Congenital hypothyroidism

Gene: POU1F1

Green List (high evidence)

Combined pituitary hormone deficiency without extra-pituitary features.

Created: 19 Feb 2017, 9:40 p.m.

Mode of inheritance
BOTH monoallelic and biallelic, autosomal or pseudoautosomal

Phenotypes
GH, TSH, Prolactin deficiency; anterior pituitary hypoplasia.

Publications

• Cretinism with combined hormone deficiency caused by a mutation in the PIT1 gene. Tatsumi K, Miyai K, Notomi T, Kaibe K, Amino N, Mizuno Y, Kohno H. Nat Genet. 1992 Apr
• 1(1):56-8.

Comment on list classification: Updated rating from Green to Red based on review by Helen Brittain: many many cases of POU1F1 mutations in combined hormone deficiency (MIM:613038) with deficiency in TRH leading to low TSH and thyroid hormone being a recurrent, although variable, feature. Confirmed DD-G2P gene for MIM:613038.

Created: 16 Feb 2017, 2:48 p.m.

The heterozygous R271W mutation acts in a dominant negative fashion (PMID:1509262).

Created: 16 Feb 2017, 2 p.m.

From Helen Brittain: PMID:16060904 reports that POU1F1 mutations have been described in a total of 46 patients from 34 families originating in 17 different countries, all of which have been associated with a broadly similar phenotype of GH, TSH and PRL deficiency. Note that although the combined pituitary hormone deficiency is more complex than pure congenital hypothryoidism, deficiency in TRH leading to low TSH and thyroid hormone is a recurrent, although variable, feature.

Created: 16 Feb 2017, 1:51 p.m.

Schoenmakers, et al., 2015 (PMID:26416826) review notes that only a minority of hypothyroid individuals will harbour mutations in known transcription factors such as POU1F1, and central hypothyroidism does not occur in isolation, but is one of the evolving pituitary hormone deficiencies. Patients with autosomal recessive and dominant POU1F1 mutations are associated with a normal or hypoplastic anterior pituitary, whilst TSH deficiency can be highly variable. Although the majority have early TSH deficiency, hypothyroidism may also occur later in childhood.

Created: 14 Feb 2017, 10:05 a.m.

In a 4.5-month-old boy who presented with severe congenital hypothyroidism and was subsequently found to have CPHD1 ( 613038), Hendriks-Stegeman et al. (2001, PMID:11297581) identified compound heterozygosity for 2 novel point mutations in the POU1F1 gene, resulting in a truncated protein and W193R. The authors state that the majority of patients with a POU1F1 defect present with growth failure, whereas less than half present with hypothyroidism as the first clinical manifestation.

Created: 14 Feb 2017, 9:32 a.m.