Congenital hypothyroidismGene: POU1F1
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
GH, TSH, Prolactin deficiency; anterior pituitary hypoplasia.
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.
22 February 2017: Promoted to Version 1. Reviews were assessed, and panel was revised according to expert review and additional curation. After discussion with the reviewer and in-house clinicians, it was agreed to include the genes for 'combined pituitary hormone deficiency' (CPHD) on the panel, since patients can present with central hypothyroidism (CH). In these cases, CH does not occur in isolation, but is one of the evolving pituitary hormone deficiencies.
This gene has been classified as Green List (High Evidence).
Mode of pathogenicity for POU1F1 was changed to Other - please provide details in the comments
Phenotypes for gene POU1F1 were set to Pituitary hormone deficiency, combined, 1, 613038 (Hypopthyroidism); congenital hypothyroidism
POU1F1 was created by rfoulger
POU1F1 was added to Congenital hypothyroidism or thyroid agenesispanel. Sources: Other