Congenital hypothyroidism

Gene: HESX1

Comment on list classification: Updated rating from Grey to Green: 1 Green review (from gene submitter). Plus >3 cases of HESX1 mutations causing combined pituitary hormone deficiency, which can present with CH. 1 case mentions hypothyroidism specifically (PMID:11136712).

Created: 21 Feb 2017, 10:09 a.m.

PMID:11136712 (Thomas et al., 2001) expanded their 1998 paper and scanned for HESX1 mutations in 228 patients with a broad spectrum of congenital pituitary defects. 3 different heterozygous missense mutations were detected in individuals with relatively mild pituitary hypoplasia or SOD, including G18C in individual II.1 who had secondary hypothyroidism from age 7 (low TSH and T4).

Created: 21 Feb 2017, 10:07 a.m.

HESX1 is an early pituitary transcription factor. Mutations in early or late pituitary transcription factors may cause central hypothyroidism (CH), a particular hypothyroid condition due to an insufficient stimulation by TSH of an otherwise normal thyroid gland. In these cases, CH does not occur in isolation, but is one of the evolving pituitary hormone deficiencies [PMID:26416826].

Created: 21 Feb 2017, 10:03 a.m.

>3 cases of HESX1 mutations causing combined pituitary hormone deficiency (CPHD5; MIM:182230).

Created: 20 Feb 2017, 10:44 a.m.

Comment on mode of inheritance: Mode of inheritance supported by OMIM.

Created: 20 Feb 2017, 10:23 a.m.

Probable DD-G2P gene for HESX1-related combined pituitary hormone deficiency.

Created: 20 Feb 2017, 10:17 a.m.

Green List (high evidence)

Variable penetrance

Created: 19 Feb 2017, 9:54 p.m.

Mode of inheritance
BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal

Phenotypes
Panhypopiuitarism; GH and evolving TSH, ACTH, LH/FSH deficiency, septo-optic dysplasia,anterior pituitary, ectopic posterior pituitary, agenesis of corpus callous, optic nerve hypoplasia

Publications

• Mutations in the homeobox gene HESX1/Hesx1 associated with septo-optic dysplasia in human and mouse. Dattani MT, Martinez-Barbera JP, Thomas PQ, Brickman JM, Gupta R, Mårtensson IL, Toresson H, Fox M, Wales JK, Hindmarsh PC, Krauss S, Beddington RS, Robinson IC. Nat Genet. 1998 Jun
• 19(2):125-33. Heterozygous HESX1 mutations associated with isolated congenital pituitary hypoplasia and septo-optic dysplasia. Thomas PQ, Dattani MT, Brickman JM, McNay D, Warne G, Zacharin M, Cameron F, Hurst J, Woods K, Dunger D, Stanhope R, Forrest S, Robinson IC, Beddington RS. Hum Mol Genet. 2001 Jan 1
• 10(1):39-45.