Congenital Hypothyroidism

Overview & Epidemiology

• Most common preventable cause of intellectual disability worldwide.
• Incidence: 1 in 2,000 to 1 in 4,000 live births.
• Female predominance: Female:Male ratio 3:1 (especially in thyroid ectopy).
• Increased risk populations: Trisomy 21, cardiac defects, preterm/low-birth-weight infants.

Fetal-Maternal Thyroid Physiology

• Fetal thyroid functional by 10-12 weeks gestation.
• Fetal TSH secretion evident by 10-12 weeks.
• Placental transfer: Maternal thyroxine (T4) crosses placenta, providing ~33% of fetal T4 requirements at term.
• Maternal T4 prevents severe fetal neurodevelopmental injury in complete fetal athyreosis, provided mother is euthyroid.
• Postnatal TSH surge: Cold-stimulated TSH release peaks at 30 minutes of life (up to 70-100 mIU/L), stimulating T4 and triiodothyronine (T3) surge. Normalizes to <5-10 mIU/L by 5-7 days.

Etiology & Classification

Primary Hypothyroidism (>95%)

Defect within thyroid gland. Manifests with low Free T4 (FT4) and elevated TSH.

Etiology Category	Frequency	Pathophysiology & Key Features
Thyroid Dysgenesis	80-85%	Abnormal glandular formation/migration.
Ectopy	70-75%	Failure of descent. Sublingual location most common.
Athyreosis/Agenesis	15-33%	Complete absence of tissue. True athyreosis: Thyroglobulin (Tg) < 2 mcg/L.
Hypoplasia	<5%	Small rudiment in orthotopic position.
Dyshormonogenesis	10-15%	Inborn errors of hormone synthesis in structurally normal/enlarged gland. Autosomal recessive. Leads to goitrous CH.
Transient Primary CH	Variable	Maternal antithyroid medications (methimazole/propylthiouracil), TSH receptor-blocking antibodies (TRBAb) (2% of screening cases), severe iodine deficiency, or iodine excess (Wolff-Chaikoff effect).

Central (Secondary/Tertiary) Hypothyroidism (<5%)

Defect in hypothalamus or pituitary.

• Incidence: 1:16,000 to 1:30,000.
• Pathophysiology: Deficient TSH stimulation.
• Associated features: Midline facial defects, hypoglycemia, micropenis, cryptorchidism, prolonged jaundice (suggests multiple pituitary hormone deficiencies).
• Undetected by isolated TSH newborn screening; requires T4-primary screening or clinical suspicion.

Peripheral / Consumptive Hypothyroidism

• Consumptive: Giant hepatic hemangiomas express high levels of type 3 deiodinase, rapidly inactivating T4 and T3.
• Transport/Receptor Defects: MCT8 (SLC16A2) mutation (Allan-Herndon-Dudley syndrome), or Thyroid Hormone Receptor (THRA, THRB) mutations causing tissue resistance.

Molecular Genetics

Genetic Defects in Thyroid Dysgenesis (Syndromic CH)

Accounts for 2-5% of dysgenesis. High discordance in monozygotic twins implies two-hit model (germline + somatic mutation).

Gene	Inheritance	Associated Phenotype (Syndrome)
NKX2.1	De novo / AD	Brain-Lung-Thyroid Syndrome: Choreoathetosis, ataxia, hypotonia, respiratory distress.
FOXE1	AR	Bamforth-Lazarus Syndrome: True athyreosis, cleft palate, spiky hair, choanal atresia, bifid epiglottis.
PAX8	AD / De novo	Dysgenesis with kidney and urinary tract malformations.
GLIS3	AR	Neonatal diabetes, congenital glaucoma, deafness, exocrine pancreas failure.
JAG1	AD	Alagille Syndrome: Dysgenesis, cardiovascular defects, liver involvement.

Genetic Defects in Dyshormonogenesis

Autosomal recessive inheritance.

Gene	Affected Protein	Pathophysiology & Diagnosis
SLC5A5	Sodium-Iodide Symporter (NIS)	Defective iodide trapping. Low scintigraphy uptake. Low saliva:serum 123I ratio.
SLC26A4	Pendrin	Defective apical transport. Pendred Syndrome: Goiter + sensorineural deafness.
TPO	Thyroperoxidase	Most common defect. Defective organification/coupling. High radioiodine uptake; positive perchlorate discharge.
DUOX2 / DUOXA2	Dual Oxidase 2 System	Defective H2O2 generation. Variable severity, permanent or transient.
TG	Thyroglobulin	Defective synthesis. Goitrous CH with low/absent serum Tg.
IYD	Iodotyrosine Deiodinase	Defective iodine recycling. Elevated urinary MIT and DIT.

Clinical Manifestations

Neonatal Period

• Most infants are completely asymptomatic at birth due to protective transplacental maternal T4.
• Early clues: Wide open anterior and posterior fontanels (posterior >0.5 cm in 97% cases).
• Prolonged unconjugated/conjugated hyperbilirubinemia (delayed glucuronide conjugation maturation).
• Lethargy, increased sleep, hoarse cry, poor feeding, choking spells.
• Large abdomen, umbilical hernia.
• Hypothermia (<35°C), cold mottled skin, peripheral edema.
• Bradycardia, asymptomatic pericardial effusion, macrocytic anemia.

Late Infancy / Childhood (Untreated)

• Progressive neurodevelopmental delay, profound intellectual disability.
• Severe stunting of linear growth, delayed skeletal maturation.
• Classic facies: Depressed nasal bridge, narrow palpebral fissures, puffy eyelids, coarse/brittle hair, low hairline.
• Macroglossia (protruding thick tongue), open mouth.
• Dentition delay.
• Kocher-Debré-Sémélaigne syndrome: Muscular hypotonia with generalized muscular pseudohypertrophy (especially calf muscles).
• Ectopic glands may hypertrophy and present later as a midline/sublingual neck mass.

Diagnostic Evaluation

Newborn Screening (NBS)

• Timing: Dried Blood Spot (DBS) collected via heelprick on filter paper at 2-4 days of life (avoiding initial 24-hour physiological TSH surge).
• Strategies:
  • Primary TSH: Highly sensitive for primary CH. Misses central CH.
  • Primary T4 with reflex TSH: Identifies primary CH, central CH, and TBG deficiency.
• Thresholds: TSH >40 mU/L usually necessitates immediate treatment. Borderline elevated TSH (e.g., 10-39 mU/L) requires confirmatory testing.
• Re-screening: Second routine screen at 2-4 weeks indicated for premature, low-birth-weight, and ill neonates (due to delayed TSH elevation) or monozygotic twins (fetal blood mixing obscures true status).

Confirmatory Serum Testing

• Venous TSH and FT4 measurements are mandatory to confirm abnormal NBS.
• Initiate treatment immediately without delaying for test results if clinical suspicion is high or screening TSH >40 mU/L.

Imaging Studies

• Radionuclide Scintigraphy (99mTc-pertechnetate or 123I): Gold standard for anatomic diagnosis.
  • Normal/Increased uptake in orthotopic gland: Dyshormonogenesis.
  • Ectopic uptake: Thyroid ectopy.
  • Absent uptake: Agenesis, TSHR blocking antibodies, or NIS defect.
• Neck Ultrasound: User-dependent. Confirms orthotopic gland presence/absence. Differentiates true agenesis from conditions preventing tracer uptake (e.g., TRBAb). Fails to reliably identify ectopic glands.
• Bone Radiography: X-ray of knee/leg. Absence of distal femoral and proximal tibial epiphyses in a term infant confirms intrauterine onset of hypothyroidism (correlates with higher risk of neurodevelopmental deficits).

Additional Biomarkers

• Serum Thyroglobulin (Tg):
  • Low/Undetectable: True athyreosis, TG synthesis defects, or complete TSHR inactivation.
  • Elevated: Ectopy, Dyshormonogenesis.

Management

Pharmacotherapy

• Drug of Choice: Oral Levothyroxine (L-T4).
• Dose: 10-15 mcg/kg/day (typically 37.5-50 mcg/day for term neonates). High-end dosing (50 mcg/day) correlates with optimal neurodevelopmental outcome at 5 years.
• Administration: Crushed and mixed in small amount of water/breastmilk. Avoid co-administration with soy, iron, or calcium supplements (impairs absorption).

Monitoring Targets & Follow-up

• Targets: Maintain TSH strictly within age-specific normal range. Maintain FT4 in the upper half of normal reference range.
• Frequency:
  • 1 week and 1 month after treatment initiation.
  • Every 1-2 months during the first 6 months.
  • Every 2-4 months from 6 months to 3 years.
  • 4-6 weeks following any dosage adjustment.

Special Considerations

• Transient CH: Re-evaluate at 3 years of age. Withdraw L-T4 for 4 weeks; if TSH rises, permanent CH is confirmed; if normal, treatment is discontinued.
• Central CH: Do not use TSH for monitoring. Adjust L-T4 dose solely based on maintaining FT4 in upper half of normal range. Ensure cortisol sufficiency prior to initiating L-T4 to avert adrenal crisis.
• Pregnancy & Genetic Counseling: Parents of children with dyshormonogenesis (AR) must be counseled on 25% recurrence risk.

Prognosis

• Neurocognitive Outcome: Excellent if diagnosed via NBS and treated adequately within first 2 weeks of life (IQ indistinguishable from siblings).
• Delayed Treatment: Leads to irreversible cognitive impairment, delayed motor milestones, speech problems, and permanent short stature.
• Predictors of Severity: Very low pre-treatment FT4 levels and absent knee epiphyses at birth represent severe fetal hypothyroidism and predict a slightly lower IQ trajectory despite optimal postnatal management. Hearing deficits (sensorineural) occur in ~10% of cases.

Delay in diagnosis of congenital hypothyroidism results in loss of 10-15 IQ points every month