Congenital hypothyroidism

Gene: PROP1

Green List (high evidence)

PROP1 (PROP paired-like homeobox 1)
EnsemblGeneIds (GRCh38): ENSG00000175325
EnsemblGeneIds (GRCh37): ENSG00000175325
OMIM: 601538, Gene2Phenotype
PROP1 is in 11 panels

2 reviews

Rebecca Foulger (Genomics England curator)

Comment on list classification: Updated rating from Grey to Green: 1 Green review (from gene submitter). Plus plenty (well over 3) cases of PROP1 mutations causing combined pituitary hormone deficiency, which can present with CH. At least 3 cases mention hypothyroidism specifically (PMID:16984240, 23652424, 15472175).
Created: 21 Feb 2017, 11:25 a.m.
PMID:16984240 (Lemos et al., 2006) perfomed a multicentre study involving 46 cases of combined pituitary hormone deficiency (CPHD); 17 cases belonging to 7 unrelated families, and 29 sporadic cases. PROP1 mutations were identified in all 17 familial cases and in 2 of the sporadic cases. All 19 patients with germline mutations had presented with growth retardation and central hypothyroidism during childhood.
Created: 21 Feb 2017, 11:22 a.m.
PMID:23652424 (Wassner et al., 2013) present two young siblings (age 6 months and 2 years) presenting with central hypothyroidism (CH). A homozygous frameshift mutation in PROP1 (296DelGA) was identified in both probands.
Created: 21 Feb 2017, 11:14 a.m.
Lee et al., 2004 (PMID:15472175) report 3 adult siblings with short stature, hypothyroidism, and lack of pubertal maturation who were homozygous for 301–302delAG PROP-1 mutation. The mother and the father are heterozygous for the mutation.
Created: 21 Feb 2017, 11:10 a.m.
PROP1 is a late 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, 10:35 a.m.
Comment on mode of inheritance: Mode of inheritance confirmed by OMIM and G2P.
Created: 20 Feb 2017, 12:07 p.m.
Confirmed DD-G2P gene for combined pituitary hormone deficiency (MIM:262600).
Created: 20 Feb 2017, 12:07 p.m.

Nadia Schoenmakers (University of Cambridge)

Green List (high evidence)

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
GH, TSH, LH, FSH, PRL deficiency with variable age of onset, evolving ACTH deficiency. Commonest cause of combined pituitary hormone deficit without extra pituitary manifestations. Hypoplastic or normal anterior pituitary although there have been reports of an enlarged anterior pituitary at initial scanning in childhood with spontaneous involution over time.

Publications

  • Fluck C, Deladoey J, Rutishauser K, Eble A,Marti U, WuW& Mullis PE 1998 Phenotypic variability in familial combined pituitary hormone deficiency caused by a PROP1 gene mutation resulting in the substitution of Arg–OCys at codon 120 (R120C). Journal of Clinical Endocrinology and Metabolism 83 3727–3734. Voutetakis A, Argyropoulou M, Sertedaki A, Livadas S, Xekouki P, Maniati- Christidi M, Bossis I, Thalassinos N, Patronas N & Dacou-Voutetakis C 2004 Pituitary magnetic resonance imaging in 15 patients with Prop1 gene mutations: pituitary enlargement may originate from the intermediate lobe. Journal of Clinical Endocrinology and Metabolism 89 2200–2206. (doi:10.1210/jc.2003-031765).

Details

Mode of Inheritance
BIALLELIC, autosomal or pseudoautosomal
Sources
  • Expert Review Green
Phenotypes
  • GH, TSH, LH, FSH, PRL deficiency with variable age of onset, evolving ACTH deficiency
  • Commonest cause of combined pituitary hormone deficit without extra pituitary manifestations
  • Hypoplastic or normal anterior pituitary although there have been reports of an enlarged anterior pituitary at initial scanning in childhood with spontaneous involution over time
  • Pituitary hormone deficiency, combined, 2, 262600
OMIM
601538
Clinvar variants
Variants in PROP1
Penetrance
Complete
Publications
Panels with this gene

History Filter Activity

22 Feb 2017, Gel status: 4

panel promoted to version 1

Rebecca Foulger (Genomics England curator)

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.

22 Feb 2017, Gel status: 4

Set Phenotypes

Rebecca Foulger (Genomics England curator)

Phenotypes for PROP1 were set to GH, TSH, LH, FSH, PRL deficiency with variable age of onset, evolving ACTH deficiency; Commonest cause of combined pituitary hormone deficit without extra pituitary manifestations; Hypoplastic or normal anterior pituitary although there have been reports of an enlarged anterior pituitary at initial scanning in childhood with spontaneous involution over time; Pituitary hormone deficiency, combined, 2, 262600

21 Feb 2017, Gel status: 4

Gene classified by Genomics England curator

Rebecca Foulger (Genomics England curator)

This gene has been classified as Green List (High Evidence).

21 Feb 2017, Gel status: 0

Set publications

Rebecca Foulger (Genomics England curator)

Publications for PROP1 were set to 9768691; 15126542; 15472175; 26416826 (2015 review); 23652424; 16984240

20 Feb 2017, Gel status: 0

Set Mode of Inheritance

Rebecca Foulger (Genomics England curator)

Mode of inheritance for PROP1 was changed to BIALLELIC, autosomal or pseudoautosomal

20 Feb 2017, Gel status: 0

Set publications

Rebecca Foulger (Genomics England curator)

Publications for PROP1 were set to 9768691; 15126542

20 Feb 2017, Gel status: 0

Set Phenotypes

Rebecca Foulger (Genomics England curator)

Phenotypes for PROP1 were set to GH, TSH, LH, FSH, PRL deficiency with variable age of onset, evolving ACTH deficiency. Commonest cause of combined pituitary hormone deficit without extra pituitary manifestations. Hypoplastic or normal anterior pituitary although there have been reports of an enlarged anterior pituitary at initial scanning in childhood with spontaneous involution over time; Pituitary hormone deficiency, combined, 2, 262600

19 Feb 2017, Gel status: 0

Created

Nadia Schoenmakers (University of Cambridge)

PROP1 was created by [email protected]

19 Feb 2017, Gel status: 0

Added New Source

Nadia Schoenmakers (University of Cambridge)

PROP1 was added to Congenital hypothyroidism or thyroid agenesispanel. Sources: Literature