Oculodentodigital Dysplasia with Massive Brain Calcification and a New Mutation of GJA1 Gene

INTRODUCTION

Oculodentodigital dysplasia (ODDD; MIM 164200) is an autosomal dominant disorder affecting the development of face, eyes, teeth, and limbs. Typical signs include type III syndactyly, microphtalmia, microcornea, microdontia, and enamel hypoplasia. Some patients develop neurological symptoms, such as spastic paraparesis, ataxia, neurogenic bladder dysfunction, and occasionally mental retardation. The disease results from mutations in the gap junction alpha 1 (GJA1) gene located on chromosome 6, encoding for connexin 43 (Cx43). Almost 250 cases and 73 mutations in the GJA1 gene have been reported so far [1–3]. Here, we describe a new case of ODDD with massive brain calcifications and a new mutation of GJA1 gene.

CASE REPORT

A 59-year-old man was admitted to our unit because of progressive gait disturbances and unsteadiness started five years earlier. He had also developed concomitant incontinence of sphincters. He was born with bilateral type III syndactyly of the third, fourth, and fifth finger, surgically corrected at the age of 1, and bilateral syndactyly of second and third toe. Microdontia, frequent caries, and premature teeth loss were present associated with decreased visual acuity since childhood. He underwent a surgical correction of bilateral glaucoma at 38 years old and of bilateral cataract at the age of 42 followed by blindness. He was affected by bipolar disorder. He was born by non-consanguineous parents both dead of cerebral ischemia. He had three older brothers, the third of whom affected by bilateral glaucoma. A paternal cousin had bilateral glaucoma and cataract. The patient’s grandfather (on the paternal branch) was referred to be blind.

Physical examination revealed microcephaly, microphtalmia, bilateral convergent squint, microdontia, and hypodontia. He had a peculiar nose with hypoplastic alae nasi, small anteverted nostrils, and a prominent columella (Fig. 1). Neurological examination showed blindness, a spastic and unsteady gait, spasticity of inferior limbs, diffusely brisk tendon reflexes with ankle clonus, and bilateral extensor plantar responses. Psychic examination showed depression and anxiety. A computerized tomography (CT) scan showed gross calcifications of basal ganglia and cerebellar nuclei bilaterally, a tetraventricular enlargement and a moderate cortical atrophy (Fig. 1); low degree leukoaraiosis was also reported. Brain magnetic resonance imaging (MRI) showed a thin corpus callosum, mildly enlarged ventricles, and leucoencephalopathy. Calcium and phosphorus metabolism testing, including parathyroid hormone, resulted to be normal. Motor evoked potentials examination showed a marked, bilateral increased time of central conduction from deltoid muscles; the motor responses after transcranial stimulation were not clearly identifiable from upper and lower limbs bilaterally.

DISCUSSION

ODDD is a rare inherited disease affecting the development of the face, eyes, limbs, and teeth with aprevalence lower than 1/1,000,000 [7]. To date almost 250 patients have been described, the majority of them belonging to Caucasian families [3]. Ocular manifestations include microphtalmia, bilateral microcornea, short palpebral fissures, and epicanthal folds. Less common ocular manifestations are glaucoma, cataract, strabismus, blindness of unspecified etiology, iris abnormalities, optic atrophy, and retinal vascular abnormalities [8]. Dentition abnormalities consist of enamel hypoplasia and consequent frequent caries, microdontia, premature teeth loss, and selective tooth agenesis. Digital manifestations are present in 80% of the cases; the most frequent is bilateral syndactyly of the fourth and fifth finger. Other digital anomalies are midpharyngeal and distal pharyngeal hypoplasia, aplasia of single digits or toes, syndactyly of second-fourth toes, camptodactyly and/or clinodactyly of the fifth finger.

Typical cranio-facial features are found in 92% of the affected families [3]. Patients usually present a thin nose with hypoplastic alae nasi, a prominent columella, and small anteverted nostrils. Other inconstantly observed facial features include microcephaly, cleft lip and/or palate, dysplastic ears, and cranial and mandibular hyperostosis.

About 30% of ODDD patients are affected by neurological symptoms, usually appearing in the second decade of life mainly characterized by gait disturbances, due to spastic paraparesis or ataxia, spastic bladder, dysarthria, bowel incontinence, seizures, anterior tibial muscle weakness, nystagmus, gaze palsy, and mild mental retardation [9]. MRI abnormalities can be found, consisting of white matter T2-weighted hyperintensities in the periventricular parieto-occipital region and in the temporal lobe extending to the posterior limbs of the internal capsule and to the cortico-spinal tracts and signal hypointensity in globus pallidus, substantia nigra, red nucleus, and thalamus [10]. In some patients, CT scan of the brain reveals bilateral calcifications of the basal ganglia and mild hydrocephalus [9]. The disease is caused by dominant missense mutations in the GJA1 gene, located on chromosome 6 (q21–q23.3) and encoding for the protein Cx43, one of the 21 transmembrane proteins that, by assembling together, form gap junctions. Specifically, the p.(Glu42Gln) mutation alters the last amino-acid residue of the first transmembrane domain (TM1) of Cx43, at the boundary with the first extracellular loop domain. At least nine other Cx43 mutations have been identified in the TM1 domain or its boundaries with the NH2-terminus or first extracellular loop domain [1–3]. In silico studies using web transmembrane prediction tools showed that some of these mutations increase the hydrophobicity of the TM relative to the wild-type sequence and others result in a shift in the residues predicted to span the cell membrane. The effects of the p.(Glu42Gln) mutation on protein function were not investigated. Nevertheless, analysis of orthologous genes, in-silico predictions of the effects of p.(Glu42Gln) mutation on protein function and absence from public databases provide unequivocal proof that this mutation has functional relevance and underlies ODDD.

The presence in our patient of many phenotypic features of the disease (face, eye, teeth, and digits involvement) led us to the diagnostic suspicion of ODDD. However, the evidence in our patient of massive bilateral calcifications is intriguing. In fact, CT calcifications have been reported in a small proportion of patients, 2/243 and 1/177, respectively, in the Loddenskemper et al. [9] and Paznekas’ [3] collection of cases, although in the former only 5 patients had performed a brain CT scan. The presence of massive brain calcifications in ODDD may suggest that, in addition to the GJA1 functions reported so far, the gene could also have a role in the homeostasis of brain microvessels, its mutation leading to the deposition of calcium, similarly to what happens in primary familial brain calcification [11]. However, the presence of three major primary familial brain calcification mutations has been excluded in our patient [12].

In conclusion, this case expands the knowledge of ODDD, by increasing the number of GJA1 mutations reported so far and by focusing on the presence of massive brain calcifications, infrequently described in literature as a feature of ODDD. Brain CT scan should be performed in all ODDD patients in order to understand the real weight of brain calcifications in this disease and to attempt to find possible genotype/phenotype correlations.