Types of Congenital Hypothyroidism
Congenital hypothyroidism (CH) can be classified into three main categories: thyroid dysgenesis, thyroid dyshormonogenesis, and central hypothyroidism, with thyroid dysgenesis accounting for approximately 85% of permanent cases.
Primary Congenital Hypothyroidism
1. Thyroid Dysgenesis (85% of cases)
Abnormal thyroid gland development during embryogenesis:
- Thyroid ectopy: Most common form - thyroid tissue located in abnormal position (usually sublingual)
- Thyroid aplasia/athyreosis: Complete absence of thyroid tissue
- Thyroid hypoplasia: Reduced size but normal location of thyroid gland
Genetic causes of thyroid dysgenesis:
- Mutations in transcription factors: PAX8, TTF-2 (FOXE1), NKX2-1 (TTF-1)
- TSH receptor loss-of-function mutations (can cause familial athyreosis)
- Most cases (85%) are sporadic with unknown etiology 1
2. Thyroid Dyshormonogenesis (10-15% of cases)
Defects in thyroid hormone synthesis despite normal gland structure:
- Sodium/iodide symporter (NIS) defects
- Thyroid peroxidase (TPO) deficiency
- Thyroglobulin synthesis defects
- Iodotyrosine deiodinase deficiency
- Pendred syndrome (associated with sensorineural hearing loss)
- Hydrogen peroxide generation defects
These conditions typically have autosomal recessive inheritance 2, 3
3. Transient Primary Congenital Hypothyroidism
Temporary forms that resolve over time:
- Maternal thyrotropin receptor blocking antibodies (TRB-Ab)
- Maternal antithyroid drug exposure
- Iodine deficiency or excess
- Prematurity-associated hypothyroxinemia
Secondary/Central Congenital Hypothyroidism
1. Isolated TSH Deficiency
- Rare genetic mutations affecting pituitary TSH production
2. Combined Pituitary Hormone Deficiencies
- Often part of congenital hypopituitarism
- May present with multiple hormone deficiencies 4
Syndromic Forms of Congenital Hypothyroidism
1. DiGeorge Syndrome (22q11.2 Deletion Syndrome)
- Most common genetic cause of thymic aplasia/hypoplasia
- Features: congenital heart defects, hypoparathyroidism, facial dysmorphism
- Thymic aplasia occurs in <1% of individuals with 22q11.2DS 5
2. CHARGE Syndrome
- Second most common genetic cause of DiGeorge-like phenotype
- Caused by CHD7 mutations
- Features: coloboma, heart defects, choanal atresia, growth retardation, genital abnormalities, ear anomalies 5
3. Nude SCID (FOXN1 Deficiency)
- Autosomal recessive condition
- Features: congenital alopecia totalis, nail dystrophy, thymic aplasia 5
4. Other Genetic Syndromes
- PAX1 deficiency (Otofaciocervical syndrome type 2)
- TBX1/TBX2 deficiency
- FOXI3 haploinsufficiency 5
Environmental Causes of Congenital Thymic Aplasia/Hypoplasia
- Diabetic embryopathy
- In utero alcohol exposure
- In utero retinoic acid exposure (excess or deficiency) 5
Clinical Presentation and Diagnosis
Most infants (>95%) with congenital hypothyroidism have few or no clinical manifestations at birth due to maternal thyroid hormone transfer 6, 4. When present, symptoms may include:
- Decreased activity and increased sleep
- Feeding difficulties
- Constipation
- Prolonged jaundice
- Myxedematous facies
- Large fontanels
- Macroglossia
- Distended abdomen with umbilical hernia
- Hypotonia
Diagnosis is primarily made through newborn screening programs using:
- Primary TSH with backup T4 or primary T4 with backup TSH measurements
- Confirmatory serum thyroid function tests (elevated TSH, low T4/free T4)
Additional diagnostic tests to determine etiology:
Management
Early treatment is crucial to prevent neurodevelopmental impairment:
- Levothyroxine is the treatment of choice
- Recommended starting dose: 10-15 mcg/kg/day
- Goal: Rapidly raise serum T4 above 130 nmol/L (10 μg/dL) and normalize TSH
- Frequent monitoring: Every 1-2 months in first 6 months, every 3-4 months thereafter 6
Prognosis is excellent with early detection and treatment, with IQs similar to sibling or classmate controls. Poorer outcomes may occur with:
- Late treatment initiation (>30 days of age)
- Lower initial levothyroxine doses
- More severe hypothyroidism at diagnosis 6