Endocrine Disorders

Etienne Sochett M.D., Shai Fuchs M.D. Ph.D

The material presented here was first published in the Residents’ Handbook of Neonatology, 3rd edition, and is reproduced here with permission from PMPH USA, Ltd. of New Haven, Connecticut and Cary, North Carolina.


Thyroid Disorders


Congenital Hypothyroidism

  • The prevalence of congenital hypothyroidism is 1:4000.
  • Diagnosed by T4 and TSH concentrations.
  • Early diagnosis and treatment of hypothyroidism is crucial to prevent or minimize cognitive impairment.
  • Most cases are asymptomatic at birth. Routine screening tests (TSH or T4) of all babies uncover the diagnosis.  The newborn screening program in Ontario measures TSH levels from blood spots on a standard filter paper card. The preferred age of screening is 3 to 5 days.
  • Screening before day 3 of life may increase the false positive rate when measuring TSH levels because of the physiological TSH surge at birth.



  • Developmental defects
    • thyroid aplasia and hypoplasia
    • ectopic thyroid
  • Inborn errors of thyroid hormone biosynthesis
    • Iodine trapping defect
    • Organification defect (mutations in thyroid peroxidase, DUOX2, DUOXA2)
    • Defects in thyroglobulin synthesis (mutations in TG).
    • Iodotyrosine deiodinase defect (mutations in IYD).
    • TSH receptor defects (TSHR mutations)
  • Thyroid hormone resistance owing to thyroid receptor β defect (THRB mutations).
  • Transient neonatal disorders of thyroid function
    • Goitrogenic agents (e.g. maternal iodide, maternal anti-thyroid medications)
    • Transplacentally derived TSH receptor blocking antibodies
  • Different complex syndromes that include congenital hypothyroidism.
    • Gsalpha and the thyroid transcription factors (TTF-1, TTF-2, and Pax-8),
    • Hypothalamic pituitary hypothyroidism
    • Panhypopituitarism.
    • Isolated TSH deficiency.


Symptoms and Signs:

  1. Prolonged jaundice (indirect bilirubin).
  2. Lethargy, poor feeding, and hypotonia.
  3. Respiratory difficulty, cyanosis, and hoarse cry.
  4. Wide fontanels, macroglossia, and umbilical hernia.
  5. Delayed bone maturation with absence of the proximal tibial and distal femoral epiphysis.
  6. Classic findings of cretinism are rare in the immediate neonatal period owing to placental transfer of some maternal thyroid hormone.


Indications for Repeat Thyroid Tests:

  1. Abnormal results on thyroid screening test (TSH value > 19.0 mIU/L for age <5 days or>9.1 for age 6-31 days).
  2. Clinical signs suggestive of neonatal hypothyroidism.



  1. TSH and free T4.
  2. If primary hypothyroidism is suspected (high TSH with a normal or low free T4), a technetium radionuclide thyroid scan will help determine etiology.
  3. If secondary hypothyroidism is suspected (low or normal TSH in the presence of a low free T4), a full evaluation of the hypothalamic pituitary axis is necessary.
  4. Genetic tests are based on the clinical, biochemical and radiological findings,


Treatment of Primary Hypothyroidism:

  • Start L-thyroxine at a dose of 10 to 15 µg/kg per day, to the nearest 25, 37.5, and 50 µg as required. The goal is to maintain the TSH and free T4 levels in the reference range. Treatment should be initiated before 45 days of age to minimize adverse developmental consequences.

Lower starting dose may be needed if only the TSH is increased.


Transient Disorders of Thyroid Function in the Premature Infant:

  • Transient hypothyroxinemia (low free T4, normal TSH,) occurs in ~50% of premature infants. Serum T4 concentration increases with gestational age, so all premature infants have some degree of hypothyroxinemia. The hypothyroxinemia corrects spontaneously over 6 to 10 weeks with normal postnatal growth and development. Treatment is not indicated as randomized trials show no improvements in either long- or short-term outcomes. However, thyroid functions should be monitored weekly.
  • Transient primary hypothyroidism (elevated TSH in the pres- ence of low free T4) is caused by: maternal treatment with antithyroid medications, maternal/neonatal iodine deficiency, exogenous iodine excess, maternal thyroid receptor blocking antibodies. Treatment with L-thyroxine replacement is initiated if abnormal thyroid function tests (elevated TSH and decreased free T4) persist for greater than 2 weeks. L-thyroxine may be required for ~8 to 12 weeks in antithyroid drug-induced hypothyroidism and 3 to 5 months for TSH receptor-blocking antibodies.
  • Sick euthyroid syndrome   is  seen  in prematurity, malnutrition, infections, and surgical stress. Free T4, TSH, and T3 values are often low with elevated levels of reverse T3 (the inactive form of thyroid hormone). Treatment is not recommended.



Neonatal hyperthyroidism is usually associated with maternal Graves’ disease where maternal thyroid-stimulating immunoglobulins (TSIs) cross the placenta acting on the fetal thyroid gland. The newborn may be asymptomatic at birth if mother received appropriate anti-thyroid therapy.  If mother was over-treated, temporary hypothyroidism may be present. In both these instances, presentation of neonatal thyrotoxicosis may be delayed by 8-10 days.


Presenting signs and symptoms of neonatal thyrotoxicosis include the following:

  1. Irritability and hyperactivity.
  2. Increased appetite.
  3. Tachycardia, arrhythmias, cardiac failure and hypertension.
  4. Vomiting and diarrhoea.
  5. Hepatosplenomegaly.
  6. Goiter.
  7. Fever.
  8. Exophthalmos.


Laboratory Values:

Increased T3 and FT4 levels with a suppressed TSH (< 0.1).



An endocrinology consultation should be obtained.

  1. No treatment is necessary for mild disorder.
  2. Antithyroid medications:
  3. Methimazole (MMZ): 0.5 to 1.0 mg/kg/day PO q 8h.
  4. If there is no response within 24 to 36 hours, the dose can be increased by 50%.
  5. In clinically severe cases consider additional measures
  6. Lugol’s iodine; 1 drop (8 mg) orally q 8h
  7. Propranolol; 1 to 2 mg/kg/day PO can be  given  q 8h
  8. Corticosteroids
  9. Sedatives and digitalization.


Differential diagnosis of Goiter

  1. Congenital hypothyroidism secondary to thyroid dyshormonogenesis
  2. Maternal ingestion of iodine or iodine deficiency.
  3. Maternal therapy with propylthiouracil.
  4. Hyperthyroidism.
  5. Rare thyroid tumors.
  6. Non-thyroid masses, e.g., cystic hygroma.


Disorders of the adrenal


Adrenocortical Hypofunction


  1. Congenital adrenal hyperplasia (Inborn errors in steroidogenesis).
  2. Congenital adrenal hypoplasia (associated with anencephaly, and DAX1 mutations)
  3. ACTH deficiency: isolated or with Congenital panhypopituitarism
  4. Destruction of the adrenal e.g., by hemorrhage, fulminating infections (rare).
  5. Maternal dexamethasone and betamethasone during the pregnancy.
  6. Relative adrenal insufficiency can present with cardiovascular instability and shock. Cortisol levels are low to normal but inadequate for the illness and response to ACTH is diminished below 500nmol/L. There has been much concern about this entity in the newborn period but to date randomized trials have not shown any benefit of non-selectivley treating infants in stress as “hypoadrenal” with exogenous therapy (dexamethsone or hydrocortisone),


Congenital Adrenal Hyperplasia

Clinical manifestations will reflect the activities of the hormones whose synthesis is defective i.e., cortisol, androgens or aldosterone.  The most common cause is 21 hydroxylase deficiency.


Symptoms and Signs:

  1. Vomiting, dehydration, intermittent fever.
  2. Hypotension, shock.
  3. Poor feeding, failure to thrive.
  4. Ambiguous genitalia (see below in section DSD).
  5. Hyponatremia, hyperkalemia, hypoglycemia, metabolic acidosis.
  6. These clinical manifestations of an Addisonian crisis will usually not appear prior to day 5-7 of life.


Diagnosis: Clinical features combined with consistent biochemical investigations—plasma cortisol, testosterone, 17OH-progesterone, other precursor steroids, and serum and urinary electrolytes. An ACTH stimulation test may be required. If congenital adrenal hyperplasia (CAH) is probable, complete investigations and start treatment immediately.



  1. Fluid and electrolyte replacement – initially 0.9% saline in 5-10% dextrose at 150 ml/kg/24h, guided by frequent estimation of serum electrolytes and blood glucose.
  2. Hydrocortisone 50 mg intravenously, then 100 mg/m2/day divided IV q 6h.
  3. If definitive diagnosis is made, long term therapy with replacement hydrocortisone and sometimes mineralocorticoid (fludrocortisone) and salt supplementation is required.
  4. Prenatal treatment of CAH has been undertaken in affected mothers to decrease in-utero virilization of female fetuses.


Ambiguous Genitalia-Disorders of Sexual Development (DSD)

Infants with a genital appearance that does not allow immediate gender assignment are said to have “ambiguous genitalia.” This includes:

  • Bilateral cryptorchidism
  • Perineal hypospadias with bifid scrotum
  • Clitoromegaly
  • Posterior labial fusion
  • Female appearance to genitalia with palpable gonads (with or without inguinal hernia)
  • Discordant genitalia and sex chromosomes

The birth of an infant with ambiguous genitalia is not only a medical emergency, but also poses a “psychosocial” emergency for the family. Therefore, involvement of an experienced multidisciplinary team including endocrinology, urology, gynecology, psychology and social work is essential in developing an appropriate therapeutic plan and providing adequate support for the family.


History and physical exam:

Prenatal exposure to androgens (e.g. progesterones, danazol, testosterone)

  • Maternal virilization during pregnancy (e.g. placental aromatase deficiency)
  • Family history of infertility or amenorrhea (androgen insensitivity)
  • Family history of unexplained, sudden infant deaths (congenital adrenal hyperplasia)
  • History of consanguinity
  • Careful inspection and palpation of the genitalia with attention to penile length (³ 2.0 cm in a normal term infant), presence or absence of gonads, location of the urethral opening, and clitoral size
  • Presence of dysmorphic features or non-genital anomalies


Core Initial Investigations:

  1. Karyotype and FISH for SRY to assess translocation to X chromosome.
  2. Electrolytes, cortisol and 17-hydroxyprogesterone (17-OHP) to assess for congenital adrenal hyperplasia. An ACTH stimulation test may be needed for less common forms of CAH
  3. A pelvic and abdominal ultrasound is essential to determine the presence of gonads, a uterus, and/or a vagina. A retrograde urethrogram is sometimes necessary to delineate the urethral and vaginal anatomy.

Further investigations depend on the results of the initial investigations. Please see Table for further details.


Clinical Examination and U/S findings Probable Diagnostic Category Most likely aetiology
No palpable gonads or U/S evidence of testicular tissue Virilized Female 21 OH deficiency
Bilateral palpable gonads + no Müllerian tissue Undervirilized Male Androgen insensitivity
Single gonad + Müllerian tissue Gonadal Intersex Mixed gonadal dysgenesis

OH =hydroxylase; U/S = ultrasound


Virilized Female

  • Karyotype 46 XX
  • Normal gonads and uterus
  • Virilization of the external genitalia – fusion/rogation/hypepigmentation of labia and or/clitoral hypertrophy



  1. 21 OH deficiency—causing CAH. Rarely 11b and 3b hydroxylase deficiency.
  2. Maternal androgen ingestion.
  3. Translocation of SRY to X-chromosome.
  4. Maternal masculinizing tumor and fetal masculinizing tumors are extremely rare.


Undervirilized Male

  • Karyotype 46 XY.
  • Normal testes.
  • Undervirilization of the external genitalia.



  1. Androgen insensitivity (end-organ resistance).
  2. Enzyme defects in testosterone synthesis and metabolism (adrenal, testis).
  3. Maternal drug ingestion; phenytoin, progesterone.
  4. 5 a reductase deficiency.
  5. Leydig cell hypoplasia.
  6. Vanishing testis syndrome.


Gonadal Intersex

  • Both testicular and Müllerian tissue present.
  • Diagnosed by laparotomy or laporoscopy with or without gonadal biopsy.



  1. Mixed gonadal dysgenesis
  2. True Hermaphroditism


Disorders of Calcium Phosphate Metabolism


Neonatal Hypocalcemia

Neonates are at risk of hypocalcemia due to a relative immaturity of their parathyroid glands, intestines, bones and kidneys.  Cutoff levels are difficult to define but a widely accepted working definition is a total calcium level < 2.0 nmol/l and or an ionized level < 1.0 nmol/l


Symptoms and Signs:

  1. Myoclonic jerks, twitching, startle responses and seizures
  2. Apnoea, cyanosis, laryngospasm
  3. Tachycardia, hypertension, heart failure



Early onset neonatal hypocalcemia occurs in the first week of life and is related to relative PTH insufficiency (<78ng/L in the presence of hypocalcemia).  Prematurity, hypoglycemia, maternal diabetes, difficult delivery and respiratory distress syndrome are common associated features.

Late onset occurs after the first week and is often due to transient resistance to PTH. However, other causes such as increased phosphate load, DiGeorge Syndrome, Vitamin D deficiency, hypomagnesemia and renal failure need to be considered



Acute treatment requires intravenous infusion of calcium salts as a 2% solution. Preferably continuous Calcium Gluconate 2% infusion started usually at 0.05mmol/Kg/hr and tapered by iCa q4h (see HSC Handbook).

Consider also oral Alfacalcidol (0.04 to 0.1 mcg/Kg daily) and an oral calcium solution.


Neonatal Rickets

This is primarily a disorder of premature infants and will generally present at 4-8 weeks of life 3


  • Calcium deficiency. Significant calcium accretion occurs in the last trimester; thus, premature infants have decreased calcium stores in addition to poor calcium retention rates.
  • Phosphorous deficiency.  Premature infants have reduced stores, and both human milk and parenteral nutrition are low in phosphorous.
  • Vitamin D deficiency. Is thought to be rare because supplementation is routine for premature infants. However, many premature and full-term babies may have reduced vitamin D stores due to low maternal vitamin D levels (high-risk mothers). Infants with defects of vitamin D metabolism are treated with alfacalcidol.



  • Pain on handling due to pathologic fracture.
  • Radiographic evidence of osteopenia, subperiosteal reaction, metaphyseal change, or pathologic fractures.
  • Biochemistry: serum calcium and phosphate may be normal or low and alkaline phosphatase may be elevated above 256 U/L. 25 (OH) D level is variable and PTH often increased above 78ng/L.



Review calcium, phosphorous, and vitamin D intake and supplement as appropriate.


Syndromes associated with Endocrine Disease:

  • Diagnosis of an endocrine abnormality can signal the presence of a syndrome.
  • It is also important to look for endocrine abnormalities in the presence of certain congenital anomalies eg, hypopituitarism with defects of mid face.


Some examples are given below:

  • Septo-optic dysplasia sequence- Hypopituitarism.
  • Prader-Willi syndrome-  Hypogonadism.
  • DiGeorge sequence-  Hypocalcemia.
  • William’s syndrome-  Hypercalcemia.
  • Beckwith-Wiedemann syndrome- Hypoglycemia.
  • Leprechaunism- Hyperglycemia, hyperinsulinemia, growth retardation.




Plasma glucose <2.2 mmol/L (<40 mg/dL), irrespective of gestational age. Recent recommendations are to consider specific interventions if blood glucose <2.6 mmol/L. (Figure I.)

Clinical signs: Lethargy, apnea, cyanosis, tremors, tachypnea, seizures.

High-Risk Situations:

  1. Severe illness, regardless of cause: sepsis, asphyxia, respiratory distress syndrome, intraventricular hemorrhage, shock, hypothermia, polycythemia
  2. Inadequate carbohydrate stores: intrauterine growth retardation (IUGR), small for gestational age (SGA), severe maternal pre-eclampsia, prematurity, transient neonatal hypoglycemia
  3. Impaired glucose mobilization: deficiency of growth hormone, cortisol, epinephrine, galactosemia, glycogen storage disease, septo-optic dysplasia (hypo-pituitarism with midface hypoplasia)
  4. Excessive glucose utilization: hyperinsulinism, infant of diabetic mother (IDM), islet cell dysplasia (nesidioblastosis), Beckwith-Wiedemann syndrome, sudden withdrawal of IV glucose


  • Monitoring for hypoglycemia in asymptomatic infants at risk should begin at <2 hours of age and in cases without hypoglycemia, be repeated at 3, 6, 12, 24, 48, and 72 hours, prior to feeds.
  • Early feeding and early IV glucose should be used for very high-risk infants.


A useful algorithm for the early detection and management of hypoglycemia is shown in Figure.


The following formula may be used to calculate the amount of carbohydrate infusing:

(10 x Glucose concentration x Total fluids mL/kg/day)   =  mg glucose/kg/min



e.g. 10 x 10% Dextrose x 120 mL fluids/kg/day ÷ 1440 (derived from 24h, 60min)

=  8.3 mg glucose/kg/min


If the infant has no obvious predisposing cause of transient hypoglycemia, or if the hypoglycemia persists into day 3 of life, other causes should be considered (Fig. 2).



Definition: Plasma glucose >10 mmol/L.

Clinical signs: Usually none.



  1. Iatrogenic, i.e., in very low-birth-weight (VLBW) infants receiving glucose along with TPN glucose intolerance is associated with immaturity
  2. Stress-associated, e.g., asphyxia, sepsis—always exclude sepsis in hyperglycemia of recent onset not caused by excessive glucose load
  3. After pancreatectomy for treatment of islet cell dysplasia
  4. Neonatal diabetes mellitus (transient or permanent)


  • Reduce IV glucose infusion rate.
  • If hyperglycemia persists, consider treatment with insulin.


Further Reading:

  1. Kirpalani, H., Moore, A.M. and Perlman, M., 2007. Residents handbook of neonatology. PMPH-USA
  2. Seminars in fetal and neonatal medicine. Vol 9. 2004
  3. van Wassenaer AG, Westera J, Houtzager BA, Kok JH. Ten-year follow-up of children born at < 30 weeks’ gestational age supplemented with thyroxine in the neonatal period in a randomized, controlled trial. Pediatrics 2005;116:e613–8.
  4. Watterberg KL, Scott  SM.  Evidence  of  early  adrenal  insufficiency in babies who develop bronchopulmonary dysplasia. Pediatrics 1995;95:120–5.
  5. Mercado AB, Wilson RC, Cheng KC, et al. Extensive personal experience: prenatal treatment and diagnosis of congenital adrenal hyperplasia owing to steroid 21-hydroxylase deficiency. J Clin Endo Metab 1995;80:2014–20.
  6. Kutteh WH, Santos-Ramos R, Ermel LD. Accuracy of ultrasonic detection of the uterus in normal newborn infants: implications for infants with ambiguous genitalia. Ultrasound Obstet Gynecol 1995;5:109–13.
  7. Backstrom MC, Kuusela AL, Maki R. Metabolic bone disease of prematurity. Ann Med 1996;28:275–82.
  8. Brook CGD. Clinical paediatric endocrinology. 3rd ed. Oxford: Blackwell; 1995.