Autosomal Recessive Oculodentodigital Dysplasia: A Case Report and Review of the Literature

Abstract

Oculodentodigital dysplasia (ODDD) is a rare condition characterized by a typical facial appearance and variable findings of the eyes, teeth, and fingers. ODDD is caused by mutations in the GJA1 gene in chromosome 6q22 and inherited in an autosomal dominant manner in the majority of the patients. However, in recent clinical reports, autosomal recessive ODDD cases due to by GJA1 mutations were also described. Here, we report on a 14-year-old boy with microphthalmia, microcornea, narrow nasal bridge, hypoplastic alae nasi, prominent columnella, hypodontia, dental caries, and partial syndactyly of the 2nd and 3rd toes. These clinical findings were concordant with the diagnosis of ODDD, and a novel homozygous mutation (c.442C>T, p.Arg148Ter) was determined in the GJA1 gene leading to a premature stop codon. His phenotypically normal parents were found to be carriers of the same mutation. This is the third family in the literature in which ODDD segregates in an autosomal recessive manner.

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

“…The molecular etiology of HSS is not yet fully understood. Individuals diagnosed with ODDD or HSS/ODDD spectrum disorder, have been reported with a recessive pattern of inheritance (4,8,9).…”

“…Alterations in Gap Junction protein Alpha 1 gene (GJA1) (OMIM 121014, HGNC ID: 4274, NM_000165.5), which is located on chromosome 6q22.31 and organized in two exons and one intron, have been reported as causative for ODDD. ODDD mode of inheritance has mostly been autosomal dominant (AD, OMIM 164200) but also occasionally autosomal recessive (AR, OMIM 257850) (2)(3)(4). With AD transmission, one affected parent transmits the variant to an affected child, and the variant may lead either to the complete spectrum of malformations or to milder manifestations.…”

“…With AD transmission, one affected parent transmits the variant to an affected child, and the variant may lead either to the complete spectrum of malformations or to milder manifestations. Only 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). In general, more severe clinical features are observed in AR ODDD (9).…”

Differentiation of Induced Pluripotent Stem Cells Into Chondrocytes: Methods and Applications for Disease Modeling and Drug Discovery

“…Oculodentodigital dysplasia is a rare disorder that is most commonly caused by heterozygous mutations in the GJA1 gene, (125) although some individuals with homozygous mutations in the same gene have been reported. (126,127) GJA1 codes for the gap junction protein connexion 43 (Cx43). (125) Affected individuals have a characteristic face with small eyes, thin nose with hypoplastic alae, and dental anomalies.…”

Recent advances in understanding connexin gap junction pathology in demyelinating diseases

“…Mutations in the Cx43 gene ( GJA1 ) are responsible for oculodentodigital dysplasia syndrome, a dominantly inherited systemic disease associated with abnormalities of the face, eyes, teeth and digits 53 . Some oculodentodigital dysplasia syndrome patients with GJA1 mutations also have a variety of CNS abnormalities, including spasticity, hypomyelination 54,55 and periventricular white matter lesions 53,56 . Mutations in the gene encoding Cx30 ( GJB6 ) have been identified in patients with a dermatological disease called hidrotic ectodermal dysplasia, also known as Clouston syndrome 57 .…”