What are the types of congenital hypothyroidism?

Types of Congenital Hypothyroidism

Congenital hypothyroidism (CH) can be classified into permanent and transient forms, which can be further subdivided based on etiology into primary (thyroidal), secondary (pituitary), or peripheral causes. 1

Primary Classification

1. Permanent Congenital Hypothyroidism

• Thyroid Dysgenesis (85% of permanent CH cases)

  • Ectopic thyroid gland (most common)
  • Thyroid aplasia (complete absence)
  • Thyroid hypoplasia (underdeveloped)

• Dyshormonogenesis (10-15% of permanent CH cases)

  • Inborn errors of thyroid hormone biosynthesis
  • Usually autosomal recessive inheritance
  • Normal-sized or enlarged thyroid gland

2. Transient Congenital Hypothyroidism

• Occurs in approximately 51.4% of children with eutopic glands 2
• Usually resolves within the first few years of life
• Requires lower levothyroxine doses during treatment compared to permanent CH

Etiological Classification

A. Genetic Causes of Congenital Thymic Aplasia/Hypoplasia (Often Associated with CH)

1. 22q11.2 Deletion Syndrome (DiGeorge Syndrome)

   • Most common genetic cause (1:4000 live births)
   • Features: thymic hypoplasia/aplasia, hypoparathyroidism, congenital heart disease
   • De novo (90-95%) or autosomal dominant (5-10%) 3

2. CHARGE Syndrome

   • CHD7 haploinsufficiency
   • Features: coloboma, heart defects, choanal atresia, growth retardation, genitourinary abnormalities, ear anomalies 3

3. Other Genetic Causes

   • TBX1 deficiency (autosomal dominant)
   • TBX2 deficiency (autosomal dominant)
   • 22q11.2 duplication (autosomal dominant/de novo)
   • FOXI3 haploinsufficiency
   • Partial monosomy 10p (de novo)
   • FOXN1 deficiency (Nude SCID) - autosomal recessive
   • PAX1 deficiency (OFCS2) - autosomal recessive 3

B. Environmental Causes

1. Maternal/Pregnancy Factors

   • Diabetic embryopathy
   • In utero overexposure to alcohol
   • In utero over/under exposure to retinoic acid
   • Maternal thyroid antibodies (transplacental passage of thyrotropin receptor blocking antibody) 3, 4

2. Iodine-Related

   • Iodine deficiency (most common cause worldwide)
   • Iodine excess 1

3. Prematurity-Related

   • More common in premature infants, twins, and low birth weight babies 2

Functional Classification

1. Primary Hypothyroidism

• Due to thyroid gland dysfunction
• Characterized by high TSH and low T4 levels

2. Secondary (Central) Hypothyroidism

• Due to pituitary dysfunction
• May occur with isolated TSH deficiency
• More commonly associated with congenital hypopituitarism
• Characterized by low/normal TSH and low T4 levels 1

3. Peripheral Hypothyroidism

• Due to resistance to thyroid hormone action
• Rare cause of congenital hypothyroidism

Clinical Predictors for Permanent vs. Transient CH

Factors Suggesting Permanent CH:

• Low free T3 at diagnosis
• Maternal levothyroxine treatment
• Family history of thyroid dysfunction
• TSH ≥10 mIU/L while receiving treatment
• Absent knee epiphyses on X-ray at diagnosis
• Requiring levothyroxine dose increases after age 3 years 2, 5

Factors Suggesting Transient CH:

• Prematurity
• Twin pregnancy
• Low birth weight
• Apgar score <7
• Lower levothyroxine requirements (≤3.95 μg/kg/day at 6 months, ≤2.56 μg/kg/day at 1 year) 2

Diagnostic Approach

Diagnosis is typically made through newborn screening programs using:

• Primary T4 with backup TSH testing, or
• Primary TSH testing

Confirmatory testing includes:

• Serum thyroid function tests (elevated TSH, low T4 or free T4)
• Thyroid scintigraphy (most accurate for detecting dysgenesis)
• Thyroid ultrasonography
• Measurement of maternal/neonatal TRB-Ab when antibody-mediated hypothyroidism is suspected 4

Early diagnosis and treatment are essential to prevent neurocognitive impairment, as delayed treatment (beyond 30 days of age) is associated with poorer outcomes 1.