Congenital hypothyroidism

Gene: OTX2

Additional evidence - PMID: 32277752 - Bando et al 2020 report defects in the pituitary glands, mandibles and eyes of otx2b mutant fish that model the features of patients with OTX2 mutations. Otx2b deficiency causes reduced cell proliferation and increased apoptosis, resulting in organ hypoplasia

Created: 30 Jul 2020, 2:03 p.m. | Last Modified: 30 Jul 2020, 2:03 p.m.

Panel Version: 2.3

Publications

• 32277752

Comment on list classification: Updated rating from Grey to Green: 1 Green review (from gene submitter). 4 cases in total reporting missense mutations in CPHD patients, including the case in Del Blanco et al (PMID:22715480) where the unaffected father also carries the Pro134Arg variant. Functional studies in both PMID:27299576 and PMID:18728160. OTX2 is in OMIM phenotypic series with other CPHD genes.

Created: 22 Feb 2017, 11:22 a.m.

Added 'missense' tag because missense mutations only reported in the 3 papers described.

Created: 22 Feb 2017, 11 a.m.

Shimada et al., 2016 (PMID:27299576) report a R89P missense mutation in OTX2 in a CPHD patient. Full text of the article is unavailable.

Created: 21 Feb 2017, 1:53 p.m.

Del Blanco et al. 2012, (PMID:22715480) report a Dutch Caucasian male born from non-consanguineous parents, with combined pituitary hormone deficiency, and where central hypothyroidism (CH) was detected at age 9. The proband carried a heterozygous missense Pro134Arg mutation in OTX2. Note that this mutation was inherited from the phenotypically normal father.

Created: 21 Feb 2017, 1:52 p.m.

PMID:18728160 (Diaczok et al, 2008) describe 2 unrelated children with CPHD who presented with neonatal hypoglycemia, and deficiencies of GH, TSH, LH, FSH, and ACTH. A novel heterozygous OTX2 mutation (N233S) was identified. Mouse functional studies point to N233S acting as a dominant negative.

Created: 21 Feb 2017, 1:19 p.m.

OTX2 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, 11:33 a.m.

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

Created: 20 Feb 2017, 11:19 a.m.

Mode of pathogenicity
Other

Green List (high evidence)

Highly variable pituitary and ocular phenotype

Created: 19 Feb 2017, 10:08 p.m.

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
GH, TSH, ACTH, LH, FSH deficiency, Anophthalmia Retinal dystrophy, normal or hypoplastic anterior pituitary, ectopic posterior pituitary

Publications

• Dateki S, Fukami M, Sato N, Muroya K, Adachi M & Ogata T 2008 OTX2 mutation in a patient with anophthalmia, short stature, and partial growth hormone deficiency: functional studies using the IRBP, HESX1, and POU1F1 promoters. Journal of Clinical Endocrinology and Metabolism 93 3697–3702. (doi:10.1210/jc.2008-0720)