TABLE 3.
Genes involved in central hypothyroidism and their associated phenotypes
| Category | Gene (OMIM) | Phenotype | Transmission mode |
|---|---|---|---|
| Isolated CeCH | TSHβ (188540) | Neonatal onset with low TSH level, high glycoprotein alpha subunit and normal PRL, reversible pituitary hyperplasia on L‐T4 | AR |
| TRHR (188545) | Normal TSH and low PRL levels, inadequate TSH/PRL responses in the TRH stimulation test | AR | |
| TBL1X (300196) | Isolated CeCH in men with normal serum TSH levels and normal response to the TRH stimulation test; associated hearing disorders | Linked to the X | |
| IRS4 (300904) | Isolated CeCH in men with normal serum TSH levels, inadequate TSH response to TRH | Linked to the X | |
| CeCH associated with other pituitary abnormalities | IGSF1 (300137) | Normal serum TSH and inadequate response to the TRH stimulation test; low PRL level, variable GH deficit, transient moderate hypocortisolism, metabolic syndrome; post‐puberty macrorchidism | Linked to the X |
| PROP1 (601538) | Variable age of onset, deficiency combined with GH, PRL LH/FSH, and ACTH deficiencies, variable pituitary volume | AR | |
| POU1F1 (173110) | Variable age of onset, associated with a GH and PRL deficiency, frontal bossing, median facial hypoplasia, nasal lordosis | AD/AR | |
| HESX1 (601802) | Hypopituitarism associated with septo‐optic dysplasia | AD/AR | |
| SOX3 (313430) | Anterior pituitary hypoplasia with ectopic post‐hypophysis (EPH), persistent craniopharyngeal canal, and learning difficulties | Linked to the X | |
| OTX2 (600037) | Anterior pituitary hypoplasia with EPH and ocular abnormalities (an‐/micro‐phthalmia/retinal dystrophy) | AD | |
| LHX3 (600577) | Hypopituitarism with inconstant corticotroph deficiency, variable pituitary volume, variable, short and rigid cervical spurs, and variable hearing defect | AR | |
| LHX4 (602146) | Variable hypopituitarism, anterior pituitary hypoplasia with EPH, Arnold‐Chiari syndrome, hypoplasia of the corpus callosum | AD/AR | |
| LEPR (601007) | Hyperphagia, obesity, hypogonadotropic hypogonadism | AR | |
| SOX2 (184429) | Variable hypopituitarism, pituitary hypoplasia, microphthalmia, variable learning difficulties | AD | |
| PCSK1 (162150) | Hyperphagia, early‐onset obesity, hypogonadotropic hypogonadism, corticotroph deficiency | AR | |
| CeCH in the context of a syndrome | PROKR2 (607123) | Variable hypopituitarism associated with septo‐optic dysplasia or a pituitary stem interruption syndrome | AD/AR |
| NFKB2 (164012) | Anterior pituitary deficiency with variable immune deficiency (DAVID) syndrome associated with corticotroph deficiency and variable GH and TSH deficiencies | AD | |
| CHD7 (608892) | CHARGE syndrome (coloboma, heart defects, choanal atresia, growth retardation, genital and ear abnormalities) with EPH and variable LH/FSH, TSH, and GH deficiencies | AD | |
| FGFR1 (136350) | Kallman syndrome (KS) and normosomal congenital hypogonadotropic hypogonadism (nCHH), variable association with other pituitary hormone deficiencies including TSH, septo‐optic dysplasia and EPH | AD | |
| FGF8 (600483) | KS and nCHH, variable associations with other pituitary hormone deficiencies, including TSH, holoprosencephaly, and agenesis of the corpus callosum | AR | |
| FOXA2 (600288) | Hypopituitarism with craniofacial abnormalities and multi‐organ malformation, hyperinsulinism | AD | |
| RNPC3 (618016) | Growth hormone deficiency, congenital cataract, retarded development, retarded puberty | AR |
Abbreviations: ACTH, adrenocorticotropic hormone; AD, dominant autosomal; AR, recessive autosomal; CeCH, central congenital hypothyroidism; GH, growth hormone; L‐T4, L‐thyroxine; OMIM, Online Mendelian Inheritance in Man (https://www.ncbi.nlm.nih.gov/omim/); PRL, prolactin; TRH, thyrotropin‐releasing hormone; TSH, thyroid‐stimulating hormone.