renal failure High High Not needed Not needed
Renal failure High High Not needed Not needed
Adrenal insufficiency May be high Normal High Low
Adrenal insufficiency May be high Normal High Low
Cyp11AS deficiency May be high Normal High Low
Cyp11AS
PHA deficiency May
Maybe be
highhigh Normal High High High Low
Normal
PHA
Gordon syndrome May be high
Normal Normal High High High High
Normal
Gordon syndrome
Cyp11AS- NormalPHA- Pseudohypoaldosteronism
Aldosterone synthetase, Normal High High
Approach APPROACH
Hyperkalemia
Exclude renal failure, tissue lysis, drugs
Plasma renin activity
Low High
Hyporeninemic hypoaldosteronism Aldosterone levels
Renal imaging
High Low
Pseudohypoaldosteronism Cortisol levels
Normal Low
Cyp11AS deficiency Adrenal insufficiency
Please refer 24.5
MANAGEMENT
Non specific
• Indications
• Potassium more than 6.0 mmol/L without ECG changes
• Potassium more than 5.5 mmol/L with ECG changes
• Measures
• Stop K containing fluid, sparing diuretic, supplementation
• Calcium gluconate
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• Mechanism- Cardioprotective effect

• Dose- 1-2 ml/kg of 10% solution iv over 5-10 minutes
• Sodium bicarbonate
• Mechanism- Intracellular shift of potassium
• Dose- 1-2 ml/kg of 10% solution over 10 minutes
• Salbutamol nebulization
• Mechanism- Intracellular migration
• Dose- 0.15 mg/kg every 20 minutes for 3 doses
• Insulin-Dextrose drip- Intracellular shift of potassium
Drug Initial Subsequent

Insulin 0.1 unit/kg 0.1 unit/kg/hour
Dextrose 500 mg/kg* 500 mg/kg/hour
• Dialysis- No response to supportive measures

• Potassium binding raisins (Kayexalate)- Long term effect
Treatment options for hyperkalemia

Drug Mechanism Dose Indication
Calcium gluconate Cardioprotection 1 ml/kg of 10% Severe
Sodium bicarbonate Intracellular shift 1 ml/kg of 10% Severe
Insulin-dextrose Intracellular shift 0.1 unit/kg insulin Severe
500 mg/kg dextrose
Salbutaol Intracellular shift Three times Moderate
Kayexalate Exchange raisin 1-2 mg 8 hourly Long standing
Specific
Disorder Treatment
Renal failure Diuretic, low potassium diet
Congential adrenal hyperplasia Hydrocortisone, fludrocortisone
Aldosterone synthetase defect Fludrocortisone
Pseudohypoaldsoteronsim Salt supplementation
Gordon syndrome Frusemide
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16. Neonatal
3.3 Metabolic Hypocalcemia
acidosis
16.1 Criteria
CRITERIA Age group Total mg/dL (mmol/L) Ionic mmol/L
• pH < 7.2
Preterm < 7 mg/dL (< 1.75 mmol/L) < 1.0 mmol/L
• Base excess > -5 mmol/L
Term < 8 mg/dL (< 2 mmol/L) < 1.1 mmol/L
• Bicarbonate < 20 mmol/L
16.2 Etiology
ETIOLOGY
Metabolic Acidosis
Reduced Alkali levels

Increased acid levels
Increased production Reduced excretion Renal loss Extra renal loss

Diabetic ketoacidosis Renal failure Proximal RTA Diarrhea
Lactic acidosis Distal RTA
Organic acidemia Acetazolamide use
Fatty acid oxidation defect Type IV RTA
EVALUATION
Clinical
• History suggestive of renal failure, liver disease
• Toxin, drugs (acetazolamide, triametrene, spironolactone)
• Polyuria, polydipsia (DKA, RTA)
• Diarrhea, ureteosigmoidostomy
• Features of hypoglycemia (GSD I, Fatty acid oxidation defects)
• Bony deformities, myopathy (RTA)
• Sib deaths, developmental delay/regression, seizures (organic academia)
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Investigations
• Initial
• Blood gas
• Serum electrolytes
• Urea, creatinine, SGPT
• Urinary ketones
• Blood Sugar, lactate
• Anion Gap
Anion gap = Na- (Cl+ HCO3)
• Normal- 10-12 mEq/L
• Increased- Increased organic anion,
• Decrease- Increased Ca/Mg/K, Li Intoxication, hyperviscocity
• Level II
• Urine Net Charge- Indicator of renal ammonia production
Urine net charge= UNa+ UK - UCl
• Positive- RTA (Impaired ammonia production)

• Negative- Extra renal loss (Normal ammonia production)
• Urine to blood CO2 difference

• Marker of distal tubular function
• To differentiate proximal RTA from distal RTA
• Oral NaHCO3 till UpH> PpH
• Distal RTA- <10 mmol/L
• Proximal RTA> 15 mmol/L
• Fractional excretion of bicarbonate

• Differentiate proximal RTA from distal RTA
• After alkalization
• > 15%- Type II RTA
• < 10%- Type I RTA
• Ammonium chloride loading test
• To differentiate proximal RTA from distal RTA
• 0.1 g/ kg NH4Cl oral
• Follow-up urine & blood pH hourly till 6 hour
• Distal RTA
• Urine pH > 5.5 at tCO2- 22.5 meq/L or
• > 5.0 at tCO2- 20.0 meq/L
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• Lactic Acidosis
• Blood sugar (Organic academia/ GSD)
• Urine Aminoacidogram (Organic academia)
• CSF Lactate (Mitochondrial disorder)
• LFT (Liver Failure)
Laboratory features of hyperchloremic metabolic acidosis

Condition Urine net charge FeHCO3 Urine pH UCO2-PCO2
Distal RTA Positive Low > 5.5 Low
Proximal RTA Positive High < 5.5 Normal
Diarrhea Negative Low Variable Normal
Acid load Negative Low < 5.5 Normal
17.5 Approach to diagnosis

APPROACH
Metabolic acidosis
Anion gap
Normal Elevated
Urine net charge Blood sugar
Negative Positive High Low Normal

GI loss Potassium DKA Organomegaly Creatinine, lactate
High Low Present Absent Normal

Type IV RTA U-B CO2 GSD Organic acidemia Organic acidemia
< 10 > 20
Distal RTA Proximal RTA
1) Phosphate, creatinine and albumin levels after exclusion of phosphate load.

a) Hypophsophatemia excludes inefficient PTH action and points to vitamin D
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related causes or hypomagnesemia. Do serum magensium.
i) Low magnesium is diagnostic of hypomagensemia.
MANAGEMENT
• Indications
• Renal failure/ RTA- pH < 7.2, HCO3 < 15 mmol/L
• Metabolizable acid – pH < 7.1
• Requirement
• HCO3 (mEq)= 0.3x weight x SBE
• HCO3 (mEq)= 0.5x weight x (Target -HCO3 ) ( pH< 7.2)
• 7.5% NaHCO3= 0.9 mEq/ml
• Specific
• DKA: Avoid sodium bicrabonate
• CRF: HCO3 22-24 mmol/L Tab Sodamint- 4meq, Powder- 12 meq/1gm
• RTA
• Type I- HCO3- 0.5-2 mmol/kg/d (Polycitra- 2 meq/ml: Na K Citrate)
• Type II- PO4- 20-40 mg/kg/d in 4DD & HCO3 > 4 mmol/kg/d
• Type IV- Aldosterone- Flurinef 0.15 mg/m2 and loop diuretics
• Salisylate Poisoning
• Gastric lavage
• Sodium bicarbonate and acetazolamide
Further reading
1. Dubose TD. Acidosis and alkalosis. In: Fauci AS, Braunwald E,
Isselbacher KJ Wilson JD, Martin JB, Kasper DL et al. (eds) Harrison’s
Principles of Internal Medicine, 14th edn. New york, McGraw Hill, 1998. Pp
277-289.
2. Tote RD, Alpern RJ. Metabolic acidosis and alkalosis. In: Fluid and
electrolytes. Eds: Kokko JP, Tannen Rl. WB Saunders Philadelphia 3rd
Edn 1996. Pp201-266.
3. Haycock GB. Potassium and acid base. In: Pediatric Nephrology Eds:
Barratt TM, Avner ED, Harmon WE Lippincot Williams and Wilkins 4th Edn
1999. Pp155-191.
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Section 4- Calcium & Bone

16. Neonatal Hypocalcemia
16.1 Criteria
4.1 Hypocalcemia
Age group Total mg/dL (mmol/L) Ionic mmol/L
Neonatal hypocalcemia
16.2 Etiology
ETIOLOGY
Neonatal hypocalcemia
Increased chelation
Decreased total calcium
Hyperphosphatemia
Cow milk, formula
Renal failure
Birth asphyxia
Alkalosis
Decreased transfer PTH related Vitamin D related

Prematurity Maternal vitamin D deficiency
Small for date 1α hydroxylase deficiency
Renal failure
Resistance to PTH
Hypoparathyroidism
Pseudohypoparathyroidism
Magnesium deficiency
Transient Permanent
Maternal hyperparathyroidism Isolated
Magnesium deficiency Activating Ca sensing receptor mutation
Infant of diabetic mother Parathyroid agenesis
PTH gene deletion
Syndromes
DiGeorge malformation complex
Kenny-caffey syndrome
Mitochondrial disorders- MELAS, KS syndrome
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CRITERIA
Age group Total mg/dL (mmol/L) Ionic mmol/L
Classification Causes
Early (before three days of life) Prematurity
Birth asphyxia (33% of all neonates)
Infant of diabetic mother (15% of all)
Late (after three days of life) Formula feed
Maternal vitamin D deficiency
Hypomagensemia
Hypoparathyroidism
Clinical
• Seizures, jitteriness, apnea
• Lethargy
• Cardiac failure
• Stridor
Investigation
• ECG- Prolonged corrected QoT interval (QoTc)
QoTc= QoT/ √RR (consider hypocalcemia if above 0.22)
QoT= Beginning of Q wave to beginning of T wave, RR- RR interval
• Features of rickets on X ray
Indication for screening

• Gestational age below 36 weeks
• Birth weight less than 1500 gm
• Infant of diabetic mother
• Cono-truncal cardiac defect
EVALUATION
History
• Age at onset
• First week- Prematurity, birth asphyxia, infant of diabetic mother
• 1-3 weeks- HP, maternal hyperparathyroidism, hypomagnesemia
• 3-6 weeks- Phosphate load, vitamin D deficiency, renal failure
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• Family history
• Hypocalcemia- VDDR, calcium sensing receptor defect, PHP
• Mother- Abdominal pain, renal colic (hyperparathyroidism), DM
• Exposure to cow milk or formula (hyperphosphatemia)
• Period of gestation (prematurity), birth asphyxia
• Exchange transfusion (chelation with citrate)
• Recurrent infections (Di George syndrome)
Examination
• Facies
• Low set ears, short philtrum, mandibular hypoplasia, small mouth,
hypertelorism (DiGeorge malforamtion complec)
• Frontal bossing, craniotabes, rachatic rosary (vit D deficiency, VDDR)
• Cardiac murmur (DiGeorge syndrome)
Investigations
• Initial
• Serum phosphate
• High- Renal failure, HP, pseudohypoparathyroidism, phosphate load
• Low- Vitamin D deficiency, VDDR, hypomagnesemia
• Creatinine
• Magnesium (low in hypoparathyroidism and hypomagnesemia)
• Alkaline phosphatase (high in vitamin D deficiency)
• X ray wrist- Rickets
• Urine calcium (high in activating calcium sensing receptor mutation)
• Investigations in mother- X ray pelvis (for osteomalcia), calcium (high
in hyperparathyroidism), alkaline phosphatase (high in vit D deficiency)
• Second Line
• Parathormone- Hyperphosphatemia, normal creatinine, no PO4 load
• Low, normal- Hypoparathyroidism
• High- Pseudohypoparathyroidism
• 25 hydroxy vitamin D- Low/ normal phosphate and normal Mg

• Low- Vitamin D deficiency
• High- 1 alpha hydroxylase deficiency, calcitriol resistance
• 1, 25 dihydroxy vitamin D- Low/normal PO4, rickets, normal 25OHD

• Low- 1 alpha hydroxylase deficiency
• High- Calcitriol resistance
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MANAGEMENT
Acute
• Injection calcium gluconate (10%, 9 mg/ml)
• Indication- Total calcium < 6 mg/dL, ionic calcium < 2.9 mmol/L
• Dose- 1-2 ml/kg (9-18 mg/kg), intravenously over 10-20 minutes
• Precaution
• Avoid extravasation as may cause tissue necrosis
• Cardiac monitoring due to risk of cardiac arrest
• Avoid combination with phosphate or bicarbonate
• Follow-up
• Good response
• Calcium (75 mg/kg/day in four divided doses) for one day
• Reduce to 50 mg/kg/day on day 2 and 25 mg/kg/day on day 3
• Start oral calcium at a dose of 50 mg/kg/day on day 3
• Stop intravenous calcium on day 4
• No response
• Repeat calcium gluconate (1-2 ml/kg)
• Magnesium (50 mg/kg, IM or IV, 0.1 ml/kg of 50%)
Long term
• Vitamin D deficiency
• Calcitriol (20-40 ng/kg/day)/alpha D (40-60 ng/kg/day) for 3 days
• Cholecalciferol (300000 IU) over five days
• Calcium carbonate (50 mg/kg/day in three divided doses)
• 1 alpha hydroxylase deficiency- Calcitriol (20-40 ng/kg/day)
• Calcitriol resistance- High dose activated calcitriol (5-10 µg/day),

calcium infusion (50-75 mg/kg/day) if no response
• Hypoparathyroidism
• Calcitriol (20-40 ng/kg/day)/ alpha D (40-60 ng/kg/day)
• Calcium carbonate (50 mg/kg/day eight hourly, avoid phosphate)
• Magnesium (50 mg/kg/day) if hypomagnesemia present
• Target calcium- 7.6-8.0 mg/dl (1.9-2.0 mmol/L)
• Hypomagnesemia
• Intramuscular magnesium sulphate- 0.1 ml/kg for three days
• Oral magnesium sulphate (50-100 mg/kg/day)
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• Maternal hyperparathyroidism- CaCO3 50-75 mg/kg/day three months
Duration of treatment
Disorder Duration
Maternal vitamin D deficiency, hyper PTH Three months
Nutritional phosphate load Three months
Vitamin D dependent rickets 1 and 2 Life long
Hypoparathyroidism, PHP Life long
Post Neonatal Hypocalcemia

CRITERIA
• Total calcium less than 8.0 mg/dL (2 mmol/L) or
• Ionic calcium less than 1.1 mmol/L
• Correction for albumin levels
Corrected calcium mg/dL = Total calcium mg/dL + 0.8 × (4- Alb g/dL)
History
• Tetany
• Numbness and tingling around the mouth and in tips of fingers
• Stridor, cardiomyopathy
• Benign intracranial tension
• Muscle cramps
Examination- Papiledema, Tetany
EVALUATION
History
• Onset
o Infancy- Vitamin D deficiency, renal failure, HP, PHP
o Childhood- Renal failure, vitamin D deficiency, hypoparathyroidism
o Adolescence- Vitamin D deficiency, renal failure, autoimmune HP
• Family history of PHP, rickets, hypoparathyroidism
• Acute onset anemia, hemoglobinuria (hemolysis), tumor lysis
• Exposure to phenytoin, phenobarbitone, cisplatinum, forscarnet
• Bony deformities (rickets, pseudohypoparathyroidism)
• Features of renal failure, liver disease
• Recurrent infections (DiGeorge syndrome, calcitriol resistance)
• Adrenal insufficiency, hypothyroidism, diabetes mellitus (APS 1)
• Recurrent diaorrhea, steatorhea (malabsorption)
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Examination
• Pubertal development
Post Neonatal Hypocalcemia (delayed in PHP, hemochromatosis)
• Facies (abnormal in DiGeorge syndrome, PHP)
Criteria
• Hyperpigmentation (addisson disease, hemochromatosis)
• Total calcium less than 8.0 mg/dL (2 mmol/L) or
• Rickets (vitamin D related cause, reanl failure)
• Ionic calcium less than 1.1 mmol/L
Correction for albumin levels
•
Corrected calcium mg/dL = Total calcium mg/dL + 0.8 × (4- albumin g/dL)
ETIOLOGY
Etiology
Hypocalcaemia
Decreased total calcium

Increased chelation
Hyperphosphatemia
Tumor lysis
Hemolysis
Renal failure
Vitamin D related PTH related
Deficiency PTH Resistance PTH deficiency

Bloomstrand disease
Dietary PHP- Ia, Ib, Ic, II
Decreased sunlight exposure Hypomagenesemia
Malabsorption
Liver disease Congenital Acquired

Celiac disease Isolated Infiltration
Decreased activation PTH gene defect (AD)
Parathyroid agenesis (X linked) Autoimmune
1α hydroxylase deficiency Hemochromatosis
Ca sensing receptor (AD)
Renal failure MELAS (mitochondrial) Histiocytosis
Malformation syndromes Wilson disease
Parathyroid insult
DiGeorge syndrome
CATCH-22 Surgery
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Table 1 Clues to diagnosis of hypocalcemia

Feature Etiology
Rickets Vitamin D deficiency, renal failure, VDDR
Cardiac murmur DiGeorge syndrome
Mental retardation PHP, MELAS, DiGeorge syndrome
Vitiligo, alopecia Autoimmune polyendocrinopathy
Brachymetacarpia Pseudohypoparathyroidism
Hyperpigmentation Hemochromatosis, adrenal insufficiency
Mucosal candidiasis Autoimmune polyendocrinopathy
Nail dystrophy Autoimmune polyendocrinopathy, PHP
Investigations
• Serum phosphate
• Low or normal- Vitamin D deficiency, VDDR, Hypomagnesemia
• High- Release of intracellular phosphate, renal failure,HP, PHP
• Creatinine (high in renal failure), X ray wrist (for evidence of rickets)
• Urine calcium (hypercalciuria in calcium sensing receptor mutation)
• Parathormone- Hypocalcemia, high phosphate, normal renal functions

• Low or normal- Hypoparathyroidism
• High- Pseudohypoparathyroidism
• Magnesium- Hypocalcemia with no rickets and normal renal functions
• 25OHD- Hypocalcemic rickets and normal/low phosphate levels

• Interpretation- In the setting of hypocalcemia rickets
• Low- Vitamin D deficiency
• High- 1α hyydroxylase deficiency, calcitriol resistance
• 1,25 dihydroxy D- Hypocalcemic rickets with normal or high 25OHD

• Interpretation- With rickets and normal 25 hydroxy vitamin D
• Low- 1α hydroxylase deficiency
• High- Calcitriol resistance
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APPROACH
Approach to diagnosis
Exclude phosphate load
Phosphate
Low, normal High

X ray for rickets Creatinine
Present Absent High Normal

25 OH vitamin D Magnesium levels Renal failure PTH
Low Normal or high Low High

Vitamin D deficiency 1, 25 OH vitamin D HP PHP
Low High
1α hydroxylase deficiency Calcitriol resistance
Management
Intravenous
Initial calciumshould
investigations shouldinclude
be administered in all children
serum phosphate, with suspected
creatinine and albumin
symptomatic hypocalcemia
levels after exclusion of phosphate after obtaining blood
load. sample. Calcium
Hypophsophatemia gluconateexcludes
2
ml/kg of 10% solution (provides 9 mg Ca++ per ml) should be infused slowly over
inefficient PTH action and points to vitamin D related causes or
10 minutes under cardiac monitoring. Care should be taken to avoid
hypomagnesemia. 25OHD levels should be done if magnesium levels are
extravasation of calcium as this may cause dermal necrosis. Intravenous calcium
normal. Low 25OHD
should be reserved for indicates vitamin
asymptomatic D deficiency
individuals while
with calcium levelsnormal 25OHD in
lower than
this6.0setting suggests
mg/dl (Ionic VDDR,
calcium less which
than 0.8 canFollowing
mmol/L). be classified with 1,25
initial correction,
dihydroxyvitamin
calcium gluconate D should
(low bein continued
1 α hydroxylase
in a dose of deficiency
75-80 mg/kg/day high(2 in calcitriol
ml/kg
resistance). Hyperphosphatemia
every 6 hourly). This should ideally in be
a child withinhypocalcemia
dissolved maintenance fluids.suggests
Care renal
dysfunction or ineffecient
should however be taken PTH function.
to not Normalgluconate
mix calcium creatinine
withinphosphate
this setting
or points
bicarbonate to avoid crystallization in the IV tubing. Intravenous
to inefficient PTH action, which could be classified with PTH levels (low in HPcalcium should
and not bein
high mixed
PHP) with phosphate or bicarbonate as this may lead to crystallization in
the IV tubing. The dose of calcium gluconate is decreased to 75% on day 2 and
50% on day 3. Intravenous calcium should be replaced with oral calcium after
stabilization and initiation of specific therapy. Magnesium sulfate (0.1 ml/kg of
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MANAGEMENT
Acute
Intravenous calcium should be administered in all children with suspected
symptomatic hypocalcemia after obtaining blood sample. Calcium gluconate 2
ml/kg of 10% solution (provides 9 mg Ca++ per ml) should be infused slowly
over 10 minutes under cardiac monitoring. Care should be taken to avoid
extravasation of calcium as this may cause dermal necrosis. Intravenous
calcium should be reserved for asymptomatic individuals with calcium levels
lower than 6.0 mg/dl (Ionic calcium less than 0.8 mmol/L). Following initial
correction, calcium gluconate should be continued in a dose of 75-80 mg/kg/
day (2 ml/kg every 6 hourly). The dose of calcium gluconate is decreased to
75% on day 2 and 50% on day 3. Intravenous calcium should be replaced with
oral calcium after stabilization and initiation of specific therapy. Magnesium
sulfate (0.1 ml/kg of 50% solution, 12 hourly for four doses IM) is indicated in
children with refractory hypocalcemia.
Long term
• Vitamin D deficiency
• Calcitriol (20-40 ng/kg/day)/alpha D (40-60 ng/kg/day) for 3 days
• Cholecalciferol (300000 IU) over five days
• Calcium carbonate (50 mg/kg/day in three divided doses)
• 1 alpha hydroxylase deficiency- Calcitriol (20-40 ng/kg/day)
• Calcitriol resistance- High dose activated calcitriol (5-10 µg/day),

calcium infusion (50-75 mg/kg/day) if no response
• Hypoparathyroidism
• Calcitriol (20-40 ng/kg/day)/ alpha D (40-60 ng/kg/day)
• Calcium carbonate (50 mg/kg/day eight hourly, avoid phosphate)
• Magnesium (50 mg/kg/day) if hypomagnesemia present
• Target calcium- 7.6-8.0 mg/dl (1.9-2.0 mmol/L)
• Hypomagnesemia
• Intramuscular magnesium sulphate- 0.1 ml/kg for three days
• Oral magnesium sulphate (50-100 mg/kg/day)
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4.2 Vitamin D deficiency- Rickets and beyond
Vitamin D plays a central role in the regulation of calcium homeostasis in

children. Besides being an important contributor to bone strength it is the main
defense against hypocalcemia. Recent studies have expanded the role of
vitamin D with non calcemic effects like regulation of immunity, cancer
surveillance and metabolic homeostasis. Prevention and treatment of vitamin
D deficiency is vital to prevent it’s short and long term adverse effects.
Physiology
An understanding of vitamin D physiology is mandatory to plan preventive and
therapeutic strategies for vitamin D deficiency.
Source- The predominant source of vitamin D is cutaneous production under

the influence of sunlight. This accounts for over 90% daily input of vitamin D.
Ultraviolet rays of the range 290-315 nm convert 7-dehydrocholesterol in the
skin to cholecalciferol (vitamin D3). The duration of sun exposure required to
produce optimal levels of vitamin D depends on skin pigmentation, proportion
of body covered, time of exposure, latitude, season and the level of
atmospheric pollution. The best time of exposure is 10 AM to 3 PM. Diet is a
minor source of vitamin D fulfilling less than 10% of daily requirement. Vitamin
D is available from plant (ergocalciferol, vitamin D2; mushrooms) and animal
sources (cholecalciferol, vitamin D3; oily fish and egg yolk). Both forms of
vitamin D are biologically equivalent and metabolized in a similar fashion.
Metabolism- Cholecalciferol and ergocalciferol are transported in the blood

bound to vitamin D binding protein to liver where the enzyme 25 hydroxylase
converts them to 25 hydroxy vitamin D (25OHD). The circulating levels of
25OHD are thus substrate dependent. This along with prolonged half life (2-4
weeks) and limited diurnal variation makes it the ideal marker of nutritional
vitamin D status. 25OHD is converted to 1,25 dihydroxy vitamin D (calcitriol) in
the kidney by 1 alpha hydroxylase. Calcitriol is the active form of vitamin D
and is responsible for it’s actions. Hepatic 24 hydroxylase metabolizes 25OHD
and calcitriol to inactive compounds. Drugs enhancing the action of 24
hydroxylase enzyme (antiepileptics, antiretroviral drugs and ketokonazole)
increase vitamin D metabolism inducing vitamin D deficiency in children on
these agents.
Actions- Calcitriol acts on intracellular vitamin D receptor, a transcription

factor, to stimulate synthesis of vitamin D dependent peptides. The most
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important role of vitamin D is to increase intestinal absorption of calcium and

phosphorus. Besides the kidney, 1 alpha hydroxylase and/or vitamin D
receptors are expressed in the osteoblast, keratinocyte, activated
macrophages colon, parathyroid gland, breast and placenta indicating
widespread role of calcitriol. These receptors mediate the non calcemic effects
of vitamin D.
Feto-placental physiology- Vitamin D is readily transferred from mother to

fetus ensuring normal vitamin D levels in newborns born to vitamin D replete
mothers. Breast milk is a poor source of vitamin D with levels of 15-56 IU/L
even in vitamin D replete mothers. In early infancy vitamin D stores are
depleted without supplementation or sun light exposure due to increased
calcium demand caused by rapid bone growth. In these settings vitamin D
deficiency becomes clinically evident around six to eight weeks of life.
Requirement- The recommendation for daily vitamin D requirement are based

on the amount required to maintain normal 25OHD levels. Vitamin D intake of
at least 400 IU in infancy and 600 IU during childhood and adolescence is
essential to maintain the revised 25OHD criteria of 15-20 ng/ml.
Effects of vitamin D deficiency

Vitamin D deficiency is associated with reduced calcium absorption causing
hypocalcemia. Calcium deficiency triggers PTH secretion causing
hypophosphatemia and increased bone resorption. Hypophosphatemia
inhibits growth plate apoptosis resulting in the development of rickets.
Hypocalcemia is usually seen during phase of rapid growth like infancy and
adolescence. Positive role of vitamin D on bone mineralization have been
shown across ages. Vitamin D deficiency reduces muscle strength resulting in
delayed motor development. Severe vitamin D deficiency is associated with
cadiomyopathy in infancy due to reduced vitamin D action on the cardiac
myocyte. The condition presents with cardiac failure amenable to treatment
with calcium and vitamin D. Delayed dentition, hypoplastic enamel and
recurrent dental caries are common in children with vitamin D deficiency. Non
calcemic benefits of vitamin D have been increasingly identified. Vitamin D
deficiency has been associated with increased risk of autoimmune diseases
(multiple sclerosis, type 1 DM, rheumatoid arthritis), respiratory infections,
insulin resistance, hypertension and cancer (breast, colon and prostate).
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Causes of vitamin D deficiency

Cause Condition
Reduced production Reduced sunlight exposure, pigmentation, sun screen
Reduced absorption Celiac disease, liver disease, pancreatitits, cystic

fibrosis
Sequestration in fat Obesity
Loss of D binding Nephrotic syndrome

protein
Increased Phenytoin, phenobarbitone, rifampicin, isoniazid,

inactivation antiretrovirals, ketokonazole
Increased Granulomatous diseases, hyperparathyroidism,

metabolism calcium deficiency
Assessment of vitamin D status

The best marker of nutritional vitamin D status is 25OHD. The levels of
25OHD are substrate dependent and stable due to long half life. They are not
affected by elevated PTH levels, commonly observed in children with vitamin
D deficiency. The cutoff of 25OHD levels to diagnose vitamin D deficiency
should be based on clinical (development of rickets or low bone mass) or
laboratory (hypocalcemia, hyperparathyroidism or elevated PTH levels)
evidence of vitamin D insufficiency. Secondary hyperparathyroidism is an
important mediator of adverse skeletal effects of vitamin D deficiency and level
of vitamin D at which PTH starts to rise has been used to define vitamin D
deficiency. In adults this corresponds to 20 ng/ml (50 nmol/L). Thus levels less
than 20 ng/ml are considered deficient and between 20-30 ng/ml as
insufficient for adults. Prevention of rickets and metabolic bone disease is the
major goal of vitamin D supplementation in children. The prevalence of rickets
falls dramatically after increase in 25OHD levels above 15 ng/ml. The levels of
bone specific alkaline phosphatase start to rise once 25OHD levels fall below
20 ng/ml.. Thus for children 25OHD lower than 15 ng/ml (37.5 nmol/L)
indicates deficiency and between 15-20 ng/ml (37.5 nmol/L-50 nmol/L)
suggests insufficiency. Calcitriol has a very short half life, circulates at a much
lower level compared to 25OHD and is tightly regulated by PTH and serum
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calcium. Thus serum calcitriol levels may be low, normal or high in children
with vitamin D deficiency making it a highly unreliable marker of vitamin D
status.
Vitamin D deficiency in children

Vitamin D deficiency is rampant in Indian children. Studies have shown
widespread prevalence of vitamin D deficiency across ages and socio
economic status. Prevalence of 80% in infants, 88% in adolescent girls and
67% pregnant women has been reported suggesting the severity of epidemic.
Vitamin D preparations
Vitamin D- Vitamin D has long half life (2-4 weeks) and is deposited in the
adipose tissue to replenish vitamin D store in the body. Ergocalciferol and
cholecalciferol have similar biological actions; cholecalciferol however is more
potent in increasing vitamin D stores in the body. Vitamin D is the preparation
of choice for prevention and treatment of vitamin D deficiency. Long half life of
vitamin D results in a lag of action making it inappropriate in the treatment of
acute severe hypocalcemia due to vitamin D deficiency. V Oral absorption of
vitamin D is excellent and provides a smooth increase in vitamin D levels.
Injectable preparations are associated with wide fluctuations of vitamin D. This
along with high risk for hypervitaminosis limits the use of injectable
cholecalciferol to children with malabsorption.
Activated vitamin D- Vitamin D analogs have short half life (24 hours for
calcitriol and 48 hours for 1 hydroxy vitamin D). The effects of 1 hydroxy
vitamin D and calcitriol are similar expect in children with liver disease where 1
hydroxy vitamin D is ineffective. High potency of these analogs increases the
risk of hypercalcemia mandating careful monitoring of calcium levels. These
agents do not replenish body store of vitamin D and have no role in long term
treatment of vitamin D deficiency. Their use should be restricted to children
with acute hypocalcemia due to vitamin D deficiency and conditions
associated with impaired 1 hydroxylase action (renal disease, liver disease,
hypophosphatemic rickets, vitamin D dependent rickets, hypoparathyroidism
and pseudohypoparathyroidism).
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Table 2- Comparison of properties of vitamin D preparations

Metabolite Dose Half life Indications
Vitamin D 50 µg/kg/day 30 day Vitamin D deficiency
1α vitamin D 0.04 µg/kg/day 2 day Inefficient PTH action, CRF, vitamin D
dependent rickets, hypophosphatemic
rickets, acute hypocalcemia
Calcitriol 0.02 µg/kg/day 1 day Ineffecient PTH action, CRF, vitamin D
dependent rickets, hypophosphatemic
rickets,
liver disease, acute hypocalcemia
Vitamin D supplementation
Indications- The aim of vitamin D supplementation is to ensure normal
calcium and bone homeostasis. Prevention of infantile hypocalcemia, rickets
and reduced peak bone mass due to vitamin D deficiency are the major goals
for the supplementation. This requires adequate vitamin D intake across
infancy, childhood and adolescence.
Dose- Estimates for daily requirement of vitamin D are based on the amount
required to achieve normal 25OHD levels. Most studies indicate that the
minimum amount of vitamin D required to achieve 25OHD levels greater than
20 ng/ml are 400 IU (10 microgram) during infancy and 600 IU (15 microgram)
between 1-18 years of age. The requirement may be as high as 1000 IU daily
in some children (Table 3).
Frequency- Vitamin D should be given daily to provide smooth coverage. In

situations where cost and compliance is an issue weekly or monthly vitamin D
may be used. Three monthly supplementation of 300000 IU ergocalciferol has
been shown to be effective in Indian adolescents to maintain normal vitamin D
levels.
Special circumstances- Vitamin D requirements are substantially higher in
children with obesity, malabsorption or those on anti epileptic or anti retroviral
drugs. The supplementation dose should be increased to up to three times in
these children.
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Table 3- Recommended doses for vitamin D supplementation
Age group Daily dose Upper limit
Below one year 400-1000 IU 2000 IU
1-18 years 600-1000 IU 4000 IU
Special circumstances (antiepileptics, 2-3 times daily 4000 IU

obesity, antiretrovital treatment) dose
Treatment of vitamin D deficiency
Treatment of vitamin D deficiency remains controversial. Conventionally large

amount of vitamin D including parenteral preparations have been used in
children with rickets. Recent studies have indicated that large doses are
unnecessary and predispose the child to the risk of vitamin D toxicity. This has
resulted in revised recommendations for vitamin D treatment (Table 4, figure
2).
Dose- Administration of 1000 IU daily for six weeks usually increases vitamin
D levels by 1 ng/ml. Vitamin D should be given at a dose of 1000 units daily
for neonates, 1000-2000 units daily for children between 1-12 months and
2000 IU daily from 1-18 years of age for six weeks. Children with low calcium
stores (rickets, hypocalcemia, high PTH or high alkaline phosphatase levels)
should receive 30-75 mg/kg/day of elemental calcium vitamin D to avoid
hypocalcemia due to increased calcium requirement during rapid
mineralization. Calcium deficiency is an important contributory factor in the
pathogenesis of rickets and combined calcium and vitamin D supplementation
is more effective than only calcium or vitamin D supplementation.
Frequency- Daily vitamin D is the most physiological way of correcting vitamin

D deficiency. Weekly 50000 IU of vitamin D for six weeks is a reasonable
option beyond infancy. Weekly administration of 60000 IU vitamin D for 4-6
weeks followed by daily dose of 600 IU was effective in treating vitamin D
deficiency in Indian adolescents. In children with compliance issue stoss
therapy (150000 for children between 1-12 months, 300000 till three years of
age and 600000 from 3-18 years of age over 1-5 days) may be used.
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Table 4- Treatment guidelines for vitamin D deficiency

Age group Daily dose Weekly dose Stoss dose
Less than one 1000 IU - -

month
1-12 months 1000-2000 IU - 150000 IU
1-18 years 2000 IU 50000 IU 300000-600000

IU
Route- Oral vitamin D is highly effective in correcting vitamin D deficiency.

Injectable vitamin D results in rapid rise of vitamin D levels with inadequate
replenishment of vitamin D stores. It is associated with high risk of vitamin D
toxicity and should be reserved for children with malabsorption.
Follow-up- 25OHD levels should be checked after six weeks to assess

adequacy of treatment. If 25OHD levels are not feasible X ray for line of
healing and calcium, phosphorus and alkaline phosphatase levels provide
reasonable idea about the adequacy of treatment. Maintenance vitamin D
should be continued in children with adequate response to vitamin D. In
children with inadequate response with no evidence of healing of rickets other
etiologies for refractory rickets should be considered.
Vitamin D toxicity
Vitamin D has a broad therapeutic window and toxicity is unlikely with oral
vitamin D. High doses of vitamin D (600000 IU or more) and parenteral vitamin
D are associated with supraphysiological levels of vitamin D. Vitamin D levels
excess of 100 ng/ml are toxic. Vitamin D toxicity causes hypercalcemia,
hypercalcicuria and renal calcification. Symptoms include polyuria, abdominal
pain, vomiting, headache and altered sensorium. Treatment is guided towards
correction of hypercalcemia (hydration, diuresis) and oral corticosteroids (1-2
mg/kg/day of prednisolone for 2-4 weeks). Children with decreased 24
hydroxylase action cannot metabolize vitamin D and are at risk of
hypercalcemia following vitamin D supplementation (idiopathic infantile
hypocalcemia).
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4.3 Refractory Rickets
CRITERIA- No response to 2 courses of vitamin D (600000 IU)
ETIOLOGY
Refractory Rickets
Phosphopenic Acidosis Calciopenic

Isolated Phosphaturia Distal RTA Malabsorption
Hypophosphatemic rickets Proximal RTA Liver disease
X linked Renal Failure Celiac Disease
Autosomal Dominant Reduced activation
McCune Albright Syndrome VDDR I
Fanconi syndrome Renal failure
Wilsons disease Inactivation
Cystinosis, Tyrosenemia Antiepileptics
Lowes disease Calcitriol resistance
Tumor induced osteomalacia VDDR II
Hemiangioma
Fibroma, Sarcoma
EVALUATION
History
• Onset
o Infancy- Vitamin D deficiency, rickets of prematurity, VDDR
o Early childhood- Vitamin D deficiency, VDDR, RTA, celiac disease
o Late childhood- Vitamin D deficiency, HPR, renal failure
o Adolescence- Vitamin D deficiency, renal failure, malabsorption
• Family history of rickets or consanguinity (HPR, VDDR, fanconi syndrome)
• Features of renal failure, malabsorption, liver disease, antiepileptic drugs
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• Polyuria, growth retardation (renal tubular acidosis)

• Tetany, seizures, parestheisa, muscle weakness (calciopenic rickets)
• Premature loss of teeth (hypophosphatasia), dental abscess (HPR)
EXAMINATION
• Growth retardation- Renal failure, RTA, malabsorption
• Pattern of limb involvement
o VDDR - Frontal bossing, rachatic rosary, wrist widening
o Hypophosphatemic rickets- Lower limb, genu valgum
o Vitamin D deficiency- Both upper and lower limb
INVESTIGATIONS
Initial
• Calcium
• Low- Vitamin D deficiency, vitamin D dependent rickets
• Normal- Vitamin D dependent rickets, HPR, RTA
• High- Hyperparathyroidism, jansens, hypophosphatasia
• Phosphate
• Low- Hypophosphatemic rickets, RTA, VDDR
• Normal- VDDR, vitamin D deficiency, distal RTA
• High- Renal failure, pseudohypoparathyroidism
• Alkaline phosphatase
• High- Vitamin D deficiency, VDDR, HPR, renal failure
• Normal- Renal failure, skeletal dysplasia, renal tubular acidosis
• Low- Hypophosphatasia
• Creatinine (high in renal failure)
Confirmatory
• Blood gas- Rickets with normal or low phosphate levels
• Severe metabolic acidosis suggestive of RTA
• Mild metabolic acidosis in secondary hyperparathyroidism
• Tubular maximum for phosphate
TMP/GFR (tubular maximum)= PPO4− UPO4 × PCr

UCr
• Low- HPR, vitamin D deficiency, VDDR, RTA
• Normal- Vitamin D deficiency, distal RTA
• High- Pseudohypoparathyroidism, renal failure
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• PTH- Rickets with normal calcium, blood gas and phosphate

• Normal- Hypophosphatemic rickets
• High- Vitamin D dependent rickets
• Urinary calcium excretion- Hypercalciuria

• Renal tubular acidosis
• Hypophsophatemic rickets with hypercalciuria, Dents disease
• 1,25 dihydroxyvitamin D- Normal phosphate and high PTH

• Low- 1α hydroxylase deficiency (VDDR I)
• High- Calcitriol resistance (VDDR II)
• Classification of RTA
• Urine pH- During acidosis
• Urine pH less than 5.5- Proximal RTA
• Urine pH greater than 5.5- Distal RTA
• Fractional excretion of bicarbonate

• FeHCO3 > 15%- Proximal RTA
• FeHCO3 < 10%- Distal RTA
• Urine to blood CO2 difference- After alkalanization

• Urine to blood CO2 difference > 20- Proximal RTA
• Urine to blood CO2 difference < 10- Distal RTA
Figure 1 Ten-year-old girl with severe bony deformities, multiple fractures and
growth retardation. Investigations showed metabolic aciodsis (bicrabonate 12
mmol/L, BE −18 mmol/L) with normal anion gap (12 mmol/L).
Nephrocalcinosis, high urine pH during metabolic aciodosis (7.8) and low urine
to blood CO2 difference after alkalinization (6 mm Hg) confirmed the diagnosis
of distal RTA.
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Approach to diagnosis
Exclude phosphate load
Phosphate
Low, normal High

X ray for rickets Creatinine
Present Absent High Normal

25 OH vitamin D Magnesium levels Renal failure PTH
Low Normal or high Low High

Vitamin D deficiency 1, 25 OH vitamin D HP PHP
Low High
1α hydroxylase deficiency Calcitriol resistance
Management
Intravenous calcium should be administered in all children with suspected
symptomatic hypocalcemia after obtaining blood sample. Calcium gluconate 2
ml/kg of 10% solution (provides 9 mg Ca++ per ml) should be infused slowly over
10 minutes under cardiac monitoring. Care should be taken to avoid
extravasation of calcium as this may cause dermal necrosis. Intravenous calcium
should be reserved for asymptomatic individuals with calcium levels lower than
6.0 mg/dl (Ionic calcium less than 0.8 mmol/L). Following initial correction,
calcium gluconate should be continued in a dose of 75-80 mg/kg/day (2 ml/kg
every 6 hourly). This should ideally be dissolved in maintenance fluids. Care
should however be taken to not mix calcium gluconate with phosphate or
bicarbonate to avoid crystallization in the IV tubing. Intravenous calcium should
not be mixed with phosphate or bicarbonate as this may lead to crystallization in
the IV tubing. The dose of calcium gluconate is decreased to 75% on day 2 and
50% on day 3. Intravenous calcium should be replaced with oral calcium after
stabilization
Figure and initiationboy
2 Five-year-old of specific therapy.deformity.
with knee Magnesium Hypophosphatemia
sulfate (0.1 ml/kg of with
normal bicarbonate, calcium and PTH hormone suggested the diagnosis of
hypophosphatemic rickets.
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MANAGEMENT
• Renal failure
• Calcitriol (20-40 ng/kg/day) or 1α hydroxy D (30-60 ng/kg/day)
• Calcium carbonate (50-75 mg/kg/day)
• Sodium bicarbonate (1-2 mmol/kg)
• Hypophosphatemic rickets
• Phosphate (40-60 mg/kg/day) in four to six doses, Joulie’s solution
(acidic, 30 mg/ml), neutral phosphate
• 1α Hydroxylase deficiency
• Calcium carbonate (50-75 mg/kg/day)
• Calcitriol resistance
• High dose calcitriol (200-400 ng/kg/day)
• Calcium carbonate (3.5-9.0 g/m2/day)
• Intravenous calcium infusion (0.8-1.4 g/m2/day in refractory cases)
• Distal RTA
• Bicarbonate- 1-2 mmol/kg/day (may require higher doses at onset)
• Potassium- 2-4 mmol/kg/day
• Thiazide diuretics (1-2 mg/kg/day) if persistent hypercalciuria
• Proximal RTA
• Bicarbonate- 4-6 mmol/kg/day
• Phosphate- 40-50 mg/kg/day in four to five divided doses
• Potassium- 2-4 mmol/kg/day
Further reading
1. Diamond FB Jr, Root AW. Disorders of calcium metabolism in newborn

and infant. In: Pediatric Endocrinology Eds: Sperling MA. WB Saunders
2002, Philadelphia, 2nd Edn Pp 97-110.
2. In: Pediatric Endocrinology, Eds: Lifshitz F, Marcel Dekker, 2003, New
York, 4th edition
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Section V- Glucose disorders

5.1 Diabetes Mellitus- Classification
DIAGNOSTIC CRITERIA
• Fating blood glucose ≥ 126 mg/dL (7 mmol/L)
• Post glucose blood glucose at 2 hr ≥200 mg/dL (11.1 mmol/L)
• In presence of classic symptoms random blood glucose ≥ 200 mg/dl
• HbA1C ≥ 6.5
Oral glucose tolerance test

! Not required routinely in children
✴Suspected DM with casual blood glucose less than 200 mg/dL
✴Screening for type 2 DM
! Preparation
✴Adequate carbohydrate intake for three days (150 g/m2/day)
✴Overnight fast
✴Anhydrous glucose (1.75 g/kg, maximum 75 g) as chilled liquid
✴Blood glucose at 0 and 120 minutes
Interpretation
Category Glucose tolerance test*
Fasting 2 hour
Normal < 100 mg/dL** < 140 mg/dL
IGT 100-125 mg/dl 140-199
Diabetes mellitus ≥ 126 mg/dL ≥200 mg/dL
Practice points
• Venous plasma glucose is recommended for diagnosis
• Whole blood glucose is 10% lower than plasma blood glucose
• Laboratory sample essential for diagnosing diabetes mellitus
• HbA1c- NGSP level 1 certified and standardized to DCCT assay
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ETIOLOGY
Diabetes mellitus
Decreased insulin production Impaired insulin action
Congenital Acquired Congenital Acquired

MODY Insulin receptor defect Type 2 DM
Dysgenesis Lipodystrophy Endocrinopathies
Infections Cushing syndrome
CMV Hyperthyroidism
GH excess
Genetic syndromes
Turner
β cell destruction Pancreatic dysfunction Down
Type 1 DM Cystic fibrosis Klinefelter
Autoimmune Hemochromatosis Prader Willi
FCPD Drugs
Drugs Steroids
L Asparginase Interferon
Tacrolimus
EVALUATION
Clinical
• Onset
• Early infancy- KATP channel, transient neonatal DM
• Late infancy to childhood- Type 1 DM
• Adolescence- Type 1 DM, type 2 DM, MODY
• Family history- MODY (three generations involved), T2DM
• Presentation
• Acute with diabetic ketoacidosis- Type 1 (60-80%), T2DM (30%)
• Insidious- MODY, type 2 DM
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WHO classification of diabetes mellitus

I Type 1 DM (Absolute insulin deficiency due to beta cell destruction):
Upto 95% of all pediatric diabetes .
IA (Autoimmune)
IB (Non-autoimmune)
II Type 2 DM (Insulin resistance with relative insulin deficiency): 10-50% of
diabetes in adolescents depending on ethnicity served.
III Other specific types of diabetes
•Genetic disorders of beta cell function- MODY, mitochondrial disorders
•Genetic disorders of insulin action- Insulin receptor defects,
lipodystrophy, type A insulin resistance, Rabson Mendenhall syndrome.
•Exocrine pancreatic disease- Cystic fibrosis, FCPD, dysgenesis,
hemochromatosis ( Primary & Secondary)
•Genetic syndromes- Turner, Klinefelter, Down, Prader Willi, Wolfram,
LMBB
•Endocrinopathies- Growth hormone excess, cushing syndrome,
hyperthyroidism
•Drugs- Steroids, L- Asparginase, cyclosporine, tacrolimus, interferon,
pentamidine, thiazides, diazoxide, dilantin.
•Infections- Congenital rubella, cytomegalovirus
IV Gestational diabetes
• Abdominal pain, steatorhea (pancreatitis)

• Respiratory symptoms , failure to thrive, steatorhea (cystic fibrosis)
• H/o exposure to corticosteroids, pentamidine, L- asparginase, tacrolimus
• Growth, pubertal development
• Body mass index
• Lean- Type 1 DM, MODY
• Obesity- Type 2 DM (rarely type 1 DM)
• Acanthosis nigricans (type 2 DM, insulin resistance syndromes)

• Disproportionate loss of subcutaneous fat (lipodystrophy)
Investigations
• Indications for disease classification
• Onset after puberty (likely to be type 2 DM or MODY)
• No ketoacidosis at diagnosis (likely to be type 2 DM or MODY)
• Obesity, acanthosis nigricans (likely to be type 2 DM)
• Abdominal pain, steatorhea (exocrine pancreatic disorder)
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• Investigation
• Ultrasound abdomen (pancreatic calcification)
• C peptide- Marker of beta cell function
• Less than 0.6 pmol/L- Type 1 DM (rarely low in type 2 DM)
• More than 0.6 pmol/L- Type 2 DM, MODY and occasionally in type
1 DM with residual beta cell function. Repeated over 6-12 months.
• Fasting insulin
• Indications
• Onset during adolescence, obesity with acanthosis nigricans
• No DKA at diagnosis
• Asymptomatic individuals for screening of insulin resistance
• Antibodies- GAD and IAA (45-70% of Indian children)
• Genetic analysis for MODY syndromes

• Indications- Features of MODY
• History of early onset diabetes mellitus in three generations
• Onset in the peri-pubertal period in a lean child
• No DKA, obesity or acanthosis nigricans
• Investigations- Gene sequencing for HNF, Glucokinase genes
Comparison of common forms of childhood diabetes mellitus

Feature Type 1 DM Type 2 DM MODY
Age at onset Any age Post pubertal Post pubertal
Presentation Acute Insidious Insidious
DKA 30-60% 5-25 % Less than 5%
Family history 5-10% 75-90% 100%
Obesity Around 20% More than 90% Unusual
Acanthosis nigricans Absent Usually present Absent
Insulin requirement Universal Variable Variable
C peptide Low High, normal Low-normal
Insulin sensitivity Normal Low Normal
Islet cell antibody 40-70% Unusual Negative
Treatment Insulin Diet, metformin Diet, sulfonylurea
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Acanthosis nigricans Absent Usually present Absent
Insulin requirement Universal Variable Variable
C peptide Low High, normal Low-normal
Resource
Insulin book
sensitivity Normal Pediatric Endocrinology
Low Normal Protocols
Islet cell antibody Positive in 80% Positive in 10% Negative
Treatment Insulin Diet, metformin Diet, sulfonylurea
MODY- Monogenic diabetes of the young, DM- Diabetes mellitus
Pubertal status
Pubertal
Pre-pubertal Obesity
Absent Present
DKA at diagnosis C peptide
Yes No
GAD, insulin antibody
Absent Present Low
Type 1 DM Consider MODY Type 1 DM High, normal

Type 2 DM
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5.2 Diabetic Ketoacidosis
CRITERIA
• Hyperglycemia- Blood glucose greater than 200 mg/dL
• Metabolic acidosis
• pH less than 7.3
• Serum bicarbonate less than 15 mmol/L
• Base excess more than −5 mmol/L
• Ketosis- Blood ketone > 3 mmol/L or urine ketone more than 2+
• Acute diabetic presentation- Polyuria, polydipsia, weight loss
• Encephalopathy
• Acute abdomen
• Unexplained dehydration
• Acidotic breathing
Differential diagnosis
• Clinical
• Encephalopathy- CNS infection, malaria, poisoning
• Acute abdomen- Pancreatitis, appendicitis
• Dehydration- Gastroenteritis
• Tachypnea- Pneumonia
• Laboratory
• Hyperglycemia with acidosis without ketosis
• Renal failure
• Septicemia
• Ketoacidosis without hyperglycemia

• Starvation
• Salicylate poisoning
• Organic acidemia
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EVALUATION
Initial- Airway, breathing, circulation, hydration, perfusion, BP
• Indications for intensive care treatment

• Age less than 5 years
• First episode
• Severe dehydration with hypoperfusion ± shock,
• pH less than 7.0
• altered sensorium, features of cerebral edema
• Clinical
• Precipitating factor
• First presentation- Infection
• Known case- Missed insulin, infection, insulin pump malfunction
• Hemodynamic status- Blood pressure, heart rate

• Neurological status
• Level of consciousness
• Pupils (dilated and fixed with cerebral herniation)
• VI nerve palsy suggests cerebral edema
• Fundus (papilledema suggestive of cerebral edema)
• Deep tendon reflexes (brisk with raised ICP)
• Investigations
• Serum sodium
• Deficit (20% of total body potassium, 4-6 mmol/kg)
• Sodium levels falsely reduced in hyperglycemia
• 1.6 mmol/L decrease per 100 mg/dL increase in BGL
Corr Na = Na + (Blood glucose mg/dL – 100) x 1.6
• 100
• Implication- Slow rise in Na risk factor for cerebral edema
• Serum potassium
• Status
• Intracellular- Deficit (3-6 mmol/kg)
• Extracellular- Elevated (acidosis, insulin deficiency)
• Implication- Treatment associated withhypokalemia
• Reversal of metabolic acidosis
• Correction of insulin deficiency
• Plasma osmolality
• Status- Elevated (300-350 mOsm/kg)
• Estimation- Effective plasma osmolality
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Osmolality- 2 × (Na + K) + Glucose mg/dL

18
• Implication
• Target fall less than 2 mOsm/kg/hour
• Fall > 2 mOsm/kg/hr a risk factor for cerebral edema
• Anion gap
• Status- Elevated (marker of plasma ketoacids)
• Anion gap = Na- Cl- HCO3
• Blood lactate
• Status- Normal (0.4-1.8 mmol/L)
• Implication- Lactic acidosis in DKA suggestive of cerebral edema,
infection, hemodynamic compromise
• Infection screening
• Status- Infection an important precipitating factor for DKA
• Investigations
• Complete blood examination
• Transient leucocytosis common in DKA
• Persistent leuckocytosis suggestive of infection
• Urine examination, Blood and urine culture
• Chest X ray if persistent tachypnea and chest signs
• Renal function tests

• Status- Urea level elevated in DKA due to dehydration
• Implication- High urea indicative of severe DKA and along with
elevated hematocrit is a marker of severity of ECF contraction
• Electrocardiography- For evidence of hypo / hyper kalemia
MANAGEMENT
• Fluid therapy
• Initial bolus normal saline 10 ml/kg
• Combination of deficit and maintenance
• Volume must not exceed 3-3.5 L/m2/day (risk for cerebral edema)
• Evenly distributed over 48 hours
• Insulin
• Timing- Should be started after rehydration as
• Blood glucose falls rapidly even without insulin
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• Premature nsulin treatment associated with drastic fall in plasma

osmolality, increased risk of cerebral edema and hypokalemia
• Hypokalemia should be corrected before initiating insulin
• Route
• Continuous intravenous infusion- Preferred route
• Avoid insulin bolus - No benefit, increased risk of cerebral edema
• Preparation
• Dissolve 50 units of regular insulin in 50 ml NS
• Avoid over dilute insulin (decreased potency)
• Flush tubing with insulin (insulin binds to plastic tube)
• Ensure separate intravenous line for insulin
• Change infusion set every 24 hours
• Use burette set if infusion set not available
• Rate- 0.1 unit/kg/hour initial dose

• Increase if fall in glucose < 50 mg/dL/hour in quantum of 0.02
• Wait for 30 minutes before further change
• Once blood sugar ≤ 300 mg/dl add dextrose
• Initial dextrose concentration in the fluid must be 5%
• Titrated upwards up to 10 % to maintain sugars above 150 mg%
• I BSf < 150 mg% inspite of dextrose being 10% decrease the
infusion by 0.02 u/kg/hr to a minimum of 0.05 u/kg/hr
• Intermittent insulin: To be used when facilities for I.V administration

are unavailable. Not the recommended standard of care
• Intramuscular Dose- 0.1 unit/kg deep intramuscular stat and hourly
• Intravenous- Avoid as high risk of cerebral edema
• Subcutaneous- Unreliable in hypoperfusion states
• Electrolyte management
• Sodium
• Significant sodium deficit in DKA (4-6 mmol/kg)
• Attenuated rise in serum sodium a risk factor for cerebral edema
• Fluid choice in the initial 4-6 hours should be 0.9% isotonic saline.
• At no point of time should fluid of < 0.45 % NS should be used
• Potassium
• Significant potassium deficit in DKA (3-6 mmol/kg)
• Extracellular levels high due to acidosis and insulin deficiency
• Risk of life threatening hypokalemia during treatment
• Correction of insulin deficiency
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• Resolution of metabolic acidosis

• Management- Potassium 40-60 mmol/L after hydration unless
• Serum potassium more than 6 mmol/L
• Electrocardiographic changes of hyperkalemia
• Anuria
• Hypokalemia should be corrected prior to initiating insulin therapy
• Phosphate
• Significant depletion (0.5-1 mmol/kg)
• Replacement not presently recommended routinely.
• Acid base management

• Acidosis resolves with hydration and insulin
• Rapid correction of acidosis associated with risk of hypokalemia
(intracellular shift of potassium) and actic acidosis
• Alkali treatment
• Indication- pH less than 6.9 with hemodynamic compromise
• Plan- Sodium bicarbonate 40 mmol/m2 as infusion over 4 hours
• Adverse effects
• Hypokalemia (intracellular shift of potassium)
• Increase in osmolar load and risk of cerebral edema
• Cerebral acidosis (low brain penetration of bicarbonate)
• Delay in recovery from ketosis
• MONITORING
• Clinical- Hourly
• Neurological status- Level of consciousness, pupil
• Hemodynamic status- Heart rate, blood pressure, respiratory rate
• Fluid input and output
• Laboratory
• Capillary blood glucose- Hourly
• Electrolytes- Sodium, potassium, anion gap
• Plasma osmolality, blood ketone
• Expected response
• Blood glucose
• Hydration phase- Rapid decrease during initial treatment due to
• Rehydration and expansion of extracellular volume
• Decrease in counter regulatory hormones
• Increased glomerular filtration rate and urinary excretion
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• Continuation phase- Decrease by 50-100 mg/dL/hours
• Metabolic acidosis
• Recovery over 6-12 hours
• Persistent acidosis- Infection, lactic acidosis, cerebral edema
• Actions- Exclude infections, consider antibiotics
• Serum potassium- Reduction in serum potassium
• Plasma osmolality
• Desired response- Gradual decrease
• Fall more than 2 mOsm/kg/hour risk factor for cerebral edema
• Serum sodium
• Desired- Increase by 3 mmol/L per 100 mg/dL fall in blood glucose
• Less increase is a risk factor for cerebral edema
• Ketones
• Rapid decrease in blood ketones
• Urine ketones may persist for up to 48 hour
Laboratory parameters and response to treatment in DKA
Parameter Concern Action

Blood sugar Decline > 100 mg/dL/hr Add dextrose to hydration fluid
Decline < 50 mg/dL/hr Prepare fresh infusion, flush
tubings with insulin
pH Persistent at 12 hours Exclude infection, cerebral
edema, lactic acidosis
Sodium Increase < 2 mmol/L/hour Increase sodium concentration
Potassium Hypokalemia Potassium infusion
Anion gap Elevated at 12 hours Exclude lactic acidosis
Osmolality Decrease by > 2 mOsm/kg/hr Increase Na, reduce fluid rate
Blood ketone Persistent at 6 hours Exclude insulin dosage error
Blood count Persistently elevated Exclude infection
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Assess airway, breathing and circulation

Oxygen, fluid bolus (10 ml/kg)
Fluid- Maintenance and deficit over 48 hour

0.45% saline with KCL 40 mmol/L
Insulin infusion 0.1 IU/kg/hour
Blood glucose
More than 270 mg/dL Less than 270 mg/dL

Increase infusion by 10% till 0.2 IU/kg/hr Acidosis
Persistent Resolved
Add dextrose in fluid SC insulin, stop infusion
Management plan
Initial management is directed towards assessing adequacy of airway,
breathing and circulation and correction of dehydration (normal saline 10 ml/kg
over one hour). Further fluid boluses should be given judiciously as level of
dehydration is usually overestimated in DKA. Following initial hydration, fluid
should be administered at a rate to replace maintenance and deficit
requirement over 48 hours (72 hours if plasma osmolality above 350 mOsm/
kg). Half-normal saline is recommended for treatment of DKA; normal saline
may be considered in the presence of hyponatremia (corrected serum sodium
less than 132 mmol/L) or high plasma osmolality (more than 350 mOsm/kg).
Potassium (40 mmol/L) should be added in the hydration fluid unless serum
potassium is above 6 mmol/L or ECG changes of hyperkalemia or anuria are
present. Insulin infusion should be started at a rate of 0.1 IU/kg/hour and
titrated to achieve desirable fall in blood glucose (50-100 mg/dL/hour). Insulin
should be continued till resolution of metabolic acidosis. 5% Dextrose should
be added once blood glucose is below 270 mg/dL (15 mmol/L) and increased
to 10% when blood sugar is below 200 mg/dL (11.1 mmol/L). Subcutaneous
insulin (0.25 IU/kg) should be given after correction of dehydration and
normalization of blood gas and sensorium. Insulin infusion should be
discontinued thirty minutes after the insulin injection. Mixed split insulin should
be started from the next meal with regular glucose monitoring.
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Discontinuation of acute treatment

Indications
• Normal hydration status
• Normal sensorium and oral acceptance
• Blood gas with pH >7.35 and HCO3 >15
Protocol
• Allow oral feed
• Insulin- 0.25 IU/kg regular subcutaneously after feed
• Discontinue insulin and fluid infusion 30 minutes after insulin
• Monitor blood glucose after one hour and two hourly for six hours
• Shift to ambulatory insulin therapy subsequently
COMPLICATIONS
Acute Chronic
Cerebral edema Growth hormone deficiency
Infection- Bacterial, fungal Mental retardation
Hypoglycemia Diabetes insipidus
Hypokalemia
Acute respiratory distress syndrome
Cerebral edema
• Incidence- 0.5-1.0% (radiological features present in most cases)
• Risk factors
• Patient related- Age less than 5 years, severe disease
• Treatment related
• Insulin- Insulin bolus, Multiple intravenous injections
• Fluid- Excessive volume (more than 4 L/m2/day), Hypo-osmolar fluid
(sodium concentration less than 60 mmol/L)
• Alkali treatment
• Early markers
• Fall in blood glucose more than 100 mg/dL/hour in continuation phase
• Fall in plasma osmolality by more than 2 mOsm/kg/hour
• Rise in serum Na less than 2.5 per 100 mg/dL fall in blood glucose
• Onset- Usually 4-12 hours of treatment (may be present at diagnosis)
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• Indicators to diagnosis
• Persistent metabolic acidosis
• Persistent hemodynamic instability
• Worsening in clinical condition after initial improvement
• Clinical features
• Early- Headache, vomiting, drowsiness, hypertension, bradycardia
• Late- Unconsciousness, focal deficits, papiledema, fixed dilated pupil
• Diagnosis- Clinical, no need to confirm with imaging
• Treatment
• Mannitol- 0.25-1 g/kg intravenous push or
• Hypertonic saline- 10 ml/kg of 3% saline over 10 minutes
• Fluid restriction- Reduce fluid rate to 50%
• Head end elevation
• Hyperventilation- Impending respiratory failure
• Outcome- Following clinically evident cerebral edema mortality in 20-30%

and significant morbidity in 30%
• Prevention
• Avoid insulin bolus
• Fluid treatment
• Use fluid boluses judiciously
• Fluid replacement less than 4 L/m2/day
• Gradual correction in children with high plasma osmolality
• Avoid sodium bicarbonate unless pH less than 6.9
• Use normal saline in children with high plasma osmolality
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5.3 Ambulatory Management of Type 1 DM
Day to day management of T1DM is as much of an art as science. It involves

medical management of glycemic control, avoidance of acute complications
and prevention of chronic complications on one hand and achieving social,
scholastic and psychological goals of the child on the other. Comprehensive
education and ongoing involvement with the family is mandatory.
STABILIZATION
• Exclude diabetic ketoacidosis (blood gas and ketones)
• Site of care
• In patient preferred
• Ambulatory care in children older than 2 year, without DKA
• Initial management
• Insulin
• Dose-Guided by pubertal status
• Pre-pubertal- 0.6 unit/kg/day
• Pubertal- 0.8 unit/kg/day
• Post-pubertal- 1.0 unit/kg/day
• Initiation of treatment- According to time of presentation

• Around meal time- Mixed split or basal bolus regimen
• In between meals
• Subcutaneous regular insulin (0.25 unit/kg) followed by
• Mixed split or basal bolus regimen from next meal
• Exclusion of associated conditions

• Hypothyroidism- TSH
• Celiac disease- Transglutaminase antibody (present in 5%)
• Eye examination for cataract
• Criteria for discharge

• No dehydration or ketoacidosis
• Blood glucose 100-200 mg/dL
• Decrease insulin by 10% at discharge
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INSULIN PREPARATIONS
Rapid acting analogs (Lispro, Aspart, Glulisine)
• Do not form hexamers after subcutaneous administration
• Rapid onset of action (5-10 minutes after injection)
• Advantage- Can be given with meal, better post-meal control
• Disadvantage- High cost, inadequate lunch time on two injection regimen
• Indications
• As bolus insulin in basal bolus regimen
• As post meal insulin in toddlers with unpredictable eating habits
• Continuous subcutaneous insulin infusion (insulin pump)
• Nigh time short acting insulin in children on mixed split regimen
• Sick day management
Short acting (Regular insulin)

• Features
• Natural insulin
• Forms hexamer after subcutaneous administration
• Delayed onset of action (30-60 minutes after injection)
• Advantage- IV use, morning insulin in children on mixed split regimen
• Disadvantage
• Gap of 30 minutes required between insulin and meal
• Post meal hyperglycemia
• Nocturnal hypoglycemia with mixed split regimen
• Indications
• Treatment of diabetic ketoacidosis
• As short acting insulin in mixed split regimen
• Sick day management
• As bolus insulin in basal bolus regimen if analogs not available
Intermediate acting insulin (NPH)

• Chemically modified insulin (protamine) with prolonged duration of action
• Indications
• Along with short acting insulin for mixed split regime
• Basal insulin for basal bolus regimen
• Advantages- Can be mixed with short acting insulins and analogs
• Disadvantages
• Need for mid meal snack because of insulin peak,
• Intra individual variability in insulin absorption
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Long acting insulin

Glargine
• Soluble in acidic media
• Precipitates in skin after injection with slow release
• Advantage- Peak less insulin, lower risk of nocturnal hypoglycemia
• Disadvantage- Can not be mixed with other insulins, high cost
Detemir
• Low intra individual variability in insulin absorption
• Advantage- Predictable insulin levels, may be mixed with other insulins
• Disadvantages- High cost, not peak less like glargine
• Indications- Basal insulin in basal bolus
Table 1 Pharmacokinetic profile insulin preparations

Preparation Onset Peak Duration Indications
Rapid Acting
Lispro 5-10 min 1-3 hr 3-4 hr Small child on mixed split
Aspart 5-10 min 1-3 hr 3-5 hr Insulin pump, MDI
Short Acting
Regular 30-60 min 2-4 hr 5-8 hr DKA, mixed split regimen
Intermediate
Lente 1-2 hr 3-10 hr 18-24 hr Mixed split regimen
NPH 1-2 hr 2-8 hr 16-24 hr Mixed split, basal bolus
Long acting
Glargine 2-4 hr Peak less 20-24 hr Basal insulin
Detemir 1-2 hr 6-12 hr 20-24 hr Basal insulin, mixed split
Factors influencing pharmacokinetic profile of insulin

Factor Effect
Dose Prolonged duration of action with larger dose
Site of injection Rapid absorption from upper limb
Depth of injection Slower absorption from deeper injection
Temperature Faster absorption with higher temperature
Exercise Faster absorption with increased activity
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INSULIN REGIMENS
• Mixed split regimen (two or three injection per day)
• Combination of short and intermediate acting insulin
• Regimens
• Conventional regimen
• Injections- Twice a day (before breakfast and dinner)
• Three injection regimen

• Injections- Thrice a day
• Breakfast- Intermediate and short acting
• Dinner- Short acting insulin
• Bedtime- Intermediate acting insulin
• Dose distribution- Initial dose recommendation

• Before breakfast- Two-third of daily dose
• Intermediate or long acting- Two-third of the dose
• Short or rapid acting- One-third of the dose
• Before dinner-One-third of daily dose at night
• Intermediate or long acting- Two-third of the dose
• Short or rapid acting- One-third of the dose
• Mixing of insulin- Steps

• Intermediate insulin vial should be re suspended by shaking
• Air equivalent to insulin should be injected in the vial
• Regular insulin should be withdrawn before intermediate insulin
• To ensure same insulin occupies the dead space
• To avoid contamination of regular with intermediate insulin
• Syringe should be rolled 10 times to ensure adequate mixing
• Administer insulin within 10 minutes of preparation
• Blood glucose monitoring- Before meals and bed time
• Meal distribution- Rigid meal pattern required

• Three major meals (breakfast, lunch and dinner)
• Three minor meals (mid morning, evening and bedtime snacks
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Breakfast Lunch Dinner Bed time
Long acting
Figure 1 Mixed split regimen. Insulin is given before breakfast (two-third of

daily dose) and dinner (one third of daily dose; hollow arrows). Each injection
is a combination of intermediate or long acting (NPH, lente or detemir; two-
third of the total dose) and short (regular) or rapid acting insulin (lispro or
aspart, one third of the total dose). Regular meal pattern is required to prevent
hypoglycemia. Long acting

Long acting
Figure 2 Modified mixed split regimen. The nighttime intermediate acting

insulin has been shifted from before dinner to bedtime. This is indicated in the
presence of nocturnal hypoglycemia and high before breakfast blood glucose
levels. Delayed peak of intermediate acting insulin reduces the risk of
Long acting
nocturnal hypoglycemia on one hand while providing reasonable cover for
morning hyperglycemia.
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Basal Bolus regimen

• Insulin selection
• Basal- Long
Longacting
acting analogs (detemir or glargine) preferred, NPH
• Bolus- Rapid acting analogs (lispro or aspart) preferred, regular insulin
• Dose distribution
• Basal insulin (bedtime)- 40-50% of daily dose
• Bolus insulin (pre-meal)- 50-60% of daily dose
• Advantages- Flexibility for meal timing, better control
• Disadvantages- Stringent monitoring, need for lunch time injection
Long acting
Figure 3 Basal bolus regimen. Intermediate (NPH or lente) or long-acting

insulin (glargine or detemir) is given at bedtime (40-50% of total daily dose).
Rapid acting insulin (aspart or lispro) is given before each meal (50-60% of
total daily dose). Initial dose recommendation for a 36 kg child on one unit/kg/
day of insulin would be 18 units of NPH (or glargine or detemir) at night and 6
units of regular (or analog) before each meal. The timing and amount of meal
is flexible as insulin is directed by meals.
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EDUCATION
Category Should know Can know Optional
Disease Life-long disease Role of insulin Glucose
Normal outcome Type 1 vs 2 DM homeostasis
possible Pathophysiology Disease
Complications classification
Autoimmunity
Associations
Treatment Insulin only treatment Insulin preparations Insulin regimens
Daily injections Time course Insulin pumps
No alternative medicine Injection devices Newer insulin
Hope for the future
Skills Insulin storage Glycemic targets Physical activity
Drawing up, mixing Insulin changes Ketone monitoring
Insulin injection Time sheet Glucagon injection
Nutrition Healthy eating RDA for age Carbohydrate
Avoid simple sugars Food exchanges counting
Mid meal snacks High fiber intake Insulin to carb ratio
Glycemic index
Follow-up Honey-moon phase Role of HbA1c DKA prevention
Hypoglycemia Complication CBGM
Sick day guidelines Physical activity
Day wise protocol

Day Disease Treatment Nutrition Practical skills
1 Role of insulin Insulin only Healthy eating Insulin storage
Life long treatment Frequent meals Injection site
Allay guilt No role of oral drugs
2 Classification Insulin regimens Age specific RDA Insulin mixing
Complications Site and rotation Diet chart Insulin injection
Cause Injection devices Time sheet
3 Hypoglycemia Glycemic goals Food exchanges Glucose testing
Sick day Dose adjustment Glycaemic index Urine ketones
4 Feed back Honey moon phase CHO count DKA prevention
Education quiz Practical guidelines Insulin to carb ratio Glucagon
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NUTRITIONAL RECOMMENDATIONS
Normal healthy diet (no diabetic diet for children)
Component Recommendation Implication

Energy 100% of RDA No restriction
Carbohydrate 50-55% of calories No restriction
Low GI carbohydrate Moderate sugar intake
Fat 25-40% of energy Less saturated fat
Saturated <10% of total energy Less red meat, whole milk
Polyunsaturated <10% of total energy
Monounsaturated >10% of total energy
Cholesterol <300 mg/day
Protein 10-15% of calorie No restriction
Fibers More than 10 gm/day More fruits, vegetable
MONITORING
• Self monitoring
• Recommended- Before each meal and at bedtime
• On different times of the day
• Post meal values if hemoglobin A1c high
• Suggested interventions according to pre-meal BG
Blood glucose Intervention

< 60 mg/dL Meal, repeat blood glucose after 30 minutes
Decrease insulin by 10% the next day
60-80 mg/dL Give meal followed by insulin
80-180 mg/dL Give usual dose of insulin
180-270 mg/dL Increase insulin dose on the next day
> 270 mg/dL Urine or blood ketones
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• Hemoglobin A1C- Marker of glycaemic control over three months

• Target
• Young children- Less than 8%
• Older children and adolescents- Less than 7.5%
• Key points
• Falsely low- Sickle cell disease, iron deficiency, hemolysis
• Falsely elevated- Uremia, high dose aspirin treatment
• Ketone- Identification of DKA

• Indications
• Blood glucose more than 270 mg/dL (15 mmol/L) with
• Recurrent vomiting
• Altered sensorium
• Abdominal pain
• Special considerations- Urine ketones may be

• False positive- Valproate, captopril treatment
• False negative- Ascorbic acid intake, air exposure to sticks
Suggested levels of glycaemic control according to age

Target < 6 years 6 -12 years > 12 years
Blood glucose
Premeal 100-180 mg/dL* 70-180 mg/dL 70-130 mg/dL
Bedtime 110-200 mg/dL 100-180 mg/dL 90-140 mg/dL
HbA1C** Less than 8% Less than 7.5% Less than 7.5%
Follow-up- Three-monthly
History
• Blood glucose, hypoglycemia, injection site
• Dietary history, physical activity
• Pointers to poor control- Failure to thrive, pubertal delay, polyuria
Examination
• Growth and pubertal status, blood pressure
• Injection sites- Lipohypertrophy, lipodystrophy
• Foot examination- Deformities, callus, infection, toe nail
• Oral examination- Caries, periodontitis
• Joint mobility
Investigations- Hemoglobin A1c
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SPECIAL CIRCUMSTANCES
Children younger than five years
Consideration Management implications
Higher risk of hypoglycemia Higher glycemic targets
Unpredictable eating habits Consider rapid acting insulin after meals
Minor dose adjustments Dilute insulin with diluent (U 10)
Less subcutaneous fat Narrow gauge, short needle (8 mm)
Persistent hypoglycemia
• Immediately after diagnosis- Decrease insulin dose
• After long standing disease- Exclude
• Adrenal insufficiency
• Hypothyroidism
• Celiac disease
• Nephropathy with decreased insulin excretion
Obesity and high insulin requirement

• Consideration- Insulin resistance
• Intervention- Physical activity,metformin
Procedures
• Major procedure
• Exclude diabetic ketoacidosis (surgery after correction of DKA)
• Insulin infusion
• Initially at 0.02 unit/kg/hour
• Modify by 10% to achieve BG of 90-180 mg/dL (5-10 mmol/L)
• Continue insulin infusion till on intravenous fluids
• Switch to subcutaneous insulin after discontinuation of intravenous
fluids and normal oral acceptance
• Minor procedure
• Admit overnight, post as first case in the morning
• Blood glucose at 6 AM
• Less than 72 mg/dL- Intravenous dextrose drip
• 72-180 mg/dL- Oral sugar containing drink 10 ml/kg
• More than 10 mmol/L- No intervention
• Give 10% of total daily dose of insulin prior to procedure
• Monitor blood glucose frequently
• Switch to subcutaneous insulin once accepting orally
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SICK DAY CARE

Key aspects of sick day management of type 1 DM include frequent blood
glucose monitoring, regular fluid intake and treatment of the intercurrent
illness. Insulin requirement usually increase during febrile illnesses but may
decrease with vomiting and diarrhea. Basal insulin should never be omitted in
sick children with type 1 DM. In children with blood glucose less than 80 mg/
dL 4.4 mmol/L) rapid acting insulin should be withheld and the dose of
intermediate acting insulin should be reduced by 20-30%. No extra insulin is
required in children with febrile illness and blood glucose between 80-270 mg/
dL (4.4-15 mmol/L). Blood or urine ketones should be measured if blood
glucose is more than 270 mg/dL (15 mmol/L). Children with moderate ketosis
(blood ketones between 1-1.5 mmol/L) should be given extra regular insulin
(10% of total daily dose). Impending DKA (blood ketone more than 1.5 mmol/
L) should be managed with extra regular insulin (15-20% of total daily) and
hourly blood glucose monitoring. In patient management should be considered
in the presence of recurrent vomiting, poor oral intake and persistent hyper or
hypoglycemia.
Encourage fluid intake

Treat intercurrent illness
Blood glucose
Less than 80 mg/dL 80-270 mg/dL More than 270 mg/dL

Oral correction of hypoglycemia Encourage fluids, rest Blood or urine ketone
Omit short acting insulin Blood glucose 4 hourly
Decrease basal insulin by 20-50%
Blood glucose after one hour
Blood < 1 mmol/L Blood 1-1.5 mmol/L Blood > 1.5 mmol/L
Urine- Negative Urine- Trace or small Urine- Moderate or large
Extra insulin 5% of TDD Extra insulin- 10% of TDD Extra insulin- 20% of TDD
Blood glucose after 2 hr Blood glucose after 1 hour Hourly glucose, ketone
Consider hospitalization
TDD- Total daily dose
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HYPOGLYCEMIA (Blood glucose less than 60 mg/dL)
Autonomic Neuroglucopenic
Sweating Headache
Palpitations Confusion
Hunger In-cordination
Tremor Drowsiness
Seizures
Treatment- According to severity of hypoglycemia

• Mild hypoglycemia
• Initial correction- Rapidly absorbed glucose (0.3 mg/kg)- Glucose
• Subsequent management- Long acting carbohydrate
• Moderate hypoglycemia- Mini dose glucagon
Age group Dose (1 mg/ml)

Amount Units on insulin syringe
Less than 2 years 20 µg 2 units
2-15 years 10 µg / year 1 unit/year
More than 15 years 150 µg 15 units
• Severe hypoglycemia
• Home- Glucagon 15 µg/kg to a maximum dose of 1 mg
• Hospital- Intravenous dextrose- 200 mg/kg (2 ml/kg of 10% dextrose)
COMPLICATION SCREENING
Complication Indication Procedure Management
Retinopathy Dilated fundus Better control
Prepubertal Duration more than 5 year* LASER
Pubertal Duration more than 2 year*
Nephropathy Urine albumin Better control
Prepubertal Duration more than 5 year* ACE inhibitor
Pubertal Duration more than 2 year* Control BP
Thyroid At diagnosis then 2 yearly TSH Thyroxin
Hyperlipidemia At diagnosis then Lipid profile Statin
Pre pubertal Five yearly
Pubertal Two yearly
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5.4 Type 1 DM- What’s New?
In the history of diabetes, invention of insulin by Banting and Best in 1920 was
considered as one of the greatest medical breakthroughs of the 20th century.
Before that, only starvation and death was the future for patients with type 1
diabetes. We have already come a long way in the management of type 1
diabetes and we still have a long way to go. The future of T1DM as well as
that of children with the condition appears bright thanks to the tremendous
advances in science and medicine. There are ever expanding hopes for
disease prevention, near physiological insulin replacement, minimally invasive
insulin delivery systems and potential cure. However despite this leap in the
science of diabetes, the art of managing children and adolescents with
diabetes remains a day to day challenge. Central to this is the need to tailor
the management according to the changing requirements of different phases
of life. The Diabetes Control and Complications Trial (DCCT) showed that in
type 1 diabetes mellitus, compared with conventional daily or twice-daily
insulin therapy, intensive insulin therapy (at least three daily insulin injections
or pump treatment) resulted in a significant decrease in micro vascular
complications, and any improvement in HbA1c resulted in a decreased risk of
complications. Intensive insulin therapy is best delivered with multiple daily
injections [MDI] or basal bolus therapy.
Continuous blood glucose monitoring
Regular self-monitoring of blood glucose is pivotal for successful management

of children with diabetes mellitus. Managing diabetes without monitoring blood
glucose is similar to driving a vehicle without a speedometer or a fuel level
indicator. Intermittent glucose monitoring by glucometers provides only a
limited glimpse or snap shot view of blood glucose profile and frequently
misses asymptomatic hypoglycemia and overnight glycemic excursions.
These limitations led to the development of continuous blood glucose
monitoring (CBGM) systems. CBGM is especially helpful in patients with
erratic glycemic control and during initiation and continuation of pump
treatment. They also help in identifying asymptomatic hypoglycemia and the
cause of morning hyperglycemia (Dawn phenomenon versus Somogyi effect).
Both invasive and non-invasive CBGM systems are available.
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INVASIVE CBGM
These systems measure interstitial blood glucose via an indwelling sensor in

the subcutaneous tissue of the abdomen or buttocks. Three to four capillary
BG measurements are performed daily and used to calibrate the CBGM
instrument, which therefore can equate the measured interstitial glucose
reading to blood glucose readings. The systems commonly used for short term
retrospective analysis (Medtronic MiniMed CGMS) make measurements over
72 hours, which are then downloaded onto the workstation computer at the
doctor’s office and the BG trends of the 72 hour period examined.
Real time continuous glucose monitoring (RT-CGM) systems are also
available that provide continuous information about “blood glucose” (hence
called “real time” which can be seen by the patient and used to execute
changes in insulin or food). They are also equipped with alarms to indicate
rapid decrease or increase in blood glucose levels to preempt the
development of hypoglycemia and diabetic ketoacidosis.
NON-INVASIVE CBGM
Electrochemical enzyme sensor- This device is worn like a wristwatch
(GlucoWatch Biographer). Glucose is extracted non-invasively via reverse
iontophoresis for collection in gel disc biosensor.
Infrared spectroscopy- Infrared spectroscopy technology is also being

developed to measure blood glucose non-invasively.
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ADVANTAGES
CBGM are superior to intermittent glucose monitoring in the identification of
post-meal hyperglycemia and asymptomatic hypoglycemia. Intermittent blood
glucose monitoring provides spot values whereas CBGM provides a graphic
reading over a 72 hour period. They are useful adjuncts to pump therapy.
Recent studies have shown improved glycemic control and higher patient
satisfaction with CBGM use in children on insulin pumps.
DISADVANTAGES
These systems are relatively imprecise and need to be validated with 3 – 4
capillary blood glucose measurements per day. They have to be continuously
worn which some of them might find it uncomfortable. Otherwise, their only
disadvantage is their high cost.
CBGM systems represent significant advances in the management of children

with DM. Further innovations and improved precision of these systems in
future are expected to result in much tighter glycemic control without the risk
of hypoglycemia. These efforts are expected to culminate in the development
of a closed loop system, where blood glucose measurements by RT CGM
drive the insulin pump, which acts as artificial β cell, collectively called artificial
pancreas.
Continuous Subcutaneous Insulin Infusion

All currently available insulin regimens are unable to replicate the pattern of
physiological insulin secretion. Under physiological circumstances, insulin is
secreted at a basal rate to suppress hepatic glucose production with extra
insulin released in the portal circulation in response to meal. While none of the
currently available systems allows portal delivery of insulin, continuous
subcutaneous infusion of insulin (CSII) using an insulin pump comes closest to
physiological insulin replacement into subcutaneous tissues.
PRINCIPLE
Insulin pumps are electronic devices that inject insulin using a subcutaneously
inserted catheter. The pump delivers insulin at a preset rate (basal rate) and
gives insulin boluses along with meals (meal bolus) and in the presence of
hyperglycemia (correction bolus). Rapid acting insulin analogs are used in
CSII due to their rapid onset and short duration of action.
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Continuos subcutaneous insulin infusion. Rapid acting insulin is continuously

infused with intermittent meal boluses using an insulin pump. Initially basal
insulin (40-50% of insulin dose) is distributed evenly over 24 hours. Insulin
boluses are given before each meal according to premeal blood glucose and
carbohydrate content of the meal.
PATIENT SELECTION
Insulin pumps are indicated in children with inadequate glycemic control
despite multiple daily injections. They are particularly helpful under following
circumstances:
1. Infants and toddlers with erratic eating habits
2. Recurrent unpredictable hypoglycemia
3. Active life style with inconsistent meal times and
4. Excessive glycemic excursions
Careful patient selection is mandatory for successful CSII therapy. Parents

should be counseled that insulin pumps are not quick fix solutions for diabetes
and the commitment required is much greater for pumps than that for
intermittent injections. Thus a family finding it difficult to manage with split-mix
regimen is extremely unlikely to succeed with insulin pumps. Another major
limitation of pump therapy is the cost (approximately Rs 1.5 lakhs at initiation
and Rs 5,000 per month).
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Pre-requisites for initiating insulin pump treatment
Before starting insulin pump therapy, it is important to ensure the following

basics:
1. Motivation on the part of the child and family

2. Willingness to perform a minimum of four blood glucose tests
3. Knowledge of carbohydrate counting and glycemic index
4. An understanding of sick day and hyperglycemia management
5. Availability of a center with expertise
INITIATION OF PUMP THERAPY
Initiation of insulin pump therapy requires intense education of the child and
family spread over multiple sessions. Close review of blood glucose logs by
health professionals during the first couple of weeks is highly recommended.
Patient education
A comprehensive review of patient and family’s knowledge about diabetes
should be undertaken. Following issues specific for insulin pumps need to be
stressed.
• Different modes, setting of basal rates, retrieval of data
• Technique of catheter insertion
• Carbohydrate counting
• Calculation factors
• Management during sick day and exercise
• Management of hyperglycemia.
INITIATION OF INSULIN TREATMENT
The total daily dose of insulin should be reduced by 20% while starting on
insulin pump because the requirement is low. The calculation of basal dose,
insulin to carbohydrate ratio and correction factor is based on the total daily
dose as highlighted below.
Basal dose – Total daily basal dose should be 40-50% of the total daily dose
(TDD). This should initially be evenly distributed throughout the day. This is
then modified according to premeal blood glucose levels in quantum of 10%.
Subsequently different basal rates may be required for different periods of the
day.
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Lower basal rates are usually required in the late evening/midnight (between 8
PM and 2 AM) and during the day (between 10 AM and 4 PM). Higher basal
rates are often needed in the early evening (from 4 PM to 8 PM) and morning
hours (from 2 AM to 10 AM). Many prepubertal children need a higher basal
rate late in the evening (9 PM to 12 midnight).
Bolus dose – The dose of meal bolus is determined by the estimated

carbohydrate content of the meal and pre-meal blood glucose level. The meal
bolus can be given as a linear dose (all insulin released immediately), square
wave (insulin released over a time period of 30-60 minutes) or a combination
of both. Square wave bolus is recommended in children with high fat intake
while linear dose is indicated if the glycemic index of the meal is high.
Insulin to carbohydrate ratio represents the amount of carbohydrate (in

grams) covered by 1 unit of insulin. This is estimated by dividing 500 by the
total daily dose of insulin. Higher insulin to carbohydrate ratio is recommended
for young children while lower levels may be required for adolescents.
Insulin to carbohydrate ratio = 500 ÷ Total daily dose of insulin g/unit
Correction bolus is determined based on insulin sensitivity (correction

factor). This provides information about the amount of blood glucose (in mg/
dL) lowered by 1 unit of insulin.
Correction factor = 1800 ÷ Total daily dose of insulin mg/dL/unit
The dose of meal bolus is calculated as below.
Meal bolus = Anticipated carbohydrate intake (g) + Blood glucose -180

Insulin to carbohydrate ratio Correction factor
Correction factor can also be used to estimate a negative correction in the

presence of hypoglycemia (in a patient on 50 units of insulin a day, giving 1
unit less at meal times should allow the blood glucose to rise by 36 mg/dL).
Correction bolus should also consider the amount of residual insulin which
represents the amount of remaining insulin of the bolus. This is determined by
the assumption that 30% of insulin bolus is used up every hour. In most
pumps these formula are loaded by the health care professional. The patient
only needs to feed the carbohydrate count and blood glucose levels and the
calculation is performed by the insulin pump.
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FOLLOW-UP
Follow-up of children on insulin pump treatment should include close

monitoring of insulin pump site and skin for any evidence of infection. Blood
glucose records should be reviewed and the dose of insulin adjusted. Total
daily dose, basal dose, bolus dose and number and amount of correctional
boluses should be reviewed. While changing the total daily dose the correction
factors and insulin to carbohydrate ratio should be appropriately adjusted.
Patients should be informed about the need for careful monitoring and dose
adjustments, on a regular basis.
DOSE MODIFICATIONS
Glucose monitoring should be done at least four times a day (pre-meals and
bed time). More frequent monitoring may be required in children with poor
control. The basal rate is adjusted according to pre meal blood glucose levels.
Post meal blood glucose provides information about the appropriateness of
meal bolus. Insulin to carbohydrate ratio should be reduced in children with
persistent post-meal hyperglycemia.
HYPERGLYCEMIA MANAGEMENT
Careful management of hyperglycemia is mandatory to prevent the

development of DKA in children on insulin pumps. This is important as insulin
pumps deliver rapid acting insulin only with no cover of basal insulin. Thus
even small interruptions in insulin pump infusion can lead to the development
of DKA. All children on insulin pump should therefore stock syringe-vial/pens
of short/rapid acting insulin. Correctional insulin boluses are required if blood
sugar is more than 180 mg/dL. Ketones (urine or blood) should be checked in
children with blood glucose more than 270 mg/dL. The pump should not be
used to correct hyperglycemia when ketones are present and insulin should
be given via pen or syringe. In the absence of ketones single correctional
bolus could be given by the pump as illustrated below.
Dose = Blood glucose mg/dL – 180 – Residual insulin

Correction factor
Individuals with persistent hyperglycemia 1 hour after the bolus should receive
short or rapid acting insulin using a pen or syringe (0.25 unit/kg). The dose of
rapid acting analog should be repeated every 4 hours (6 hours for short acting
insulin) till the pump failure has been corrected. The pump should be carefully
examined for battery status, the amount of insulin in the reservoir and site and
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patency of the catheter. Catheter should be removed and new tubing should
be inserted if these measures are unsuccessful.
ADVANTAGES
Insulin pumps are associated with better glycemic control, lower insulin dose
resulting in reduced hypoglycemia and weight gain and greater flexibility in life
style. A meta-analysis of 12 randomized controlled trials, mainly in adults but
with some adolescents, reported that pump patients had lower mean HbA1c
by 0.51% and lower insulin requirements by 14% compared to patients on
optimized insulin injections. Overall, hypoglycemia is much less frequent with
pumps than in intensive injection regimens. Observational studies have
reported significant improvements in HbA1c, reduction in hypoglycemia and
higher patient satisfaction. The capability of insulin pump to react to real time
changes in blood glucose (closed loop system) is expected to provide
significant advancement in the insulin treatment.
DISADVANTAGES
High cost is an important limitation in the use of insulin pump. The

approximate cost of insulin pump is Rs 1.5 lakh at initiation with approximately
Rs 5000 monthly expenses on consumables and insulin. There is also a need
for close monitoring of blood glucose to avoid hypoglycemia and
hyperglycemia. The risk of development of DKA with pump dysfunction and
compromise in insulin delivery should also be considered.
ILLUSTRATIVE CALCULATIONS
Insulin plan for a child on split-mix regimen on 50 units insulin per day
· Initial calculations
! Total daily dose on subcutaneous insulin = 50 units
! Total daily dose on insulin pump (reduce dose by 20%)= 50 –
10 = 40 units
! Total daily basal dose (50% of daily dose) = 20 units
! Initial hourly basal insulin rate = 20 ÷ 24 = 0.8 unit/hour
! Insulin to carbohydrate ratio = 500 ÷ 40 = 12.5 g/unit
! Correction factor = 1800 ÷ 40 = 45 mg/dL/unit
· Meal bolus
! Parameters
! Pre-meal blood glucose = 270 mg/dL
! Anticipated carbohydrate intake = 75 g
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! Calculation
Insulin required to correct BG = (270 – 180) ÷ 36 = 2.5 units
Insulin required for carbohydrate intake = 75 ÷ 12.5 = 6 units
Bolus = Correction factor + Correction = 6 + 2.5 = 8.5 units
· Correction bolus
! Parameters
Blood glucose two hour post-meal = 305 mg/dL
Pre-meal insulin 5 units
! Calculation
Residual insulin – 30% used per hour (2 units left at two hours)
Correction dose = (305 – 180) ÷ 42 = 3 units
Correction required = (3 – 2) = 1 unit
FUTURE OF T1DM
Living with T1DM is not the same as a decade ago and would not be the same
a decade later. The changes in the management of the condition are
happening at a brisk pace and it is important for physicians caring for T1DM to
keep abreast with them. Some of these advances are highlighted below.
Hope for prevention- The efforts for prevention of T1DM have completed a
full circle. Large studies have failed to show benefit of oral and subcutaneous
insulin, nicotinamide and immunosuppressive agents in preventing the
development of T1DM. The outcome of ongoing research using inhaled
insulin, vitamin D analogs, delayed cow milk exposure and newer
immunosuppressant is also far from encouraging.
Hope for monitoring- Severe hypoglycemia remains a major hindrance in

achieving good glycemic control. Continuous glucose monitoring with real time
sensors have added a new dimension to T1DM management. These systems
with in-built alarms provide the opportunity to achieve near normal blood
glucose levels while avoiding hypoglycemia. While their use is currently limited
by high cost, they are expected to play an important role in future. Prediction
of long term complications using advanced glycation products is expected to
provide opportunity to prevent and treat them at an early stage.
Hope for treatment- The aim of T1DM management is to provide near

physiological insulin replacement using minimally invasive measures. Insulin
analogs and continuous subcutaneous infusion of insulin have gone a long
way in achieving this goal. The need for parental administration however
represents a formidable barrier. Inhaled insulin, considered a big breakthrough
in T1DM management, was withdrawn due to market considerations. Phase III
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trials of oral insulin IN-105 are ongoing and if successful would be a welcome
development for children with T1DM. Ultra long acting insulin analogs injected
once a week are in the pipeline and would further reduce the burden of T1DM.
Finally the development of sensor augmented pump therapy is expected to
achieve the long sought goal of developing artificial pancreas.
Hope for cure- Given the need for lifelong treatment in T1DM, it is only
expected that most patients seek permanent cure from the malady.
Unfortunately no such cure is available at the moment. The efforts at
developing cure for T1DM are directed towards reversing the autoimmune
process or restoration of β cell mass. Immunosuppressive agents (steroids,
cyclosporine A, azathioprine, anti-thymocyte globulin and anti-CD3 antibody)
have resulted in only partial and transient response. Moreover these strategies
are limited by significant adverse effects. Recently autologous stem cell
transplant after high dose immunosuppression has been utilized to reset the
immune process with some success in young adults with T1DM. These
strategies are limited by the fact that over 95% of β cell mass is destroyed by
the time of diagnosis of the disease.
The other, more appealing approach for cure for T1DM involves restoration of
β cell mass using pancreatic, islet cell or stem cell transplantation. Pancreatic
transplant is a major endeavor requiring long term immunosuppression and
clearly out of question for adolescents with T1DM. Studies have failed to show
long term remission with islet cell transplantation T1DM. There is currently no
evidence of efficacy of stem cell therapy in the cure of T1DM. Thus while
parents should be counseled about the feasibility of cure of T1DM in the fore
seeable future, they should be cautioned about the tall claims of cure of the
disease by mushrooming stem cell centers.
T1DM is going through an exciting phase. The advances in management over

the last 80 years have enabled the transition of this fatal disease to easily
manageable condition with hope for long term cure. At the moment insulin
however represents the one and only treatment for the disease. The whole art
lies in how we hold hands together with children and families with type 1
diabetes to enable them to live a fruitful life with good control and without
hypoglycaemia.
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5.5 Hypoglycemia
32. Neonatal Hypoglycemia

Neonatal hypoglycemia
32.1 Criteria
CRITERIA
• Blood
• Blood glucose less
glucose less than
than2.82.8
mmol/L (50 mg/dL)
mmol/L (50 mg/dL)
• Practice
• Practice points
points
o oWhole
Wholeblood
blood glucose
glucose is 10-15%
is 10-15%lowerlower
than venous
thanglucose.
venous glucose.
o Arterial glucose 10-15% higher than venous
o Arterial glucose 10-15% higher than venous glucose glucose
o oGlucometer
Glucometer unreliable
unreliable in low BG range
in low (laboratory confirmation required)
BG range
o Glucose values erroneously high after skin exposure to isopropyl alcohol
ETIOLOGY
26.2 Etiology
Neonatal hypoglycemia
Decreased glucose production Increased glucose utilization
Decreased production Decreased substrate

Metabolic disorders Small for gestational
Organic academia
MSUD, tyrosinemia
Carbohydrate
disorders Insulin independent Insulin dependent
Galactosemia Cardiac failure
Glycogenolytic defect Septicemia
Gluconeogenic defect
Endocrinopathies
Transient Prolonged Persistent

Infant of diabetic Stress Hereditary
mother Birth asphyxia KATP mutation
Maternal treatment SGA GDH mutation
β agonist GCK mutation
Sulfonylurea Sporadic
High UAC insertion
SGA- Small for gestational age, GSD- Glycogen storage disease, UAC- Umbilical
artery catheter, BW- Beckwith Weidemann syndrome, GDH- Glutamate
dehydrogenase, GCK- Glucokinase
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Important causes (in order of importance)

Transient
• Small for gestational age (10% with weight less than 2.0 kg)
• Prematurity (20% with gestational age less than 34 weeks)
• Infant of diabetic mother (30% of all cases)
• Birth asphyxia
Persistent
• Hyperinsulinism
• Endocrine deficiency
• Galactosemia
Unlikely causes of neonatal hypoglycemia

• GSD, gluconeogenic defect (levels maintained due to frequent feeding)
• Fructose intolerance (no fructose exposure)
• GCK and GDH mutation (mild disorders compensated by frequent feeds)
• Ketotic hypoglycemia
Clinical
! Lethargy
! Hypotonia
! Seizures
! Jitteriness
! Hypothermia
! Cardiac failure, respiratory distress
! Recurrent apnea
Screening indications
• Small for gestational age (weight < 10th percentile for age)
• Large for gestational age (weight > 90th percentile for age)
• Prematurity (period of gestation less than 34 weeks)
• Infant of diabetic mother
• Birth asphyxia
• Rh incompatibility
• Cardiac disease
• Micropenis
• Protocol- 0, 2, 6, 12, 24 and 48 hours
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EVALUATION
History
• Birth weight
• Low- Small for gestational age
• LGA - Infant of diabetic mother, BW syndrome, hyperinsulinism
• Gestational age- Prematurity
• Onset
• Immediate postnatal period- Hyperinsulinism, hypopituitarism
• After initiation of feeds- Galactosemia, organic acidemia
• Around three weeks of life- Congenital adrenal hyperplasia
• Glucose requirement
• Supra physiological (>12 mg/kg/minute)- Hyperinsulinism
• Physiological (6-12 mg/kg/minute)- Substrate defect
• Perinatal history
• Pregnancy induced hypertension, diabetes mellitus
• Treatment with beta agonist, thiazide, Rh incompatibility
• Birth asphyxia, features of septicemia
• Interventions- Exchange transfusion, umbilical artery catheterization

• Family history of consanguinity, sibling death (metabolic disorders)
• Failure to thrive, polyuria (adrenal insufficiency)
• Neonatal cholestasis (galactosemia, hypopituitarism)
Examination
Pointer Diagnosis
Micropenis Hypopituitarism, DAX1 mutation
Hyperpigmentation CAH, DAX1 mutation
Midline defect, blindness Hypopituitarism
Hepatomegaly Hyperinsulinism, BW syndrome, GSD
Cataract, jaundice Galactosemia
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Investigation
Indications
• Supra-physiological glucose requirement (GIR >12 mg/kg/minute)
• Persistent hypoglycemia (seventh postnatal day)
• No underlying cause
Critical samples during hypoglycemia

Processing Blood Urine
Immediate pH, lactate, ketone Ketone, RS
If required Insulin, C peptide, GH, Organic & amino acids
cortisol, organic acids
Screening investigations
• Ketone- Blood or urine
• Ketosis physiological response to hypoglycemia
• Lack of ketosis during hypoglycemia suggests
• Disorders of fatty acid oxidation
• Inhibition of ketogenesis (hyperinsulinism)
• Impaired ketogenesis (galactosemia)
• Interpretation
• Elevated- Ketotic hypoglycemia
• Hypopituitarism
• Glycogen storage disease
• Absent, low- Hypoketotic hypoglycemia
• Hyperinsulinism
• Galactosemia
• FAO oxidation defect (mild in SCHAD defect)
• Blood gas
• Acidosis- Organic acidemia, adrenal insufficiency
• Normal- Hyperinsulinism
• Urine reducing substances- Hypoketotic hypoglycemia

• Role- Identification of galactosemia, fructose intolerance
• Serum lactate- Ketotic hypoglycemia

• Elevated- GSD I, organic acidemia
• Normal- Hypopituitarism, adrenal insufficiency
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Confirmatory investigations
• Serum insulin
• Indication- Hypoketotic hypoglycemia, negative urine RS
• Considerations
• Should be obtained in the presence of hypoglycemia
• Sample should be refrigerated immediately
• Insulin should be undetectable during hypoglycemia
• Hyperinsulinism- insulin detectable during hypoglycemia
• GALT assay
• Indication- Hypoketotic with positive urine RS
• Interpretation- Low levels in galactosemia
• Growth hormone and cortisol

• Indications- Ketotic hypoglycemia
• Interpretation- Endocrine deficiency if during hypoglycemia
• Growth hormone less than 10 ng/ml
• Serum cortisol less than 330 nmol/L (10 µg/dL)
• Organic acids- Ketotic hypoglycemia with lactate acidosis
Characterization of underlying diagnosis

• Adrenal insufficiency- Adrenal imaging, 17 OHP, steroid metabolites
• Hypopituitarism- Genetic studies, neuroimaging
• Hyperinsulinism
• Criteria- When blood glucose < 2.8 mmol/L, 50 mg/dL
• Detectable insulin (more than 2 µU/ml)
• Blood β hydroxybutyrate less than 2 mmol/L
• Increase in blood glucose be more than 30 mg/dL (1.7 mmol/L) 30
minutes after glucagon injection (30 µg/kg)
• Evaluation
• Onset
• Early- Infant of diabetic mother, KATP defect
• Late- GDH, GCK mutation
• Severity
• Mild- GDH, GCK mutation and focal form
• Severe- KATP channel defect and diffuse form
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• Macrosomia
• Present- IDM, BWS, KATP defect, diffuse form
• Absent- Prolonged form, GDH or GCK mutation
• Features of Beckwith weidemann syndrome
Comparison of prolonged and persistent hyperinsulinism

Feature Persistent hyperinsulinism Prolonged
Macrosomia` Common Usually absent
Perinatal stress Uncommon Common
Severity Severe Mild to moderate
Birth weight Large for gestational age Usually SGA
Diazoxide response Poor (< 40%) Good (>90%)
Resolution Rare All by 6 months
APPROACH
Hypoglycemia work-up should be restricted to neonates with severe (glucose
requirement greater than 12 mg/kg/minute), persistent (beyond one week) or
unusual (in the absence of identifiable cause or risk factors) hypoglycemia.
Critical samples should be obtained during the episode of hypoglycemia. The
processing of these samples is guided by blood lactate, urine ketones and
reducing substances. Assessment of ketone production is the first step of
evaluation of neonatal hypoglycemia. All neonates with hypoglycemia are
expected to produce ketone bodies unless ketogenesis is defective (fatty acid
oxidation defect) or suppressed (hyperinsulinism or galactosemia). Urine
reducing substances should be measured in neonates with hypoketotic
hypoglycemia to identify galactosemia. Hypoketotic hypoglycemia without
urinary reducing substances is a pointer to hyperinsulinism and should be
confirmed by serum insulin levels. Normal insulin levels in this setting indicate
the diagnosis of fatty acid oxidation defect. Neonates with ketotic
hypoglycemia should be evaluated for endocrine deficiencies (growth
hormone and cortisol) and organic acidemia. GSD is a rare cause of ketotic
hypoglycemia in the neonatal period and should be considered after exclusion
of other causes. Initial evaluation of a neonate with hyperinsulinism should be
directed towards identifying transient (infant of diabetic mother, maternal beta
agonist treatment, high umbilical artery catheterization) and prolonged causes
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Severity Severe Mild to moderate
Birth weight Large for gestational age Usually small for gestational age
Diazoxide response Poor (< 40%) Good (>90%)
Resolution Rare All by 6 months
Table 32.3- Comparison of genetic forms of hyperinsulinism
Features KATP defect GDH defect GCK defect
ofOnset
hyperinsulinism (birthEarly
asphyxia, small for gestational age,Late
Late BW syndrome).
Elevated serum ammonia levels are suggestive of activating GDH mutation
Severity
high Severeto diazoxide.Mild-
likelihood of response moderate
Genetic Mild-not
studies are moderate
routinely
indicated
Macrosomiain the evaluation of infantile hyperinsulinism.
Common Rare Neonates
Rare with normal
serum ammoniadelay
Developmental levelsCommon
should be startedUncommon
on diazoxide. Poor response to
Uncommon
diazoxide should prompt localization studies (preferably F18 DOPA PET) to
Diazoxide
identify response
focal Poor
form. Diazoxide responsive Good
children should beGood
given a trial of
weaning of the drug atNormal
Serum ammonia the age of six months. Persistent hypoglycemia
Elevated* Normal after
discontinuation of diazoxide indicates the need for localization studies.
*- Serum ammonia elevated around 2-3 times upper normal limit; no clinical effects
Persistent neonatal hypoglycemia

Critical samples (please refer 32.33)
Ketone (blood or urine)
Negative
Positive
Reducing substances
Serum lactate
Elevated Normal Positive Negative

Organic acids GH, cortisol Galactosemia Serum insulin
Elevated Normal Normal High

Organic acidemia GSD FAO defect Hyperinsulinism
32.41 Approach to persistent neonatal hypoglycemia

MANAGEMENT
Hypoglycemia work-up should be restricted to neonates with severe (glucose
Non specific
• Acuterequirement greater According
management- than 12 mg/kg/minute), persistent (beyond one week) or
to clinical features
• Asymptomatic- Dextrose at the rate of 6 mg/kg/minute
unusual (in the absence of identifiable cause or risk factors) hypoglycemia.
Critical samples should be obtained during the episode of hypoglycemia
• Symptomatic without seizure
(32.3). The processing of these samples is guided by blood lactate, urine
• Dextrose bolus (200 mg/kg; 2 ml/kg of 10% dextrose)
• Dextrose infusion at the rate 6 mg/kg/minute
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• Symptomatic with seizures

• Dextrose 500 mg/kg (5 ml/kg of 10% dextrose)
• Followed by dextrose infusion at GIR of 6 mg/kg/minute
• Stabilization
• Dextrose- Glucose infusion rate (GIR)- 6 mg/kg/minute
Dextrose concentration (%) = GIR × fluid volume(ml/kg/day)

144
GIR- 10% dextrose; rate of 150 ml/kg/day = 9.6 mg/kg/min
• Monitoring
• Blood glucose 30 minutes after infusion and hourly
• Target blood glucose- Above 60 mg/dL (3.3 mmol/L)
• Adjustments in glucose infusion rate

• Blood glucose less than 60 mg/dL
• Increase GIR by 2 mg/kg/minute
• Measure blood glucose after 30 minutes
• Increase GIR by 2 mg/kg/min to achieve target BG
• Central venous catheterization if dextrose > 12.5%
• Evaluation if GIR more than 12 mg/kg/minute
• Blood glucose greater than 60 mg/dL

• Continue same infusion rate for 24 hours
• Decrease GIR by 2 mg/kg/min hourly after 24 hours
• Allow orally after GIR less than 4 mg/kg/minute
• Discontinue infusion if glucose level > 60 mg/dL
• Medical treatment- GIR > 12 mg/kg/minute, uspected hyperinsulinism

• Options
• Glucagon- Counter regulatory hormone, 30 µg/kg intramuscular
• Hydrocortisone- 5 mg/kg/day in 2 divided doses intravenously
Approach to treatment of neonatal hypoglycemia

Adequacy of airway, breathing and circulation should be assessed in a
neonate with hypoglycemia. Initial management is guided by clinical features.
Neonates with asymptomatic hypoglycemia should be started on dextrose
infusion to achieve glucose infusion rate of 6 mg/kg/minute. Symptomatic
neonates should receive intravenous dextrose bolus (500 mg/kg in the
presence of seizures and 200 mg/kg without seizures) followed by dextrose
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infusion at a rate of 6 mg/kg/minute. Blood glucose should be measured thirty

minutes after initiation of dextrose infusion, hourly thereafter and thirty minutes
after modification of glucose infusion rate. Dextrose infusion should be
continued till 24 hour after stabilization of blood glucose levels (60 mg/dL, 3.3
mmol/L). Glucose infusion rates should be decreased by 2 mg/kg/minute
every hour. Oral feedings should be added once glucose infusion rate has
been reduced to 4 mg/kg/minute. Dextrose infusion should be discontinued
after feeding is established. In neonates with persistent hypoglycemia glucose,
infusion rate should be increased in increments of 2 mg/kg/minute to achieve
target blood glucose (60 mg/dL, 3.3 mmol/L). Dextrose concentrations greater
than 12.5% should be administered through central line. Neonates with
persistent hypoglycemia and/or high glucose requirement should be evaluated
for etiology of hypoglycemia and need for medical treatment (glucagon or
hydrocortisone).
Neonate with hypoglycemia

Assess clinical features
Symptomatic Asymptomatic
Dextrose bolus* Glucose infusion 6 mg/kg/min

Repeat BG after 30 minutes
Blood glucose > 60 mg/dL Blood glucose < 60 mg/dL

Continue infusion for 24 hours Increase GIR by 2 mg/kg/min

Decrease GIR by 2 mg/kg/min/hour Increase GIR up to 12 mg/kg/min

Allow orally once GIR < 4 mg/kg/min Hypoglycemia work-up
Decrease GIR to 2 mg/kg/min and stop
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Specific
Hyperinsulinism
• Medical treatment
• Diazoxide- Potassium channel opener
• Initial dose- 15 mg/kg/day in three divided doses then 5-20 mg/kg/
day in three divided doses
• Combination with hydrochlorothiazide (4-8 mg/kg/day) due to
synergistic effect on potassium channel and reduced fluid retention
• Adverse effects- Fluid overload, cardiac failure, hypertrichosis
• Efficacy- Dependent on clinical form; overall 20-50%
• KATP channel defect- Very poor (less than 10%)
• Diffuse form- Less than 40%
• Focal form, GDH, GCK defect- More than 70%
• Prolonged hyperinsulinism- 80-100%
• Glucagon- Counter-regulatory hormone

• Role- Temporary stabilization of glucose levels
• Indication- Hyperinsulinism refractory to diazoxide
• Dose- 1 µg/kg/hour subcutaneous infusion
• Adverse effects- Vomiting, tachyphylaxsis
• Octreotide- Somatostatin analog (inhibitor of insulin release)

• Hyperinsulinism unresponsive to diazoxide
• Contraindications to hyperinsulinism
• Dose- 5-40 µg/kg/day subcutaneously in two divided doses
• Adverse effects- Tachyphylaxsis, NEC, steatorhea
• Nifedipine- Calcium channel blocker

• Contraindications to diazoxide (fluid overload)
• Recurrence following surgery with no response to diazoxide
• Dose- 0.5-2.0 mg/kg/day in two divided doses
Medical treatment for hyperinsulinism

Drug Mechanism of action Dose Adverse effect
Diazoxide Potassium channel opener 5-20 mg/kg/day Fluid overload
Hypertrichosis
Glucagon Counter-regulatory hormone 1 µg/kg/hour Tachyphylaxis
Octreotide Inhibition of insulin release 5-40 µg/kg/day NEC
Tachyphylaxis
Nifedipine Calcium channel blocker 0.5-2.0 mg/kg/d Hypotension
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• Surgical treatment
• Indications- Focal lesion, KATP channel mutation, lack of response to
diazoxide
• Procedure
• Focal form- Focal resection
• Diffuse form
• Initial procedure- Subtotal pancreatectomy (95%)
• Recurrence- Total pancreatectomy (99%)
• Response
• Focal resection- Good response
• Diffuse form- Recurrence in 30-50% cases
• Galactosemia- Galactose free diet
• Hypopituitarism- Growth hormone and cortisol supplementation
• Prolonged hyperinsulinism
• Diazoxide (5-15 mg/kg/day) till six months
• Discontinue diazoxide with monitoring of blood glucose
• No hypoglycemia- Monitor blood glucose off diazoxide
• Hypoglycemia- Continue diazoxide
Post neonatal Hypoglycemia
CRITERIA- Plasma glucose less than 2.8 mmol/L (50 mg/dL)
• Seizures
• Encephalopathy
• Episodic ataxia
ETIOLOGY
Important causes
Age group Etiology in order of prevalence
Late infancy Hyperinsulinism, GSD, hypopituitarism
Early childhood Adrenal insufficiency, FAO defect, GSD
Late childhood Adrenal insufficiency, FAO defect, insulinoma
Adolescence Insulinoma, adrenal insufficiency
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33.1 Criteria
•Plasma glucose less than 2.8 mmol/L (50 mg/dL)
•Practical points
! Venous glucose 10% lower than arterial glucose
! Whole blood glucose 15% lower than plasma glucose
! Glucometer unreliable at low levels of blood glucose
33.2 Etiology
Post neonatal hypoglycemia
Decreased glucose production

Increased glucose utilization
Decreased production Decreased substrate

Hormone deficiency Malnutrition
Hypopituitarism Accelerated starvation
GH insensitivity
Adrenal insufficiency
Glycogenolytic defect
Glucose 6 Phosphatase
Debranching enzyme
Insulin independent Hyperinsulinism
Phosphorylase
Fatty acid oxidation Endogenous
defect Genetic- GCK, GDH
Gluconeogenic defect
Reye syndrome Sporadic- Focal form
PEPCK, FDPase
IGF 2 excess Insulinoma
Galactosemia
Hepatoblastoma Dumping syndrome
Fructose intolerance
Wilms tumor Exogenous
IGF 2- Insulin like growth factor II, GCK- Glucokinase, GDH- Glutamate
EVALUATION
dehydrogenase, PEPCK- Pyruvate pyrophosphate carboxykinase, FDPase- Fructose 1,
History
• 6Gap
Diphosphatase
between meal and hypoglycemia
• Less than 2 hours- Galactosemia, HFI, dumping syndrome
• 2-4 hours- Hyperinsulinism
• 4-6 hours- GSD I
• 6-10 hours- GSD, gluconeogenic defect
• Prolonged fasting- FAO defect, accelerated starvation
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• Course
• Acute transient- Reye, toxin, insulin, oral hypoglycemic agents
• Acute, persistent- Hyperinsulinism
• Chronic- GSD, gluconeogenic defect, fructose intolerance
• Recurrent- Accelerated starvation, FAO defect
• Glucose requirement
• Supra physiological (> 12 mg/kg/min)- Hyperinsulinism
• Physiological (6-12 mg/kg/minute)- Substrate defect
• Polyuria, salt craving, pigmentation (adrenal insufficiency)

• Growth retardation (GSD, fructose intolerance, hypopituitarism)
• Recurrent episodes of unconsciousness (FAO defect)
• Neonatal cholestasis (galactosemia, fructose intolerance)
• Floppiness (GSD, FAO defect)
• Suspected drug, toxin intake
• Family history of consanguinity, sibling deaths (metabolic disease)
• Aversion to sweets (fructose intolerance)
• Intestinal surgery, pyloric stenosis (dumping syndrome)
Examination
• Hepatomegaly- GSD, FI, FAO defect, gluconeogenic defect
• Cataract- Galactosemia, fructose intolerance
• Hypotonia- GSD, FAO defects
• Pigmentation- Adrenal insufficiency
• Abdominal lump- Hepatoblastoma, wilms tumor
• Renomegaly- GSD I
• Eruptive xanthoma- GSD I, gluconeogenic defect
• Jaundice- Liver disease, fatty acid oxidation defect
Features of common causes of post neonatal hypoglycemia

Diagnosis Features
GSD Organomegaly, hypotonia, doll like facies
Adrenal insufficiency Hyperpigmentation, salt craving
Fructose intolerance Diarrhea, cataract, failure to thrive
FAO defect Myopathy, cardiomyopathy, encephalopathy
Ketotic hypoglycemia Early morning hypoglycemia, growth failure
Hypopituitarism Micropenis, midline defects, blindness
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Investigations
• Critical samples
• In the presence of hypoglycemia- Prior to dextrose bolus
• In the absence of hypoglycemia
• Diagnostic fast- Start overnight duration dependent on age
• Less than 6 months- 12 hours
• 6-12 months- 18 hours
• More than 1 years- 24 hours
• Glucose monitoring- Initially two hourly than hourly
• Critical samples when blood glucose < 2.8 mmol/L
• Screening investigations
• Ketone- Blood β hydroxybutyrate or urine ketosticks
• Ketotic (Urine negative or one + blood > 0.6 mmol/L)
• Accelerated starvation (diagnosis of exclusion)
• Gluconeogenic defects
• Hypoketotic (urine two + or more, blood < 0.6 mmol/L)

• Hyperinsulinism
• Fatty acid oxidation defects
• Fructose intolerance
• Urine reducing substances- In hypoketotic hypoglycemia

• Positive- Galactosemia, fructose intolerance
• Negative- FAO defect, hyperinsulinism
• Blood lactate- In ketotic hypoglycemia

• Elevated- GSD I, gluconeogenic defect
• Normal-Adrenal insufficiency, ketotic hypoglycemia
• Serum ammonia- In hypoketotic hypoglycemia high ammonia suggests

• Activating GDH mutation
• Reye syndrome
• Fatty acid oxidation defect
• Confirmatory investigations
• Serum insulin
• Indication- Negative urinary ketones and RS
• Any detectable insulin is significant
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• GALT assay
• Indication- Hypoketotic hypoglycemia with urine reducing substance
• Low levels diagnostic of galactosemia
• Growth hormone and cortisol- With ketotsis and normal lactate

• Growth hormone less than 10 ng/ml
• Serum cortisol less than 330 nmol/L (10 µg/dL)
• Urinary organic acid- With hypoketotic hypoglycemia and normal insulin

• Elevated organic acids- Organic acidemia
• Elevated dicarboxylic acids- FAO defects
• False positive- Ketosis, medium chain triglyceride intake
• False negative- Carnitine, CPT deficiency
• Characterization of underlying diagnosis

• Adrenal insufficiency- CT scan, ACTH levels, VLCFA (ALD)
• Hyperinsulinism
• Serum ammonia (elevated in activating GDH mutation)
• Imaging- High resolution ultrasound, MRI, F18 DOPA PET
• Glycogen storage disease- Liver biopsy and enzyme assay
• Fatty acid oxidation defects- Serum Carnitine
Laboratory features of post-neonatal hypoglycemia

Disorder Ketone Lactate RS VBG Gluc response
GSD I Positive Elevated Negative Acidosis Absent

GNG defect Positive Elevated Negative Acidosis Present
GSD III, VI Positive Normal Negative Normal Absent during fast
Adrenal failure Positive Normal Negative Normal Present
Ketotic Positive Normal Negative Normal Present
Galactosemia Negative Normal Positive Normal Present
HFI Negative Normal Positive Normal Present
FAO defect Negative Normal Negative Acidosis Present
Hyperinsulinism Negative Normal Negative Normal Exaggerated
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APPROACH
Collection of critical blood and urine samples before correction of
hypoglycemia is vital. The processing of the samples is decided according to
the results of blood lactate and urinary ketone and reducing substances.
Ketosis is a physiological response to hypoglycemia; hypoketotic
hypoglycemia suggests disorders associated with impaired ketogenesis (fatty
acid oxidation defects, hyperinsulinism, galactosemia and fructose
intolerance). Urine reducing substances should be measured in these children
to identify galactosemia and fructose intolerance. Insulin levels should be
measured in children with hypoketotic hypoglycemia with no urinary reducing
substances. Normal insulin level in this setting is suggestive of fatty acid
oxidation defects which should be confirmed by estimation of urinary organic
acids. Lactic acidosis in children with ketotic hypoglycemia suggests GSD I or
gluconeogenic defects. Diagnostic considerations in children with ketotic
hypoglycemia without lactic acidosis include milder GSD variants (GSD III and
VI), endocrine deficiencies (hypopituitarism and adrenal insufficiency) and
accelerated starvation. Accelerated starvation is a diagnosis of exclusion and
should be considered only after work-up for other causes are non-contributory.
Blood or urine ketone
Elevated Low, absent

Serum lactate Reducing substances
Elevated Normal Positive Negative

Organomegalyy Galactosemia Serum insulin
Glucagon response
Present- GNG defect
Absent- GSD I
High
Present Absent Normal
Hyperinsulinism
GSD III, VI GH, Cortisol FAO defect
Low Normal
Endocrine deficiency Accelerated starvation
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MANAGEMENT
• Hyperinsulinism
• Medical treatment
• Diazoxide- 10 mg/kg/day with hydrochlorothiazide (7-10 mg/kg/day)
• Glucagon- 1-10 µg/kg/hour as subcutaneous infusion
• Octreotide- 5-10 µg/kg 4-6 hourly
• Nifedipine- 0.7-2.5 mg/kg/day in two divided doses
• Surgical treatment- Focal resection in insulinoma
• Galactosemia- Galactose free diet
• Hypopituitarism- Growth hormone and cortisol supplementation

• Uncooked corn starch- 1-2 g/kg 4-6 hourly
• Continuous nasogastric dextrose- Overnight
• High protein diet (GSD III)
• Gluconeogenic defect- Frequent feeds, avoidance of fructose
• Accelerated starvation- Frequent feeding, avoidance of fasting, bedtime

snack
• Fructose intolerance- Avoidance of fructose containing food
• Fatty acid oxidation defects

• Avoidance of fasting (risk of cardiac arrhythmia)
• Increase glucose intake during inter-current illnesses
• Carnitine deficiency- Carnitine (100 mg/kg/day in 3 doses)
• LCHAD deficiency- Medium chain triglycerides
• MAD deficiency- Riboflavin (100-200 mg/day once daily)
Further reading
1. In: Pediatric Endocrinology Eds: Sperling MA. WB Saunders 2002,
Philadelphia, 2nd Edn Pp 97-110.
2. Wolsdorf JI, Weinstein DA. Hypoglycemia in children. In: Pediatric
Endocrinology, Eds: Lifshitz F, Marcel Dekker, 2003, New York, 4th edition
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Section VI- Thyroid

6.1 Congenital Hypothyroidism
Thyroid hormones play a crucial role in the regulation of growth, development

and metabolism of an infant. Given the narrow window of opportunity timely
diagnosis and management is essential. This is particularly true for congenital
hypothyroidism where neonatal screening is the norm across the industrialized
world. Unfortunately this is not the case everywhere in India where majority of
children with congenital hypothyroidism are still diagnosed late with intellectual
sequel.
Intrauterine Thyroid Physiology and Post natal Adaptation
Thyroid gland is derived from a median analge derived from pharyngeal floor
and paired lateral analges developed from fourth pharyngobronchial pouch.
Following fusion of the median and lateral analges the thyroid gland migrates
caudally to attain its position behind the thyroid cartilage in the neck.
Remnants of thyroid tissue in this tract of descent may persist as thyroglossal
cyst. Incomplete migration of thyroid gland results in ectopic thyroid, a
common cause of congenital hypothyroidism.
Independent thyroid hormonogenesis by the fetus is established by 18-20

weeks of gestation. The hypothalamic-pituitary-thyroid axis however does not
fully mature till late third trimester. Placenta forms a substantial barrier for
passage of TSH and T3 and partial barrier for T4. It is however permeable to
TRH, TSH receptor stimulating and blocking antibody and thio urea anti
thyroid drugs (figure 1). Transplacentally passed T4 however plays an
important role in early pregnancy as untreated maternal hypothyroidism during
this period adversely effects intellectual development of the fetus. Similarly
maternally transferred T4 is responsible for detectable thyroid hormone levels
in athyroid newborns. Trasnplacental passage of TSH receptor blocking, TSH
receptor stimulating antibodies and anti-thyroid drugs result in constellations of
findings of infants born to mother with graves disease ranging from transient
hypothyroidism to hyperthyroidism.
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Assessment of Thyroid Function

It is critical to interpret thyroid functions during infancy against age specific
norms. Importantly most laboratory results quote adult reference ranges
resulting in misinterpretation of thyroid functions. In particular the levels of
TSH and free T4 are higher during early infancy as highlighted in table 1.
During the first two weeks of life TSH levels < 20 mU/L are normal. Most
children with primary hypothyroidism have levels > 50 mU/L. Between two to
six weeks TSH levels up to 9.1 mU/L are normal.
Table 1- Norms for thyroid functions in infants

Age T3 T4 TSH FT4
Before 2 weeks 15-210 ng/dL 76-276 nmol/L < 20 mU/L 15-34 pmol/L
2-6 weeks 100-300 ng/dL 84-210 nmol/L 1.7-9.1 mU/L 10-20 pmol/L
After 6 weeks 70-180 ng/dL 60-160 nmol/L 0.5-5 mU/L 9-20 pmol/L
Hypothyroidism
Congenial hypothyroidism has profound impact on the outcome of the child

and is the most important treatable cause of mental retardation. The condition
is relatively common in India with an estimated prevalence of 1 in 2500 live
births as against 1 in 4000 in western countries. There is a trend of increasing
prevalence of congenital hypothyroidism in western countries. Early diagnosis
and treatment is mandatory to achieve good intellectual outcome in the
condition.
Etiology
Congenital hypothyroidism may be due to disorders of thyroid development
(dysgenesis), defective thyroid hormone synthesis (dyshormonogenesis),
hypothalamic-pituitary defect (central hypothyroidism) and trans placental
passage of TSH receptor blocking antibody (TBA) (Figure 2).
Thyroid Dysgenesis: The term thyroid dysgenesis encompasses anatomical

abnormalities ranging from absent thyroid to partial agenesis to abnormally
located thyroid gland (ectopic thyroid). Dysgenesis is the commonest cause of
congenital hypothyroidism accounting for around 80% of all cases. The
condition is usually sporadic. Less than 2% of infants with thyroid dysgenesis
have mutations in TTF1, TTF2 and PAX1 genes. The identification of the
condition implies life long treatment. No or ectopic uptake of radionuclide
scan, absent thyroid on ultrasound and low or undetectable thyroglobulin
levels is diagnostic of the condition.
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Dyshormonogenesis: Synthesis of thyroid hormones involves a series of

events. Abnormality in any of these could result in defective thyroid
hormonogenesis accounting for around 10-15% of all children with congenital
hypothyroidism. Defective organification is readily identified on thyroid uptake
scan by increased uptake followed by rapid discharge following administration
of perchlorate. These include defect in sodium iodine symporter, thyroid
peroxidase, TSH receptor and deiodinase enzyme. Deletion of TSH beta gene
and TSH resistance present with similar picture. Pendred syndrome, defect in
iodide-chloride transporter, is associated with thyroid dyshormonogenesis
along with congenital sensory neural deafness. Hearing assessment should
therefore be done in all children with congenital hypothyroidism. Unlike most
other causes of congenital hypothyroidism children with dyshormonogenesis
have goiter.
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Iodine deficiency: Iodine deficiency is an important cause of hypothyroidism

in endemic areas. The condition is characterized by reduced urinary iodine
excretion. Iodization of salt is highly effective in preventing the condition.
Central hypothyroidism: Central hypothyroidism usually occurs in the setting

of multiple pituitary hormone deficiency. Clues to diagnosis include midline
defects like cleft palate, holoprosencephaly, micropenis and ketotic
hypoglycemia. Isolated central hypothyroidism is exceedingly rare and the
diagnosis should only be considered after excluding non thyroidal illness. Low
or normal TSH levels in the setting of low free T4 levels are diagnostic. The
condition accounts for around 5% of all cases of congenital hypothyroidism
and is not picked on screening strategy based on TSH alone.
Transient hypothyroidism: In vast majority of cases the diagnosis of

congenital hypothyroidism mandates life long thyroid hormone replacement.
However 10% children with congenital hypothyroidism have transient
hypothyroidism. This is most often related to trans placental passage of TSH
receptor blocking antibody. The condition mimics thyroid agenesis in that
thyroid scan is associated with absent uptake. Presence of ectopic thyroid on
ultrasound and evidence of thyroid autoimmunity in mother indicates the
diagnosis. The condition is usually self limiting and resolves by 3-6 months.
Other causes of transient congenital hypothyroidism include maternal or fetal
iodine deficiency and excess and trans placental passage of anti-thyroid drugs
in mothers with graves disease.
Thyroid dysfunction in prematurity: Thyroid dysfunction in prematurity

represents a combination of prematurity of thyroid hormonogenesis on one
hand and effect of non thyroidal illness on the other. Transient primary
hypothyroidism is associated with low T4 levels and elevated TSH levels and
should be treated if it persists beyond two weeks of life. Transient
hypothyroxinemia of prematurity (THOP) on the other hand most likely
represents the effects of non thyroidal illness and does not require treatment.
Clinical Features
Features of congenital hypothyroidism are non specific resulting in delayed
diagnosis in the absence of neonatal screening. This mandates the need for
screening for the disorder. Pointers to the diagnosis of congenital
hypothyroidism include increased sleepiness, prolonged jaundice,
hypothermia, poor feeding, post-term gestation (period of gestation more than
42 weeks), constipation and cold intolerance. Examination usually reveals
wide anterior and posterior fontanel (greater than 1 cm), coarse skin and
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facies, widely separated skull sutures, protuberant abdomen, umbilical hernia

and macroglossia.
Neonatal screening
Neonatal screening for hypothyroidism has been one of the most gratifying
preventive interventions in pediatrics and has resulted in prevention of mental
retardation in a large number of children world wide.
Indications: Ideally all neonates should be screened for congenital

hypothyroidism. If this is not feasible due to any reason thyroid functions
should be assessed in neonates with history of maternal autoimmune thyroid
disease, hypothyroidism in siblings, prolonged jaundice and genetic
syndromes like Downs syndrome and Turner syndrome.
Strategies: Most screening programs use a primary TSH strategy at day 3 of

life to obviate the effects of TRH surge. Earlier screening has been done in
some centers due to early neonatal discharge. Higher TSH cutoffs should be
used in these situations. TSH strategy has the advantage of higher sensitivity
but is limited by the inability to detect central hypothyroidism. Some strategies
use primary T4 or T4 and TBG and back-up TSH to detect greater number of
cases with central hypothyroidism. Repeat TSH levels be recommended in
preterm infants and those with stormy neonatal period as TSH levels may be
suppressed due to non thyroidal illness masking the rise in TSH levels.
Interpretation: TSH levels above 40 mU/L are suggestive of hypothyroidism.

Levels between 20-40 mU/L should be reconfirmed and if persistently high
need treatment. Levels below 20 mU/L are normal. False positive results can
result from early sample or isolated hyperthyrotropinemia. False negative TSH
strategy occurs in 5% cases and results most commonly from human error.
Other potential causes of false negative results include central
hypothyroidism, mild dyshormonogenesis, dopamine treatment and rarely twin
to twin transfusion.
Evaluation
Comprehensive evaluation is mandatory for appropriate management; the
treatment should not be delayed if these facilities are not available.
Clinical: Detailed family history including congenital hypothyroidism, maternal

autoimmune thyroid disease and anti-thyroid treatment in mother should be
enquired. The presence of goiter excludes dysgenesis or maternal TBA related
transient hypothyroidism and points towards dyshormonogenesis or maternal
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ant thyroid treatment. Neonatal hypoglycemia, midline defects or micropenis

should raise the possibility of hypopituitarism.
Investigations: Step wise evaluation is mandatory to ascertain the diagnosis

of congenital hypothyroidism (Table 2, Figure 3).
Radionuclide scan: Radionuclide scan is the most important initial

investigation in a child with congenital hypothyroidism. Radionuclide scan
should be done prior to starting therapy with thyroid hormone. Increased
radionuclide uptake is suggestive of dyshormonogenesis or iodine deficiency
while lingual uptake confirms the diagnosis of ectopic thyroid. Increased tracer
intake with discharge after administration of perchlorate suggests
dyshormonogenesis. Absent radiotracer uptake is most likely due to thyroid
agenesis but could also occur in the setting of transplacentally passed TSH
receptor blocking antibody (TBA), TSH receptor defect and sodium-iodine
transporter (NIS) defect.
Ultrasound thyroid: Ultrasound of thyroid should be done in children with no

thyroid radiotracer uptake. Non visualized thyroid gland in this setting
suggests thyroid agenesis while the presence of ectopic thyroid should prompt
evaluation for maternal TBA related hypothyroidism.
Thyroglobulin: Thyroglobulin levels are helpful in establishing the diagnosis of

thyroglobulin deficiency and thyroid agenesis. Undetectable levels suggest
athyrosis or thyroglobulin deficiency while levels above 1000 pmol/L indicate
dyshormonogenesis.
TSH receptor blocking antibody (TBA): These antibodies should be measured

in children with suspected transient hypothyroidism and should be measured
in the setting of hypothyroidism, absent radionuclide uptake and ectopic
thyroid on ultrasound.
Table 2. Investigations in primary congenital hypothyroidism
Disorder Scan USG TG TBA Urine I

Dysgenesis Absent Absent Low Negative Normal
Dyshormonogenesis Increased Normal Variable* Negative Normal
Iodine deficiency Increased Normal Increased Negative Low
TBA related Absent Normal Normal Positive Normal
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Treatment
Immediate treatment of congenital hypothyroidism is mandatory to avoid
intellectual deterioration. Close monitoring of thyroid functions and
development is essential.
Medication: Tablets of levothyroxine are recommended due to instability of

liquid preparations. Recommended dose is 10-15 µg/kg/day with higher doses
for infants with athyrosis and lower dose with those with dyshormonogenesis,
hemi thyroid or central hypothyroidism. Aim should be to normalize free T4
levels by 1-2 weeks and TSH by 2-4 weeks. Delay of two weeks in achieving
these goals may result in compromise of up to 10 IQ points.
Follow-up: Regular assessment of thyroid functions is mandatory. Thyroid

functions should be assessed two weeks after initiation of treatment, monthly
for the next two months and bimonthly in the first year of life. Subsequently
thyroid levels should be measured every three months. Both free T4 and TSH
levels should be measured in the first two years of life after which TSH alone
may be followed. The aim is to maintain free T4 levels in the high normal
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range (13-20 pg/ml) and TSH in the normal range (below 5 mU/L; ideally
between 0.5-2.0 mU/L). TSH levels may be persistently high for up to two
years of age in some infants due to reset of the hypothalamic-pituitary axis.
Duration: Treatment for most children with congenital hypothyroidism is life

long. Short term treatment may be required for children with TBA related
hypothyroidism or maternal ant thyroid medications.
Outcome: Good intellectual outcome is expected if the treatment is started

within two weeks of life. Delayed treatment or evidence of fetal hypothyroidism
(epiphyseal dysgenesis) or maternal hypothyroidism are indicators of poor
outcome.
Special Conditions
Central hypothyroidism: Treatment of central hypothyroidism should be
initiated only after excluding and treating ACTH deficiency. This is important as
thyroid replacement may precipitate covert cortisol deficiency due to increased
metabolism resulting in disastrous consequences.
Premature infants: Routine thyroid replacement in premature infants is

controversial. Thyroid replacement should be considered in the presence of
low FT4 and elevated TSH levels corrected for gestation age.
Further Reading
1. American Academy of Pediatrics; Rose SR; Section on Endocrinology

and Committee on Genetics, American Thyroid Association; Brown RS;
Public Health Committee, Lawson Wilkins Pediatric Endocrine Society;
Foley T, Kaplowitz PB, Kaye CI, Sundararajan S, Varma SK: 2006.
Update of newborn screening and therapy for congenital
hypothyroidism. Pediatrics 117:2290–2303.
2. Balhara B, Misra M, Levitsky LL: 2011. Clinical monitoring guidelines
for congenital hypothyroidism: laboratory outcome data in the first year
of life. J Pediatr 158:532–537.
3. Brown RS, Huang S: 2005. The thyroid and its disorders. In Brook
CGD, Clayton PE, Brown RS eds. Clinical Pediatric Endocrinology.
London, Blackwell publishing, 5th Edition, 218-253.
4. Fisher DA, Grueters: 2008. Disorders of the thyroid in the newborn and
infant. In Sperling MA, eds. Pediatric Endocrinology. Philadelphia,
Saunders Elsevier 2008, 3rd Edn, 198-226.
5. LaFranchi SH, Austin J: 2007. How should we be treating children with
congenital hypothyroidism? J Pediatr Endocrinol Metab 20:559-78
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6.2 Acquired Hypothyroidism

12. Acquired Hypothyroidism
ETIOLOGY
12.1 Etiology
Acquired hypothyroidism
Central Primary
CNS insult
Infection
Radiotherapy
Neurosurgery
Trauma
Brain tumor
Craniopharyngioma
Germinoma
Glioma
Arachnoid cyst
Goiterogen exposure Thyroid insult Infiltration

Drugs Surgery Lymphocytic thyroiditis
Propylthiouracil Radiation Hemochromatosis
Methimazole Infection Histiocytosis
Lithium Sarcoidosis
Amiodarone
Dietary
Soy protein
Goitrin
Important
Important causes presenting
causes presenting after after infancy
infancy (inoforder
(in order of importance)
importance)
• Autoimmune (chronic lymphocytic thyroiditis CLT, hashimotos’s disease)
Autoimmune
• • Iodine (chronic lymphocytic thyroiditis CLT, hashimotos’s disease)
deficiency
• • Missed congenital hypothyroidism
Iodine deficiency
• Missed congenital hypothyroidism
• Mild dyshormonogenesis
• Thyroid hemi agenesis
• Ectopic thyroid
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• Goiterogen exposure
History
• Growth retardation
• Cold intolerance
• Chronic constipation
• Precocious puberty with growth retardation in girls
• Chronic urticaria
• Proximal myopathy
• Unexplained cardiac tamponade
• Delayed dentition
Examination
• Coarse skin
• Bradycardia with narrow pulse pressure
• Pseudohypertrophy of calf muscles
• Hypothermia unrelated to systemic illness
• Macro-orchidism
• Galactorrhea
• Papiledema
Investigations
• Hyperprolactinemia
• Hypercholesterolemia
• Low voltage ECG complexes
• Enlarged pituitary on neuro-imaging
Indications for screening for acquired hypothyroidism
• Autoimmunity- Type 1 DM, adrenal insufficiency, hypoparathyroidism
• Dysmorphic syndrome- Down, turner syndrome, klinefelter syndrome
• Growth hormone treatment
• Anterior pituitary defect
Confirmation of diagnosis
Free T4 TSH Interpretation
Normal Normal Normal
Normal High Compensated hypothyroidism
Low High Primary hypothyroidism
Low Low, normal Central hypothyroidism
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EVALUATION
History
• Onset
• Early childhood- Dyshormonogenesis, ectopic thyroid, CLT
• Late childhood- CLT, dyshormonogenesis
• Adolescence- Chronic lymphocytic thyroiditis, iodine deficiency
• Family history- Chronic lymphocytic thyroiditis, dyshormonogenesis

• Residence in endemic iodine deficient area (iodine deficiency)
• Autoimmune endocrinopathy (type 1 DM, addison disease, HP)
• Deafness (Pendred syndrome)
• Features of neurological involvement, CNS insult (central cause)
• History of thyroid infection, radiation, surgery
Examination
• Goiter
• Absent- Thyroid dysgenesis, central hypothyroidism
• Present
• Soft- Iodine deficiency, dyshormonogenesis
• Firm, bossolated- Chronic lymphocytic thyroiditis
• Severe growth retardation (missed congenital hypothyroidism)

• Alopecia, vitiligo (chronic lymphocytic thyroiditis)
• Rash, seborrhea, organomegaly (histiocytosis)
• Eye crystals (cystinosis)
• Neurological examination, visual field (central hypothyroidism)
Investigations
• Antithyroid antibodies- Thyroid peroxidase antibody (TPO)
• Central hypothyroidism- MRI head, cortisol
MANAGEMENT
• Principles
• Exclude adrenal insufficiency in children CLT and central
hypothyroidism
• Initiate at low doses (50% of target) in long standing hypothyroidism
• TSH is the most sensitive indicator of thyroid status
• Indication of treatment
• Overt hypothyroidism- All cases
• Compensated hypothyroidism- Positive TPO antibody, goiter,
increase in TSH during follow-up
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• Dose- Levo-thyroxine sodium 100 µg/m2/day
Age group Dose µg/kg/day

Less than 6 months 6-10 µg/kg/day
6-12 months 5-8 µg/kg/day
1-5 years 4-6 µg/kg/day
Adult 1-2 µg/kg/day
• Administration
• Oral, once daily, empty stomach (food interferes with absorption)
• Avoid co administration with- Iron, calcium, phosphate
• Monitoring
• Clinical- Growth, pubertal status, goiter size
• TSH - Target level- 0.4- 4 mU/L
• Six weeks after initiation of treatment
• Eight weeks after dose modification
• Symptoms of hypo or hyperthyroidism
• Six monthly for two years, annually thereafter
• Duration of treatment
• Dyshormonogenesis, dysgenesis- Life long
• Chronic lymphocytic thyroiditis
• Non-goitorus- Life long
• Goitorus- Stop after resolution of goiter, TSH after six weeks
• High- Life long treatment
• Normal- Follow-up with TSH three monthly for one year
Further reading
1. Dallas JS, Foley TP Jr. Hypothyroidism. In: Pediatric Endocrinology, Eds:
Lifshitz F, Marcel Dekker, 2003, New York, 4th edition Pp 371-392.
2. Fisher DA. Disorders of the thyroid in the newborn. In: Pediatric
Endocrinology Eds: Sperling MA. WB Saunders 2002, Philadelphia, 2nd
Edn. Pp 161- 286
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6.3 Hyperthyroidism
ETIOLOGY
Congenital
Neonatal graves disease (TSH receptor antibody related, incidence 1:25000)

Activating mutation of TSH receptor (autosomal dominant)
Pituitary resistance to thyroid hormone (autosomal dominant)
13. Acquired Hyperthyroidism

Acquired
13.1 Etiology
Acquired hyperthyroidism
TSH dependent TSH independent

Thyrotroph adenoma
Pituitary resistance to T3
Increased hormone production

Increased hormone release
Subacute thyroiditis
Chronic lymphocytic thyroiditis
Autonomous TSH receptor activation

Toxic adenoma Graves’s disease
Toxic goiter HCG secreting tumor
McCune Albright syndrome

1. Graves diseases (> 95% of all cases)
2. Early phase of chronic lymphocytic thyroiditis (CLT)- Hashitoxicosis
3. Toxic nodule
4. Activating TSH receptor mutation
5. McCune Albright syndrome
13.2 Pointers to diagnosis
218 13.21 HISTORY Grow Society
• Weight loss with increased appetite
• Behavioral abnormality- Anxiety, insomnia, emotional lability
• Fever of unknown origin
• Unexplained diarrhea
History
• Palpitations, increased appetite and weight loss, tremor, heat intolerance
• Irritability unrelated to metabolic and neurological cause
• Behavioral abnormality- Anxiety, insomnia, emotional lability
• Advanced linear growth
• Unexplained diarrhea
• Periodic paralysis and rarely unexplained fever
Examination
• Tachycardia, wide pulse pressure and high output cardiac failure
• Tremors
• Exophthalmos
• Proximal myopathy
• Rarely hepato-splenomegaly and jaundice without intrauterine infections
EVALUATION
• Clinical
• Hyperthyroidism in mother (neonatal graves disease)
• Family history (activating mutations of thyroid receptor)
• Onset
• First two days- Neonatal graves, TSH receptor activating mutations
• Around 10 days- Neonatal graves, antithyroid treatment to mother
• After 15 days- Simultaneous passage of TRA and TBA antibodie
• Chilhood- Graves disease, activating mutations of TSH receptor
• Adolescence- Graves disease, hashitoxicosis, functional adenoma
• Course
• Self limiting- Subacute thyroiditis, chronic lymphocytic thyroiditis
• Non-remitting- Graves disease, activating TSH receptor mutation
• Features of autoimmunity, myasthenia gravis (graves disease)

• Hyperactivity, deafness (pituitary resistance of T3)
• Pain in thyroid region (subacute thyroiditis)
• Precocious puberty (McCune Albright syndrome, HCG secreting tumor)
• Thyroid enlargement
• Tender- subacute thyroiditis
• Nodular enlargement- Toxic nodule
• Diffuse with pebbly consistency- Chronic lymphocytic thyroiditis
• Diffuse- Graves disease, pituitary resistance to T3, TSHR mutation
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• Infiltrative ophthalmopathy (graves disease)

• Pretibial myxedema- Graves disease
• Café-au-lait
13.43 e Alpha unit ofspots,
TSH bony lesions (McCune albright syndrome)
• Principle- Alpha unit of TSH increased in thyrotroph adenoma
Investigation
• Role- Differentiation of thyrotroph adenoma from pituitary resistance to T3
• TSH• Indication- Hyperthyroidism with high TSH
• <• 0.1 mU/L- Graves
Interpretation- αTSHdisease, activating
to TSH ratio (molar) TSH receptor, Thyroiditis
• > 0.1
• Less than 1- Pituitary resistance to
mU/L- Pituitary resistance T3, Thyrotroph adenoma
to T3
• More than 1- TSH secreting thyrotroph adenoma
• TSH receptor antibody
• Positive- Graves disease
13.43 e Association/ complications
• Negative- Thyroiditis, Activating mutation of TSH receptor
• TSH secreting adenoma- MRI head, visual field, pituitary function test
•
•McCune
Thyroid scan-Albright
Tecnitiumsyndrome
99
• Skeletal survey or bone scan (fibrous dysplasia)
• Diffuse increase in uptake- Graves disease
• Ultrasound ovary (ovarian cyst)
• Focal increase in uptake- Functional adenoma
• X ray wrist (rickets)
• Patchy decreased uptake- CLT, subacute thyroiditis

TSH
High Low
Thyrotroph adenoma Thyroid scan
Pituitary resistance to T3
No uptake Focal increase Diffuse increase

CLT Functional adenoma Graves’s disease
Sub acute thyroiditis
1) First step in evaluation of hyperthyroidism is estimation of TSH levels

2) High TSH indicates thyrotroph adenoma or pituitary resistance to T3 (PRTH).
MRI head (abnormal in thyrotroph adenoma) and alpha TSH levels (low in PRTH)
are helpful in classifying the two disorders.
3) Low TSH suggests TSH independent hyperthyroidism. Do thyroid scan
220 a) Diffuse increase in radiotracer uptake suggests

Grow graves disease
Society
b) Focal increase in radiotracer uptake is found in functional thyroid adenoma
c) Decreased radiotracer uptake is diagnostic of CLT and subacute thyroiditis
MANAGEMENT
• Non-specific
• Propanolol- 1-2 mg/kg/day in three divided doses
• Prednisolone- 1-2 mg/kg/day in two divided doses
• Iodine preparations- Severe thyrotoxicosis, sodium ipodate 100 mg/d
Table Agents effective in hyperthyroidism
Agent Mechanism of action Dose
Propanolol Suppression of sympathetic features 1-2 mg/kg/day
Propyl thiouracil Decreased T4 to T3 conversion* 5-10 mg/kg/day
Prednisolone Decreased T4 to T3 conversion* 1-2 mg/kg/day
Sodium iopadate Decreased T4 to T3 conversion* 100 mg/day
* Inhibitor of type 1 mono deiodinase
Specific
Neonatal graves disease
• Antenatal
• Monitor thyroid function and TRAbs in mother
• Titrate anti thyroid doses to achieve high normal free T3
• Fetal monitoring
• Tachycardia- Increased antithyroid drugs in mother
• Cardiac failure- Digitalis to mother
• Postnatal
• Risk 1-3% of mothers with graves disease
• Onset
• Usually by two days
• Delayed with anti thyroid drugs and TSH receptor blocking antibody
• Duration- 3-12 weeks (half life of TRA is 2 weeks)
• Activating TSH receptor mutation- Near total thyroidectomy
Acquired
• Thyroid storm
• General measures
• Ensure normal airway, breathing and circulation
• Correct hyperthermia, precipitating factors
• Monitor for cardiac arrhythmias, digitalis for cardiac failure
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• Specific treatment
• Carbimazole- 0.5-1 mg/kg/day in three divided doses
• Propanolol- 1-2 mg/kg/day in three divided dose
• Prednisolone- 1-2 mg/kg in two divided doses
• Sodium iopadate- 100 mg/day
• Graves disease
• Symptomatic treatment- Propanolol 1-2 mg/kg/day for 4-6 weeks
• Medical Management
• Carbimazole
• Lag- 4-8 wks depending on amount of preformed thyroid hormone
• Dose- 0.5-1 mg/kg/d initially till euthyroid followed by maintainance
• Propyl thiouracil: Not recommended for use in children
• Surgery
• Indications
• Non remitting hyperthyroidism
• Contraindications to antithyroid medication and radioactive I
• Large goiter
• Suspicious malignancy
• Procedure- Near total thyroidectomy
• Complications- Hypoparathyroidism, recurrent laryngeal nerve
palsy, thyroid hematoma, hypothyroidism
• Radioactive iodine ablation

• Indication
• Patients ≥ 10 years with non remitting graves disease.
• May be considered as an option if the child is ≥ 5 years.
• First line in children ≥ 10 years with high risk for relapse
• Preparation- 1-2 weeks

• Propanolol- 1-2 mg/kg/day
• Stop antithyroid drugs two weeks before radioactive iodine
• Procedure- Oral I131 150-200 µ Curie/gram of thyroid tissue
• Response
• Initial flare in symptoms (1-2 weeks)
• Fibrosis and reversal of hyperthyroidism (4-12 weeks)
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• Repeat dose after three months in case of no improvement

• Complications
• Acute- Radiation thyroidits, worsening of graves ophthalmopathy
• Long-term- Hypothyroidism (universal), thyroid adenoma
Other conditions
• Chronic lymphocytic thyroiditis
• No effect of antithyroid drugs as thyroid hormone synthesis is normal
• Propanolol (1-2 mg/kg/day) for symptomatic relief
• Self-limiting ; monitor for subsequent hypothyroidism
• Sub acute thyroiditis

• Self limiting disease, no role of antithyroid drugs
• Propanolol 1-2 mg//kg/day, analgesics
• Functional adenoma- Surgical resection
• TSH receptor activating mutation- Near total thyroidectomy
Further reading
1. Brown RS, Huang S. The thyroid and its disorders. In: Clinical Pediatric
Endocrinology, Eds Brook CGD, Clayton PE, Brown RS, Blackwell
publishing, 2005, London, 5th Edition. Pp 218-253.Fisher DA. Disorders of
the thyroid in the newborn and infant. In: Pediatric En
2. docrinology Eds: Sperling MA. WB Saunders 2002, Philadelphia, 2nd Edn.
Pp 161-186. Vilet GV. Thyroid disorders in infancy. In: Pediatric
Endocrinology, Eds: Lifshitz F, Marcel Dekker, 2003, New York, 4th edition.
Pp 347-358.
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6.4 Thyroid Swelling
Goiter
GRADING
Thyroid Swelling
Grade Feature Professor Anju Seth,
I Thyroid
Department swelling
of Pediatrics, palpable
Kalawati Saranbut not visible
Children’s Hospital, LHMC, New Delhi
II Thyroid swelling visible with neck in extended position only
Goiter
III Thyroid swelling visible with neck in flexed position
IV Criteria- Large
Visible or palpable thyroid tissue
thyroid swelling
WHO grading
ETIOLOGY
Goiter
Infiltration Stimulation of TSH receptor

Chronic lymphocytic thyroiditis (CLT)
Colloid goiter
Hemochromatosis
TSH independent TSH dependent

TSH receptor stimulating antibody
HCG producing tumor
Activating TSH receptor mutation
Decreased thyroid hormone production

Increased thyroid hormone production
Dyshormonogenesis
Thyrotroph adenoma
Iodine deficiency
Pituitary resistance to thyroid hormone
CLT
Goiterogens
Drugs- PTU, carbimazole, lithium
14.2 Etiology
224 Grow Society

EVALUATION
History
• Onset
• Neonatal period- Dyshormonogenesis, maternal anti thyroid drug
• Early childhood- Iodine deficiency, dyshormonogenesis
• Late childhood- Iodine deficiency, CLT, colloid goiter
• Adolescence- CLT, iodine deficiency, colloid goiter, graves disease
• Family history (iodine deficiency, dyshormonogenesis)

• Features of thyroid involvement
• Deafness (iodine deficiency, pendred syndrome)
• Compressive symptoms- Dysphagia, horaseness of voice, stridor
Examination
• Consistency
• Firm- Chronic lymphocytic thyroiditis
• Soft- Dyshormonogenesis, I deficiency, colloid goiter, graves disease
• Surface
• Bossolated- Chronic lymphocytic thyroiditis
• Smooth- Dyshormonogenesis, I deficiency, colloid goiter, graves
• Size
• Large- Iodine deficiency, antithyroid treatment
• Small- CLT, dyshormonogenesis
• Compressive signs- Stridor, facial flushing, distended vein
Investigations
• Free T4
• High- Graves, TSH receptor mutation, thyrotroph adenoma
• Normal- Colloid goiter, CLT, I deficiency, dyshormonogenesis
• Low- CLT, iodine deficiency, dyshormonogenesis
• TSH
• Low- Graves disease, activating TSH receptor activating mutation
• Normal- Colloid goiter, chronic lymphocytic thyroiditis
• High- CLT, dyshormonogenesis, goiterogen exposure, I deficiency
• Thyroid scan- With high free T4 with low TSH
• TPO antibody- Positive in chronic lymphocytic thyroidtis
GROW Society ! 225

• Decreased radiotracer uptake- Thyrotoxic phase of CLT

APPROACH
TSH
Normal
Low High
TPO
TPO
Negative Positive Negative

Radionuclide uptake Urine iodine CLT Urine iodine
Normal Low Normal

Colloid goiter I deficiency Dyshormonogensis
Increased Decreased
Graves disease Hashitoxicosis
TSH receptor defect
14.33 c Thyroid peroxidase antibody

MANAGEMENT- According
• Role- Diagnosis to lymphocytic
of chronic thyroid status
thyroiditis
• Hypothyroidism-
• Indication- High Thyroxine
or normal TSHrepalcement
• Interpretation- Positive in chronic lymphocytic thyroidtis
• Hyperthyroidism-
14.33 d Urinary iodine Antithyroid drugs, Radio I, surgery
• Role- Diagnosis of iodine deficiency
• Euthyroid
• Indications- High or normal TSH, residence in iodine deficient region
• Interpretation- < 100 µg/L- Iodine deficiency
• Follow-up for size of goiter
• 14.33
Thyroxine (1-2
Perchlorate µg/kg/day)
dischage if increase
test (please in size or obstructive effects
refer 10.53)
• Role- Confirmation of dyshormonogenesis
• Principle- Unorganified iodine released after perchlorate adminstration
• Decrease in intake after perchlorate- Dyshormonogenesis
226 Grow Society

Solitary thyroid nodule

15. Solitary Thyroid Nodule
ETIOLOGY
.1 Etiology
Solitary thyroid nodule
Benign Malignant
Primary
Papilary cacinoma
Follicular carcinoma
Medullary carcinoma
Anaplastic carcinoma
Infiltrative disorders Tumor Secondary
Chronic lymphocytic thyroidits Colloid cyst Lymphoma
Histiocytoisis Thyroid duct cyst
Adenoma

• 1)Cyst
Cyst
• 2)Chronic
Chroniclymphocytic thyroidits
lymphocytic thyroidits
• Adenoma
• 3)Malignancy
Adenoma
(20-30% of children with solitary nodule
4)• Malignancy
Papilary carcinoma (70% with
(20-30% of children of thyroid malignancy in children)
solitary nodule
• Follicular carcinoma (20% of thyroid malignancy in children)
a) Papilary carcinoma (70% of thyroid malignancy in children)
• Medullary carcinoma (10% of thyroid malignancy in children)
b) Follicular carcinoma (20% of thyroid malignancy in children)
EVALUATION
c) Medullary carcinoma (10% of thyroid malignancy in children)
History
• .2OnsetEvaluation
15.21 HISTORY
• Infancy- Cyst, teratoma
Onset childhood- Cysts, adenoma, medullary carcinoma (in MEN 2A)
•• Early
• Infancy-
• Late Cyst, teratoma
childhood- Cysts, chronic lymphocytic thyroiditis, malignancy
• Early childhood- Cysts, adenoma,
• Adolescence- Thyroiditis, cysts,medullary
adenoma, carcinoma (in MEN 2A)
malignancy
• Late childhood- Cysts, chronic lymphocytic thyroiditis, malignancy
• • Adolescence- Chronic lymphocytic thyroiditis, cysts, adenoma, malignancy
Progression
• Progression
• Static- Cyst, chronic lymphocytic thyroiditis
• Static- Adenoma
• Gradual- Cyst, chronic lymphocytic thyroiditis
• Gradual- Adenoma
• Rapid- Malignancy
• Sudden increase in size- Hemorrhage in a nodule
• Features of thyroid involvement
• Hyperthyroidism- Functional thyroid adenoma
GROW Society ! 227

• Rapid- Malignancy
• Sudden increase in size- Hemorrhage in a nodule
• Family history- Medullary carcinoma thyroid (MEN 2A)

• Malignancy- Family history, rapid increase in size, radiation exposure
• Compressive symptoms- Dysphagia, stridor, hoarseness of voice
Examination
• Consistency
• Solid- Malignancy, chronic lymphocytic thyroiditis
• Cystic- Colloid cyst, thyroid duct cyst
• Tenderness (acute thyroditis)
• Bruit (hemnagioma)
• MEN 2- Hypertension, marfanoid habitus, swelling in the lips
• Pointer to malignancy- Solid mass, fixity, enlarged lymphnodes
Investigations
• Thyroid function tests- Free T4, TSH
• Hyperthyroidism- Functional thyroid adnoma
• Hypothyroidism- Chronic lymphocytic thyroiditis
• Normal- Cyst, teratoma, chronic lymphocytic thyroiditis, malignancy
• Ultrasound- Suspected thyroid cyst
• Thyroid scan- With high free T4
• FNAC- All cases without features of malignancy
• Surgical biopsy- In the presence of

• History of radiation exposure
• Size greater than 1.5 cm, rapid increase in size
• Family history of thyroid malignancy or MEN 2 A
• Solid nodule fixed to thyroid tissue, cervical lymphnodes
• Vocal cord paralysis
• Calcitonin- Screening for medullary thyroid carcinoma (C cell marker)
MANAGEMENT
• Benign
• Functional adenoma- Surgery
• Cyst- Aspiration
• Chronic lymphocytic thyroiditis- Follow-up for hypothyroidism
228 Grow Society

• Malignancy
• Papilary-follicular carcinoma- Near total thyroidectomy
• Radio active I ablation
• Suppression
15.23 g Association of TSH- Thyroxine 100 µg/m2/day
and complications
• Malignancy- Chest X ray
• Medullary
• Screeningcarcinoma
for MEN 2
• Surgery-
• UrinaryToal thyroidectomy
catecholamines (phaeochromocytoma)
• Prophylactic
• Serum calcium,thyroidectomy- MEN 2 mutation before five years
phosphate (hyperparathyroidism)
• RET mutation
15.3 Approach to diagnosis APPROACH
Risk factors for malignancy (15.2)
Present Absent
Surgical biopsy TSH
Low Normal or high

Functional adenoma Fine needle aspiration
Do thyroid scan
Benign Inconclusive Malignant
Ultrasound guided FNA

Surgical biopsy
Further reading
1) Assess risk factors for malignancy
1. Zimmerman D. Thyroid tumors in children. In: Pediatric Endocrinology,
a) Do surgical biospy if one or more risk factors (radiation exposure, family
Eds: Lifshitz F, Marcel Dekker, 2003, New York, 4th edition Pp 407-420.
2. Fisher DA.lymphnodes,
history, Disorders solidoflesion,
thefixation
thyroid in the structure)
to underlying newborn. In: Pediatric
are present
Endocrinology Eds: Sperling MA. WB Saunders 2002, Philadelphia,
b) Thyroid functions should be assessed in children without risk factors 2nd
Edn. Pp 161- 286
i) Low TSH suggests functional adenoma, confirm with thyroid scan
ii) Fine needle aspiration (FNA) if TSH is high or normal
(1) Ultrasound guided FNA if initial FNA is inconclusive
(2) Surgical biopsy is indicated if
GROW Society ! 229
(a) Initial FNA is suggestive of malignancy
GROW India
Why GROW India?

Growth is an integral part of
childhood that differentiates a
child from an adult. The term
Physician Awareness
Teacher Sensitization
growth alone but encompasses
holistic development of an
and pubertal development and
Lack of growth in short stature,

Patient
potential and reduced boneSupport
mass Public Awareness
and access to preventive and approachable to children with growth disorders, providing support
therapeutic health care for to children with chronic growth disorders and developing novel
growth disorders has resulted in strategies for improving care of these children. The key players of
Dept of Pediatric Endocrinology, Regency
piloted at Kanpur with Hospital Limited,
subsequent nationA2 Sarvodaya
wide implementation.
the development of lifestyle
Nagar,
diseases like diabetes and Kanpur,
heart 208001, Email- grow-india@yahoo.com
disease.
230
PEDIATRIC ENDOCRINOLOGY PROTOCOLS
Learning through partnership
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GROW India

Growth & Obesity Workforce

Glucose Disorders Workshop

Lack of growth in short stature,

Section Page number

1.1 Growth Assessment 6

1.2 Growth chart- Which, when & how? 10

1.3 Bone age assessment 15

1.4 Management of growth failure 20

2.1 Pubertal assessment 35

2.2 Precocious puberty 41

2.3 Delayed puberty 55

2.5 Turner syndrome 72

2.6 Disorders of sexual differentiation 84

2.7 Undescended testis 96

2.8 Gynecomastia 100

3.1 Sodium disorders 103

3.2 Potassium disorders 113

3.3 Metabolic acidosis 125

4.1 Hypocalcemia 129

4.2 Vitamin D deficiency 138

4.3 Refractory rickets 145

5.1 Diabetes mellitus- Classification 150

5.2 Diabetic ketoacidosis 155

5.3 Ambulatory management of type 1 DM 164

5.4 Type 1 DM- What’s new? 176

5.5 Hypoglycemia 185

6.1 Congenital hypothyroidism 203

6.2 Acquired hypothyroidism 211

6.3 Hyperthyroidism 215

6.4 Thyroid swelling 221

Pediatric Endocrinology Protocols

Growth & Obesity Workforce 5

Why GROW India? GROW Society Team

Dr Yuthika Bajpai, Treasurer

Lack of growth in short stature, Dr Alok Bajpai, Executive

6 Growth & Obesity Workforce

From the Editor’s Desk

Growth & Obesity Workforce 7

Careful growth assessment is the cornerstone of successful evaluation of a

RECOMMENDATIONS FOR GROWTH MONITORING

ASSESSMENT OF LINEAR GROWTH

Cross sectional assessment

8 Growth & Obesity Workforce

Assessment of genetic potential

! Calculation of mid parental height

Mid parental height = Father height + Mother height

Growth & Obesity Workforce 9

• Height in target height range- Normal

Norms for growth velocity

ASSESSMENT OF BODY PROPORTIONS

10 Growth & Obesity Workforce

BMI is interpreted in light of population reference.

Growth & Obesity Workforce 11

1.2 Growth Charts- Which, When & How

Shortcomings of growth charts: Although generally very useful growth

12 Growth & Obesity Workforce

HOW TO USE GROWTH CHARTS?

STEPS IN EVALUATING GROWTH CHART

! Current height and weight status- As reflected by percentile.

Growth & Obesity Workforce 13

! Now draw a perpendicular to this point till the X axis.