Oculodentodigital dysplasia with mandibular retrognathism and absence of syndactyly: a case report with a novel mutation in the Connexin 43 gene

doi:10.1016/j.ijom.2007.03.004

International Journal of Oral and Maxillofacial Surgery

Volume 36, Issue 9, September 2007, Pages 858-860

https://doi.org/10.1016/j.ijom.2007.03.004 Get rights and content

Abstract

Oculodentodigital dysplasia (ODDD) is a rare, autosomal dominant pleiotropic disorder, caused by mutations in the Connexin 43 (Cx43 or GJA1) gene. Described here is the case of a 10-year-old girl with enamel hypoplasia, typical facies and mental delay, initially thought to be related to an unknown metabolic disorder. Careful clinical re-evaluation revealed a type of ODDD, characterised by the predominance of facial and ophthalmological involvement with mandibular retrognathism, and by the absence of cutaneous hand or foot syndactyly. A novel single-sequence variation (Nt460A>G) in exon 2, resulting in the substitution of alanine for threonine at amino acid 154, was found. These findings confirm once again the highly variable phenotypic expression caused by Cx43 mutations.

Section snippets

Case report

The girl is the first of two children from healthy and non-consanguineous parents. The family history is negative. Her first referral to the children's hospital occurred at age 2 years 3 months because of a collapse due to ketotic hypoglycemia. There was mild psychomotor delay with sitting at 11 months and walking at 22 months. At that time no etiological diagnosis could be made. Extensive metabolic studies showed normal results, as did conventional karyotyping.

Her first maxillofacial

Connexin 43 analysis

Mutational analysis of the GJA1 gene revealed a single-sequence variation (Nt460A>G) in exon 2, resulting in the substitution of alanine for threonine at amino acid 154 (T154A) (courtesy of Dr E. Wang Jabs, Baltimore, MD, USA). This is a novel mutation within the cytoplasmic loop of the connexin protein. The parents did not carry this mutation (courtesy A. v.d. Wijngaard, Maastricht, the Netherlands).

Discussion

The patient described has a new mutation in the Cx43 gene, as is the case in about half of all patients with ODDD and, also as often, the diagnosis of ODDD was made only after careful re-evaluation of all clinical findings.

An extensive overview of the ODDD syndrome was carried out by Gorlin et al.² To the best of the authors’ knowledge, new findings in this case are the recurrent ketotic hypoglycemia in early childhood, peri-membranous VSD, mandibular retrognathism and novel single-sequence

Acknowledgement

We thank Jackie Senior for reviewing the manuscript.

References (10)

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There are more references available in the full text version of this article.

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CNS glia and neurons express connexins, the proteins that form gap junctions in vertebrates. We review the connexins expressed by oligodendrocytes and astrocytes, and discuss their proposed physiologic roles. Of the 21 members of the human connexin family, mutations in three are associated with significant central nervous system manifestations. For each, we review the phenotype and discuss possible mechanisms of disease. Mutations in GJB1, the gene for connexin 32 (Cx32) cause the second most common form of Charcot–Marie–Tooth disease (CMT1X). Though the only consistent phenotype in CMT1X patients is a peripheral demyelinating neuropathy, CNS signs and symptoms have been found in some patients. Recessive mutations in GJC2, the gene for Cx47, are one cause of Pelizaeus–Merzbacher-like disease (PMLD), which is characterized by nystagmus within the first 6 months of life, cerebellar ataxia by 4 years, and spasticity by 6 years of age. MRI imaging shows abnormal myelination. A different recessive GJC2 mutation causes a form of hereditary spastic paraparesis, which is a milder phenotype than PMLD. Dominant mutations in GJA1, the gene for Cx43, cause oculodentodigital dysplasia (ODDD), a pleitropic disorder characterized by oculo-facial abnormalities including micropthalmia, microcornia and hypoplastic nares, syndactyly of the fourth to fifth fingers and dental abnormalities. Neurologic manifestations, including spasticity and gait difficulties, are often but not universally seen. Recessive GJA1 mutations cause Hallermann–Streiff syndrome, a disorder showing substantial overlap with ODDD. This article is part of a Special Issue entitled: The Communicating junctions, composition, structure and functions.
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As a way of understanding the molecular basis of disease based on single site-specific amino acid mutations, we explored whether oligomer stability plays a role in their dysfunction. M34T and V84L in Cx26 are both recessive, nonsyndromic deafness mutations, whereas Cx43T154A is a dominant mutation in ODDD (14), causing small eyes, underdeveloped teeth, syndactyly, and finger malformations. Cx32P87L causes CMTX, producing axonal loss, clusters of regenerating fibers, and paranodal demyelination (25).
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Oculo-dento-digital dysplasia: Lack of genotype-phenotype correlation for GJA1 mutations and usefulness of neuro-imaging
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Ocular anomalies consist of microphthalmia, microcornea, glaucoma, cataract, iris anomalies, and uveitis. Oral abnormalities include broad alveolar ridges, enamel hypoplasia, selective dental agenesis, microdontia, premature loss of teeth and caries [9,16,17]. Hyperostosis of the skull and the spine may be present [2].
Oculo-dento-digital dysplasia (ODDD) is an autosomal dominant disorder with complete penetrance and high intra- and interfamilial phenotypic variability. The key features in this syndrome are microphthalmia, enamel hypoplasia and syndactyly of the 4th–5th fingers. ODDD is caused by mutations in the connexin 43 gene (GJA1). We report here four patients from three families with GJA1 mutations, one of them diagnosed prenatally. The three mutations (c.52T > C/p.Ser18Pro, c.689_690delTA/p.Tyr230CysfsX6, c.442C > G/p.Arg148Gly) have been reported once before. Two patients had white matter hypersignal anomalies, associated in one case with mental retardation, but asymptomatic in the other one, an observation that leads us to discuss systematic neuroradiological imaging for ODDD. One case has optic atrophy, another has hypospadias. The patient carrying a truncating mutation of Cx43 did not have palmoplantar keratoderma, in contradiction with the previously suggested genotype–phenotype correlation between truncating mutation and skin involvement.

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Case ReportCongenital Craniofacial AnomaliesOculodentodigital dysplasia with mandibular retrognathism and absence of syndactyly: a case report with a novel mutation in the Connexin 43 gene

Abstract

Section snippets

Case report

Connexin 43 analysis

Discussion

Acknowledgement

J Pediatr

Am J Hum Genet

Malocclusion and orthodontic treatment need of 15–74-year-old Dutch adults

Community Dent Oral Epidemiol

Oculodentodigital dysplasia

Co-expression and regulation of connexins 36 and 43 in cultured neonatal rat pancreatic islets

Can J Physiol Pharmacol

Case Report
Congenital Craniofacial Anomalies
Oculodentodigital dysplasia with mandibular retrognathism and absence of syndactyly: a case report with a novel mutation in the Connexin 43 gene