Congenital Hypothyroidism

Congenital hypothyroidism (CH) is deficiency of thyroid hormone present at or developing soon after birth. It is the single most common preventable cause of intellectual disability worldwide — and the prototype "screen-and-treat" disease of paediatrics, because timely levothyroxine virtually normalises IQ while delay causes irreversible neurological damage.

Definition and importance

Congenital hypothyroidism is an inadequate production of thyroid hormone (T4/T3) by the neonatal thyroid, present from birth, leading to a hypometabolic state and — if untreated — to the syndrome historically called cretinism (severe growth failure plus profound intellectual disability).

• Incidence: roughly 1 in 2000–4000 live births (one of the commonest neonatal endocrine disorders).
• Female:male ratio approximately 2:1 (especially for thyroid dysgenesis).
• The developing brain depends on thyroid hormone for myelination, dendritic arborisation and synaptogenesis during the first 2–3 years of life. The "window" for irreversible damage is narrow — hence screening urgency.

High-yield: Congenital hypothyroidism is the most common preventable cause of mental retardation/intellectual disability. Outcome depends almost entirely on how early levothyroxine is started.

Classification

CH is broadly divided by the level of the defect (gland vs hypothalamic-pituitary axis) and by duration (permanent vs transient).

Type	Site of defect	Serum TSH	Serum free T4	Picked up by TSH screening?
Primary CH	Thyroid gland itself	High ↑↑	Low	Yes (most cases)
Central (secondary/tertiary)	Pituitary / hypothalamus	Low or inappropriately normal	Low	Missed by TSH-only screen
Peripheral	Thyroid hormone resistance / transport	Variable	Variable	Variable

Permanent vs Transient

• Permanent CH — requires lifelong therapy. Causes: thyroid dysgenesis, dyshormonogenesis, TSH-resistance.
• Transient CH — recovers over weeks–months. Causes: maternal antithyroid drugs, transplacental TSH-receptor blocking antibodies, iodine deficiency or iodine excess (povidone-iodine antiseptics, amiodarone), prematurity. Re-evaluation off therapy at ~3 years confirms which type.

Etiology and pathophysiology

Primary CH (gland-level) — the large majority (~85% in iodine-sufficient regions)

1. Thyroid dysgenesis (~80–85% of permanent primary CH) — a developmental defect; usually sporadic.
   • Ectopia (lingual/sublingual thyroid) — the commonest single anatomical cause.
   • Aplasia/agenesis (athyreosis) — most severe.
   • Hypoplasia.
2. Dyshormonogenesis (~10–15%) — inborn errors of hormone synthesis; usually autosomal recessive, hence higher in consanguineous populations and may cause a goitre.
   • Defects in: sodium-iodide symporter (NIS), thyroid peroxidase (TPO) — commonest, Pendrin (Pendred syndrome = goitre + sensorineural deafness), thyroglobulin, DUOX2/THOX2.
   • Pendred syndrome classic eponym: dyshormonogenetic goitre + congenital deafness; "Perchlorate discharge test" is positive.

Central CH

Deficiency of TSH or TRH — usually part of congenital hypopituitarism (look for hypoglycaemia, micropenis, midline defects, septo-optic dysplasia). TSH is not elevated, so a TSH-based screening programme misses it.

Endemic / iodine-related

• Endemic cretinism from maternal + neonatal iodine deficiency (sub-Himalayan belt, central Indian goitre belt). Two forms: neurological (deaf-mutism, spasticity, mental retardation — from first/second-trimester deficiency) and myxoedematous (severe hypothyroidism, growth failure). Universal salt iodisation is the public-health answer.
• Iodine excess (e.g. topical povidone-iodine in neonates/premies) → Wolff-Chaikoff effect → transient CH.

Maternal / transplacental causes (transient)

• Maternal antithyroid drugs (carbimazole, propylthiouracil) crossing the placenta.
• Maternal autoimmune thyroid disease → TSH-receptor blocking antibodies crossing placenta.

High-yield: Thyroid dysgenesis is the most common cause of permanent primary CH overall; ectopic (lingual) thyroid is the commonest single anatomical defect; dyshormonogenesis is the commonest cause that produces a goitre and is inherited (autosomal recessive).

Clinical features

The crucial teaching point: most affected newborns appear NORMAL at birth. Maternal T4 crosses the placenta and partially protects the fetus, so the classic signs are subtle initially and emerge over weeks — which is precisely why we cannot rely on clinical detection and must screen.

Early / neonatal clues

• Prolonged neonatal jaundice (unconjugated; impaired hepatic glucuronidation) — a key early sign.
• Lethargy, poor feeding, hypotonia, hoarse/hoarse cry.
• Constipation; abdominal distension; delayed passage of meconium (>20 h).
• Hypothermia, cold mottled skin, peripheral cyanosis.
• Large posterior fontanelle (>0.5 cm) and wide-open fontanelles.

Evolving / florid features (weeks to months)

• Coarse facies, macroglossia (large protruding tongue), depressed nasal bridge.
• Umbilical hernia.
• Dry skin, myxoedema, puffiness.
• Hypotonia ("floppy infant"), developmental delay, poor head control.
• Bradycardia, pericardial effusion.
• Goitre (in dyshormonogenesis or maternal-drug cases).
• Growth failure (length affected more than weight), delayed bone age.

Mnemonic — "6 P's" of CH: Prolonged jaundice, Poor feeding, Pot belly (umbilical hernia), Puffy myxoedematous face, Pale & cold (hypothermia), Protruding tongue (macroglossia). Add constipation and large fontanelle.

High-yield: A neonate with prolonged jaundice + constipation + umbilical hernia + large fontanelle + macroglossia + hypotonia is congenital hypothyroidism until proven otherwise.

Screening — the heart of the topic

Why screen

Clinical features are absent/subtle in the newborn period; by the time signs are obvious, irreversible CNS damage may have occurred. Hence universal newborn screening.

How (the heel-prick)

• Sample: heel-prick capillary blood on a filter-paper (Guthrie) card.
• Timing: ideally 48–72 hours of life (after the physiological neonatal TSH surge has settled). Avoid the first 24–48 h because of the transient post-natal TSH spike that causes false positives.
• Primary analyte in most programmes (incl. India): TSH (cheap, catches the common primary CH). Some programmes use primary T4 with backup TSH; the ideal but costlier strategy is combined T4 + TSH (only this reliably detects central CH).

Screening strategy	Detects primary CH	Detects central CH	Comment
Primary TSH	Yes	No	Cheapest; most widely used (India)
Primary T4 + backup TSH	Yes	Partially	Misses delayed TSH rise
Combined T4 + TSH	Yes	Yes	Best but expensive

Special timing situations

• Preterm, low-birth-weight, sick or twin neonates have a delayed/blunted TSH rise → screen and then repeat at ~2 weeks (or 36 weeks corrected) to avoid missing a delayed-rise case.

Confirmation (after a positive screen)

A positive screen is never the diagnosis — confirm with venous serum TSH and free T4 before/at the start of treatment, but do not delay treatment waiting for ancillary imaging.

Stepwise approach:

Abnormal heel-prick TSH → recall infant → venous serum free T4 + TSH → if TSH high & fT4 low = primary CH → start levothyroxine immediately → then (without delaying treatment) etiologic work-up: thyroid ultrasound and technetium-99m / I-123 scintigraphy ± thyroglobulin, maternal antibodies, knee X-ray for bone age.

Investigation of choice

• Diagnosis/confirmation: serum TSH (raised) + free T4 (low) = investigation of choice for confirming primary CH.
• Etiology (anatomy/uptake): radionuclide scan (Tc-99m pertechnetate or I-123) is the investigation of choice to localise the gland — distinguishes athyreosis (no uptake), ectopia (lingual uptake), enlarged in-situ gland (dyshormonogenesis), and gland-in-place. Ultrasound complements it.
• Skeletal maturity: X-ray knee in a term newborn — absent distal femoral and proximal tibial epiphyses indicates intrauterine hypothyroidism and delayed bone age.

High-yield: Heel-prick TSH is the screening test; serum free T4 + TSH is the confirmatory test; Tc-99m/I-123 thyroid scan is the test to find the cause/anatomy. Never withhold levothyroxine while awaiting the scan.

Management — drug of choice and urgency

Drug of choice: Levothyroxine (L-thyroxine, oral). T3 is not used for maintenance.

• Start as early as possible — ideally within the first 2 weeks of life. Every week of delay erodes the eventual IQ.
• Starting dose: 10–15 µg/kg/day (the highest dose per kg used at any age — aim for the upper range in severe athyreosis).
• Goal: normalise serum free T4 (upper half of normal) within ~2 weeks and TSH within ~1 month.
• Administration: crush the tablet, give in a little breast milk/water/formula. Avoid co-administration with soya formula, iron, calcium and fibre, which impair absorption. There is no reliable liquid suspension in many settings — use crushed tablets.

Monitoring schedule

Age / situation	Frequency of TSH + fT4
2 & 4 weeks after starting	Then
First 6 months	Every 1–2 months
6 months – 3 years	Every 3–4 months
After 3 years	Every 6–12 months
After any dose change	At 4 weeks

Re-evaluation: If the cause was not clearly permanent (e.g. a gland-in-place on scan, no firm dysgenesis), trial off levothyroxine at ~3 years of age for 4–6 weeks and re-test to confirm permanent vs transient CH. Do not trial-off before 3 years (brain still vulnerable).

High-yield: Levothyroxine 10–15 µg/kg/day, started ideally before 2 weeks of age, normalising fT4 in 2 weeks and TSH in 1 month — these exact numbers are repeatedly tested.

Consequences of delayed diagnosis / complications

• Irreversible intellectual disability — the dominant complication. Each ~3–4 weeks of delayed treatment and severe initial disease lowers eventual IQ.
• Neurodevelopmental deficits — even with treatment, very late or undertreated cases show lower IQ, attention and fine-motor problems; severe untreated = "cretinism."
• Endemic cretinism — deaf-mutism, spasticity, squint, mental retardation (neurological type).
• Growth failure / short stature, delayed bone age, delayed dental eruption.
• Slipped capital femoral epiphysis and pseudoprecocious puberty (Van Wyk–Grumbach syndrome: long-standing severe primary hypothyroidism → precocious puberty + multicystic ovaries due to TSH cross-reacting with FSH receptor).
• Associated anomalies: congenital heart disease is more frequent; up to ~10% of CH have other congenital malformations. CH is also commoner in Down syndrome.
• Over-treatment risks: craniosynostosis, premature fontanelle closure, accelerated bone age, irritability — hence careful monitoring.

High-yield: Van Wyk–Grumbach syndrome = juvenile primary hypothyroidism with precocious puberty (and multicystic ovaries) — a classic eponym.

Key differentials

Condition	Distinguishing point
Down syndrome	Hypotonia, macroglossia, flat facies overlap; karyotype + thyroid tests (and CH itself is commoner in Down)
Mucopolysaccharidoses (e.g. Hurler)	Coarse facies, hernia, organomegaly, corneal clouding; normal thyroid tests, urinary GAGs
Beckwith–Wiedemann syndrome	Macroglossia + macrosomia + omphalocele + hypoglycaemia; normal TSH
Breast-milk / physiological prolonged jaundice	Jaundice without other CH signs; normal TSH/fT4
Storage disorders / GM1 gangliosidosis	Coarse features, neuroregression; metabolic work-up
Constitutional hypotonia / neuromuscular causes	Floppy infant with normal thyroid function

A prolonged-jaundice or floppy-infant work-up should always include thyroid function — CH hides among these.

Recently asked / exam angle

• "Most common preventable cause of mental retardation" → Congenital hypothyroidism (very frequent one-liner).
• Best time for newborn TSH heel-prick screening → 48–72 hours of life (to avoid the physiological postnatal TSH surge causing false positives); cord blood or <24 h gives false positives.
• Most common cause of permanent CH → thyroid dysgenesis; commonest anatomical type → ectopic (lingual) thyroid.
• Commonest cause of CH with goitre / inherited CH → dyshormonogenesis (TPO defect commonest; autosomal recessive).
• Investigation to localise gland / find cause → Tc-99m or I-123 thyroid scintigraphy.
• Drug & dose → Levothyroxine 10–15 µg/kg/day orally, start <2 weeks.
• Screening test that misses central CH → primary TSH-only screening.
• Pendred syndrome → dyshormonogenetic goitre + sensorineural deafness; positive perchlorate discharge test.
• Van Wyk–Grumbach → hypothyroidism + precocious puberty.
• X-ray sign of intrauterine hypothyroidism → absent distal femoral/proximal tibial epiphyses at term.
• Substances impairing levothyroxine absorption → soya, iron, calcium, fibre.
• Endemic cretinism → maternal iodine deficiency; neurological (deaf-mutism, spasticity) vs myxoedematous types; prevented by salt iodisation.

High-yield: Cord blood/very-early TSH gives false positives because of the physiological neonatal TSH surge (peaks ~30 min after birth, settles by 24–48 h). Screen at 48–72 h.

Rapid revision

1. CH = commonest preventable cause of intellectual disability; incidence ~1 in 2000–4000; F:M ≈ 2:1.
2. Most newborns look normal at birth (placental maternal T4) — hence universal screening, not clinical detection.
3. Earliest clue is often prolonged unconjugated jaundice; full picture: macroglossia, umbilical hernia, large fontanelle, hypotonia, constipation, hoarse cry, dry skin.
4. Thyroid dysgenesis = commonest permanent cause; ectopic (lingual) thyroid = commonest anatomical defect.
5. Dyshormonogenesis = commonest cause with a goitre, autosomal recessive, TPO defect most frequent.
6. Screen via heel-prick filter-paper TSH at 48–72 h; repeat in preterm/LBW/sick/twins (delayed TSH rise).
7. Confirm with venous serum free T4 (low) + TSH (high); localise cause with Tc-99m / I-123 scan.
8. Primary TSH-only screening misses central (pituitary) CH — that needs T4-based screening.
9. Levothyroxine 10–15 µg/kg/day, start <2 weeks of age; normalise fT4 in 2 weeks, TSH in 1 month.
10. Avoid giving levothyroxine with soya, iron, calcium, fibre; do not co-administer with these.
11. Trial off therapy at ~3 years to separate permanent vs transient CH (transient = maternal drugs/antibodies, iodine deficiency/excess).
12. Remember the eponyms: Pendred (goitre + deafness), Van Wyk–Grumbach (hypothyroidism + precocious puberty); endemic cretinism is prevented by universal salt iodisation.