11

Paediatric endocrine and metabolic

emergencies

P. C Z E R N I C H O W
P. C. SIZONENKO

The symptomatology of paediatric endocrine and metabolic emergencies at

the newborn period and during infancy differs from that during childhood
and adulthood. During childhood, endocrine and metabolic emergencies
resemble those observed in the adult. However, for dehydration and shock,
techniques and dosage of drugs should be adapted to the weight and height
of the patient. Most of the emergency conditions in older children are very
similar to those described in other chapters concentrating mainly on adult
endocrinology. Here the focus will be on acute problems during the
perinatal period and the first years of life.
Before birth the fetus depends on maternal substrates supplied through
the placental unit. At birth the supply is abruptly interrupted, and the
newborn has to adapt rapidly to the extrauterine life. Such adaptation is
usually achieved without difficulty. Certain neonatal emergencies including
hypoglycaemia and hypocalcaemia can be predicted to a certain extent:
prematurity, smallness for gestational age, etc. Other endocrine disorders
that develop rapidly after birth are familial and such information may
provide diagnostic clues. Unexplained neonatal death during previous
pregnancies should arouse suspicion of undiagnosed metabolic or endocrine
disease. Genetic counselling is now widespread and helps to manage the
present and subsequent pregnancies, Maternal endocrine diseases, such as
gestational or insulin-dependent diabetes mellitus, treated or untreated
hyperthyroidism, hyperparathyroidism, are of importance for the diagnosis
of potential problems for the newborn. Conversely, in rare cases, neonatal
emergencies may lead to the recognition of an unknown maternal endocrine
disease.

DISORDERS OF CALCIUM AND PHOSPHORUS METABOLISM

Hypocalcaemia
During the last trimester of gestation, the fetus receives from the mother
100-150 mg/kg of fetal weight of calcium and 80 mg/kg of phosphorus per
Bailli~re' s Clinical Endocrinology and Metabolism-- 193
Vol. 6, No. 1, January 1992 Copyright© 1992,by Bailli~reTindall
ISBN0-7020-1485-0 All rights of reproductionin any formreserved
194 P. CZERNICHOW AND P. C. SIZONENKO

day (Shaw, 1976; Widdowson et al, 1963). During pregnancy, supplemen-

tation with calcium and vitamin D has been suggested in mothers with low
intake of milk or sun exposure. Maternal milk contains a low supply of
calcium and phosphorus. Its calcium concentration being 300mg/1, an
amount of less than 50 mg/kg/day is supplied to the newborn, while with a
phosphorus concentration of 150 rag/l, less than 25 mg/kg/day is supplied. In
the preterm baby, intestinal absorption of calcium is low and results in a
retention of only 30 mg/kg/day of calcium (Baltrop et al, 1977). Feeding with
cows' milk (1200mg/l of calcium and 900mg/1 of phosphorus) or other
high-phosphorus formula may reduce the intestinal absorption of calcium.
Furthermore, in such cases, the inability of the neonate to excrete sufficient
phosphorus in the urine may contribute to the high concentration of plasma
phosphorus observed in some babies.
Neonatal hypocalcaemia is divided into 'early' and 'late' forms (Table 1).
The late form includes after the first week of life prolonged hypocalcaemia
(persistent hypocalcaemia).
Clinical signs of hypocalcaemia include twitching of the extremities,
agitation, tachypnoea with episodes of apnoea, tachycardia, hypotonia,
high-pitched voice, convulsions, swelling of the fontanel and cardiac failure.
These symptoms are not specific since they can also be found in normo-
calcaemic infants, particularly in the case of hypoglycaemia. So, blood
Table 1. Aetiology of hypocalcaemia in infants and in children.
Neonatal period
Early neonatal hypocalcaemia (during the 1st 72 h)
Prematurity
Perinatal incident: asphyxia, respiratory distress syndrome, sepsis, infant of diabetic
mother
Late neonatal hypocalcaemia (after 72 h)
Transient hypoparathyroidism
secondary to maternal diabetes
secondary to maternal hyperparathyroidism
idiopathic (high phosphorus intake, vitamin D deficiency)
Persistent hypocalcaemia
Congenital chronic hypoparathyroidism
Di George syndrome
familial, idiopathic
Primary hypomagnesaemia

During childhood
Rickets, vitamin D deficiency
Abnormal vitamin D metabolism, pseudoresistant rickets
Transient hypoparathyroidism, late onset, remission before one year of age
Congenital chronic hypoparathyroidism
Acquired hypoparathyroidism
post-thyroidectomy
idiopathic, autoimmune
Pseudohypoparathyroidism, disorders of protein G
Miscellaneous causes
during therapy of leukaemia secondary to acute cell destruction induced
hyperphosphoraemia
Association with severe hypoproteinaemia
PAEDIATRIC EMERGENCIES 195

glucose should be checked. Electrocardiographic recording is less useful as

the signs (lengthening of the Q-T interval) do not always correlate with the
fall in plasma total calcium. These symptoms should disappear with
normalization of blood calcium. Hypocalcaemia is usually defined as a total
plasma calcium of less than 1.75mmol/1 (7.5mg/ml) evaluated on two
sequential blood samples within the first 72 h of life (Tsang, Donovan and
Steichen, 1976). Plasma calcium ionic activity measured directly with ion-
specific electrodes has recently been found to reflect more accurately the
state of calcium in blood than total calcium (Lynch, 1990).

Early neonatal hypocalcaemia

Early neonatal hypocalcaemia observed during the first 3 days of life occurs
with increased frequency in preterm babies, asphyxiated newborns and
infants from diabetic mothers (R6sli and Fanconi, 1973). In term babies,
plasma concentrations of total and ionized calcium correlate with gestational
age (Tsang et al, 1979). Reasons for this fall in calcium are still debated:
transient hypoparathyroidism or diminished calcium response to parathyroid
hormone, increased calcitonin concentrations, defects in metabolism of
vitamin D may play a role. Early hypocalcaemia should be readily treated
because of the danger of apnoea.
Calcaemia less than 2mmol/1 can be prevented by adding calcium
gluconate (8,75mmol/kg/day, i.e. 35mg/kg/day) to the dextrose infusion
(Salle et al, 1977). Oral supplementation of calcium has also been advocated
(70-100 mg/kg/day) but is often poorly tolerated. Vitamin D supplemen-
tation of the newborn has a weak effect on the hypocalcaemia. In urgent
situations, 5 mg/kg/min of calcium (1-2 ml of 10% calcium gluconate) should
be administered intravenously over 10-15 min (Salte, 1989). Calcium salts
should not be added to sodium bicarbonate solutions as calcium carbonate
precipitates. Maternal administration of vitamin D during the last semester
of gestation reduces the fall in plasma calcium occurring at day 4 of life
(Delvin et al, 1986).

Late neonatal hypocalcaemia

Late neonatal hypocalcaemia is much rarer than the early type. It usually
appears between the third day of life and the end of the first week of life
(Table 2). Classical clinical signs consist of focal, multifocal or generalized
repetitive rhythmic jerking of short duration. Other non-specific signs
include tachypnoea with episodes of apnoea, tachycardia, cardiac failure,
and vomiting. Classical Signs of tetany, such as hyperresponses of" the
reflexes, clonus, carpopedal spasm, Chovsteck's sign are not usually
observed. Plasma calcium, phosphorus and magnesium estimations are
mandatory.
Hypocalcaemia can be associated with high levels of plasma phosphorus,
and moderately low magnesium concentrations. Low plasma concentrations
of parathyroid hormone, 1,25(OH)2-vitamin D, and 25(OH)-vitamin D
have been reported. The observation of a reduced vitamin D pool suggests
196 P. CZERNICHOW AND P. C. SIZONENKO

Table 2. Neonatal hypocalcaemia.

Early type Late type
Age (days) 0-2 3-21
Patients Prematurity Term babies
Factors Maternal diabetes Formula milk
Perinatal asphyxia Primary hypoparathyroidism
Prematurity Maternal hyperparathyroidism
Hypomagnesaemia
Seasons No relation End of winter
Early spring
Frequency +++ +
Clinical signs + +++
Non-specific Convulsions
Phosphoraemia Normalor elevated Elevated
iPTH* Elevated Decreased
iCT? Elevated Normal
Pathophysiology Low calcium i n t a k e Hypoparathyroidism
Transient Vitamin D deficiency
Hypersecretion of calcitonin
* iPTH, immunoreactiveparathyroid hormone; t iCT, immunoreactivecalcitonin.

that the late neonatal hypocalcaemia may be a premature form of rickets.

Plasma maternal calcium, phosphorus and parathyroid hormone should be
determined to rule out maternal hyperparathyroidism. On chest radiogram,
the size of the thymus should be evaluated, as aplasia of the thymus is
present in the Di George syndrome.
Hypocalcaemia is treated by a slow intravenous infusion of 10% calcium
gluconate (0.4 ml/kg/h during 8 h) along with a cardiac monitoring. Infusion
is progressively replaced by oral calcium gluconate (400 mg/kg/day) in four
to six divided doses.
Long-term chronic therapy is not essential as hypocalcaemia rarely
recurs. Late neonatal hypocalcaemia can be prevented by promotion of
breast feeding, as hypocalcaemia is exceptionally seen in the breast-fed
baby, or by the use of modified dried milk with low phosphate content.

Persistent hypocalcaemia
Persistent hypocalcaemia beyond the first week of life suggests neonatal
hypoparathyroidism, when it is not associated with a high phosphorus intake
(cows' milk) or maternal hyperparathyroid disease (Table 1). Transient
idiopathic hypoparathyroidism requires calcium and/or vitamin D treatment
for a few months ( l a O H - D 3 in a dose approximating 0.03-0.08 ~g/kg/day).

Hypomagnesaemia
Hypomagnesaemia impairs the hormone secretory function of the para-
thyroid gland and induces tissue resistance to the action of parathormone
(Anast et al, 1972). It is defined by plasma magnesium concentrations below
0.6retool/1 (1.5mg/dl) and is usually associated with hypocalcaemia,
PAEDIATRIC EMERGENCIES 197

particularly in infants of diabetic mothers(Tsang, 1972). Newborns may

present transient hypomagnesaemia or chronic primary hypomagnesaemia
with hypocalcaemia (Paunier et al, 1968). In the transient form, plasma
magnesium concentration either normalizes spontaneously or after the slow
intravenous infusion or intramuscular administration of 10-:20mg/kg of
magnesium sulphate, followed by calcium normalization. It is important to
treat both hypomagnesaemia and hypocalcaemia. If hypomagnesaemia
persists, hypocalcaemia is resistant to calcium therapy.

Hypercalcaemia
Hypercalcaemia is a rare event where plasma calcium levels are moderately
elevated (above 3.1 mmol/1, 13 mg/dl). Clinical manifestations may develop
above 3.5 mmol/1 and range from anorexia, constipation, hypotonia in the
mildest form to respiratory disorders, vomiting, encephalopathy with
convulsions due to intracranial hypertension, polyuria, polydipsia and blood
hypertension in the most severe form. Dehydration can also be observed
since severe hypercalcaemia can block the action of vasopressin on the renal
collecting duct. Long-term hypercalcaemia may lead to calcifications of
kidney, skin, subcutaneous tissue, cardiac arteries, and gastric mucosa.
Blood electrolytes, phosphorus, alkaline phosphatases, magnesium, para-
thyroid hormone, vitamin D metabolites, urinary calcium and phosphates
should be measured and kidney functions and skeletal X-rays be performed.
Untreated or inadequately treated maternal hypoparathyroidism may lead to
chronic fetal hypercalcaemia and intrauterine hyperparathyroidism despite
an active maternal-fetal transport of calcium. Determinations of plasma
levels of maternal blood calcium and phosphorus are recommended.
Primary neonatal hyperparathyroidism is a rare disorder which causes
marked bone resorption with signs of rickets, and often multiple fractures.
Ultrasonographic examination can reveal hyperplasia of the parathyroid
glands, or, although rare, an adenoma. Plasma immunoreactive parathyroid
hormone is very high. Surgical treatment requires total parathyroidectomy
since subtotal resection may lead to recurrent hypercalcaemic crisis (Spiegel
et al, 1977).
The inheritance of this condition is autosomal dominant or recessive. It
can be associated with familial hypocalciuric hypercalcaemia. Subcutaneous
fat necrosis can be another cause of neonatal hypercalcaemia. The patho-
physiology of this rare condition is not known: hypercalcaemia being not
associated with hypersecretion of parathyroid hormone or increased vitamin
D metabolites (Veldhuis et al, 1979). Onset of hypercalcaemia occurs within
the first week of life and causes a blue-reddish skin discoloration above
subcutaneous nodular indurations located mainly on the shoulders and on
the back of the infant (Michael, Hong and West, 1962). In some cases,
prostaglandins E2 and E3 can be elevated making possible the therapy with
prostaglandin antagonists.
Idiopathic hypercalcaemia of infancy or Williams's syndrome has been
described on rare occasions during the neonatal period and is usually
diagnosed ata later age (Williams, Barrat-Boyes and Lowe, 1961). It refers
198 P. CZERNICHOW AND P. C. SIZONENKO

to the association of infantile hypercalcaemia with supravalvular aortic

stenosis or other congenital cardiac abnormalities, elfin faci6s, various
systemic anomalies and mental retardation. Cardiac lesions are the pre-
dominant clinical manifestations.
Hypercalcaemia ameliorates and disappears with time except for some
patients in whom it can persist during childhood. Biochemical hyperpara-
thyroidism as well as abnormal metabolism of vitamin D have been sug-
gested (Garabedian et al, 1985). The blue diaper syndrome with indicanuria
is a very rare cause which associates hypercalcaemia, nephrocalcinosis, and
a disorder of intestinal absorption of tryptophan (Drummond et al, 1964).
Other causes of hypercalcaemia in infants or older children include intoxi-
cation by vitamin D or its metabolites, bed immobilization with large cast,
sarcoidosis, and pneumocystis pneumonia.
Forms of therapy for acute hypercalcaemia consist in rehydration, and
correction of sodium, potassium and acidobasic disorders. In acute crisis
furosemide (2 mg/kg every 3 h) causes a significant reduction in blood calcium
concentration accompanied by increased urinary calcium. Calcitonin
(2 units/kg every 8 h) has been advocated in particular for patients with
increased osteolysis. Combined glucocorticoids (prednisone, 1 mg/kg/day)
and low calcium diet can be effective for long-term therapy.

DISORDERS OF SEXUAL DIFFERENTIATION

Sexual abnormal differentiation in a newborn infant represents a medical

and psychosocial emergency. Two issues should be immediately addressed:
firstly, the relation of sexual ambiguity to a life-threatening disease, and
secondly, the sex for rearing of the infant should be assigned early. Gender
role is governed by the physical appearance of the child. Parents and peers
must be reinforced within the selected gender role. Reassignment of child's
sex after the newborn period because of inappropriate advice causes
immense distress to the family!
Sexual differentiation of the fetus results from a series of programmed
genetic and hormonal phenomena (Grumbach and Conte, 1985; Conte and
Grumbach, 1990). Schematically, presence of the Y chromosome in the
fetus mediates the differentiation of the primitive gonad into a testis. The
fetal testis secretes testosterone, a steroid hormone that induces differen-
tiation, growth of the male internal genital organs, and virilization of the
urogenital sinus and external sex organs. The fetal testis also secretes the
antimiillerian hormone that inhibits development of the mtillerian ducts
involved in the differentiation of the uterus, fallopian tubes and upper part
of the vagina (Josso, 1981). Classification of disorders of sexual differen-
tiation is based on histology of the gonads provided that they are present
(Table 3). Although males with micropenis do not have ambiguous
genitalia, they warrant further evaluation in the newborn period (Pagon,
1987).
Familial history may orientate the diagnosis. Physical examination of the
newborn should be made in the presence of the parents. Anatomical findings
PAEDIATRIC EMERGENCIES 199

Table 3. Management of sexual ambiguity in the newborn.

Vagina with Vagina
Sex cervix and without
Gonads chromatin uterus* uterus* Possible diagnosis
Not palpable Positive Present -- Female pseudohermaphroditism
Congenital virilizing adrenal
hyperplasia
Present True hermaphroditism
- - Present True hermaphroditism
Female pseudohermaphroditism
with complete virilization
Palpable
Symmetrical Negative -- Present Male pseudohermaphroditism
testosterone biosynthetic
defect
5e~-reductase deficiency
androgen insensitivity
syndrome
Asymmetrical Negative Present Dysgenetic male pseudo-
hermaphroditism
Mixed gonadal dysgenesis
* As observed on ultrasonography of the pelvis and genitography (adapted from Josso, 1981).

such as the degree of development of the genital tubercle, existence of folds

between the ventral side of the genital tubercle and perineum, presence of a
vaginal introitus representing vaginal opening, exact location of the urethral
meatus should properly govern choice of sex of the newborn. Careful
palpation of the genital swellings as well as the inguinal canal should permit
one to locate the gonads. A diagnosis of simple hypospadias when both
testes are palpable is usually made. However, any hypospadias associated
with unilateral or bilateral cryptorchidism should be thoroughly investigated
for disorder of sexual differentiation. Infants with hypospadias and bilateral
absence of palpable gonads are very likely to be females with 21-hydroxylase
deficiency. A malformation syndrome should be suspected in babies with
abnormal genitalia and other multiple anomalies.
Sex chromatin determined on buccal smear may sometimes be helpful.
Lymphocyte karyotype can detect sex chromosome abnormalities within 2-5
days. Ultrasonographic examination of the pelvis and genitography may
reveal the existence of a urogenital sinus, and remaining miillerian structures,
such as uterus, blind vagina, and gonad location. The degree of virilization is
classified according to Prader's criteria (Prader, 1954). Because of the
possible consequences of a salt-losing form of congenital adrenal hyperplasia,
mainly by 21-hydroxylase deficiency, plasma 17oL-hydroxyprogesterone
should be rapidly estimated (see later).
It is incumbent upon a multidisciplinary team consisting of the neo-
natologist, paediatric surgeon, paediatric endocrinologist, and often clinical
psychologist or psychiatrist to make the proper assignment of sex for
rearing. It will be based on the physical examination (length and diameter of
the penis, degree of development of corpora cavernosa, presence of vaginal
200 P. C Z E R N I C H O W A N D P. C. S I Z O N E N K O

structure with or without uterus, with presence or absence of ovaries)

without waiting for results of the karyotype analysis and hormone determi-
nations. In most instances, decision will be based on the potential of the
internal genital organs to function, in particular for fertility, and on the
possibility of achieving cosmetic and functional external genitalia by surgical
means. The presence of a uterus and a positive X-chromatin pattern suggest
a diagnosis of congenital virilizing adrenal hyperplasia. During pregnancy,
administration of potential virilizing drugs or possible virilizing disease
should be ruled out. Consideration of a female sex assignment is always
indicated in these conditions.
In the case of a negative X-chromatin pattern and the presence of a uterus,
female sex of rearing is recommended, although aetiology will be
determined after complete hormonal and surgical investigations. In the case
of negative X-chromatin pattern, absence of uterus, and presence of
urogenital sinus with palpable gonads, a decision of male sex of rearing
should be considered after ascertaining the capacity of the penis for further
growth by administering androgens and after assessing the feasibility of
surgical reconstruction if necessary. If such surgical correction is not
possible and in case of androgen-insensitivity, the sex of rearing should be
female.
Hypertrophia of the clitoris in a newborn assigned as a girl should be
corrected during the first 2 weeks of life to give a feminine aspect to the
external genital organs as quickly as possible. This could exclude inappro-
priate questions from relatives who take care of the child outside the
parents. Surgical correction of the clitoris can also consolidate conviction of
the parents that their child is being reared in her own gender identity.
The choice of sex for rearing should always take into consideration ethnic
and sociocultural origin of the parents. Educating the family about normal
sex differentiation is an important step to understand the situation of their
child. Parents should also be reassured that their child is either a boy or a girl
and not an 'ambiguous' child and that abnormalities of the external genitalia
will not affect psychosocial sex of the child. If ambivalence remains within
the family, psychological help is always recommended to identify its source
and clarify the situation. In addition to the decision of sex assignment,
information on future medical therapy and surgery at the different steps of
development of the child, as well as information on future sexuality,
fertility, and sterility should be fully given. Genetic counselling may be
planned for patients with chromosomal or inherited disorders.

SALT-LOSING SYNDROMES

Hyponatraemia occurs at a serum sodium concentration below 130 mmol/l.

This condition is common during infancy and childhood. Clinical mani-
festations of hyponatraemia develop at a plasma sodium concentration of
less than 125 mmol/1. They become severe at a level below 120 mmol/1 and
require immediate therapy.
Neurological symptoms consist of nausea, vomiting, agitation, headache,
PAEDIATRIC EMERGENCIES 201

anorexia and apathy. Muscular cramps and weakness may occur and cardio-
vascular symptoms depend on the underlying disorder. Occasionally, hypo-
natraemia may become severe leading to altered consciousness, seizures,
and coma.
Evaluation of the hyponatraemic infant or child is based on the history of
the disease and physical examination. A careful review of the episodes
preceding the hyponatraemia (vomiting, diarrhoea, polyuria, pre-existing
diseases), and of laboratory tests such as serum electrolytes, creatinine, urea
nitrogen, glucose, plasma osmolality measured simultaneously with urine
electrolytes, urea, creatinine and osmolality will permit classification of
hyponatraemia and an accurate diagnosis among hyponatraemic disorders.
Hyponatraemia can be categorized into three groups: (1) hypotonic hypo-
natraemia associated with hypervolaemia or oedema, (2) hypotonic hypo-
natraemia associated with normal or only slightly increased extracellular
fluid, and (3) hypotonic hyponatraemia associated with hypovolaemia
(Table 4). Differential diagnosis of (1) and (2) will be considered later in
relation to the syndrome of inappropriate secretion of antidiuretic hormone.
Hypovolaemic hyponatraemia is associated with total body sodium
depletion and extracellular volume contraction which can be due to renal or
extrarenal losses (Table 4). In the preterm newborn and low-birth-weight
infant, hyponatraemia is relatively common, usually due to immature
proximal and distal tubular reabsorption of sodium (Oh, 1976).
Hyponatraemia may result from the inappropriate administration of
hypotonic fluids to the mother or infant or from drug therapy to mother such
as the use of diuretics for toxaemia, and oxytocin for inducing labour.
Inappropriate antidiuretic hormone secretion in the newborn or infant may
also be observed (Table 4).

Congenital adrenal hyperplasia

In fact, the most common endocrine cause of hyponatraemia is the salt-
losing form of congenital adrenal hyperplasia due to 21-hydroxylase
deficiency. The most frequent enzymatic disorder is the 21-hydroxylase
deficiency which induces, in addition to adrenal insufficiency, virilization of
the fetus. Adrenogenital syndrome with deficiency of 20,22 desmolase or
3[3-hydroxylase is rarely observed (Lee et al, 1977).
In girls affected with 21-hydroxylase deficiency, sexual ambiguity consists
in clitoromegaly, posterior fusion of the labia majora into an empty pseudo-
scrotum, with non-palpable gonads, and an abnormal vaginal introitus
leading to a urogenital sinus. A male infant may appear normal, except for a
possible macrogenitosomia. Because of the high levels of ACTH, skin
pigmentation, particularly of the genitalia, can be observed in both sexes.
Sexual ambiguity will alert the paediatrician to the possible risk of salt
loss. Hypoglycaemia is not a usual sign and salt-wasting can appear before
the first week of life. The initial symptoms and signs are vomiting, diarrhoea,
dehydration and if this condition is not recognized in time, the child is at risk
for circulatory collapse and shock. In boys looking normal, pyloric stenosis
may be mistakenly diagnosed and unnecessarily operated. Patients with
202 r,. C Z E R N I C H O W A N D P. C. S I Z O N E N K O

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21-hydroxylase deficiency have high plasma potassium concentrations with

acidosis and hyponatraemia if salt loss persists. As a result of dehydration,
caused by vomiting, newborns decrease body weight sometimes to less than
birth weight. The major risk in addition to the circulatory collapse is the
cardiac arrest attributed to hyperkalaemia. Diagnosis is confirmed by the
elevated concentrations of plasma 17a-OH-progesterone, and renin
activity, reflecting the dehydration and sodium loss (Hughes and Winter,
1976).
Correction of hyponatraemia is achieved by using intravenous 0.9% saline
infusion. Specific therapyconsists in the administration of 16-24 mg/mZ/day
of hydrocortisone or 20-30 mg/mZ/day of cortisone acetate (Rappaport and
Limal, 1977). A higher dose (30-40 mg/m2/day) of hydrocortisone can be
safely used during the first 2-4 weeks of therapy (Wilkins et al, 1951). In
emergency situations, intravenous or intramuscular hydrocortisone hemi-
succinate should be administered as well as daily intramuscular injection of
1-2 mg of deoxycorticosterone acetate during the first 2 days, along with a
close monitoring of blood pressure as severe hypertension caused by a rapid
sodium retention may develop. Oral administration of 0.05-0.1 rag/day of
9et-fludrocortisone must be instituted as soon as the patient's condition
permits. Oral salt supplements(2-3 g of sodium chloride daily, in 2-3 divided
doses) are still recommended by some authors during the first 2 years of life.
Serial measurement of plasma levels of renin activity is a very sensitive index
of mineralocorticoid therapy (Hughes and Winter, 1977).

Adrenal cortex insufficiency

Acute episodes of adrenal cortex insufficiency or Addison's disease usually
occur at the time of acute infection, surgery, trauma or prolonged fasting.
The patient develops vomiting and diarrhoea which contribute to sodium
depletion. These episodes may provide the clue to the presence of a yet
undiagnosed adrenal insufficiency. History of recent loss of weight, fatigue,
thirst, and search for salted food should be looked for. Clinically, the most
suggestive and characteristic sign is pigmentation of the skin and mucosae.
Evaluation of the patient is based on the severity of dehydration, arterial
hypotension, presence of convulsions, and on degree of hyperkaliaemia,
reflected in the abnormal electrocardiogram with high voltage and sym-
metrical T waves.
Hyperkaliaemia is associated with hyponatraemia, acidosis, and hypo-
glycaemia. Urinary sodium excretion is elevated compared with serum
sodium. Rehydration is imperative. Before administering hydrocortisone
and mineralocorticoids, blood samples (5-10ml) should be collected on
EDTA, centrifuged and kept frozen at -20°C for further determinations of
cortisol, ACTH, aldosterone levels, and plasma renin activity.
Therapy is the same as that of congenital adrenal hyperplasia. For
diagnosed cases, prevention of such acute adrenal crisis should include
information of the family and child who should triple the usual oral dose of
hydrocortisone during fever, surgery and trauma. Hydrocortisone should be
administered intramuscularly in patient's with vomiting. The child should
204 P. CZERNICHOWAND P. C. SIZONENKO

Table $. Biology of salt-wasting syndromes in the infant and child.

Aefiology 17-OH-P Cortisol PRA Aldosterone ACTH
Congenital adrenal hyper- High Low High Low High
plasia (21-hydroxylase
deficiency)
Isolated hypoaldosteronism N N or High High Low N
Pseudohypoaldosteronism N N or High High Very High N
Congenital adrenal hypo- Low Low High Low High
plasia (chronic adrenal
insufficiency)
N, normal.

carry a card or a tag to indicate his or her disease. Differential diagnosis of

acute adrenal insufficiency is presented in Table 5.

Congenital adrenal hypoplasia

Congenital adrenal hypoplasia is indistinguishable from congenital adrenal
hyperplasia in its salt-losing form, except for the absence of sexual
ambiguity, and for the low plasma concentrations of cortisol metabolites
such as 17~-OH-progesterone and adrenal androgens which fail to respond
to ACTH administration. Two familial forms have been described: the first
affects only males and is transmitted as a X-linked recessive disorder (Weiss
and Mellinger, 1970), the second type is an autosomal recessive trait (Roselli
and Barbosa, 1965). Adrenal haemorrhage, particularly following birth
trauma, can occur in the newborn and may lead to adrenal insufficiency
when bilateral (Black and Williams, 1973). After therapy with gluco-
corticoids longer than 6 weeks, which may induce secondary adrenal hypo-
plasia or atrophy and insufficiency, glucocorticoids should be progressively
stopped over a period of several weeks. Such adrenal insufficiency observed
with high therapeutic doses of glucocorticoids can be prevented by gluco-
corticoid administration every second day.

Disorders of aldosterone biosynthesis

Disorders of aldosterone biosynthesis usually present the typical symptoms
and signs of the salt-losing syndrome. These rare disorders appear to be
caused by two different types of defect: deficiency in corticosterone-methyl-
O-oxidase type I or 18-hydroxylase (Visser and Cost, 1964), and deficiency
in corticosterone-methyl-O-oxydase type II or 18-OH-hydroxylase (Ulick,
1976). In both cases, syntheses of cortisol and adrenal androgens are within
normal limits. Treatment consists of salt supplementation and 9¢-fludro-
hydrocortisone administration. The salt-losing syndrome seems to dis-
appear with age. A transient form of isolated hypoaldosteroni~m has also
been reported (Russell et al, 1963).

Pseudohypoaldosteronism
Pseudohypoaldosteronism can be responsible for severe salt-losing
PAEDIAI'RIC EMERGENCIES 205

syndrome that begins very early in life and does not respond to mineralo-
corticoids (Cheek and Perry, 1958; Limal et al, 1978). This rare disorder is
characterized by increased urinary sodium and aldosterone excretion, high
plasma levels of aldosterone and renin activity (Table 5). It results from
unresponsiveness to aldosterone of receptors in renal tubule, colonic
mucosa and salivary and sweat glands (Oberfield et al, 1979). High sodium
diet decreases the elevated concentrations of atdosterone and renin and can
usually be stopped after 2 years of age.

A CTH insufficiency
ACTH insufficiency caused by hypothalamopituitary tumour induces a
deficiency of cortisol secretion. Clinical signs are rarely observed in children
and are those of water intoxication with headache, vomiting, abdominal
pain, hypoglycaemia and hyponatraemia (Table 4). No pigmentation is
observed.
Administration of glucocorticoids to pregnant women may induce ACTH
and adrenal insufficiency in the neonate. Such newborns should be carefully
monitored for hypoglycaemia which should be corrected by glucose given
either orally or intravenously. Severe adrenal insufficiency is exceptional in
these newborns. However, it has been suggested that such neonates should
receive small doses of hydrocortisone (10 rag/day) during 4-6 weeks. Female
newborns affected with prenatally diagnosed congenital adrenal hyperplasia
whose mothers received dexamethasone during the whole pregnancy for the
prevention of fetal sexual ambiguity, should be observed during the first
days of life with repeated determinations of plasma 17~-OH-progesterone
and electrolytes, particularly if the family index case is a salt loser, in order
to substantiate definitively the diagnosis in the newborn (David and Forest,
1984).

HYPOGLYCAEMIA

Detection of hypoglycaemia is of particular importance in infancy in view of

the high risk of permanent brain damage due to prolonged hypoglycaemia.
Hypoglycaemia has been defined as a true glucose concentration below
2.2 mmol/l (Cornblath and Schwartz, 1976). This value does not take into
account the term or the age of the infant and seems more appropriate than
the previous limit which considered acceptable blood glucose below
2.2 retool/1 in low-birth-weight or preterm infants (Sexson, 1984).

Pathogenesis
Neonates and infants tolerate fasting less well than older children and
develop hypoglycaemia after prolonged.starvation or malabsorption. In
developed countries nutritional hypoglycaemia occurs rarely and hypo-
glycaemia in infancy usually results from abnormal production of glucose
due to inborn errors of metabolism, such as abnormal regulation of glucose
206 P. C Z E R N I C H O W A N D P. C. S I Z O N E N K O

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PAEDIATRIC EMERGENCIES 207

production, storage or use. The therapeutic approach has to be adapted to

the underlying cause.

Diagnosis and management of hypoglycaemia

Pallor, convulsion and tremor are specific signs of hypoglycaemia. Other
non-specific manifestations include feeding problems, hypotonia, hyper-
excitability, respiratory problems, and hypothermia. Hypoglycaemia may
be asymptomatic. A strict surveillance of high-risk patients is now routine
and determination of capillary blood glucose using reflectance meters
facilitates the monitoring of neonates and infants. Measurements at 6, 12, 24
and 48 h of life are adequate for the neonates at risk. When blood glucose
level is below 2.2 retool/l, the value should be confirmed by venous blood
determinations and more frequent sampling.
Prevention of hypoglycaemia is crucial. Early feeding and close surveil-
lance are usually sufficient. Intravenous dextrose (5-10%) is sometimes
necessary in low-birth-weight infants.
Symptomatic hypoglycaemia will be immediately treated with 25%
glucose given intravenously (2 ml/kg) followed by a continuous infusion of
15% glucose (80-100ml/kg/24 h or 0.5 to 0.6 g glucose/kg/h).

Aetiology
Causes of neonatal hypoglycaemia can be multiple. Age of presentation,
neonatal history, nature of hypoglycaemia (permanent or transient) are
helpful for the investigation. Routine chemical parameters can be performed
on a single plasma sample. Further clinical investigations will depend upon
the evolution of the hypoglycaemic attack (Table 6).

Transient hypoglycaemia
This is by far the most frequent and most of the time is preventable.
Prematures and infants who are small for gestational age can suffer from
neonatal hypoglycaemia. Most of these patients have transient asympto-
matic hypoglycaemia and should remain asymptomatic with careful super-
vision.

Transient hyperinsulinism
Infants of diabetic or gestational diabetic mother may develop fetal hyper-
insulinism due to chronic hyperglycaemic stimulation by the mother.
Hypertrophy and hyperplasia of the endocrine pancreas could be due in part
to the transfer of antibody-bound insulin from the insulin-treated diabetic
mother to the fetus (Menon et al, 1990). Infants with erythroblastosis fetalis
can present hyperinsulinaemia sharing many clinical features with infants of
diabetic mothers. Wiedemann-Beckwith syndrome (omphalocoele, macro-
glossia and visceromegaly) is associated in 30% of the cases with hyper-
insulinism due to islet cell hyperplasia.
208 p. C Z E R N I C H O W AND P. C. S I Z O N E N K O

Hypoglycaemia occurs in stressful situations where decreased production

of glucose coexists with increased demands of energy substrate, such as in
hypoxia, respiratory distress and hypothermia. These are risk factors
deserving close surveillance of blood glucose concentration.

Permanent hypoglycaemia
Hyperinsulinism with symptomatic, persistent profound hypoglycaemia
during the first days or weeks of life, is the most frequent cause of persistent
or recurrent hypoglycaemia. Later the symptomatology is less typical:
hypoglycaemia can be totally silent or be revealed by convulsions, the
disease being frequently intermittent (Labrune et al, 1989). Diagnosis is
easier when the infant can be observed during the hypoglycaemic episodes
since hypoglycaemia occurs in presence of normal lactate levels and absence
of ketonuria. A raised plasma insulin concentration or an abnormal ratio of
glucose to insulin confirms the diagnosis. To restore blood glucose within
normal limits, patients should be treated with intravenous infusion of large
doses of glucose (15-20 mg/kg/min) and with continuous gastric feeding of
dextrose-enriched formula (Aynsley-Green et al, 1981). Very few neonates,
if any, respond adequately to diazoxide. Blood should be collected before
treatment to measure glucose and insulin. Glucagon or somatostatin might
be helpful to control blood glucose (Bougneres et al, 1985) but is rarely
efficient in treating the hyperinsulinism (Hindmarsh and Brook, 1987).
Hyperinsulinism diagnosed after the first trimester is usually less severe
and more efficiently treated with diazoxide (8-15 mg/kg) and if necessary
with oral starch (Amendt et al, 1988). If an appropriate control of blood
glucose cannot be obtained, subtotal pancreatectomy should be performed
without delay.
The physiopathology of hypoglycaemia is still not known. Patients rarely
have true adenomas and insulin, glucagon, and somatostatin pancreatic
contents are usually normal. According to Rahier the anomaly is an
increased nuclear size of the [3-cell (Rahier, 1984). Pancreatic venous
sampling may distinguish between diffuse or focal lesions (Brunelle, 1989).
The presence of 'tumour blush' may help to localize the turnout before
surgery.
Leucine-sensitive hypoglycaemia is less frequently diagnosed than
before. It was originally classified to occur in children with 'idiopathic
hypoglycaemia' in whom protein feeding, specifically leucine-rich, triggered
hypoglycaemic attacks. Subsequently, it was demonstrated that leucine-
sensitive hypoglycaemia was associated with excessive insulin secretion after
ingestion of leucine, and that [3-cell hyperplas~a was associated with hyper-
insulinaemia in response to leucine, tolbutamide, and other provocative
tests. Leucine-sensitive hypoglycaemia is a special form of hyperinsulinism
due to an unknown dysfunction of the [3-cell.

Endocrine disorders
Isolated or combined GH and ACTH deficiencies are frequent causes of
PAEDIATRIC EMERGENCIES 209

severe hypoglycaemia. Either idiopathic or part of multiple facial or

cerebral malformations, they should be quickly recognized and treated with
growth hormone and hydrocortisone.
Congenital adrenal hypoplasia is a rare cause of hypoglycaemia due to
severe glucocorticoid deficiency. Elevated ACTH is diagnostic. It can be
associated with elevated glycerol due to glycerol kinase deficiency (Wise et
al, 1987).

Inborn errors of carbohydrate metabolism

Hypoglycaemia caused by inborn errors of metabolism becomes apparent
during late infancy and childhood with the exception of glucose-6-phosphatase
deficiency. Hypoglycaemic episodes are severe and occur after fasting.
Inborn errors of metabolism include galactosaemia, hereditary fructose
intolerance, type I glycogen storage disease (glucose-6-phosphatase defi-
ciency), and fructose-l,6-diphosphatase deficiency. These infants usually
demonstrate failure to thrive and hepatomegaly. In patients with galactos-
aemia and hereditary fructose intolerance, non-glucose-reducing substances
may be found in urine, and elevated plasma transaminases may indicate liver
dysfunction. Hereditary fructose intolerance can be diagnosed by the occur-
rence of lactic acidosis, hypophosphataemia, and hypoglycaemia after oral
or intravenous fructose administration.

HYPERGLYCAEMIA

Neonatal hyperglycaemia has been defined as a blood glucose level greater

than 6.9mmol/1. It occurs most commonly in low-birth-weight infants
receiving intravenous dextrose solutions or total parenteral nutrition (Lilien
et al, 1979) and may be due to increased secretion of catecholamines. This
situation should be prevented by close surveillance of blood glucose levels.
Hyperglycaemia can be an early manifestation of organic aciduria during
the neonatal period. The severity of hyperglycaemia can mimic true insulin-
dependent diabetes (IDDM). Acidosis and ketonuria may also be present
(William et al, 1981). Organic aciduria should be considered in the differ-
ential diagnosis of hyperglycaemic ketoacidosis.
On rare occasions IDDM is seen in infants. Typically infants are small-for-
gestational-age and have lost weight. Blood glucose concentrations are very
elevated and in a range not observed later in childhood (>5mmol/1)
(Dorchy et al, 1975). Ketonuria is either absent or mild (Goldman, 1979), an
observation which is not clearly understood. It has been postulated that
patients with hyperglycaemic hyperosmolar coma have enough circulating
insulin to minimize lipolysis but not enough to prevent glucose metabolism.
This is not supported by immunohistochemical studies in very young
patients where a severe depletion of the [3-cells has been reported (Gepts
and De Mey, 1978). In several cases the diabetic state lasts weeks or months
and disappears without explanation, probably due to a delayed pancreatic
13-cell maturation.
210 P. C Z E R N I C H O W AND P. C. S I Z O N E N K O

True permanent IDDM rarely occurs in infancy, less than 2% of all cases
being observed in childhood (Levy Marchal et al, 1990). Genetic and
autoimmune markers seem to be identical to those observed in older
children although infants have higher titres of circulating insulin auto-
antibodies.
Treatment of an acute episode is critical because of the hyperosmolar
state. Brain damage should be avoided by careful rehydration. Cerebral
oedema is a severe complication particularly at this age (Rosenbloom,
1990). Continuous subcutaneous insulin infusion is the treatment of choice
of IDDM in infancy (Bougneres et al, 1984).

DISORDERS OF WATER METABOLISM

Diabetes insipidus
In newborn and infants the clinical picture of diabetes insipidus is very
different from that of older patients. However, the disease should be
recognized early because, as long as the infant is unable to express thirst,
there is a risk of severe dehydration and brain damage.
The common leading manifestation is repeated episodes of hyperthermia
and vomiting. Failure to thrive, anorexia or vomiting after feeding are
frequent. Polyuria may be part of the neonatal picture causing poly-
hydramnios although urine volume is usually normal in the newborn.
Polyuria appears only when extra water is given to the patient.
Urinary tonicity can be low or slightly above plasma values. In the
presence of dehydration with or without polyuria, nephrogenic diabetes
insipidus should be excluded (Czernichow et al, 1985). Desmopressin test
(10 txg intranasally or 5 ixg/m2 i.v.) is useful for estimating the maximum
renal concentration capacity. Full-term newborns normally concentrate
urine up to 600.700mosmol/kg H20 and preterm infants up to 300-
555 mosmol/kg H 2 0 (Svenningen and Aronson, 1974; Rees et al, 1984a,b).
Measurement of plasma vasopressin is diagnostic, high values being the
hallmark of nephrogenic diabetes insipidus.
Central diabetes insipidus is rare in infancy. It may occur after asphyxia,
intraventricular haemorrhage or severe infections. Autosomal dominant
familial diabetes insipidus may be seen in infancy. The condition may also be
part of a complex syndrome of hypodipsia and hypernatraemia associated
with brain malformation (dysplasia and absence of septum pellucidum)
(Czernichow et al, 1985). Treatment of central diabetes insipidus should be
rapidly started using desmopressin (1-deamino-8-I>arginine vasopressine).
Doses of 1-2 ~xg, two to three times a day by the nasal route, are efficient.
Desmopressin can also be taken by the oral route with doses, usually 1"0to 20
times greater than those used for the nasal administration (Fjellestadt et al,
1988).

Syndrome of inappropriate secretion of vasopressin (SIADH)

SIADH is a common problem in newborn and preterm infants (Nutman et
PAEDIATRIC EMERGENCIES 211

al, 1981; Rees et al, 1984b), particularly when mechanical ventilation is

required. The more frequent causes are hypoxic brain injury, intracerebral
haemorrhage, asphyxia, pulmonary infection, pneumothorax, ligations of
patent ductus arteriosus, and positive pressure ventilation (Pomarede et al,
1978; Ruth et al, 1988).
Determination of plasma AVP levels is of little diagnostic help to
differentiate between the main causes of hypo-osmolality. The key for
distinguishing SIADH from hyponatraemic haemocontraction is frequent
measurement of weight, plasma sodium, urinary osmolality, and sodium
excretion.

THYROID DISORDERS

Neonatal Graves's disease

Neonatal thyrotoxicosis occurs as a rare complication of maternal Graves's
disease. Neonatal thyrotoxicosis has also been reported in infants born of
euthyroid women with a history of previous Graves's disease and of
euthyroid or hypothyroid women with Hashimoto's thyroiditis (Fisher,
1986).
In most cases the disease is caused by transplacental passage of maternal
thyroid-stimulating immunoglobulins (TSI). It is possible to predict neo-
natal hyperthyroidism in offspring of women with high TSI titres (Zakarija
et al, 1986). Some infants acquire multiple TSH-receptor antibodies from
the mother, and the presence of such antibodies has been reported to block
the effect of TSI transiently and to delay the onset of neonatal thyrotoxicosis
by several weeks (Zakarija et al, 1983).
This type of thyrotoxicosis may be present at birth or soon after birth, and
tends to be mild and self-limited. Spontaneous recovery occurs within 3
months, and is usually complete by 6 months. Recurrence has not been
reported (Hollingsworth, 1985).
Hyperthyroidism can occur later during infancy. This type is rare, tends to
be more severe and may persist for several years. Treatment is often
difficult, and recurrences have been reported. Most of these cases have
occurred in families with a strong history of Graves's disease similar to that
seen in older children. Late sequelae such as craniosynostosis,
microcephaly, mental retardation, learning disorders, advanced bone age
and short stature have been reported in these children (Hollingsworth and
Mabry, 1976).
The clinical manifestations are similar in the two types and include irrita-
bility, tachycardia, hypertension, poor weight gain, thyroid enlargement
and exophthalmos. Thrombocytopenia, hepatosplenomegaly, jaundice and
hypoprothrombinaemia have also been observed. Arrhythmias, cardiac
failure and death may occur if the thyrotoxicity is severe and the treatment
inadequate. Mortality rate approaches 25%.
The treatment of hyperthyroidism in the newborn includes sedatives and
digitalization as necessary. Lugol's solution (5% iodine and 10% potassium
212 P. CZERNICHOW AND P. C. SIZONENKO

iodide; 126 mg of iodine per ml) is given in doses of one drop (about 8 mg)
three times daily. Methimazole, carbimazole or propylthiouracil are
administered in total doses of 0.5-1.0mg, 0.5-1mg or 5-10mg/kg,
respectively, given three times daily. A therapeutic response should be
observed within 24-36 h. If a satisfactory response is not observed, the dose
of antithyroid drug and iodide can be increased by 50%.
Propranolol hydrochloride (2 mg/kg orally given in three divided daily
doses) is effective in controlling symptoms such as tachycardia. In severe
cases, the use of glucocorticoids(prednisone 2 mg/kg per day) may be useful.
Supportive therapy including temperature control and adequate fluid and
caloric intake is important in all affected infants.

Hypothyroidism
The devastating effects of congenital hypothyroidism on the mental
development of children with this condition has been known for decades.
Paediatricians have tried in the past to recognize the disease in order to treat
the thyroid hormone deficiency early enough to prevent the psychomotor
sequelae. The physical signs and symptoms of hypothyroidism in the new-
born are few and often delayed beyond the time when treatment would be
most effective (Maenpaa, 1972). The screening programme for congenital
hypothyroidism is therefore a significant advancement in the improvement
of the prognosis. Hypothyroidism is not an acute neonatal emergency.
However, very early recognition and treatment are so important that this
problem deserves to be covered here.
Thyroid dysgenesis (ectopic or hypoplastic gland or total thyroid agenesis)
is the aetiological factor in most infants with permanent congenital hypo-
thyroidism. The prevalence approximates to 1:4000 in Caucasians and is
less common in Blacks (1 : 32 000) (Brown et al, 1981).
Filter paper TSH determination together with screening for phenyl-
ketonuria are the most widely used procedures. Negative cases have been
reported in infants with secondary or tertiary hypothyroidism or with
delayed postnatal rise of TSH (Leger, 1990). It is important for the clinician
to remember that an infant with congenital hypothyroidism may escape
detection through the screening network and that these infants must be
diagnosed on clinical grounds and plasma TSH and s e r u m T4, T3 levels.
The treatment should be started promptly with synthetic thyroid
hormones. The recommended dosage varies between 7 and 9 ~g/kg. Most of
the affected infants when treated with this dosage have normal mean IQ
values and satisfactory school performances (Glorieux et al, 1985; Rovet et
al, 1987).
Congenital hypothyroidism may occur as a transient defect persisting for a
variable period after birth and is usually caused by maternal ingestion of
goitrogenic substances, the most frequent being iodide.
In premature infants, a low T3 syndrome may be observed. Serum T4 is
normal or low and TSH levels are normal. This condition does not require
exogenous thyroid hormone therapy (Delange et al, 1989).
PAEDIATRIC EMERGENCIES 213

REFERENCES

Amendt P, Kohnert KD & Kunz J (1988) The hyperinsulinemic hypoglycemias in infancy: a

study of six cases. European Journal of Pediatrics 148: 107-112.
Anast CS, Mohs JM, Kaplan SL & Burns TW (1972) Evidence for parathyroid hormone failure
in magnesium deficiency. Science 177" 606-608.
Aynsley-Green A, Polak JM, Bloom SR et al (1981) Nesidioblastosis of the pancreas: definition
of the syndrome and the management of the severe neonatal hyporinsulinemic hypo-
glycemia. Archives of Disease in Childhood 56: 496-508.
Baltrop D, Mole RH & Sutton A (1977) Absorption and endogenous faecal excretion of
calcium by low birth-weight infants on feeds with varying contents of calcium and
phosphate. Archives of Disease in Childhood 52: 41-49.
Berry PL & Belsha CW (1990) Hyponatremia. Pediatric Clinics of North America 37: 351-
363.
Black J & Williams D (1973) Natural history of adrenal haemorrhage in the newborn. Archives
of Disease in Childhood 48: 183-190.
Bougneres PF, Landier F, Lemmel C, Mensire A, Chaussain JL (1984) Insulin pump therapy in
young children with type I diabetes. Journal of Pediatrics 105: 212-216.
Bougneres PF, Landier F, Gamier P, Job JC & Chaussain JL (1985) Treatment of insulin excess
by continuous subcutaneous infusion of somatostatin and glucagon in infant. Journal of
Pediatrics 106: 792-794.
Brown AL, Fernhoff PM, Milner J, McEwen C, Elsas LS (1981) Racial differences in the
incidence of congenital hypothyroidism. Journal of Pediatrics 99: 934-936,
Cheek DB & Perry JW (1958) A salt wasting syndrome in iofancy. Archives" of Disease in
Childhood 33: 252-256.
Conte FA & Grumbach MM (1990) Recent insights into sex determination. In Sizonenko PC &
Aubert ML (eds) Developmental Endocrinology, pp 49-55.
Cornblath M & Schwartz R (1976) Carbohydrate Metabolism in the Neonate. Philadelphia: WB
Saunders.
Czernichow P, Pomarede R, Brauner R & Rappaport R (1985) Neurogenic diabetes insipidus
in children. Frontiers of Hormone Research 13: 190-209.
David L & Forest MG (1984) Prenatal treatment of congenital adrenal hyperplasia resulting
from 21-hydroxylase deficiency. Journal of Pediatrics 105: 799-803.
Delange F, Dalhem A, Bourdoux P e t al (1984) Increased risk of primary hypothyroidism in
preterm infants. Journal of Pediatrics 92: 974-976.
Delvin EE, Salle BL, Glorieux FH et al (1986) Vitamin D supplementation during pregnancy:
effect on neonatal calcium homeostasis. Journal of Pediatrics 109: 328-334.
Dorchy H, Pardou A, Weemaes I & Loeb H (1975) Coma hyperosmolaire acido-cetosique sans
c6tonurie initiale: evolution favorable. Pediatrie 30: 19-27.
Drummond KN, Michael AF, Ulstrom RA & Good RA (1964) The blue diaper syndrome:
familial hypercalcemia with nephrocalcinosis and indicanuria. American Journal of
Medicine 37: 928--930.
Fischer D & Foley BL (1989) Early treatment of congenital hypothyroidism. Pediatrics 83:
785--789.
Fisher DA (1986) Neonatal thyroid disease in the offspring of women with autoimmune thyroid
disease. Thyroid Today 9: 1-7.
Fjellestadt Paulsen A, Crosnier H & Czernichow P (1988) Diab6te insipide central chez le tr~s
jeune enfant. Archives Franciases de Pediatric 45: 787-790.
Garabedian M, Jacoz E, Guillozo H et al (1985) Elevated plasma 1,25-dihydroxyvitamin D
concentrations in infants with hypercalcemia and elfin facies. New England Journal of
Medicine 312: 948-952.
Gepts W & De Mey J (1978) Islet cell survival determined by morphology. An immunocyto-
chemical study of the islets of Langerhans. Diabetes 27 (supplement 1): 251-261.
Glorieux J, Dussault JH, Morissette J, Desjardins M, Let/trte J & Guyda H (1985) Follow-up at
ages 5 and 7 years on mental development on children with hypothyroidism detected by
Quebec Screening Program. Journal of Pediatrics 107: 913-915.
Goldman SL (1979) Hyperglycemic hyperosmolar coma in a 9-month-old child. American
Journal of Diseases of Children 133: 181-183.
214 1,. CZERNICFIOW AND P. C. SIZONENKO

Grumbach MM & Conte FA (1985) Disorders of sexual differentiation. In Wilson JD & Foster
DW (eds) Williams' Textbook of Endocrinology, pp 312-401. Philadelphia: WB Saunders.
Hindmarsh P & Brook CG (1987) Short-term management of nesidioblastosis using the
somatostatin analogue SMS201-995, New England Journal of Medicine 316: 221-222.
Hollingsworth DR (1985) Neonatal hyperthyroidism. Pediatric Thyroidology 14: 210-222.
Hollingsworth DR & Mabry CC (1976) Congenital Graves' disease: four familial cases with
long-term follow-up and perspective. American Journal of Diseases in Children 130: 148--155.
Hughes IA & Winter JSD (1976) The application of a serum 17-OH-progesterone radio-
immunoassay to the diagnosis and management of congenital adrenal hyperplasia. Journdl
of Pediatrics 88: 766773.
Hughes IA & Winter JSD (1977) 17-Hydroxyprogesterone and plasma renin activity in
congenital adrenal hyperplasia. In Lee PA, Plotnick LP, Kowarski A A & Migeon CJ (eds)
Congenital Adrenal Hyperplasia, pp 149-156. Baltimore: University Park Press.
Josso N (1981) The lntersex Child, 272 pp (Pediatric and Adolescent Endocrinology, vol. 8).
Basel: Karger.
Labrune P, Bonnefont JP, Nihoni-Fdk~t6 C et al (1989) Evaluation des m6thodes diagnostiques
et th~rapeutiques de l'hyperinsulinisme du nouveau-nEe et du nourrisson. Archives
Francaises de Pediatrie 46: 167-173.
Lee PA, Plotnick LP, Kowarski AA & Migeon CJ (1977) CongenitalAdrenal Hyperplasia,
5342 pp. Baltimore: University Park Press.
Leger J (1990) Screening for congenital hypothyroidism in France. European Journal of
Pediatrics 149: 605-607.
Levy Marchal C, Papoz L, de Beaufort C et al (1990) Incidence of juvenile type 1 (insulin-
dependent) diabetes mellitus in France. Diabetologia 33: 465-469.
Lilien LD, Rosenfield RL, Baccaro MM & Pildes RS (1979) Hyperglycemia in stressed small
premature neonates. Journal of Pediatrics 94: 545-549.
Limal JM, Rappaport R, Dechaux Met al (1978) Familial dominant pseudohypoaldosteronism.
Lancet i: 49-55.
Lynch RE (1990) Ionized calcium: pediatric perspective. Pediatric Clinics of North America 52:
373-389.
Maenpaa J (1972) Congenital hypothyroidism. Etiological and clinical aspects. Archives of
Disease in Childhood 47: 914-923.
Menon RK, Cohen RM, Sperling MA, Cutfield QS, Mimouni F & Khoury JC (1990) Trans-
placental passage of insulin in pregnant women with insulin-dependent diabetes mellitus.
New England Journal of Medicine 323: 309-315.
Michael AF, Hong R & West CD (1962) Hyperealcemia in infancy: association with sub-
cutaneous fat necrosis and calcification. American Journal of Diseases in Children 104:
235-237.
Nutman J, Wilunsku E, Avni A & Reisner SH (1981) Syndrome of inappropriate antidiuretie
hormone secretion in newborn infants with respiratory problems. IsraelJournal of Medical
Sciences 17: 1009-1013.
Oberfield SE, Levine LS, Carey RM et al (1979) Pseudohypoaldosteronism: multiple target
organ unresponsiveness to mineralocorticoid hormones. Journal of Clinical Endo-
crinology and Metabolism 48: 228-234.
Oh W (1976) Disorders of fluids and electrolytes in newborn infants. Paediatric Clinics of North
America 23: 601-609.
Pagon RA (1987) Diagnostic approach to the newborn with ambiguous genitalia. Pediatric
Clinics of North America 34: 1019-1031.
Paunier L, Radde IC, Kood SW et al (1968) Primary hypomagnesemia with secondary hypo-
calcemia in an infant. Pediatrics 41: 385-402.
Pomarede R, Moriette R, Czernichow P & Relier JP (1978) Etude de la vasopressine
plasmatique chez les enfants prrmaturOs soumis ~ la ventilation artificielle. Archives
Franeaises de Pediatrie 35: 75-79.
Prader A (1954) Das genitalbefund beim des pseudohermaphroditismus feminimus des
kongenitalen adrenogenitalen syndroms: Morphologie, hhufigkeit, entwicklung und
vererbung des verschiedenen genitalformen. Helvetica Acta Paediatrica 9: 231-248.
Rahier J, FSlt K, Mtintefering H et al (1984) The basic structural lesion of persistent neonatal
hypoglycemia with hyperinsulinism: deficiency of pancreatic D cells or hyperactivity of 13
cells? Diabetologia 26: 281-289.
PAEDIATRIC EMERGENCIES 215

Rappaport R & Limal JM (1977) Linear growth and suppressive effects of hydrocortisone and
%-fludrohydrocortisone in long term therapy in congenital adrenal hyperplasia. In Lee
PA, Plotnick LP, Kowarski A A & Migeon CJ (eds) Congenital Adrenal Hyperplasia,
pp 263-272. Baltimore: University Park Press.
Rees L, Brook CGD, Shaw JCL & Forsling ML (1984a) Hyponatremia in the first week of life
in preterm infants. I. Arginine vasopression secretion. Archives of Diseases in Childhood
59: 414-422.
Rees L, Brook CGD, Shaw JCL & Forsling ML (1984b) Hyponatremia in the first week of life
in preterm infants. II. Sodium and water balance. Archives of Disease in Childhood 59:
423-429.
Roselli A & Barbosa LT (1965) Congenital hypoplasia of the adrenal glands. Report of two
cases in sisters with necropsy. Pediatrics 35: 70-75.
Rosenbloom AL (1990) Intracerebral crises during treatment of diabetic ketoacidosis. Diabetes
Care 13: 22-33.
R6sli A & Fanconi A (1973) Neonatal hypocalcemia. 'Early Type' in low birth weight
newborns. Helvetica Paediatrica Acta 28: 443-457.
Rover J, Ehrlich R & Sorbara D (1987) Intellectual outcome in children with fetal hypo-
thyroidism. Journal of Pediatrics 5: 700-704.
Russel A, Levin B, Sinclair Let al (1963) A reversible salt-wasting syndrome of the newborn and
infant. Possible infantile hypoaldosteronism. ArchivesofDiseasein Childhood38" 313-325.
Ruth V, Autti-Ramo I, Granstrom ML, Korkman M, Raivio KO (1988) Prediction of perinatal
brain damage by cord plasma vasopressin, erythroprotein, and hypoxantine values.
Journal of Pediatrics 113: 880-885.
Salle BL (1989) M6tabolisme pdrinatal min6ral et vitaminique D. In Relier JP, Laugier J &
Salle BL (eds) MOdecine POrinatale, pp 464-477. Paris: M6decine-Sciences Flammarion.
Salle BL, David L, Chopard P, Grafmeyer DC & Renaud H (1977) Prevention of early
neonatal hypocalcemia in low birth weight infants with continuous calcium infusion: effect
on serum calcium, phosphorus, magnesium and circulating immunoreactive parathyroid
hormone and calcitonin. Pediatrics Research 11: 1180-1185.
Sexson WR (1984) Incidence of neonatal hypoglycemia: a matter of definition. Journal of
Pediatrics 105: 149-150.
Shaw JCL (1976) Evidence for defective skeletal mineralization in low birthweight infants: the
absorption of calcium and fat. Pediatrics 57: 16-25.
Spiegel AM, Harrison HE, Marx SJ et al (1977) Neonatal primary hyperparathyroidism with
autosomal dominant inheritance. Journal of Pediatrics 90: 282-293.
Svenningsen NN & Aronson AS (1974) Postnatal development of renal concentration capacity
as estimated by DDAVP-test in normal and asphyxiated neonates. Biology of the Neonate
25: 230-233.
Tsang RC (1972) Neonatal magnesium disturbances. American Journal of Diseases of Children
124: 282-293.
Tsang RC, Abrams L, Joyce TH III, Buncher CR & Steichen JJ (1979) Ionized Ca in neonates
in relation to gestational age. Journal of Pediatrics 94: 126-129.
Tsang RC, Donovan EF & Steichen JJ (1976) Calcium physiology and pathology in the
neonate. Pediatric Clinics of North America 23: 611-626.
Ulick S (1976) Diagnosis and nomenclature of the disorders of the terminal portion of the
aldosterone biosynthetic pathway. Journal of Clinical Endocrinology and Metabolism 43:
92-96.
Veldhuis JD, Kulin HE, Demers LM & Lambert PW (1979) Infantile hypercalcemia with
subcutaneous fat necrosis: endocrine studies. Journal of Pediatrics 95: 460-462.
Visser HKA & Cost WS (1964) A new hereditary defect in the biosynthesis of aldosterone:
urinary C-21 corticoid pattern suggesting an 18-oxidation defect. Acta Endocrinologica 47:
589-612.
Weiss L & Mellinger RC (1970) Congenital adrenal hypoplasia--an X-linked disease. Journal
of Medical Genetics 7: 27-32.
Widdowson EM, McCance RA, Harrison GE & Sutton A (1963) Effect of giving phosphate
supplements to breast-fed babies in absorption and excretion of calcium, strontium,
magnesium and phosphorus. Lancet i: 1250-1251.
Wilkins L, Lewis RA, Klein R et al (1951) Treatment of congenital adrenal hyperplasia with
cortisone. Journal of Clinical Endocrinology 11: 1-13.
216 P. CZERNICHOW AND P. C. SIZONENKO

William M, Peden H & Hillman RE (1981) Isovaleric acidemia appearing as diabetic keto-
acidosis. American Journal of Diseases of Children 135: 1068-1069.
Williams JCP, Barrat-Boyces B G & Lowe JB (1961) Supravalvular aortic stenosis. Circulation
24: 1311-1315.
Wise JE, Matalon R, Morgan AM & Cabe ERB (1987) Phenotypic features of patients with
congenital adrenal hypoplasia and glycerol kinase deficiency. American Journal of
Diseases of Children 141: 744-747.
Zakarija M, McKenzie JM & Munro DS (1983) Immunoglobulin G inhibitor of thyroid-
stimulating antibody is a cause of delay in the onset of neonatal Graves' disease. Journal of
Clinical Investigation 72: 1352-1356.
Zakarija M, McKenzie JM & Hoffman WH (1986) Prediction and therapy of intrauterine and
late onset neonatal hyperthyroidism. Journal of Clinical Endocrinology and Metabolism
62: 368--371.