Primary thyroid failure present at birth
- Increasing incidence worldwide
- Due to stricter newborn screening thresholds, changing demographics
- Overall incidence: about 1 in 2,000 births
- Severe congenital hypothyroidism: 1 in 3,000 to 4,000 births
- Male-to-female ratio is 1:2 to 1:3 among severe cases but 1:1 among mild cases.
- 70% dysgenesis; 30% dyshormonogenesis
- Dysgenesis is usually sporadic.
- Familial occurrence in 2–5%
- Mutations have been found in the TSH receptor (TSHR) and in thyroid transcription factors PAX8, NKX2.1, and FOXE1.
- Dyshormonogenesis is often inherited in autosomal recessive fashion, but many cases do not have a defined genetic cause.
- Most commonly mutated genes are thyroglobulin (TG), thyroperoxidase (TPO), DUOX2, and TSHR (relative distribution depends on ethnicity).
- Pendred syndrome: Mutations in SLC26A4 cause a common syndromic form of deafness, as well as a mild iodine organification defect that can cause hypothyroidism, usually later in childhood.
- Dysgenesis: failure of normal thyroid gland formation. Includes:
- Agenesis—absent thyroid gland
- Ectopy—failure to descend to normal position
- Abnormally formed (e.g., hypoplastic) thyroid
- Defects in thyroxine (T4) synthesis, including in iodide transport and organification
- Transient hypothyroidism
- Maternal treatment with antithyroid drugs (methimazole, propythiouracil)
- Transplacental transfer of maternal TSH receptor-blocking antibodies
- Iodine deficiency or exposure to high levels of iodine (e.g., topical antiseptics, radiographic contrast)
- Mild forms of dyshormonogenesis
- Infants with trisomy 21 have a significantly increased incidence of congenital hypothyroidism.
- Newborns with congenital hypothyroidism have a slightly increased risk for congenital heart and kidney malformations.
- Higher incidence of congenital hypothyroidism in infants with low birth weight (<2,500 g), preterm birth (<37 weeks)
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