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

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>G NM_000165.4: c.561C>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.

Generalised hypomineralisation of enamel in oculodentodigital dysplasia: comprehensive dental management of a case

Oculodentodigital dysplasia (ODDD) is a rare congenital disorder characterised by developmental abnormalities of the eye, dentition and digits of the hands and feet, with neurological symptoms reported in 30% of individuals. Dental anomalies associated with ODDD include enamel hypoplasia and subsequent caries, microdontia, missing teeth, amelogenesis imperfecta, pulp stones and delayed tooth development. Here, we describe the comprehensive dental management of a 3-year-old girl who presented with rapid deterioration of the primary dentition due to generalised enamel hypomineralisation. Conservative, comprehensive restorative management was performed under general anaesthesia. Within 6 months, further breakdown of the remaining unrestored enamel was noted. This case documents the challenges of conservative management in dental anomalies that are not well documented due to the extreme rarity of the disorder.

Oculodentodigital Dysplasia: A Case Report and Major Review of the Eye and Ocular Adnexa Features of 295 Reported Cases

Oculodentodigital dysplasia (ODDD) is a rare genetic disorder associated with a characteristic craniofacial profile with variable dental, limb, eye, and ocular adnexa abnormalities. We performed an extensive literature review to highlight key eye features in patients with ODDD and report a new case of a female patient with a heterozygous missense GJA1 mutation (c.65G>A, p.G22E) and clinical features consistent with the condition. Our patient presented with multiple congenital anomalies including syndactyly, microphthalmia, microcornea, retrognathia, and a small nose with hypoplastic alae and prominent columella; in addition, an omphalocele defect was present, which has not been reported in previous cases. A systematic review of the published cases to date revealed 91 literature reports of 295 individuals with ODDD. There were 73 different GJA1 mutations associated with these cases, of which the most common were the following missense mutations: c.605G>A (p.R202H) (11%), c.389T>C (p.I130T) (10%), and c.119C>T (p.A40V) (10%). Mutations most commonly affect the extracellular-1 and cytoplasmic-1 domains of connexin-43 (gene product of GJA1), predominately manifesting in microphthalmia and microcornea. The syndrome appears with an approximately equal sex ratio. The most common eye features reported among all mutations were microcornea, microphthalmia, short palpebral fissures, and glaucoma.