Table 1. Classification and etiology of congenital hypothyroidism .

Permanent congenital hypothyroidism

1.Primary hypothyroidism a) Thyroid dysgenesis: ectopia, athyreosis, hypoplasia, hemiagenesis i) Familial or genetic (2-5% of dygenesis cases): syndrome or associated features (1) NKX2.1: Brain-lung-thyroid syndrome (respiratory distress, choreatetosis) (2) FOXE1: Bamforth-Lazarus syndrome (cleft palate, chonal atresia, spiky hair) (3) PAX8: Hypoplasia, genitourinary anomalies (rare) (4) GLIS3: Athyreosis, neonatal diabetes, cystic kidneys, cholestasis (5) NKX2.5: Athyreosis/ectopy, congenital heart malformations (6) JAG1: Hypoplasia/ectopy, Alagille syndrome type 1 (7) CDC8 (BOREALIN): Ectopy, athyreosis, hemiagenesis (8) NTN1 (Netrin1), TUBB1 (Tubulin1): Ectopy ii) Sporadic (95-98% unknown etiology) b) Dyshormonogenesis: impaired hormone production (±goiter) due to defects in i) Iodide uptake by sodium-iodide symporter (NIS-SLC5A5) ii) Iodide transport from follicular cell into colloid (1) SLC26A4 (PDS): Pendred syndrome (deafness with goiter) (2) SLC26A7: Normal hearing iii) Iodide organification by TPO iv) Hydrogen peroxide generation (1) Dual oxidase 2 (DUOX2) or activator/maturation factor 2 (DUOXA2) (2) Dual oxidase 1 (DUOX1) or activator/maturation factor 1 (DUOXA1) v) Thyroglobulin synthesis (TG) vi) Deiodination by iodotyrosine deiodinase/dehalogenase (IYD-DEHAL1) c) TSH resistance i) Defect in TSH receptor (TSHR): Normal-sized thyroid to severe hypoplasia ii) Defect in G-protein signalling (GNAS): Pseudohypoparathyroidism type 1a d) Syndromic primary hypothyroidism (usually with normal thyroid morphology) i) TBX1: Di George syndorme ii) ELN: Williams-Beuren syndrome iii) DYRK1A: Down syndrome iv) SALL1 (Townes-Brocks), URB1 (Johanson-Blizzard), KMT2D, KDM6A (Kabuki)

2. Central hypothyroidism a) Secondary (pituitary) hypothyroidism i) Isolated TSH deficiency (TSHβ): Low TSH, pitutary hyperplasia ii) TRH receptor resistance (TRHR): Low TSH and prolactin iii) Combined pituitary deficiencies (HESX1, LHX3, LHX4, PIT1, PROP1, SOX3, OTX2) b) Tertiary (hypothalamic) hypothyroidism i) IGSF1: X-linked, low TSH/prolactin, delayed puberty, postpubertal macroorchidism ii) TBLX1, IRS4: X-linked, inappropriately normal TSH, sensorineural deafness iii) Combined pituitary deficiencies (LEPR, PROK2, FGF8, FGFR1, SOX2, CHD7)

Transient congenital hypothyroidism

1) Primary hypothyroidism a) Maternal iodine deficiency (endemic goiter) b) Maternal and neonatal iodine exposure c) Maternal antithyroid medications (methimazole, propylthiouracil) d) Maternal TSH receptor-blocking antibodies e) Genetic defects (DUOX2, DUOXA2, TPO)

2) Central hypothyroidism a) Maternal hyperthyroidism b) Prematurity (particularly <27 weeks of gestation) c) Drugs: Dopamin, steroids

TPO: thyroid peroxidase, TSH: thyroid-stimulating hormone, FT4: free thyroxine, NHT: neonatal hyperthyrotropinemia