ESPE Abstracts (2019) 92 RFC15.2

BMP4 Mutations as a Novel Cause of Normosmic Hypogonadotropic Hypogonadism

A. Kemal Topaloglu1, Ruken Yildirim2, Leman Damla Kotan3, Gamze Akkus4, Edip Unal5, Ihsan Turan6, Semine Dilek3, Mehmet Tastan3, Fatih Gurbuz3, Bilgin Yuksel3


1University of Mississippi Medical Center, Jackson, MS, USA. 2Diyarbakir Pediatric Hospital, Diyarbakir, Turkey. 3Cukurova University, Faculty of Medicine, Adana, Turkey. 4Antakya State Hospital, Antakya, Turkey. 5Dicle University, Faculty of Medicine, Diyarbakir, Turkey. 6Sanliurfa Training and Research Hospital, Sanliurfa, Turkey


BMP4, a member of the bone morphogenetic protein family which is part of the transforming growth factor-beta superfamily, is involved in the embryonic development of various organ and tissues including the cranio-facial structures, olfactory placode, pituitary, eyes, heart, and kidneys. Mutations in this gene are associated with orofacial cleft and microphthalmia in human patients. BMP4 plays an important role in the embryonic development of the GnRH neurons (Forni et al 2013, Layman et al 2011) and anterior pituitary by regulating diverse cellular responses, such as cell differentiation, migration, adhesion, and proliferation (Massague et al 2000). BMP4 also has been described as particularly inhibiting FSH production (Nicol et al 2008). Recently, a heterozygous truncating mutation was described in a 6 years old prepubertal age child with combined pituitary hormone deficiency (Rodriguez-Contreras et al 2019). Mutations in the BMP genetic network including BMP4 were reported to be found in patients with hypogonadotropic hypogonadism (HH) in a meeting abstract (Cassatella et al ASHG 2013). However, no detailed description of BMP4 mutations in the etiology of HH has been found in the literature. Here we present three independent patients with isolated HH apparently due to deleterious sequence variants in BMP4.

Methods: We screened the whole exome sequencing data from 215 HH patients.

Patient numberDNA changeZygosityProtein changeMinor allele frequency in gnomADCADD score
1NM_001202.3:c.450C>GHomNP_001193.2:p.(Asn150Lys)0.0000122.5
2NM_001202.3:c.41G>AHetNP_001193.2:p.(Cys14Tyr)0.0000124.9
3NM_001202.3:c.751C>THetNP_001193.2:p.(His251Tyr)0.000129.6

Results: We identified apparently deleterious rare BMP4 sequence variants in three independent patients with HH. All patients were normosmic. The patients did not have deficiencies of other pituitary hormones. These variants were not found in in-house controls. Variant p.N150K was found in homozygosity in a patient from a consanginous family. Interestingly, this same variant has been reported to cause renal hypodysplasia in heterozygosity as well as homozygosity in two independent patients (Weber et al 2008). In all three patients both FSH and LH were similarly deficient, i.e. there was not a particularly more pronounced deficiency of FSH over LH. Functional studies have been planned.

Conclusions: These results strongly suggest that inactivating variants in BMP4 are novel causes of normosmic hypogonadotropic hypogonadism. This phenotype is consistent with previously described role of BMP4 in the ontogeny of the GnRH neurons and the anterior pituitary.

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