General pediatrics 9 (Calcaterra) 26.11.

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Sbob: Bottura
Topics covered:
• Congenital adrenal hyperplasia
• The thyroid
- Congenital hypothyroidism
- Fetal/neonatal hyperthyroidism
- Acquired hypothyroidism
- Hyperthyroidism and Graves’ disease

Disclaimer: prof. Calcaterra could not hold this lecture, and just sent the material to be studied by our own. She
sent 3 presentations, that probably she couldn’t have covered in one lecture, hence the length of this sbobina. I
integrated the slides she sent with sbobine from previous years. Parts that are not at all present in slides but
were taken purely from the sbobina are added in grey

CONGENITAL ADRENAL HYPERPLASIA

Definition and etiology

Congenital adrenal hyperplasia (CAH) comprises a group of autosomal recessive defects resulting into deficiency
in one of the enzymes required for cortisol and aldosterone synthesis in the adrenal cortex. All the enzymes
that participate in steroidogenesis may be affected, the most common being:
• 21α-hydroxylase (CYP21), is the most frequent defect, present in > 90% of cases. This enzyme is aa
cytochrome P450 enzyme involved both in the synthesis of cortisol and aldosterone
- It catalyzes the conversion of 17-hydroxyprogesterone to 11-deoxycortisol, a precursor of cortisol,
- It catalyzes the conversion of progesterone to deoxycorticosterone, a precursor of aldosterone
Thus, in case of total or partial absence of this enzyme, the synthesis of cortisol and aldosterone is stopped.
• 11β-hydroxylase (∼ 5% of CAH)
• 17α-hydroxylase (rare)

Figure 1: adrenal steroidogenesis

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Pathophysiology
Aldosterone and cortisol are two hormones produced by the adrenal cortex involved in electrolyte and water
homeostasis and stress response, respectively.
The patients affected by this disease are not able to produce cortisol and aldosterone completely or partially
according to the degree of deficiency of enzymes. Due to the negative feedback that normally controls
steroidogenesis, there are increased ACTH levels to stimulate the adrenal cortex, which will only overproduce
precursors of cortisol. Some of these hormones are diverted to sex hormones synthesis, leading to androgen
excess and causing the clinical manifestation of the disease: ambiguous genitalia in newborn females and rapid
postnatal growth in both sexes.
On the other hand, aldosterone deficiency is responsible for salt wasting, with failure to thrive, hypovolemia
and shock.
For example, in the case of 21-hydroxylase deficiency, progesterone becomes 17-hydroxyprogesterone instead
of becoming deoxycorticosterone; then 17-hydroxyprogesterone becomes androstenedione.
Depending on which enzyme is affected, the following endocrine changes are seen:
Enzyme deficiency Cortisol Aldosterone Androgens
21-hydroxylase ↓ ↓ ↑
11β-hydroxylase ↓ ↓ ↑
17α-hydroxylase ↓ ↓ ↓

Although an increase in aldosterone would be expected in 17α-hydroxylase deficiency, ↑ 11-

deoxycorticosterone (which has aldosterone-like activity) inhibits renin and so also aldosterone production.

Classification of clinical forms

• Severe type (classic CAH/classic 21-hydroxylase deficiency)
- It is present since birth. It can be divided into:
a. Simple virilizing type: due to the deficiency of cortisol alone, with normal aldosterone
b. Salt-wasting type: both cortisol and aldosterone are deficient. Present in 75% of classic congenital
adrenal hyperplasia cases.
- Not very frequent (1 case/16000 newborns)
• Mild type (non-classic CAH)
- Usually asymptomatic in newborns
- Later on in life, patients develop signs of postnatal androgen excess
- It affects 0.2% Caucasian population, and is more frequent in certain populations, such as Jews of
eastern Europe origin (1-2%)
- Diagnosis is usually done in the evaluation of precocious puberty

Clinical presentation
Simple virilizing type
Patients with this phenotype synthetize adequate aldosterone, with sodium balance, but do not synthetize
cortisol efficiently. Adrenals produce excess 17OHP and progesterone, which are metabolized to DHEA and
androstenedione, i.e. resulting in androgen excess.
Androgen excess does not affect male sexual differentiation, in fact, males usually have morphologically normal
external genitalia, with the only anomaly being scrotal hyperpigmentation. This is a consequence of the negative
feedback that leads to increased ACTH levels, as ACTH derives from proopiomelanocortin (POMC), which is also
the precursor of MSH (Melanocyte-Stimulating Hormone).

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On the opposite, in female fetus androgen excess leads to ambiguous external genitalia:
• Fused vagina and urethra: normally, a urogenital septum should form to create two separate canals, but
adrenal androgen production in the female fetus starts during the process of septation of the urogenital
sinus, inhibiting the formation of separate canals
• Clitoral enlargement, due to interaction of androgens with androgen receptors in genital skin
• Labial folds fusion, also due to interaction of androgens with androgen receptors in genital skin
Uterus and gonads are not affected by malformations and internal wolffian structures (prostate and spermatic
ducts) are not virilized, so the only alteration is external.
At birth, severely affected female newborns may have ambiguous genitalia or genitalia that cannot be
distinguished from cryptorchid males with hypospadia, without palpable testes (fused labia majora may
resemble a scrotum, hypertrophied clitoris may resemble a penile shaft).
Another key feature present in both males and girls is postnatal virilization. In undiagnosed or inadequaltely
treated pts, pubic and axillary hair may develop early, clitoral growth may continue in girls, males may have
penile growth associated with small testes.
Excess androgens also affect growth. The chronic exposure to androgen excess promotes an acceleration of
height and bone maturation, resulting in final short stature due to the prematurity of epiphyseal closure in long
bones. Even in well-treated patients, adult height is 1.4 SD below the population mean.
Diagnosis of this form of CAH is precocious in females, due to ambiguous genitalia, while may be retarded in
males, if not submitted to neonatal screening. Males are usually diagnosed when clinical signs of androgen
excess develop. Adult height may be severely compromised in these cases.

Salt wasting CAH

These patients constitute 75% of classic CAH cases. They cannot adequately synthetize aldosterone, the
hormone that regulates urinary sodium resorption, and also cortisol, so they have both cortisol and aldosterone
deficiency, and will therefore present not only with virilization, but also with symptoms due to aldosterone
deficiency.
If not treated, due to aldosterone deficiency they will excrete too much sodium, and therefore present with
signs and symptoms of salt loss:
• Hypovolemia
• Hyperreninemia
• Hyperkalemia
• Dehydration
• Shock
It is a life-threatening form that may lead to cardiocirculatory collapse and hyperkalemia-induced cardiac
arrhythmias and paralysis.

Non-classic form
Affected males and females produce normal amounts of cortisol and aldosterone at the expense of moderate
overproduction of androgens. Many patients never develop overt androgen excess. Response to stress is
normal, as cortisol levels are enough to avoid adrenal crises.
It is not so dangerous for life, and it usually only affects the development of secondary sexual characteristics,
final height, as there is advanced bone age and rapid growth, and ovarian function.
Signs of virilization include:
• In girls: premature appearance of pubic hair at puberty (pubarche), acne, irregular menses, hirsutism and
clitoral enlargement, PCOS
• In boys: increased shaft volume without testicular volume enlargement, premature pubarche

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Diagnosis
• Neonatal screening:
- It is based on the determination of serum 17-hydroxyprogesterone level, using dried blood on filter
paper. In classic 21-hydroxylase deficiency there is elevated level of 17-HOP since birth. Besides 17-
OHP, also androstenedione and progesterone are usually elevated
- The cut-off is low to avoid missing any case of a newborn with classic form, and for this reason the rate
of false positives is high.
- Premature newborns and sick newborns can have very elevated levels of 17-hydroxyprogesterone
independently from the presence of CAH, so reference values for weight and gestational age have been
determined considering this characteristic of premature newborns.
- When screening is positive for CAH, the newborn must be submitted immediately to further
evaluations.
In case newborn screening is not performed or it is normal, males can be diagnosed when clinical signs of
androgen excess develop. In this case, adult height may be damaged by androgen overproduction and they
may suffer from adrenal crises in conditions of high stress.
• Hormone testing: measurement of serum 17-hydroxyprogesterone (↑), androstenedione (↑) and
progesterone (↑) + urinary pregnanetriol (↑), a 17-OHP metabolite.
• Electrolyte dosage for salt wasting form
• ACTH test: it is the gold standard for the diagnosis of 21-hydroxylase deficiency
- Synthetic IV ACTH (0,125-0,250 mg) is administered, to maximally stimulate the adrenal cortex.
- Then, the levels of 17- hydroxyprogesterone are evaluated: in patients with CAH they are pathologically
elevated.
- Severity of hormonal abnormalities depends on the type of 21-hydroxylase deficiency: patients with
salt-wasting form have the highest level of 17-OHP, followed by simple virilizing pts, pts with non-classic
disease and heterozygotes (who have a level slightly more elevated than normal).
There are normograms that allow to classify the obtained value into classic CAH, non-classic CAH,
heterozygous and general population. In a normogram, basal levels are put on the x axis, stimulated
levels on y axis. The crossing of the two lines indicates whether the subject is on the normogram.
Pathological results are obtained when the intersection of the above values is high.
• Genetic analysis to look for autosomal recessive mutations in CYP21 gene located in the short arm of
chromosome 6 near the HLA region.
Since females have ambiguous genitalia, the diagnosis may be immediate at birth, even before the screening
test is available, while in males the condition is not easy to suspect it on the basis of the clinical aspects.
Sometimes, it may be difficult to assign a sex to the affected child because in severe cases the appearance of
genitalia is the same for girls as for boys. For this reason, helpful diagnostic tools are, apart from ACTH test and
hormonal levels (17-OHP, androstenedione, renin, aldosterone, Na, K):
• Karyotyping, with which it is possible to understand if the newborn is genetically a female or male
• Pelvic US, to investigate internal anatomy: the presence of ovaries and uterus can be assessed.

It is important to perform the differential diagnosis with other forms of CAH due to other enzymatic defects,
for example 11-betahydroxylase, and 3-betahydroxysteroid dehydrogenase

Prenatal diagnosis
When in a family there is a case of CAH, it is possible to control the presence of the disease in case of other
pregnancies, or in case an affected patient wants to have children.
Preconception counselling if fundamental, to explain to the patient the risk of having an affected child, and the
possible prenatal diagnostic methods and prenatal therapies.

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The carrier rate for the causative mutation in the general population is 1.6% for the classic form, therefore the
chance for a patient with classic CAH to have a child with classic CAH is 0.8% (1/120). In a patient with a non-
classic form, the risk of having a child with classic CAH is 1/400. These are the risks in general, without knowing
the karyotype of the partner.
Therefore, before conception, it is advisable that the partner of a patient with CAH undergoes genetic analysis
and genotyping, as if the partner for example is confirmed to have a heterozygous mutation, so he is an
asymptomatic carrier, the risk of having an affected child significantly rises.
Prenatal diagnosis is performed through amniocentesis and villocentesis. The problem is that villocentesis can
be performed only after the 8th week of gestation and amniocentesis only after the 16th, while sex organs
development starts at week 6.
For this reason, in case of pregnancy in an at-risk situation, precocious treatment is started in the first trimester,
the mother is given dexamethasone to suppress hyperandrogenism in the fetus and prevent or reduce the
ambiguity of external genitalia of a female fetus. Then, amniocentesis is performed and if the fetus is affected
by CAH and is a female, the treatment with dexamethasone is continued for the entire duration of pregnancy.
In case the affected fetus is a male or the fetus is not affected, the treatment is progressively decreased and
stopped because there is no need to treat ambiguity of external genitalia and giving steroids to the mother with
no reasons, as it may be harmful for her (in fact, she is already exposed to the risk of gestational diabetes, and
there is no need to increase the risk of other metabolic derangements).
Long-term safety of dexamethasone treatment is not known, and possible complications in the mother are
Cushing syndrome, excessive weight gain, hypertension.

Treatment
The treatment must be started as soon as possible to avoid adrenal crisis or dehydration.
The therapy consists of chronic hormonal replacement with glucocorticoids +/- mineralocorticoids that must be
taken lifelong. The purpose of treatment is to decrease the excessive secretion of CRH and ACTH and to reduce
adrenal hormone levels, since they have an androgenic effect.

Excess androgens
The drug of choice to avoid virilizing symptoms is hydrocortisone, which not available in Italy.
In children, the dosage is 10-20 mg/m2/day in 3 divided doses (1 in the morning and the other two after meals),
because the half-life is short and this could minimize the effect. The morning dose is usually higher than the
other two to mimic physiological cortisol secretion. The goal of the treatment is to use the lowest dose that is
able to suppress the adrenal androgens, and at the same time to maintain a linear height growth and avoid
excessive weight gain.
In case of stressful situations (disease, surgery, trauma), the dose can be increased up to 10 times the basal
values to avoid adrenal crisis (up to 100mg/m2/day).
Another drug, cortisone acetate, is also available, but it is less similar to endogenous cortisone and it is
administered at higher doses (+20%) than hydrocortisone.
The follow up of this patient includes periodical evaluation of:
• ACTH
• 17-hydroxyprogesterone level, which must not be totally suppressed but only partially, in order not to
impact growth too negatively
• Androstenedione
• Bone age
• Height and weight
In adults, treatment is the same but other than hydrocortisone (13.75 mg/m2/day), other options are either
prednisolone (4.75 mg/day) or dexamethasone (0.5 mg/day), that can be used once a day instead of three times

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a day. These drugs cannot be used in children because they suppress the height growth too much, while in
adults it is not a problem.
The treatment of non-classic form is indicated if there is early onset and rapid progression of the apperance of
pubic and axillary hair, increased growth velocity and advanced bone age. The treatment must be stopped at
the end of puberty, in order to allow the patient to grow as regularly as possible.

Salt loss
For mineralocorticoid replacement treatment, the drug of choice is fludrocortisone acetate (commercial name
florinef), which is not available in Italy. The dose is 0.1-0.2 mg/die, so 1-2 tablets a day. This steroid has mainly
a mineralocorticoid effect, which helps normalizing water and salt levels: it reduces hyponatremia and
hyperkalemia.
In young children, sodium supplementation (1-2 g/day) is also administered to prevent hyponatremia.
It is important to monitor blood pressure, renin, Na+ and K+. high renin indicates insufficient treatment, low
renin means overtreatment.
Overtreatment may lead to:
• Hypernatremia and hypertension – for this reason, it is important to monitor blood pressure and
electrolytes and renin
• Low renin
• Tachycardia
• Edema
• Suppressed growth
In adults, treatment is the same but with lower doses (0.05-0.1/day). Also in this case blood pressure, renin,
Na+ and K+ must be monitored.

Ambiguity of sex genitalia

In females, surgical correction of clitoral enlargement and fusion of labia needs to be performed; if there is a
urogenital sinus with a single opening, vagina and urethra must be divided. It is important to correct genitalia
as soon as possible to avoid psychological trauma, so surgery is usually performed between 2 and 6 months of
age by experienced surgeons.
Since the correction involves reconstruction of vagina, during adolescence the adequacy of vaginal introitus
should be evaluated because adolescents can have sexual problems in case of introital stenosis. They can
undergo a surgical correction or use devices to enlarge progressively the introitus of vagina.
Pre-pregnancy and during pregnancy women with this disease must be carefully followed with frequent
controls of gluco- and mineralocorticoids, ACTH, renin, electrolytes.
Treatment must be increased to stress doses during the labor and delivery. Blood pressure and glucose
tolerance must be monitored during pregnancy of women with CAH.
Often cesarean section is needed in case of previous genitoplasty.
Psychological support to the families should be provided throughout this.

Psychosexual aspects
Females born with ambiguity of external genitalia can have psychosexual problems during their life.
First of all, they are exposed to excess androgens during prenatal and postnatal life till the moment of
diagnosis, which has some consequences at the brain level:
• They can have problems in gender identity
• They are not very interested in maternity and children
• They show a masculinized behavior in body movements, games, and choice of occupations.
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• There is an increased incidence of homosexuality and bisexuality
• The wish to change to the male gender is higher than in general population
There can also be problems in sexual function and reduced clitoral sensitivity due to a bad vaginal
reconstruction.
Furthermore, fertility rate can be reduced, especially in the classic form.
Males with classic CAH can have reduced fertility due to due to hypogonadotrophic hypogonadism for
glucocorticoid overtreatment; on the opposite, in case of undertreatment or lack of compliance, due to
androgen excess they can develop the so called “Testicular adrenal rest tumors” (TARTs).
Since the embryological origin of gonads and adrenal is the same – then there is separation and different
migration of the gonads with respect to the adrenals, which remain in the abdomen – some adrenal cells can
migrate with testicular cells and be found within the testis.
When treatment is not well performed and hormonal control is inadequate, ACTH is elevated and stimulates
the adrenal cells to increase the production of cortisol and there is androgen excess. In this case, the islets of
the adrenal cells in the testis increase in volume to become hyperplasic and cause the appearance of adrenal
tumors in the testis.
These TARTs compress the seminiferous tubules and cause irreversible damage and azoospermia. Since TARTs
are very frequent starting from prepubertal age, testicular US is necessary during follow up. In case of
noncompliance, it is fundamental to explain the consequence of this behavior to patients.
Sometimes it may happen that there is an incorrect attribution of the sex to the newborn, and a female can be
considered a male only to realize later in life that she was actually a female. This usually occurs during a US to
examine cryptorchidism, during which the ovaries and the uterus are discovered. This has of course a huge
impact on the family, both in psychological and bureaucratic aspects.

THE THYROID
Thyroid physiology
The thyroid gland secretes two thyroid hormones: T3 (triiodothyronine) and T4 (thyroxine, tetraiodothyronine).
Furthermore, the C cells of the thyroid gland produce calcitonin, which regulates calcium balance.
More T4 is produced than T3, but T4 is less potent. Peripheral 5'-deiodinase in the blood converts T4 into the
biologically active T3; T4 is therefore considered a hormonal precursor.
The half-life of T3 is about one day (∼ 20 hours), whereas the half-life of T4 is about one week (∼ 190 hours).
This longer half-life makes T4 suitable for use as a depot form that can be used replacement therapy.
Thyroid hormones are essential for the growth and the maturation of many target tissues, including the brain
and skeleton
Euthyroid status depends on:
• Normal development of thyroid gland
• Normal production and action of thyroid hormones
• Iodine availability
Effects of thyroid hormones:
• ↑ Basal metabolic rate (↑ oxygen consumption, and ↑ body temperature)
• Stimulation of carbohydrate metabolism
• Anabolism of proteins (in high doses: catabolism of proteins)
• Lipolysis or liponeogenesis, depending on metabolic status

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• Permissive effect on catecholamines (particularly via β receptors)
• In children: stimulation of bone growth (act synergistically with GH)
• CNS effects
- Perinatal period: maturation of the brain
- Hyperthyroidism: hyperexcitability, irritability
- Hypothyroidism: somnolence, slowed speech, impaired memory
• Reproductive effects
- Fertility, ovulation and menstruation
- Hypothyroidism leads to increase levels of TRH, TRH in turn stimulates secretion of TSH and PRL and
PRL inhibits gonadotrophins
Feedback mechanism:
Hypothalamus produces TRH → TRH stimulates secretion of TSH by the pituitary gland → TSH stimulates release
of T3 and T4 by the thyroid gland
• Stimuli: exposure to extreme cold, stress
• Inhibition:
- T3/T4 inhibit TRH and TSH, which inhibits T3/T4 secretion and iodine uptake
- Somatostatin, dopamine, and glucocorticoids inhibit the production of TSH.

Thyroid embryology
Ontogenesis of thyroid function involves:
• The development and maturation of the fetal thyroid
• The evolution of the hypothalamic-pituitary-thyroid axis
The thyroid gland starts to develop in the third week of pregnancy (embryonic 20-22 days) as a diverticulum of
the pharyngeal floor. It is located initially near the base of the tongue (i.e. foramen caecum), then it descends
through the anterior midline of the neck, forming the thyroglossal duct, to settle into its adult anatomical
position at around week 7 of gestation, so after 1 month from the beginning of its development.
The thyroglossal duct usually obliterates after the thyroid gland has descended, while the foramen cecum
remains as a part of the tongue (small midline depression at the border between the anterior and the posterior
portions of the tongue).
The synthesis of the hypothalamic factor TRH starts at the 6-8th week of pregnancy, while during the 12th week
of gestation, fetal TSH starts to be produced. The fetal thyroid is now capable of concentrating iodine and
synthesizing iodothyronines, and secretion of thyroid hormones (T3, T4) also starts. However, little hormone
synthesis occurs until the 18th to 20th week. Thereafter, fetal thyroid secretion increases gradually over the
entire period of gestation up to a peak at birth.
In the first months, due to low fetal thyroid hormone concentration, the fetus is completely dependent on
mother’s thyroid hormones:, thus mother’s thyroid function and diseases greatly influence fetus and newborn’s
thyroid function and neurological development: if the mother is affected by hypothyroidism, the newborn will
have hypothyroidism and present a severe neurological delay1.
After the first month of gestation, if the fetus has a normal functioning thyroid he can develop normally. If both
mother and fetus are hypothyroid during the whole pregnancy, the newborn will have an irreversible
neurological delay.

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The slides add: “Tranplacental passage of T4 from the mother to the fetus can assure an almost normal neurological
development to the hypothyroid fetus, if postnatal replacement therapy is precocious”. This doesn’t make much sense,
but I think that postnatal may have been meant to be prenatal, and that this means that if in a hypothyroid mother
hormonal replacement therapy with T4 is started early, T4 can cross the placenta and prevent neurologic delay in the
fetus.
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Thyroid hormones continue to increase gradually over the entire period of gestation. Pituitary-thyroid feedback
mechanism becomes functioning during the second trimester of pregnancy and it reaches complete maturation
at the moment of delivery.
After delivery, there are some important variations in the levels of thyroid hormones: immediately after delivery
there is an important peak in TSH level: in full-terms infants this peak can reach 60-80 mU/ml due to the stress
of delivery and to the decrease of temperature compared to the intrauterine environment. This peak causes a
marked stimulation of thyroid gland and therefore also T3 and T4 increase in the first hours of extrauterine life,
then both TSH and thyroid hormones slowly decrease during the first 7 days of life.
At the moment of delivery, thyroid hormones levels are lower in premature infants and they vary according to
gestational age; there are the same variations but they’re of less magnitude.
During pregnancy and after birth, thyroid hormones are essential for the growth and maturation of many
target tissues, including the brain and the skeleton. Somatic growth can be recovered during the first years of
life, whereas brain damage due to untreated hypothyroidism during pregnancy and in the first month/year of
life cannot be recovered.

CONGENITAL HYPOTHYROIDISM
Congenital hypothyroidism is a deficiency of thyroid hormones present at birth. It’s a heterogeneous condition
that is not usually familiar, but a sporadic condition resulting from decreased or absent action of thyroid
hormones on thyroid tissues.

Epidemiology
Congenital hypothyroidism is the most frequent congenital endocrinopathy. It’s more frequent in iodine
deficient areas.
Incidence depends on many factors: ethnicity, geographical location, diagnosis methodology (if based on
screening programs or clinical manifestation), TSH cut off value of neonatal screening.
There’s higher incidence in Asian, Hispanic, Native American and lower incidence in American black population
as compared to the white population. Incidence is increased in twins, premature newborns and females.
Congenital hypothyroidism is the most frequent cause of treatable mental retardation. If treated early and in
an appropriate way, the child will have a normal development. If treatment is initiated late and is not adequate
the child will have mental retardation for the whole life.

Classification
It can be classified on the basis of etiology or duration.
According to etiology:
• Primary: when the defect is in the thyroid
• Secondary: when the problem is at the level of the pituitary or hypothalamus
• Peripheral: when there is a problem of thyroid hormone receptors. The thyroid is normal and it secretes
normal levels of hormones, but these cannot exert their action because of the absence of peripheral
receptors
• Syndromic: when the thyroid disease is accompanied by other malformations and/or diseases
On the basis of its duration:
• Permanent, when it requires long life treatment
• Transient, if there is a temporary deficiency of thyroid hormones at birth but then there’s a spontaneous
recovery to normal thyroid hormones production in the first few months or years of life

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Permanent CH
Primary CH
Primary CH can be due to:
• Thyroid dysgenesis (85%). This is due to abnormalities of thyroid embryological development.
- Thyroid agenesis: absence of thyroid tissue
- Thyroid ectopia: the thyroid can stop at different sites along its migration pathway (e.g. it can remain
at the base of the tongue). The most frequent condition is partial migration, meaning that the thyroid
at the end of migration remains in an upper position with respect to the normal one.
- Thyroid hypoplasia: the thyroid is in its normal place but it is smaller than normal.
- One of the most common forms of thyroid hypoplasia is hemiagenesis, which is the lack of a lobe.
Usually these cases of thyroid dysgenesis are sporadic; in a very low percentage of cases (2%) some
mutations of transcription factors involved in thyroid development and migration have been found (TTF-2,
NKX2.1, NKX2.5, PAX-8).
• Dyshormonogenesis (15%): caused by a genetic defect in one of the steps involved in thyroid hormone
production, causing an impaired production of thyroid hormones. The thyroid has a normal size (sometimes
goiter may be present) and it is normally placed.
It is usually an autonomic recessive condition; the mutations usually involve transcription factors or
enzymes necessary for the synthesis of thyroid hormones. Associated mutations are:
- Sodium iodine symporter defect;
- Thyroid peroxidase defects (DUOX2, DUOX2A)
- Pendrin defect (causing Pendred’s syndrome). This is one of the most frequent conditions:
a. Genetic disorder leading to congenital bilateral sensorineural hearing loss and goitre with
euthyroid or mild hypothyroidism.
b. It is due to an organification defect of the iodine (i.e. its incorporation into thyroid hormone)
- Thyroglobulin defect
- Iodotyrosine deiodinase defect (DHEAL 1, SECISBP2)
• Resistance to TSH binding (rare): it is due to absence of TSH receptor on thyroid cell wall; which in turn do
not get stimulated and thus cannot produce T3 and T4. Associated mutations are:
- TSH receptor gene defect
- G-protein mutations for pseudohypoparathyroidism type 1a.

Secondary CH
Secondary CH is also called central congenital hypothyroidism. It is rare (1:50.000). It can be due to:
• Isolated TSH deficiency: due to TSH b-subunit gene mutation
• TRH deficiency: it can be isolated or due to pituitary stalk interruption syndrome (e.g. due to vascular
problems during delivery) or other hypothalamic lesions (infections or traumas).
• TRH resistance: mutation of TRH receptor gene
• Deficient production or function of transcription factors involved in pituitary development or function
(HESX1, LHX3, LHX4, PIT1, PROP1 gene mutations);
In this case TSH deficiency is associated to other pituitary hormone deficiencies (e.g. GH, ACTH,
gonadotropins) – the clinical manifestations of adrenal insufficiency and GH deficiency are more precocious
and easier to be recognized compared to hypothyroidism manifestations.

Peripheral CH
It can be due to:
• Thyroid hormone resistance (thyroid receptor-β gene mutation)
• Abnormalities of thyroid hormone transport (Allan-Herdnon-Dudley syndrome MCT8 gene mutation)
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Syndromic CH
There are many syndromes where congenital hypothyroidism is associated to other congenital malformations
or manifestations:
• Pendred syndrome: hypothyroidism with goiter + deafness (pendrin gene mutation)
• Bamforth-Lazarus syndrome: hypothyroidism + cleft palate + spiky hair
• Ectodermal dysplasia: hypothyroidism + hypoidrotic + ciliary dyskinesia
• Kocher-Debrè-Semelaigne syndrome: muscular pseudohypertrophy + hypothyroidism
• Hypothyroidism + polydactyly + mental retardation
• Hypothyroidism + choreoathetosis + neonatal respiratory distress
• Hypothyroidism + obesity + colitic + cardiac hypertrophy + developmental delay
All these conditions are permanent and thus need long life treatment.

Diagnostic exams in different types of permanent CH

• Dysgenesis
- In case of agenesis the thyroid can’t be detected at US and at scintigraphy there is no uptake; in case of
ectopia at US the thyroid is not located in its normal position, and at scintigraphy there is ectopic
uptake; and in case of hypoplasia the thyroid is smaller than normal, with decreased uptake at
scintigraphy.
- TSH is much more elevated in the absence of thyroid tissue, but it’s elevated also in case of ectopia and
hypoplasia. T4 is not detectable in case of thyroid agenesis and it’s decreased in the other cases.
- The same for thyroglobulin, whose levels are related to the quantity of thyroid tissue present in the
subject.
• Dishormonogenesis
- At US the volume can be normal or increased if the child has a goiter. Scintigraphy can give very different
results on the basis of the genetic defect.
- TSH is always increased; T4 and TG levels depend on the cause of dishormonogenesis.
• Central hypothyroidism
- Central hypothyroidism refers to thyroid hormone deficiency due to a disorder of the pituitary,
hypothalamus, or hypothalamic-pituitary portal circulation, resulting in diminished thyroid-stimulating
hormone (TSH), thyrotropin-releasing hormone (TRH), or both2.
- It is very rare (1:50.000) and characterized by a hypoplastic gland at US and by reduced uptake at
scintigraphy. Differently from the other conditions, TSH is not increased but it is normal or very low.

2
Definition from UpToDate
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Transient CH
Transient congenital hypothyroidism is a condition of temporary deficiency of thyroid hormone that is
discovered at birth but recovers to normal in the first few months or years of life.
Transient CH can be due to:
• Maternal intake of antithyroid drugs (e.g. women with Graves’ disease taking drugs during pregnancy), that
can cross the placenta
• Transplacental passage of maternal TSH-receptor-blocking antibodies from a mother with autoimmune
thyroiditis to the fetus
• Maternal and neonatal iodine deficiency or excess
• THOX2 or DUOXA2 heterozygous gene mutations
• Congenital hepatic hemangioma or hemangioendothelioma: liver tumors producing enzymes that convert
T4 into a non-biologically active form of T3. With resolution of the hepatic disease the thyroid function
becomes normal.
Digression: molecules that can cross the placenta:
• TRH, TSH, thyroid hormones
• IgGs
• Drugs (e.g. propylthiouracil, methylmazole, β-blockers, lithium)
• Radioactive iodine (I131)

Iodine deficiency and excess

Optimal iodine nutrition in the pregnant woman is required for full development of the fetus; this because T3
and T4 are iodine-containing hormones and iodine deficiency leads to the impossibility of synthetizing thyroid
hormones. If maternal thyroid hormone level is not able to ensure adequate thyroid hormone concentration to
the fetus, especially in the first trimester of pregnancy, transient hypothyroidism develops.
Transient congenital hypothyroidism is thus much more frequent in areas with environmental iodine deficiency
(internal and mountainous areas) than in areas with normal iodine. In some nations in the world this problem
represents the most frequent cause of congenital and acquired hypothyroidism, e.g. in some regions of Africa,
Andes in South America and in Asia; in Italy on the other hand this problem is not really seen as the salt that is
on the market is iodinated and thus able to correct the environmental deficiency naturally present in Calabria,
Sicilia, and in the Alps.
A transient hypothyroidism can lead to developmental delay. An increased frequency of Attention Deficit and
Hyperactivity Disorder has been reported in the children of mothers living in iodine deficient areas. Premature
infants are more susceptible to the effects of iodine deficiency.
Transient hypothyroidism can also be caused by iodine excess both in the fetus and in the newborn.
This occurs secondarily to the Wolff-Chaikoff effect, according to which large doses of iodine transiently inhibit
thyroid iodide organification, through inhibition of the enzyme thyroid peroxidase (TPO) so that thyroid
hormone synthesis and thyroid hormone release are inhibited. This can happen, for example, due to maternal
disinfection with povidone iodine (betadine) before or during delivery. The effect should only last for a couple
of days as a protective mechanism against hyperthyroidism, after which an escape mechanism ensues, TPO
goes back to function normally and normal organification of iodine is resumed; but in the newborn/fetus it can
last longer, so hypothyroidism ensues.
Iodine overload can occur in the newborn directly, or also in the mother and then if the newborn drinks
maternal milk this affects also the newborn. It can be caused by:
• Maternal factors
- Drugs (amiodarone)
- Disinfection with iodinated products such as povidone - Betadine®- (C-section, vaginal applications,
epidural anesthesia)
12
• Newborn factors
- Iodinated disinfectants (e.g. disinfection of umbilical cord or surgery in the first days of life, for example
due to esophageal atresia, anal atresia or congenital heart malformation. The iodine is absorbed and
blocks the thyroid function of the child.
- Iodinated contrast medium (e.g. used for CT scan)

Mother with autoimmune thyroiditis

During pregnancy, IgGs (including antithyroid Abs) and medications (including antithyroid drugs) may be
transmitted to the fetus through the placenta. Transplacental passage of these substances can cause thyroid
function abnormalities in the fetus and subsequently in the newborn.
The decreased thyroid function of the newborn normalizes when these substances (antibodies and drugs)
disappear form infant blood, and the thyroid function recovers. The velocity of elimination of these factors
depends on the clearance rate and starting quantity. Usually antibodies disappear in about 3-4 months and so
does iodine, whereas antithyroid drugs disappear in about 1-2 weeks.
In case of transient CH due to maternal thyroid autoimmune disease, most commonly the mother is affected
by non-goitrous autoimmune thyroiditis with hypothyroidism. This is a form of atrophic thyroiditis,
characterized by thyroid autoantibodies (blocking anti-TSH receptor antibodies), functional hypothyroidism,
and absence of goiter.
Blocking antibodies can inhibit development and function of fetal gland. The persistence of antibodies in the
child is directly related to the initial titer, the half-life of the antibodies is about 2-3 weeks.
Clinical manifestations and treatment are the same as in other forms of congenial hypothyroidism and
treatment is usually discontinued between the age of 2-3 years.
There is a high recurrence rate in subsequent offspring due to the tendency of these antibodies to persist for
many years in maternal circulation. Thus, if a woman with autoimmune thyroiditis has a child with transient
congenital hypothyroidism, she’s at risk of having other children with the same problem even after years.

Diagnostic imaging and exams in Transient CH

The finding of thyroid hormone deficiency during screening, associated with a normal thyroid position, size and
morphology at US and/or scintigraphy is a clue to the diagnosis of transient hypothyroidism.
In this case, replacement therapy with levo-thyroxine (T4) is started and is necessary until normal thyroid
function is restored.
It is necessary to re-evaluate the diagnosis at the age of 2-3 years, when most T4-dependent brain development
is complete and there’s no risk of neurological damage by stopping therapy in case the child still has
hypothyroidism: therapy is stopped for 4 weeks/30 days (trial-off), and after this time has passed, the levels of
FT4 and TSH are re-evaluated:
• Normal TSH: the diagnosis of transient hypothyroidism is confirmed and therapy is definitively suspended.
Still, follow-up is necessary to monitor possible TSH increases, especially during puberty and pregnancy.
• Increased TSH: it means that CH is permanent (even though the cause cannot be found); therapy must be
re-started and taken life-long.
It is mandatory to re-evaluate after 2-3 years newborns that at the time of diagnosis present with:
• Normal thyroid position, size and morphology at US and/or scintigraphy
• Children born to a mother with autoimmune thyroiditis or in therapy with anti-thyroid drugs
• Children exposed to iodine excess/deficiency
On the other hand, it is unnecessary to re-evaluate babies who surely have permanent CH:
• Thyroid dysgenesis
• Thyroid dyshormogenesis
• Babies who have TSH level has been found elevated during therapy in the first years of life
13
Clinical manifestations
There are some precocious signs and clinical manifestations at birth, but they are not specific and so they’re
not always sufficient to make a diagnosis. Late signs are much more diagnostic and specific but if the diagnosis
is made at this stage, the child will be mentally retarded for whole life (cretinism).
Manifestations at birth Precocious signs Late signs
• Post-term birth (> 41 WoG) • Long term jaundice 3 • Dry skin and hair
• Birth weight > 4kg • Quiet sleeping • Wide nasal bridge
• Transient hypothermia • Hypoactivity • Hypotonia
• Large posterior fontanel (> 0.5 cm) • Poor feeding • Umbilical hernia
• Goiter (rare) • Poor suction • Macroglossia
• Respiratory distress during meals • Mixedema
• Constipation • Hoarse cry
• Abdominal distension • Developmental delay
• Poor feeding
• Lethargy
• Severe constipation
When a child has all the late signs he’s surely hypothyroid and mentally retarded. The classic manifestations
develop in the first 3 months of life and cannot/shouldn’t be seen in countries where neonatal screening for
hypothyroidism is performed because these screening programs allow a diagnosis of congenital hypothyroidism
in the first 2-3 weeks of life and thus newborns are treated before reaching these clinical conditions. Babies
identified by screening present with only some vague symptoms.

Diagnosis
Neonatal screening
Neonatal screening for congenital hypothyroidism has been introduced in Italy in 1992. The first screening
program has been introduced in Canada in 1974, then in Europe the first country to introduce it was Switzerland
(both Canada and Switzerland are countries with mountains and thus with iodine deficiency, and for this reason
the problem was more frequent in these countries with respect to the others).
Only 25% of newborns worldwide are submitted to neonatal screening for congenital hypothyroidism, which
means that in 75% of countries the risk of having mentally retarded subjects is still present.
CH has all the characteristics of a disease for which newborn screening is justified. It’s a common condition and
early diagnosis (preferably in the first few days of life) and early treatment can prevent mental retardation. At
birth, clinical picture is difficult or impossible to recognize so a test is needed to make the diagnosis.
Screening tests are specific, sensitive and cheap + the treatment is effective, which means that benefit-cost
ratio is highly favorable.
Screening methods consist usually in either:
• Dosage of TSH level: central hypothyroidism cannot be diagnosed because in this case TSH is not increased
• Dosage of TSH + T4: central hypothyroidism and Thyroxin-Binding Globulin deficiency can be diagnosed, but
it’s not very used because it costs too much compared to the other method
Blood specimen is taken at 2-3 days of life of the newborn. A full drop of blood is obtained by skin puncture of
the heel and dried on filter paper. Samples are sent to regional screening laboratories 4, where they determine
the level of TSH and call the hospital when a test is pathological.
If the screening gives back abnormal results, the child needs to be submitted to further investigations; if
hypothyroidism is confirmed he can start immediately the replacement treatment.

3
Infants who are breastfed can suffer from maternal milk jaundice, that is confounding factor that can delay diagnosis
4
In Italy there’s one screening laboratory for every region; in Lombardia the screening is performed in Ospedale Buzzi in
Milano
14
False negatives
Despite the technical development in laboratory methods, some false negative results still occur: it has been
calculated that 5% of hypothyroid newborns are not diagnosed by screening. The most common mistakes are:
• No blood specimen obtained
• Sample error in taking the blood (ex. small drop of blood)
• Blood sample does not reach the laboratory
• Mistakes in laboratory determination
• No communication from the laboratory to the hospital, or from the hospital to the family.
Furthermore, another limit is that in some cases there may be CH with late increase of TSH (1:18000),
particularly in premature infants, SGA [small for gestational age], fullterm newborns with severe diseases, so a
second test has been introduced to catch these cases (see next paragraph).
Therefore, when a pediatrician encounters a child with mental retardation of unknown origin, the level of
thyroid hormones must always be checked because neonatal screening may not always be trustworthy.

Cut-off values
Cut-off level for TSH in newborn screening is 10 mU/mL:
• If TSH>10 mU/ml, the newborn must be immediately submitted to a second test on capillary and venous
blood to confirm the diagnosis (T4, TSH). This must be regarded as a medical urgency.
• When TSH level is 6-10 mU/mL, a second screening is recommended at 15-30 days, especially if the mother
has subclinical hypothyroidism, or autoimmune diseases like type 1 diabetes, iodine overload (TC, vaginal
medications with povidone), amiodarone therapy during pregnancy.
A second screening test is also necessary at 15-30 days in newborns with:
- Down syndrome
- Mother treated during pregnancy for thyroid disease (both hyper and hypothyroidism)
- Severe diseases
- After blood transfusions
- Gestational age <33 weeks and birth weight <2000 g
In these cases, a delayed increase in TSH levels could occur.
Before the introduction of the newborn screening program, the incidence of CH diagnosed on the basis of
clinical manifestations was in the range of 1:7000- 1:10.000. After the introduction of screening programs, the
incidence had been found in the range of 1:3000- 1:4000 worldwide. The inclusion of transient CH may have
contributed to the increased reported incidence, as well as the lowering of TSH cut-off (once was 20 mU/ml),
with the detection of more infants with milder forms. Now in Italy the prevalence is 1:1500-2000 newborns.

Diagnostic exams
When the screening test for CH is pathological, the child has to be urgently called back to carry out other
investigations, confirm the diagnosis and start treatment as soon as possible. It must be regarded as an urgency
not because is a life-threatening condition, but because every day without treatment can lead to a reduced IQ.
Evaluations after recall include:
• To confirm the diagnosis: determination of serum T4 and TSH serum levels: T4 is low and TSH is high.
Reference values according to age:

15
 Reference values in premature infants in the first week of age according to gestational age:

• To find the cause and determine whether CH is transient/permanent:

- Imaging (Tn 99 or I123 scan and/or US): check if thyroid tissue is present or dislocated, the size and the
morphology of the thyroid gland.
a. Scintigraphy: never performed with 131I because the half-life is too long (8 days) and could be
potentially dangerous, so it better to use 99Tc or 123I scan. I
It is more invasive than US, but it is the most appropriate exam to evaluate ectopia and establishing
the exact localization of ectopic tissue.
If there is no uptake, it is still important to do a US, as the combination of the two exams is able to
distinguish true atresia from dyshormonogenesis and maternal antibodies.
b. Echography: needed to confirm agenesis, less useful for ectopia. In case of dyshormonogenesis it
can show an enlarged gland/ goiter.
- Anti-TSH receptor antibodies in the newborn and mother, due to transplacental passage of antibodies,
as blocking antibodies can inhibit development and function of the fetal gland
- Thyroglobulin level determination: it is directly related to the quantity of thyroid tissue present. It’ll be
low or absent in case of agenesis, high in case of goiter (dyshormonogenesis) or intermediate in case of
ectopia.
- Iodine dosage in urine to see if there’s iodine deficiency or iodine excess, should be performed in case
of a neonate living in areas with iodine deficiency or in the suspect of iodine overload.
• Determination of bone age: X-Rays of foot and knee are performed after the age of 6 months, to determine
bone age, in particular at X-Ray carpal bones are evaluated. This is important for the developmental
prognosis of the child. Normally at birth the nuclei of ossifications are:
- One core of ossification in the cartilage of distal femur (Béclard nucleus)
- One in the proximal epiphysis of the tibia
- In the foot: calcaneus, talus and metatarsal/phalanges
In case of hypothyroidism these nuclei will be absent or hypoplastic: the severity depends on the time of
onset and the cause (e.g. with thyroid agenesis there will be no nuclei).
This exam is thus fundamental for prognosis: it allows to determine the time of onset of hypothyroidism
and the severity of thyroid hormone deficiency during pregnancy. The more delayed the bone age, the
worse the hypothyroidism and thus the neurological prognosis, as mental retardation is related to the
severity of hypothyroidism and the time of initiation of the deficiency during pregnancy.

16
• Cardiological evaluation: ECG + echocardiography.
This is important to evaluate the possibility of starting the specific therapy without risks, since levo-
thyroxine has pro-arrhythmic effects;
Furthermore, it is important to evaluate the presence of cardiac malformations, as thyroid dysgenesis is
often associated with alterations in other organs, e.g. heart (8.4%), genitourinary tract, CNS, cleft palate.
• Transfontanellar cerebral US to evaluate CNS malformations
• Other investigations according to the clinical picture, e.g. karyotype analysis, molecular genetics analysis…
The technique used for imaging differ between centers and depends mostly on local experience and availability.
Thyroid function is not routinely checked in the mother at the beginning of pregnancy or during pregnancy as
it’s not included in the protocol, but now many mothers are starting to do these controls in the first and also in
the end of pregnancy.

Therapy
It’s very important to start the replacement therapy as soon as possible to avoid neurological sequelae, or in
general to have a better neurologic prognosis.
Treatment must never be delayed to perform investigations to look for CH etiology: it’s better to start the
treatment immediately and then perform other investigations.
The drug used is levo-thyroxine, which is available in tablets or drops.
There are some food or drug (e.g. soya milk, calcium, iron, aluminium hydroxide) that can lower thyroxine
absorption. If the child needs to take one of these, e.g. soya milk for an allergy to cow milk, then it is important
not to give them together with levo-thyroxine.
The dosage in newborns is much higher than in adults: 10-15 mcg/kg/die per os, in the morning, at least 2 hours
after the last meal and 20 minutes before the next one. It’s important to wait at least 20 minutes to have an
empty stomach and a complete absorption of the drug.
Dosage is usually higher (15 mcg/kg/die) in agenesis in respect to other forms of CH because hypothyroidism is
more severe. With therapy, there is usually a rapid normalization of TSH and T4 levels in 10 days.
17
In case of overdosing, the child can present some clinical manifestations similar to those of thyrotoxicosis:
tachycardia, agitation, craniostenosis, bone age acceleration.

Follow up
After starting treatment, the levels of TSH and T4 must be checked routinely 5; T4 must be kept near the upper
reference limit. If TSH is high even during treatment, it could be possible that:
• The drug is under-dosed and thus it’s necessary to increase the dosage
• The feedback is malfunctioning: even with normal T4, TSH does not decrease (this is especially seen when
initial levels were very high and when the therapy is delayed)
• Poor family compliance (for example, if the child cries because he’s hungry, the mother doesn’t wait 20
minutes and so the absorption of levothyroxine could be incomplete)
• Milk regurgitation, eliminating the drug as well.
Even if hypothyroidism may be transient, treatment must be continued till to the age of 2-3 yrs, with evaluation
after 1 month off-therapy
Other things to be checked include:
• Auxometry (child growth), bone age
• IQ + neurological exam, especially in children born with severe hypothyroidism; important to perform it
before starting school because if they have some problems, the school can provide special teachers for
them.
• Audiometry: hypoacusia is more frequent in children with CH than the general population.
Frequency of evaluation:
• Once a week in the first month of therapy
• Every 1-2 months till 6 months
• Every 3-4 months between 6 months and 3 years
• Every 6 and 12 months till puberty
• Always 1 month after dosage modifications (at any age) to see if modification of treatment has normalized
the values.

Prognosis
Neurological and somatic prognosis of CH depends on many factors:
• Etiology: prognosis is better in cases of hypoplasia, ectopia or dyshormonogensis with respect to agenesis
of the thyroid gland.
• Time of diagnosis and initiation of replacement therapy (now therapy is started in first 15 days of life)
• Time of onset of hypothyroidism during prenatal life
• Initial dose of levo-thyroxine
Before the introduction of screening, the mean IQ was:
• 89 in children diagnosed before the age of 3 months
• 71 in children diagnose between 3 and 6 months
• 54 in children diagnosed after the age of 6 months.

5
Actually, only TSH dosage is usually performed: it is the so-called TSH reflex: if it is too high, the laboratory automatically
checks T4, if it is too low it checks T3 and T4; if normal thyroid hormones are not measured.
18
 FETAL AND NEONATAL HYPERTHYROIDISM

As for hypothyroidism, also hyperthyroidism can be present in newborns when the mother is affected, or has
been affected in the past, by Graves’ disease. Indeed, a minority of newborns from mothers with GD develop
transient hyperthyroidism.
It can be very severe; if not well treated, the new-born can die due to heart failure or can develop
craniosynostosis with mental delay in later years.

Epidemiology
It is not as common as congenital hypothyroidism due to the passage of placental anti-thyroid antibodies; it has
a prevalence of 1/50,000 newborns.
About 1-2% of the offspring of mothers with an active Graves’ disease (diagnosed before or during pregnancy),
but also an inactive Graves’ disease (i.e. disease in remission after medical, surgical or radiometabolic
treatment), are affected by fetal or neonatal hyperthyroidism; the prevalence of GD during pregnancy is 0.1-
0.4%.

Pathogenesis
It is due to transplacental passage of antibodies directed against TSH receptors, with pathological manifestation
of hyperthyroidism resulting both in the fetus (from the II trimester) and in the newborn.
There are also other very rare non-autoimmune or permanent forms (i.e. not due to transplacental passage of
autoantibodies), usually due to genetic causes, so due to familiar (autosomal dominant) or non-familial sporadic
activating mutations of the TSH receptor (de novo germline or somatic mutation), which induce chronic
stimulation of the thyroid of the newborn.
The thyroid function of children of mothers with Graves’ disease become normal after TSH-receptor antibodies
disappear from the infant blood; hence, the clearance rate and the initial titer of TSH receptor antibodies are
the factors that influence the duration of the disease.
A minority of newborns develop transient central hypothyroidism (low TSH and low T4) due to impaired
maturation of the fetal hypothalamic-pituitary system following exposure to high levels of maternal thyroid
hormone levels. This can cause developmental delay.

Clinical manifestations
The disease may become apparent during pregnancy or immediately after birth. If the mother has been taking
anti-thyroid drugs until delivery (the drugs can cross the placental barrier and can have an action on the thyroid
of the child until their disappearance from the blood) or in case there are both inactivating and stimulating TSHR
Ab with different clearance rates, the manifestations can be delayed to a few days after birth.
Fetal hyperthyroidism presents with:
• Tachycardia
• IUGR (intrauterine growth restriction), low birth weight
• Goiter
• Prematurity
Neonatal manifestations are:
• Tachycardia (>160 bpm), arrhythmias and even heart failure if untreated (about 25% of newborns with
hyperthyroidism die of HF);
• Goiter (but it is a more common manifestation in cases of hypothyroidism during pregnancy);
• Irritability, hyperactivity, restlessness and hyperreflexia
• Sleep disturbances, with the tendency to sleep for only short periods;
19
• Hyperphagia nevertheless poor weight gain, vomiting and diarrhea;
• Prominent eyes due to lid retraction;
• Hepatosplenomegaly;
• A complication might be craniosynostosis, a precocious closure of the sutures of the skull (presenting with
small fontanelle), with mental development consequences;
• Advanced bone age
Correct management and treatment of GD during pregnancy may prevent development of intrauterine
hyperthyroidism, while overdose of antithyroid drugs may cause iatrogenic fetal hypothyroidism and goiter.
The presence of goiter in the fetus can cause labor dystocia, with non-physiological presentation, while
prolonged use of β-blockers by the mother can cause intrauterine growth retardation, post-natal bradycardia
and hypoglycemia. Early diagnosis and treatment of the newborns are essential for a good prognosis.
The half-life of the antibodies is about 2-3 weeks, so usually the disease lasts 3-4 months (unless
hyperthyroidism is caused by the non-autoimmune form due to TSH gene activating mutations; in this case the
disease is permanent). When the antibodies are cleared, the thyroid returns to normal with no permanent
structural changes.
Short- and long-term outcome depends on activity and duration of fetal and neonatal hyperthyroidism.

Diagnosis
Prenatal diagnosis can be made through:
• Fetal criteria:
- Heart rate
- Growth: assessed by sonographic evaluation
- Bone maturation: distal femoral centers at 32 weeks of gestation
- Fetal thyroid dimensions, through sonography.
• Maternal criteria during pregnancy include:
- Anti-TSH receptor antibody titers
- Anti-thyroid therapy use and dosage.
Previously, PTU (Propylthiouracil) was considered a better choice during pregnancy, since methimazole
was associated with certain malformations (aplasia cutis, corneal atresia, tracheo-esophageal fistula,
esophageal atresia, athelia6 or hypothelia); but now PTU is no longer used due to its liver toxicity
Neonatal hyperthyroidism is diagnosed just like in older patients:
1. Low TSH
2. High T3 and T4
3. Positive anti-TSH receptor antibodies.

Treatment
Since it is a transient condition, treatment is usually based on:
• Anti-thyroid drugs: the drug that is usually used is methimazole (0.5-1 mg/kg/die in 3 doses);
NB: Propylthiouracil should be avoided both in newborns and in the mother during lactation, because a
serious and potentially fatal dose-independent hepatotoxicity has been reported in children.
• In severe forms, high dose inorganic iodine (Lugol’s drops: 1 every 8 hours for few days) or iodinated
contrast agent (iopanoic acid 0.1-0.2 g/d);
• Alternative treatment: IV human immunoglobulins in analogy with other autoimmune diseases of the
newborns.
• In the future: blocking-type human mAb for the TSH receptor;

6
Athelia is the congenital absence of one or both nipple-areola complexes. It is a rare condition.
20
Furthermore, β-blockers can be used for tachycardia, but for short periods of time (propranolol, 1-2 mg/kg/d
in divided doses).
The child must be treated for the entire length of the disease, and the treatment should be stopped as soon as
TSH receptor antibodies become negative, to reduce the risk of relapse.
During treatment, the levels of T3, T4 and TSH must be controlled very often because of the risk of both
hyperthyroidism and hypothyroidism due to overtreatment.
The treatment for persistent hyperthyroidism due to activating TSH receptor mutation is thyroidectomy or
radioactive iodine ablation.

Prognosis
The prognosis depends on the severity of fetal hyperthyroidism, TSHR Ab levels at birth and clearance rate in
the newborn.
Long-term morbidities, which start most frequently in the fetal period, include:
• Brain damage (hyperactivity, impaired intellect)
• Skeletal damage (craniosynostosis, advanced bone age)
It is very important to treat the child properly to avoid these impairments, even though it is not easy, especially
when blood must be drawn from these patients, since veins are yet to develop completely and there is a higher
risk for anemia from blood withdrawal.

ACQUIRED HYPOTHYROIDISM

It is a form of hypothyroidism diagnosed in the first month of life or that presents at birth, but that was not
present in the pre-natal period. 7

Causes
Primary acquired hypothyroidism:
• Autoimmune thyroiditis: most common cause, presenting with a goiter
• Drugs
- Antithyroid drugs
- Antiepileptics: in particular, valproic acid, which seems to accelerate T4 catabolism due to enzymatic
induction at hepatic level
- Lithium: mood stabilizer in adolescents
- Antiarrhythmics e.g. iodine-containing amiodarone
- Thalidomide (immunomodulator)
- Antiretrovirals
• Iodine deficiency
• Environmental pollutants e.g. pesticides, herbicides
• Thyroid injury/infiltration
- External irradiation due to radiotherapy for Hodgkin lymphoma or neck cancer: these patients need a
30-40 year long follow-up

7
This definition comes from a previous sbob, so I think it is something that was said in class. I think this may refer to
acquired hypothyroidism specifically in children. In general, acquired hypothyroidism occurs when at birth the thyroid
was completely normal, but afterwards, at any point in life, there was some kind of disease that impaired the production
of thyroid hormones
21
 - Radioiodine due to therapy or incidental exposition
- Total or partial thyroidectomy
- Cystinosis: it is a rare, multisystem genetic disorder characterized by the accumulation of cystine in
different tissues and organs of the body, including the kidneys, eyes, muscles, liver, pancreas and brain.
Generally, cystinosis is broken down into three different forms known as nephropathic cystinosis,
intermediate cystinosis and non-nephropathic (or ocular) cystinosis
- Hemochromatosis
- Histiocytosis
• Congenital hypothyroidism with late-onset manifestations

Central acquired hypothyroidism: pituitary adenoma, germinoma, glioma, meningioma, craniopharyngioma,

cranial traumatism, autoimmune hypophysitis, metastasis, vascular alterations, histiocytosis, sarcoidosis,
hemochromatosis.

Clinical manifestations
Acquired hypothyroidism has many clinical manifestations, some typical of pediatric age and some present also
in adults.
Typical of pediatric age Present in both children and adults
• Progressive growth velocity retardation • Weight gain (not justified by increased food
• Bone age delay intake)
• Delayed puberty • Lack of appetite
• Worsening of school performance • Sleepiness, asthenia
• Precocious puberty with galactorrhea (when • Constipation
there is also increased prolactin – it is stimulated • Dry skin and hair
by TRH) • Intolerance to cold
• Menstrual irregularity
• High cholesterol
When the diagnosis is not performed immediately and the condition becomes long-lasting and more severe,
other serious manifestations can ensue:
• Hypothermia
• Heart failure with pericardial and pleural effusion
• Pseudo-bowel obstruction
• Neurological disorders such as depression, psychosis, ataxia, seizures
• Myxedematous coma

Autoimmune thyroiditis
The group of autoimmune thyroid disease (ATD) can present with different clinical forms depending on the type
of autoantibodies present.
• The most common is autoimmune (Hashimoto’s) thyroiditis
• Graves’ disease: patients with autoimmune thyroiditis can develop Graves’ diseases later in life, or a
subject with Graves’ disease can also have an autoimmune thyroiditis.
• Non-goitrous (atrophic) thyroiditis
• Post-partum thyroiditis
• Drug-induced: due to the administration of interferon a for hepatitis C infection, or amiodarone.
• CTL4-blocking antibodies for solid tumors.
Autoimmune (Hashimoto’s) thyroiditis is the most common cause of acquired hypothyroidism in both pediatric
age and in adults. It can be defined as a chronic inflammation of the thyroid gland whose etiopathogenesis
seems to be autoimmune (but is still incompletely defined).
22
Although Hashimoto’s thyroiditis and Graves’ disease have different phenotypes, they are generally believed to
share a number of common etiological factors. Both conditions may aggregate in the same family and may
coexist in the same thyroid gland in different periods of life, so some individuals may progress from one form
to the other. It is more frequent that Graves’ disease spontaneously culminates in hypothyroidism, while the
development of Graves’ disease from Hashimoto’s thyroiditis is rare.

Epidemiology
Autoimmune thyroiditis is the most common autoimmune disease, the most common endocrine disorder, the
most common cause of hypothyroidism in iodine-repleted areas and the most common thyroid disorder in the
pediatric age range, affecting 2-3% of individuals after the age of 6 years.
It’s more frequent in females than in males (F:M = 4-7:1) and it’s more frequent in patients with Turner
syndrome, Down syndrome or other autoimmune diseases (celiac disease, Diabetes Mellitus type 1…),
therefore people affected by any of these must be screened frequently for possible thyroiditis.

Pathogenesis
It is an organ-specific autoimmune process characterized by interstitial infiltration of lymphocytes in the gland
(it is also known as chronic lymphocytic thyroiditis) and the presence of serum antibodies against thyroid
antigens, mainly thyroid peroxidase (TPO) and thyroglobulin (Tg).
Autoimmune thyroiditis results from the interaction between
genetic predisposition and environmental triggers of different kinds,
leading to the breakdown of immune tolerance, with expression of
MHC class II on the surface of thyroid cells. This leads to the
development of auto-antibodies directed against the thyroid cells.

Autoimmune hypothesis
The autoimmune hypothesis about the pathogenesis of Hashimoto’s disease is justified by:
• Presence of specific auto-antibodies (TgAb, TPO)
• Association with MHC and cytotoxic T-lymphocyte antigen 4 (CTLA-4) gene polymorphism
• Association with other autoimmune disorders, including celiac disease, vitiligo, type 1 diabetes, atrophic
gastritis, multiple sclerosis, Addison’s disease, Sjögren syndrome, LES, rheumatoid arthritis
NB: patients with any of these must be screened for thyroid antibodies
• Association with other autoimmune pathologies in the form of an autoimmune
polyglandular/polyendocrine syndrome (APS):
- APS-1: ≥2 of cardinal components: hypoparathyroidism, primary adrenal insufficiency (Addison’s),
chronic mucocutaneous candidiasis. Hashimoto Thyroiditis is not a cardinal component but might be
present.
- APS-2: autoimmune thyroiditis + adrenal insufficiency (invariably present), type 1 diabetes and ovarian
insufficiency
- APS-3: autoimmune thyroiditis + other autoimmune disease (excluding autoimmune adrenal
insufficiency, hypoparathyroidism, chronic candidiasis)
- APS-4: everything that does not fall under APS-1, 2, 3.

Genetic predisposition
It is mainly demonstrated by:
• Class II MHC genes: HLA-DR3 in non-goitrous thyroiditis; HLA-DR4 and HLA-DR5 in Hashimoto’s thyroiditis
• Non-MHC genes: AIRE (autoimmune regulator gene) which is mutated in APS-1, CTLA-4 costimulatory
molecule genes
• Familiarity for thyroid disease (i.e. often positive family history for autoimmune diseases of the thyroid or
other organs).
23
Environmental triggers
The precise environmental trigger(s) leading to the development of AIT remains unclear. Probable ones are:
• High iodine diet, which induces Tg autoantibodies by increasing the immunogenicity of thyroglobulin. This
has been proven in animal studies: highly iodinated Tg synthesized by animals fed with a high iodine diet is
significantly more immunogenic than Tg containing fewer iodine atoms. Furthermore, epidemiologic data
in humans show an increase of HT in countries after correction of iodine deficiency through the addition of
iodine to table salt
• Drugs (amiodarone, INF-α, IL-2)
• Infections: viral (coxsackie B virus, rubella) and bacterial (Yersinia enterocolitica, Helicobacter pylori),
probably due to some mechanisms of molecular mimicry between thyroid antigens and bacterial antigens
• Stress (H-P-A axis activation)
• Hormones, in particular estrogens (sex predisposition is F>M)
• Smoking
• Pollutants
• Irradiation of the thyroid (thyroid autoantigen exposition)
• Radioiodine (thyroid autoantigens exposition).

Clinical manifestations
Clinical features can include both local and systemic manifestations.
• Goiter (not always present): the thyroid gland is often diffusely enlarged, seldom nodular, with a rubbery
consistency; it can also be asymmetric. When extremely enlarged (which is not very common), it can cause
compression of cervical structures that are close to the thyroid, inducing:
- Dysphonia (involvement of the recurrent laryngeal nerve)
- Dysphagia (from the impingement upon the esophagus)
- Dyspnea (from restriction of the trachea)
• Systemic manifestations originate from loss of function of the thyroid and subsequent hypothyroidism,
however, in many cases of autoimmune thyroiditis, there is normal thyroid function (euthyroidism)
• Clinical manifestations of the associated autoimmune disease can be present (e.g. celiac disease, psoriasis,
type 1 diabetes).
At the moment of diagnosis, the subject can present with:
• Transient hyperthyroidism (5-10% of cases), due to discharge of preformed thyroid hormones from the
damaged gland
• Euthyroidism (many of the patients)
• Euthyroidism → hypothyroidism (overt or subclinical)
• Hypothyroidism
• Hypothyroidism → euthyroidism (not very frequent).

Clinical evolution
The clinical evolution of autoimmune thyroiditis over time is not the same in all cases.
Natural history seems to be characterised by a trend towards progressive deterioration of thyroid function in
~50% of children affected by autoimmune thyroiditis but euthyroid at diagnosis. For this reason, even the
patients with normal thyroid hormone levels must be regularly checked and follow up is mandatory.
The presence of goiter and elevated antibody levels at presentation may be considered as predictive of future
development of hypothyroidism. The association with other autoimmune diseases does not influence the
evolution of thyroid function.

24
Risk factors for the development of hypothyroidism:
• Large goiter
• High antibodies titer
• Young age at presentation of AIT
• Familiarity for autoimmune thyroid disease (ATD)
• Down syndrome
• Turner syndrome.
Subjects with any risk factor must be followed more strictly.

Hashimoto’s encephalopathy8
It is a lesser-known type of encephalopathy that can be present in a patient with autoimmune thyroiditis.
The clinical picture is heterogeneous, and it can be present both in euthyroid and hypothyroid patients.
It is characterized by the presence of:
• Impairment of cognitive function
• Behavioral and mood disorders
• Epilepsy-like seizures resistant to anti-convulsive treatment
• Motor symptoms such as tremors, myoclonus, chorea, nystagmus, ataxia
• Confusion, headaches, hallucinations
• Stroke-like episodes
• Presence of high thyroid antibody levels, especially anti-TPO Ab
Although all of the pathogenic components have not yet been clearly elucidated, it is believed that brain
vasculitis and autoimmunity directed against common brain-thyroid antigens represent the most likely etiologic
pathway.
The MRI manifestations of HE can vary from normal appearance, ischemic lesions, demyelination, and vasogenic
edema to atrophy. Once the diagnosis is made, corticosteroid treatment usually provides a dramatic recovery.
The disease is rare and hard to diagnose; in reported cases it affects females and only in very few cases it affects
children < 10 years.

Diagnosis
Diagnosis can be reached thanks to:
• Presence of typical clinical signs and symptoms (goiter, poor linear growth in case of thyroid hypofunction)
• Routine examination
• Screening in patients with other autoimmune diseases or familiarity for ATD (in these subjects, screening
through thyroid hormones and thyroid autoantibodies is periodically performed).
Laboratory evaluation includes:
• Anti-thyroglobulin and anti-TPO antibodies concentrations in serum: anti-TPO are more strongly associated
with hypothyroidism than TgAb (i.e. anti-TPO antibodies are more sensitive screen for AIT).
There is also a relationship between thyroid gland volume and anti-TPO concentration.
• TSH serum level and, in case of elevation, serum T4 evaluation. However, abnormal thyroid hormone levels
are not necessary to diagnose AIT.
After laboratory tests, an ultrasonography of the thyroid is needed because it can detect typical and diagnostic
alterations. In the past, before the individuation of these characteristic, a fine needle aspiration used to be
performed for demonstration of lymphocytes infiltration, but after the discovery of the classical findings of AIT
at US, FNA has no longer be performed.

8
This whole paragraph is not present at all on the slides, but was in the sbobina.
25
Thyroid ultrasonography shows a diffusely heterogeneous tissue with hypoechogenic areas9 (reflecting either
reduction of colloid content or lymphocytic tissue infiltration), coarse echotexture, thick fibrous septa; on Color
doppler, the vascularity is normal or decreased.
Other factors to be evaluated include:
• Screening for other autoimmune diseases: tTG IgA (celiac disease), anti-GAD65 and anti-IA2 Ab (DM1), PCA
(parietal cell antibodies, for autoimmune gastritis), ANA, anticardiolipin Ab, cortisol, ACTH, calcium, PTH.
Since antibodies against adrenal gland antigens are difficult to detect in routine laboratory setting, checking
cortisol and ACTH is necessary to exclude concomitant adrenal involvement (Addison’s disease is a possible
autoimmune condition associated with AIT). For hypoparathyroidism, calcium and PTH are checked
• Auxometry (height and weight), bone age.
• Thyroid uptake scan (radioactive iodine uptake test) and FNAB (fine needle aspiration biopsy) are not
needed for the diagnosis of autoimmune thyroiditis, but they have to be performed in case of nodules,
since thyroid cancer is more frequent in patients with autoimmune thyroid diseases than in the general
population.

Treatment
Replacement therapy with levothyroxine must be started only in case of thyroid hypofunction (if the patient is
euthyroid, no treatment is needed), in order to normalize the secretion of TSH, FT4, reduce the size of the
goiter 10 and minimize the potential development of side effects (e.g. deterioration of school performance, short
attention span, behavioral problems). If TSH levels are very high, it will require a lot of time to normalize.
There is no general agreement on the management of subclinical hypothyroidism (i.e. normal FT3 and FT4 levels
but elevated TSH) in children and adolescents. There is no general need for replacement, but close observation
must be done to start treatment in case of progressive increase in TSH and to avoid the evolution to overt
hypothyroidism. And to reduce cardiovascular risk and hypercholesterolemia.
The dose of levothyroxine is established based on weight and age. The dose is higher in children than in adults.
There is no need to start with a high initial dose like in newborns with congenital hypothyroidism (10 μg/kg/die
in newborns and infants, 2 μg/kg/die in older children), since after the first years of life, subjects are not at risk
of developing mental retardation. So, the starting dose in acquired hypothyroidism is usually lower than the
presumed need of the patient and is progressively increased every 2 weeks until reaching a dose that normalizes
TSH and FT4.
Before starting replacement therapy, it is mandatory to evaluate the adrenal function, because in case of
Addison’s disease, starting treatment for hypothyroidism before treating the hypoadrenalism can cause an
adrenal crisis11. So, if a patient has both Addison’s disease and Hashimoto’s thyroiditis, hypocortisolism must
be treated first, and when cortisol and ACTH levels become normal, replacement therapy for hypothyroidism
can be started.
During the initial period of the replacement therapy, the levels of FT4 and TSH have to be evaluated every 4-6
weeks. Once euthyroid state has been reached (i.e. normalization of both hormones), patients should be
monitored every 6 months, after 1 month in case of dosage modification, or immediately in case of clinical signs
or symptoms.

9
The presence of hypoechoic micronodules (1-6 mm) with surrounding echogenic septations is also considered to have a
relatively high positive predictive value. This appearance may be described as pseudonodular or a giraffe pattern.
10
Thyroid mass increases not only due to lymphocytic infiltration but also due to the overstimulation from high levels of
TSH
11
Adrenal crisis (also known as Addisonian crisis and acute adrenal insufficiency) is a potentially life-threatening medical
emergency requiring immediate treatment. Characteristic symptoms are: sudden penetrating pain in the legs, lower back
or abdomen, confusion, psychosis, slurred speech, severe lethargy, convulsions, fever, hyperkalemia, hypercalcemia,
hyponatremia, hypotension, hypothyroid (low T4 level), severe vomiting and diarrhea, resulting in dehydration, syncope.
26
Usually thyroidectomy is not necessary in case of Hashimoto’s thyroiditis. However, it is indicated if the thyroid
is really big and causes local manifestation or in case of nodules, since subjects with autoimmune thyroid
disease are at higher risk of thyroid carcinomas, more than subjects without thyroid autoimmunity.
Some drugs and foods can interfere with thyroxine absorption, in particular iron, calcium carbonate, fibers and
soya.
Iron especially should be taken into consideration and monitored, because of its widespread use. In the case
the subject needs both treatments, iron must not be given with thyroxine but after some hours.
Like for newborns, thyroxine must be taken before breakfast, and the patient must wait at least 20 minutes
before eating.
Other drugs can increase thyroxine clearance, e.g. anti-epileptic drugs like sodium valproate and phenobarbital,
as well as rifampicin. In children treated for seizures with these drugs, thyroid hormones must be evaluated
during follow up.
Patients who take levothyroxine have increased sensitivity to digoxin and a decreased sensitivity to
anticoagulants.
In a subject with undertreated hypothyroidism, narcosis is enhanced, so the patient might have more difficulty
in waking up after anesthesia. For this reason, it is better to check the thyroid function in patients who needs
narcosis, e.g. for surgery reasons or other reasons.
On the other hand, in case of overtreatment, clinical manifestation of thyrotoxicosis can develop.

HYPERTHYROIDISM
Thyrotoxicosis is a condition characterized by an excess of thyroid hormones in the body, whereas
hyperthyroidism is defined as an increase in thyroid hormones synthesis and secretion. Thyrotoxicosis can have
both an endogenous and exogenous cause, while hyperthyroidism is due to hypersecretion.
The clinical manifestation of thyrotoxicosis, both endogenous and exogenous, i.e. the tissue effects of high
concentrations of thyroid hormones, can be different according to:
• The severity of the disease
• The age of the patient
• The presence of extrathyroidal manifestations (like ophthalmopathy)
• The pathogenesis of the condition.

Etiology
• Graves’ disease, the most common and most important condition;
• Hashitoxicosis: initial temporary phase of Hashimoto’s thyroiditis;
• Subacute thyroiditis: hypersecretion of thyroid hormones during a subacute thyroiditis due to viral
infection;
• Exogenous thyroid hormone excess (factitious hyperthyroidism): for instance, some people, especially
adolescents, take thyroid hormones to lose weight, which can lead to a condition with clinical
manifestations of thyrotoxicosis other than weight loss; antibodies are not present, thyroglobulin is always
low, while in Grave’s disease and in all the other cases of real hyperthyroidism, thyroglobulin is always
increased;
• Iatrogenic/drug-induced hyperthyroidism;
• TSH-secreting adenomas of the pituitary gland, which causes continuous thyroid stimulation;
• Autonomous overproduction of thyroid hormones by one (solitary toxic adenoma) or multiple (toxic
multinodular goiter, more frequent in areas of low iodine intake) hyperfunctioning nodules; thyroid cancer
27
• Iodine excess;
• Some genetic conditions characterized by pituitary resistance to the action of thyroid hormone, so that the
negative feedback is not functioning, causing the pituitary to continuously produce TSH despite the increase
in T3 and T4 levels.

Graves’ Disease
It is the most common cause of thyrotoxicosis, affecting 2.7-3% of females, while being much more uncommon
in males (about 10x less frequent).
This condition, like Hashimoto’s thyroiditis, has an autoimmune pathogenesis, with the presence of specific
autoantibodies stimulating the thyroid gland to produce T4 and T3. The thyroid is characterized by an interstitial
infiltration of lymphocytes and usually there is a familiarity for thyroid diseases. Also this condition can be
associated with other autoimmune disorders, like diabetes, coeliac disease or others.

Etiopathogenesis
The antibodies responsible for the continuous stimulation of the thyroid are anti-TSH receptor autoantibodies
(TSHR Abs), which are specific for Graves’ disease. They bind to the TSH receptors on thyroid cells, stimulating
the production of T3 and T4.
TSH level is low because negative feedback due to thyroid hormones is normally functioning, but stimulation is
not due to TSH as it should be, but to the autoantibodies.
These antibodies also cause an increase in volume of the thyroid, together with an increase in vascularisation
of the gland.
In some cases, an infection by Yersinia enterocolitica, a bacterium that causes gastrointestinal disease, precedes
of some months the onset of Graves’ disease, which raises the suspect of molecular mimicry of the TSH receptor
as a possible pathogenetic mechanism.
Genetic factors are more important than environmental factors in the pathogenesis of Graves’ disease, with
80% of the risk being due to genetic mechanisms, while 20% by environmental influences.
• The genetic susceptibility is demonstrated by the family history of relatives positive for other autoimmune
disorders of the thyroid or other organs, along with the association with some HLA class II antigens, like
HLA-DR3 and DQA1*0501.
• On the other hand, environmental influence is shown by association with:
- Some infectious diseases, mainly Y. enterocolitica
- Stress
- Smoking
- Hormones, i.e. estrogens (F/M = 7-10/1)
- Ageing
These last two factors correlate with the high incidence of Grave’s disease in post-pubertal women
- In some cases, the use of some drugs containing iodine, like amiodarone, can be the cause of
autoimmune hyperthyroidism.

Clinical manifestations
The main clinical manifestations in pediatric age are related to hyperthyroidism, but clinical manifestations of
Grave’s disease are not limited to the thyroid gland: ophthalmopathy and dermopathy can also occur, although
they are much more frequently seen in adults than children, in whom the main clinical manifestation are related
to the thyroid.
Triad of Graves disease:
• Goiter: usually present, diffuse and symmetric goiter, rarely nodular, with normal or firm consistency. A
thyroid bruit can be heard by auscultation (due to increased vascularity).
28
• Ocular involvement:
- Usually a retraction of the upper lid can be seen (either mono- or bilateral)
- Tremors of the closed lids,
- Infiltrative ophthalmopathy or ophthalmomyopathy are usually not present in childhood and
adolescence.
- Exophthalmos, when one or both eyes protrude for more than 2 cm (this can be measured through
exophthalmometry)
- Lagophthalmos, which means that the eyes do not completely close during sleep.
- Both the two latter eye conditions can lead to other ocular symptoms like: irritation, excessive tearing,
blurred vision, loss of visual acuity, conjunctivitis and corneal ulcerations and infections.
• Skin involvement: infiltrative dermopathy, a hyperpigmented induration of the skin of the legs in the
pretibial area (pretibial myxoedema), is usually absent in paediatric age; it is not common in adults either
(only in 5-10% of cases).
Other symptoms include those of hyperthyroidism:
• Heat intolerance
• Weight loss despite increased/normal food intake
• Increased frequency of bowel movements
• Tachycardia
• Tremors of the outstretched fingers or during fine movements (the child changes handwriting
characteristics, is not able to draw anymore…)
• Growth acceleration
• Neuropsychiatric symptoms
- Anxiety
- Irritability
- Insomnia
- Emotional instability
The severity of Graves’ disease is major in young children: when a child of 5-7 years of age has the disease,
controlling it with medical treatment is usually not as easy as in older patients, and they usually have to undergo
a thyroidectomy.

Clinical evolution
The evolution of Grave’s disease following treatment can be different:
1. Permanent remission with maintenance of euthyroidism.
2. Remission followed by relapse.
3. Permanent hypothyroidism.
Both the first and last case (remission with euthyroid and hypothyroidism) are good prognostic evolution of
Graves’ disease, while in case of relapse after medical treatment the management approach has to be changed,
going for thyroidectomy or radiometabolic treatment with radioiodine.

Diagnosis
Lab tests
• Low TSH levels (below normal range) and an increase in T3 and T4;
• Anti-thyroid antibodies (TSHR Ab, TPO, TgA) are usually positive; in particular, the most specific are anti-
TSH receptor antibodies;
• Increased thyroglobulin;

29
Imaging
• Thyroid US has some specific characteristics: diffusively heterogeneous, coarse echostructure, presence of
thick fibrous septa, and, as opposed to Hashimoto’s, there is hypervascularization of the gland at Color
Doppler;
• Thyroid scinti scan is not usually performed in children
In pediatric age and until puberty, growth has to be checked, so height, weight and bone age, which is usually
advanced and accelerated due to thyroid hyperfunctioning.

Treatment
There are 3 treatment options to choose from after diagnosis has been established: anti-thyroid drugs,
radioiodine or surgery.
The choice varies in different countries, in particular, in Europe, the first-line treatment is usually medical, with
the use of antithyroid drugs, while radioiodine and surgery are used when medical treatment has failed or for
severe side effects. In other countries (like the U.S.), mainly for economic reasons, the first-line is radioiodine,
because it has a cheaper follow-up after treatment, since the patients do not need to be checked every 3
months with antibody dosage, US and thyroid hormones measurement.
The choice among these treatments needs to take into account:
• Likelihood of remission with drugs;
• Age of the patient (radioiodine is not performed in very young children);
• Possibility of future pregnancy;

30
• Size of the goiter (for very big goiters, the dose of radioiodine must be higher, so it is not the ideal treatment
in this case);
• Possible comorbidities

Indications Advantages Disadvantages

Antithyroid drugs Newly diagnosed Grave’s Non-invasive, outpatient Low cure rate (average
disease, short-term therapy, low initial cost, 30-50% in Grave’s
therapy before easily applicable, low disease), adverse effects
radioiodine or surgery, risk of permanent (1-5%) which ay be
children, pregnancy hypothyroidism, possible severe, frequent
immunomodulatory follow up and
effects compliance required
Radioactive iodine Newly diagnosed Grave’s Effective cure of Slow induction of
disease, relapsed hyperthyroidism, euthyroidism, induction
Grave’s disease, toxic outpatient therapy, of permanent
nodular hyperthyroidism easily applicable, hypothyroidism in >60%
reduction of goiter size patients, potential
worsening of
ophthalmopathy,
deferral of pregnancy for
6 months (might be
teratogenic), adherence
to radiation protection
guidance required
Surgery Presence of large goiter, Rapid control of Invasive, expensive,
pregnancy (if clinically hyperthyroidism, rapid permanent
significant drug relief of compressive hypothyroidism,
sideeffects), serious symptoms, 100% cure inpatient treatment, risk
ophthalmopathy, severe of complications
adverse reaction to (recurrent laryngeal
antithyroid drugs nerve damage,
hypoparathyroidism),
pain, scarring

Antithyroid drugs
Not many anti-thyroid drugs are available, there are only 3:
• Methimazole, which is available also in Italy;
• Propylthiouracil (PTU), which was used in the past but is no longer used, at least in pediatric age and during
pregnancy, due to hepatotoxicity (there have been some cases of death by liver failure);
• Carbimazole
These drugs act by inhibiting the organification12 of iodine, thus decreasing the synthesis of thyroid hormones,
but do not decrease level of autoantibodies, or just slightly do so. Propylthiouracil (PTU) also has the ability of
limiting the peripheral conversion of T4 into T3 (but is no longer used anyways). These drugs can also be
immunosuppressive.
Methimazole and carbimazole can be taken once or better twice a day, while PTU had to be administered three
times a day due to its short duration of action.

12
Organification is a biochemical process that takes place in thyroid glands. It is the incorporation of iodine into
thyroglobulin for the production of thyroid hormone, a step done after the oxidation of iodide by the enzyme thyroid
peroxidase (TPO).

31
These drugs cross the placental barrier and can inhibit fetal thyroid function, so they can cause hypothyroidism
in the fetus during pregnancy, with consequent mental delay afterbirth.
They can be used for a short term to prepare for radioiodine or surgery, but also as long-term treatment, for at
least 2 years, to try to induce long lasting remission.
The starting dose of methimazole is 15-20 mg/day (5mg/tablet, so 3-4 tablets) that is usually decreased after 4
weeks to maintenance levels (5-10 mg/day), if the thyroid hormone levels had a significant decrease. Starting
dose for PTU was 150-200 mg (50 mg/tablet).
At the beginning of treatment, thyroid function must be assessed often, every 4-6 weeks; later on, follow up
can be done every 3 months.
Overtreatment can cause reversible hypothyroidism. The main cause of treatment failure is lack of compliance;
patients must be checked very often and sometimes do not regularly come to control visits.
The duration of this treatment is variable, but it must continue for at least 12-18 months. Determination of TSH
blocking antibodies before drug withdrawal might indicate the risk of relapse, while their negativization can be
considered a reason to stop the treatment and is considered a good prognostic factor.
With medical treatment, the rate of permanent remission is <50%.
Negative prognostic factors are represented by:
• Severe disease with a very high initial level of T3 and T4
• Male sex
• Young age.

All these drugs can have severe side effects; the most severe is death due to liver failure by propylthiouracil,
and for this reason PTU should not be used in pediatric age.
Also carbimazole and methimazole can cause severe side effects, the most severe is represented by drastic
decrease of neutrophils (agranulocytosis), which is usually reversible, but medical treatment must be
completely stopped if it happens, and the patient must undergo surgery or radiometabolic treatment.
Other side effects include cholestatic hepatitis, teratogenic effects (in case of pregnancy, even after
discontinuation of drugs), aplastic anemia, thrombocytopenia and hypoglycemia.
More common and less severe side effects are rash, arthralgia, fever and transient granulocytopenia - but not
agranulocytosis. Uncommon side effects include: nausea and vomiting, abnormalities of taste and smell, and
arthritis. Thus, all of these drugs can cause some severe side effects, for this reason patients must be followed
up at least every three months for thyroid hormones determination, but also for evaluation of blood cells and
hepatic enzymes.

32
During the treatment of Graves’ disease, especially at the beginning, other drugs may be necessary, like β-
blockers to decrease the adrenergic manifestations of the disease, e.g. tachycardia, tremors and retraction of
the lids; usually propranolol is used in three doses (1-2 mg/kg per day) but this drug can cause hypoglycemia,
and it also must be avoided in asthmatic patients and patients with respiratory obstructive disease because it
can worsen respiratory obstruction; so, a thorough medical history for these conditions is necessary. These
drugs must be avoided during pregnancy, because β-blockers can cause low heart rates and malformations in
the fetus.
If anti-thyroid drugs cannot obtain permanent remission, or in case they have to be stopped because of side
effects, or even just due to lack of compliance, the other two treatment options must be used.

Radioiodine
Radioiodine treatment induces fibrosis of the gland, decreases the secretion of thyroid hormones and causes
long-term, permanent hypothyroidism.
Graves’ ophthalmopathy is a contraindication to the use of radioiodine because it worsens eye manifestations
(exophthalmos or the others).
Long-term side effects are not fully known, but radioiodine may increase the risk of cancer, not only of the
thyroid but also of the breast and esophagus, since also these structures can have an uptake of radioiodine, and
may cause malformation in the fetus, particularly if used in very young patients.

Surgery
Finally, if previous therapeutic approaches have failed or cannot be employed, surgery can be used.
Thyroidectomy is not total, like in cancer, but subtotal, so a small part of the gland is left in place, also in order
to avoid hypoparathyroidism.
Indications for surgery in Graves’ disease are:
• Large goiter, because in such cases the dose of radioiodine would be very high carrying the risk of more
severe side effects;
• Suspicion of coexisting thyroid cancer;
• Presence of a severe ophthalmopathy;
• Pregnancy – or desire for pregnancy in short-term;
• Relapse after anti-thyroid drugs.
Complications can be more or less frequent according to the ability and experience of the surgeon, so
thyroidectomy should always be done by surgeons who are experienced in this kind of procedure.
Complications are:
• Recurrence of hyperthyroidism, if residual thyroid is too big (0.6-9.8%)
• Occurrence of permanent hypothyroidism (5.8-75%)
• Permanent hypoparathyroidism, in case the surgeon also removes all the 4 parathyroid glands together
with the thyroid (0.0-3.6%)
• Damage to the laryngeal recurrent nerve, which causes problems in speech (0-3.4%).
Patients should be returned to euthyroid state with antithyroid drugs before surgery, to avoid release of high
quantity of hormones from the thyroid during surgery, which would lead to a thyroid storm, a very severe
thyrotoxicosis characterized by high fever, high heart rate, sometimes epilepsy.
Lugol’s solution (potassium iodide) is also administered for at least 7-15 days prior to surgery to reduce thyroid
blood flow and intraoperative blood loss.

33