A Novel Homozygous Variant in GJA1 Causing a Hallermann-Streiff/Oculodentodigital Dysplasia Overlapping Phenotype: A Clinical Report

Alexandra Jimenez-Armijo,Bouchra Bousfiha,Samira El Arabi,Khadja Oumensour,Agnès Bloch-Zupan,Virginie Laugel-Haushalter,Tristan Rey

doi:10.3389/fdmed.2021.675130

Abstract

This paper reports the case of a Moroccan girl with a phenotype within the clinical spectrum of both Hallermann-Streiff (HSS, OMIM 234100) and Oculodentodigital Dysplasia (ODDD, OMIM 164200) syndromes. The patient presented with repeated dental abscesses and severe early childhood caries. She had no learning deficit nor psychomotor regression; however, a language delay was noted. She also presented with obstructive sleep apnea syndrome and specific craniofacial features pathognomonic of HSS. Radiographic examination showed enamel and dentin defects, giving a ghost-like tooth appearance. Several clinical features of ODDD overlap those of HSS and may confuse diagnosis, considering that the inheritance of HSS is not described yet. The diagnostic odyssey of this patient ended with the identification by exome sequencing of a novel homozygous alteration in the GJA1 gene. A missense substitution in exon 2 [Chr6(GRCh37): g.121768554C&gt;G NM_000165.4: c.561C&gt;G p.Cys187Trp] was identified by whole-exome sequencing (WES), suggesting a diagnosis of ODDD. This is the first report of a homozygous mutation affecting the second extracellular loop of the CX43 protein.

Highlights

Hallermann-Streiff syndrome (HSS, OMIM 234100) is a highly recognizable rare disease characterized by developmental delay, proportionate short stature, skeletal, chest, respiratory and skin defects, as well as distinct craniofacial features such as sparse hair, skin atrophy over scalp and nose, brachycephaly, frontal bossing, micrognathia, low set ears, microphthalmia, small pointed nose, microstomia, and developmental tooth anomalies
We report the case of a Moroccan girl with a phenotype within the spectrum of both HSS and oculodentodigital dysplasia (ODDD), whose diagnostic odyssey ended with the identification of a novel homozygous GJA1 variant
ODDD is caused by alterations in GJA1 gene and mostly inherited in a dominant manner

Summary

INTRODUCTION

Hallermann-Streiff syndrome (HSS, OMIM 234100) is a highly recognizable rare disease characterized by developmental delay, proportionate short stature, skeletal, chest, respiratory and skin defects, as well as distinct craniofacial features such as sparse hair, skin atrophy over scalp and nose, brachycephaly, frontal bossing, micrognathia, low set ears, microphthalmia, small pointed nose, microstomia, and developmental tooth anomalies. Few individuals with recessive variants in GJA1 have been reported [4,5,6,7], and a single one was described as presenting an overlapping HSS/ODDD spectrum associated to variant c.227G>A, p.R76H [8]. We report the case of a Moroccan girl with a phenotype within the spectrum of both HSS and ODDD, whose diagnostic odyssey ended with the identification of a novel homozygous GJA1 variant. This clinical case was conducted in compliance with the CARE guidelines. This variant was classified as class 4, likely pathogenic, according to ACMG criteria [18]

DISCUSSION

Findings

ETHICS STATEMENT