Congenital Hypothyroidism

Congenital hypothyroidism (CH) is a heterogeneous group of disorders present at birth that lead to deficient thyroid hormone action during critical periods of brain development and growth.

Etiology and pathophysiology

Thyroid dysgenesis (60–85% overall in iodine-sufficient populations)

• Subtypes: agenesis (aplasia), ectopy (lingual/infrahyoid), hypoplasia.
• Embryologic basis: disrupted migration from foramen cecum, abnormal morphogenesis; often sporadic but occasional familial forms reflect defects in transcription factors.
• Pathophysiology: absent or poorly functioning tissue → lifelong severe primary hypothyroidism without intrinsic dyshormonogenesis.

Thyroid dyshormonogenesis (10–20%)

• Enzyme/transport defects: TPO, thyroglobulin (TG), sodium/iodide symporter (NIS/SLC5A5), Pendrin (SLC26A4), DUOX2/DUOXA2, IYD (DEHAL1), TG, TSHR activating/inactivating mutations.
• Phenotype: goitre common, variable severity from transient to permanent; often autosomal recessive or dominant depending on gene.

Central congenital hypothyroidism (secondary/tertiary)

• Causes: pituitary hypoplasia, septo-optic dysplasia, PROP1, POU1F1, HESX1, LHX3/4 mutations, hypothalamic defects.
• Distinguishing features: low/normal TSH with low free T4, frequent combined pituitary hormone deficiencies (CPHD), risk of unmasked adrenal insufficiency.

Transient congenital hypothyroidism

• Causes: maternal TSH receptor–blocking antibodies, maternal antithyroid drugs (methimazole, PTU) in late pregnancy, iodine excess or deficiency, prematurity, neonatal iodine exposure (contrast/antiseptics), immature hypothalamic‑pituitary axis, placental dysfunction.
• Temporal profile: biochemical hypothyroidism resolving over weeks–months.

Syndromic and chromosomal associations

• Down syndrome, Turner syndrome, dyadic midline defects; genetic syndromes with extrathyroidal manifestations.

Environmental and epidemiologic modifiers

• Iodine status, consanguinity (increases dyshormonogenesis), ethnicity-related mutation spectra, and screening protocol differences influence observed prevalence and case-mix.

Genetics, molecular mechanisms, and genotype–phenotype correlations

• Transcription factor mutations (dysgenesis-related): TSHR (loss-of-function), PAX8, NKX2-1 (TTF1), NKX2-5, FOXE1 (TTF2) — often sporadic de novo but familial clusters occur; PAX8 and NKX2-1 mutations may have extrathyroidal features (renal anomalies, chorea).
• Biosynthetic pathway genes (dyshormonogenesis): TPO, TG, SLC5A5 (NIS), SLC26A4 (Pendrin), DUOX2/DUOXA2, IYD; biallelic mutations usually cause permanent CH with goitre, some monoallelic DUOX2/Duoxa2 variants cause transient or milder disease.
• Central CH genes: PROP1, POU1F1, HESX1, LHX3/LHX4, OTX2; high index of suspicion for CPHD warrants pituitary imaging and adrenal assessment.
• Testing strategy: targeted gene panel or whole exome sequencing when dyshormonogenesis suspected, familial recurrence, syndromic features, or unexplained permanent CH; interpret variants with correlation to phenotype and family studies.

Diagnosis and investigation

Newborn screening (NBS) strategies and limitations

• Primary TSH screening detects primary CH efficiently but misses central CH and early TSH-latent cases; primary T4 with reflex TSH improves sensitivity for central CH but increases recall.
• Timing: optimal specimen at 48–72 hours; cord blood has higher false positives in preterms and during maternal drug exposure.
• False negatives/positives: prematurity, NICU medications, iodine exposure, delayed TSH rise in premature neonates, sampling before 48 hours.

Biochemical confirmation

• Urgent venous assays: serum TSH, free T4 (fT4) measured by reliable assays calibrated for neonatal ranges. Obtain total T4, free T4 index or mass‑spec fT4 if assay interference suspected.
• Interpretive patterns:
  • Primary CH: elevated TSH (often >40–100 mIU/L) with low fT4.
  • Partial/compensated: mildly elevated TSH (6–20 mIU/L) with normal fT4 requiring repeat testing and clinical correlation.
  • Central CH: low/normal TSH with low fT4; monitor other pituitary hormones
• Additional tests: serum thyroglobulin (absent/low in agenesis; elevated in dyshormonogenesis), antithyroid antibodies (maternal TSHR‑blocking), urinary/serum iodine, and maternal thyroid history.

Imaging

• Radionuclide thyroid scintigraphy (99mTc-pertechnetate or 123I) assesses presence, position, and uptake; best performed after starting levothyroxine only if it will not meaningfully reduce diagnostic yield, otherwise perform as soon as possible.
• High-resolution neck ultrasound evaluates gland anatomy and helps identify ectopy vs agenesis vs normally located gland; combine with scintigraphy for full characterization.
• Imaging strategy: if imaging will alter counselling/genetic workup, obtain before or shortly after treatment start; do not delay LT4 if diagnostic uncertainty exists.

Endocrine and systemic evaluation

• For suspected central CH: adrenal axis (morning cortisol or stimulated testing if concern), GH axis, electrolytes, hypoglycaemia history, and dedicated pituitary MRI.
• For dyshormonogenesis: look for neonatal goitre, family history, consanguinity, and arrange genetic testing.
• For suspected maternal antibody-mediated CH: measure maternal and neonatal anti-TSHR antibodies.

Management: acute, titration, and long-term strategies

Principles

• Prevent irreversible neurodevelopmental injury by rapid restoration of euthyroidism. Treat on presumptive diagnosis when NBS positive and clinical/lab features indicate CH; do not delay for imaging or genetic results

Initial levothyroxine dosing

• Full-term infants with severe biochemical hypothyroidism: 10–15 µg/kg/day oral levothyroxine; many specialists favour 12–15 µg/kg/day for severe cases to normalise fT4 rapidly
• Mild/compensated CH or borderline TSH elevation: 10 µg/kg/day with close biochemical follow-up; individualise for low-birth-weight or cardiac diseases
• Special formulations: use liquid preparations or crushed tablets dispersed in water/milk to improve dosing accuracy; verify stability and bioavailability of local products. Avoid switching formulations without monitoring.

Administration and interactions

• Single morning dose on empty stomach where feasible; avoid co-administration with iron, calcium, soy formula, cholestyramine, or certain anticonvulsants that impair absorption; give spacing of 2–4 hours when interactions are unavoidable.

Monitoring schedule

• First check TSH and fT4 at 2 weeks after treatment initiation, then every 2–4 weeks until stable and euthyroid, thereafter every 1–3 months in the first year, every 2–4 months in years 1–3, and at least every 6–12 months thereafter or with growth/clinical concerns.
• Target biochemical goals: fT4 in the upper half of the age-specific reference range and TSH within the normal reference range; avoid persistent mild elevation of TSH. For central CH, monitor fT4, not TSH.
• Adjust dose based on weight changes and biochemical trends; expect dose (µg/kg) to decline with age but absolute dose to increase.
• Re-evaluation for transient vs permanent CH
• Trial off therapy at age 2–3 years if etiology suggests transient CH (prematurity, maternal drugs, maternal antibodies, borderline initial results). Withdraw LT4 for 4 weeks and measure TSH and fT4; if TSH >10 mIU/L or fT4 low, restart lifelong therapy. For clear permanent causes (agenesis, ectopy, confirmed biallelic dyshormonogenesis mutation), continue lifelong therapy.

Management of central CH

• Exclude/ treat adrenal insufficiency before or contemporaneously with LT4 initiation to avoid precipitating adrenal crisis. Monitor for and treat other pituitary hormone deficiencies; use fT4 for dose titration.
• Surgical and radioiodine considerations
• Rarely required in CH itself; in dyshormonogenesis with large goitre causing obstructive symptoms, surgical consult indicated. Radioiodine not used in neonatal period for therapy; scintigraphy is diagnostic only.
• Genetic counselling and family screening
• Offer targeted carrier testing and genetic counselling in families with confirmed pathogenic mutations or dyshormonogenesis. Screen siblings if inherited mutation known.

Complications, outcomes, and transition of care

Neurodevelopmental outcome determinants

• Age at treatment initiation and adequacy of early biochemical control are primary determinants of IQ and motor outcomes; delays beyond 2–4 weeks or undertreatment associate with cognitive deficits.
• Other modifiers: severity of hypothyroidism at diagnosis, adherence, coexisting neonatal illness, prematurity.

Long-term endocrine complications

• Poor growth if undertreated, abnormal lipid profile in untreated/undertreated adults, fertility issues if poorly controlled in adolescence/adulthood.
• Central CH patients need lifelong surveillance for other pituitary hormone deficiencies that may evolve.

Transition to adult care

• Structured transition by adolescence with education on lifelong therapy, adherence, reproductive counseling, and adult endocrine follow-up.

• Always treat while investigating; do not delay LT4 for scans or genetics when biochemical diagnosis is clear.
• In an infant with low fT4 and low/normal TSH, prioritise adrenal assessment and pituitary MRI before attributing to primary CH.
• Use thyroglobulin measurement to help distinguish dysgenesis (low/absent) from dyshormonogenesis (normal/high).
• Consider DUOX2/DUOXA2 monoallelic variants as causes of transient or mild CH, especially in populations with high consanguinity.
• When switching formulations or brands, recheck TSH/fT4 within 4–6 weeks.
• For borderline TSH elevations in preterm infants, repeat testing and consult neonatology/endocrinology before committing to lifelong therapy.