SOX10 mutations mimic isolated hearing loss

Abstract

Ninety genes have been identified to date that are involved in non-syndromic hearing loss, and more than 300 different forms of syndromic hearing impairment have been described. Mutations in SOX10, one of the genes contributing to syndromic hearing loss, induce a large range of phenotypes, including several subtypes of Waardenburg syndrome and Kallmann syndrome with deafness. In addition, rare mutations have been identified in patients with isolated signs of these diseases. We used the recent characterization of temporal bone imaging aspects in patients with SOX10 mutations to identify possible patients with isolated hearing loss due to SOX10 mutation. We selected 21 patients with isolated deafness and temporal bone morphological defects for mutational screening. We identified two SOX10 mutations and found that both resulted in a non-functional protein in vitro. Re-evaluation of the two affected patients showed that both had previously undiagnosed olfactory defects. Diagnosis of anosmia or hyposmia in young children is challenging, and particularly in the absence of magnetic resonance imaging (MRI), SOX10 mutations can mimic non-syndromic hearing impairment. MRI should complete temporal bones computed tomographic scan in the management of congenital deafness as it can detect brain anomalies, cochlear nerve defects, and olfactory bulb malformation in addition to inner ear malformations.

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“…SOX10 mutations associated with the KS phenotype are mainly missense loss-of-function or frameshift mutations present in the heterozygous state. To date, relatively few cases of KS linked to SOX10 mutations have been described (124)(125)(126)(127)(128)(129). However, their number may well increase rapidly, simply because this gene will be more frequently analyzed in patients with KS/nCHH as next-generation sequencing methods are adopted (see below) (129).…”

“…However, their number may well increase rapidly, simply because this gene will be more frequently analyzed in patients with KS/nCHH as next-generation sequencing methods are adopted (see below) (129). At the phenotypic level, this genetic form of KS is characterized by a high prevalence of neurogenic deafness associated Page 16 of 55 with semi-circular canal defects similar to those seen in CHH patients with CHD7 mutations (124)(125)(126)130). Other noteworthy clinical signs in these patients with SOX10 mutations include abnormal iris pigmentation (124,126,127) and wisps/patches of white hair.…”

“…Other noteworthy clinical signs in these patients with SOX10 mutations include abnormal iris pigmentation (124,126,127) and wisps/patches of white hair. In the few KS/CHH pedigrees so far described, transmission of SOX10 mutations is autosomal dominant but again, as with FGFR1 and CHD7, the penetrance of the various clinical signs is variable even among related individuals carrying the same SOX10 mutation (124)(125)(126)(127)(128)(129)(130).…”

“…If we exclude de novo mutations of FGFR1 or CHD7 (described below), typical AD inheritance is usually associated with more than one affected generation with members exhibiting a CHH/KS phenotype; males and females are equally affected; and both female-to-male and male-to-male transmission may be observed (Fig.2). One important point is that, in families with AD inheritance of KS, penetrance and expressivity can vary both for the main signs (CHH and impaired sense of smell) and associated signs (2,95,96,(118)(119)(120)(121)(124)(125)(126). This means that members of a family harboring the identical same CHH/KS mutation may have either a complex form with many associated signs, or isolated CHH/KS, nCHH, or isolated anosmia, transient delayed puberty and potentially evident phenotype (95).…”

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“…Based on these findings MRI should be performed in patients with congenital deafness and in case when adequate sequences are available other CNS anomalies including olfactory bulb malformation can be detected [94,95].…”