From the Guidelines
Congenital hypothyroidism is primarily caused by insufficient production of thyroid hormones due to thyroid dysgenesis or dyshormonogenesis, and early treatment is crucial to prevent irreversible neurological damage and growth impairment. The pathophysiology of congenital hypothyroidism involves a complex interplay of genetic and environmental factors that affect the development and function of the thyroid gland. According to the ACOG Practice Bulletin on Thyroid Disease in Pregnancy 1, untreated maternal hypothyroidism increases the risk of preeclampsia and low birth weight in neonates, highlighting the importance of maternal thyroid function in fetal development.
Key Factors in Congenital Hypothyroidism
- Thyroid dysgenesis: abnormal gland development, including thyroid agenesis, hypoplasia, or ectopic placement, accounts for approximately 85% of cases
- Dyshormonogenesis: genetic defects in enzymes necessary for thyroid hormone synthesis, such as thyroid peroxidase deficiency or iodide transport defects, representing about 15% of cases
- Central hypothyroidism: pituitary or hypothalamic dysfunction affecting TSH production
- Maternal factors: iodine deficiency, antithyroid medications, or transplacental passage of TSH receptor-blocking antibodies can cause transient congenital hypothyroidism
Importance of Early Treatment
Early treatment with levothyroxine is essential to prevent irreversible neurological damage and growth impairment. The American Academy of Pediatrics recommends starting treatment with levothyroxine at 10-15 mcg/kg/day in newborns, with dose adjustments based on regular monitoring of thyroid function tests. Newborn screening for congenital hypothyroidism is offered throughout the United States, and treatment in the first several weeks of life can result in nearly normal intelligence and growth 1.
From the FDA Drug Label
The FDA drug label does not answer the question.
From the Research
Pathophysiology of Congenital Hypothyroidism
The pathophysiology of congenital hypothyroidism is complex and involves multiple genetic and environmental factors.
- Congenital hypothyroidism is most commonly caused by defects in thyroid development, leading to thyroid dysgenesis (80-90%), which consists of thyroid agenesis, ectopy, or hypoplasia 2.
- The remaining 10-20% of congenital hypothyroidism is due to defects in thyroid hormone biosynthesis, collectively called thyroid dyshormonogenesis, which are inherited autosomal recessively 2.
- A genetic component has been identified in many cases of congenital hypothyroidism, with mutations in specific genes implicated in thyroid dysgenesis and dyshormonogenesis 3, 4.
Genetic Causes
- Mutations in five genes have been implicated in thyroid dysgenesis, the primary cause of congenital hypothyroidism (85%), including TSHR, FOXE1, NKX2-1, PAX8, and NKX2-5 3.
- Mutations in seven genes have been implicated in thyroid dyshormonogenesis, including SLC5A5, TPO, DUOX2, DUOXA2, SLC6A4, Tg, and DEHAL1 3, 4.
- These genes encode for proteins that regulate genes expressed during the differentiation of the thyroid, such as TPO and Tg genes, or genes that regulate iodide organification, thyroglobulin synthesis, iodide transport, and iodotyrosine deiodination 3, 4.
Clinical Implications
- The identification of the underlying genetic defects of congenital hypothyroidism is important for genetic counseling of families with an affected member, for identifying additional clinical characteristics or the risk for thyroid neoplasia, and for diagnostic and management purposes 3, 4.
- A definite molecular diagnosis of thyroid dyshormonogenesis allows genetic counseling and has prognostic value in differentiating transient from permanent congenital hypothyroidism and predicting the response of patients to iodine supplementation as adjunct or alternative treatment to L-T4 replacement 4.