Pituitary hormone deficiency

Gene: BMP4

Comment on list classification: Promoting from red to amber. 3 cases reported, but in one another gene was also deleted, and in the other only 3 genes were sequenced.

Created: 16 Sep 2022, 5:41 p.m. | Last Modified: 16 Sep 2022, 5:41 p.m.

Panel Version: 2.35

PMID: 31120642 - Rodríguez-Contreras et al 2019 - report a 6 yo patient with combined pituitary hormone deficiency (CPHD ) who was found to have a de novo pathogenic loss-of-function variant (NM_001202.5:c.794G > A, p.(Trp265*)) in BMP4 following NGS using a custom 310 gene panel. His clinical phenotype included macrocephaly, myopia/astigmatism, mild psychomotor retardation, anterior pituitary hypoplasia and ectopic posterior pituitary, clinically diagnosed with growth hormone deficiency, and central hypothyroidism.

PMID: 24289245 - Breitfeld et al 2014 - sequenced BMP2, 4 and 7 in 19 subjects with combined pituitary hormone deficiency (CPHD). 1 proband was found to have a p.Arg300Pro variant in BMP4 that is predicted to have functional consequences.

PMID: 18252212 - Bakrania et al 2008 - screened 215 individuals with ocular malformation defects for variants in BMP4 and gene deletions by MLPA. They report 1 case with pituitary abormalities along with bilateral anophthalmia, microcephaly, sensorineural deafness, cryptorchidism, partial callosal agenesis, cerebellar abnormalities, and developmental delay . The proband had a deletion of del(14)(q22.2q23.1) which encompasses BMP4 and OTX2. Using in situ hybridization in human embryos, they showed expression of BMP4 in optic vesicle, developing retina and lens, pituitary region, and digits.

Also:
PMID: 35633847 - Calcaterra et al 2022 - report a child with a novel variant p.Glu93* in exon 3 of BMP4. She was found to have an ectopic posterior pituitary but normal hormonal assessment, associated to craniocervical junction dysmorphism and limb anomaly.

Created: 16 Sep 2022, 5:39 p.m. | Last Modified: 16 Sep 2022, 5:39 p.m.

Panel Version: 2.32

Review on behalf of Professor Mehul Dattani, UCL GOS Institute of Child Health/Great Ormond Street Hospital for Children. Rodrguez-Contreras FJ, Marbn-Calzn M, Vallespn E, Del Pozo , Sols-Lpez M, Lobato-Vidal N, Fernndez-Elvira M, Del Valle Rex-Romero M, Heath KE, Gonzlez-Casado I, Campos-Barros .Am J Med Genet A. 2019 Aug;179(8):1591-1597. doi: 10.1002/ajmg.a.61201. Epub 2019 May 23.PMID:31120642

Created: 14 Sep 2022, 4:44 p.m. | Last Modified: 14 Sep 2022, 4:44 p.m.

Panel Version: 2.15

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown

Phenotypes
LEARNING DIFFICULTIES

Publications

• 31120642

Red List (low evidence)

BMP4 is confirmed to be associated with the listed phenotypes in OMIM and Gene2Phenotypes; however, there is only one reported case of a patient with pituitary hormone deficiency with a missense variant in the BMP4 gene. In silico prediction programs suggested that it is pathogenic; however, there were no functional studies performed.

Created: 10 Dec 2018, 3:10 p.m.