Radiological phenotyping in patients with SOX10 pathogenic variants: insights into neck, brain and temporal bones abnormalities

Purpose: The SOX10 gene is essential for developing neural crest-derived tissues, including the temporal bone, peripheral and central nervous systems, and melanocytes. Pathogenic SOX10 variants are linked to a broad clinical spectrum, including Waardenburg syndrome (WS) in isolation, Kallmann syndrome (KS), as well as an entity characterised by the combination of peripheral demyelinating neuropathy, central dysmyelinating leukodystrophy, Waardenburg syndrome, and Hirschsprung disease (PCWH). This study aims to characterise the full spectrum of abnormalities in the brain, temporal bone and neck regions, and their syndromic associations. Methods: 15 pediatric patients with genetically confirmed SOX10 germline pathogenic variants were included. All underwent MRI, and 9 also had CT of the temporal bone. Imaging and clinical data were systematically analysed by two pediatric neuroradiologists. Results: Phenotypic analysis revealed bilateral temporal bone abnormalities in all patients, mainly characterised by a specific combination of semicircular canal (SCC) dysplasia/hypoplasia (with high prevalence of severely hypoplastic or absent posterior SCC) and a very reproducible form of cochlear hypoplasia called "flattened cochlea". Olfactory bulb agenesis or hypoplasia was identified in all patients but two. Other abnormalities include white matter changes suggestive of a hypomyelination pattern or deficient myelination in four and neck findings typically characterised by parotid gland aplasia/hypoplasia (15/15, 100%) or lacrimal gland aplasia/hypoplasia (13/15, 86%). Clinical phenotypes ranged from SNHL to WS type II or IV and PCWH. Conclusions: These results confirm the strong correlation between pathogenic SOX10 variants and characteristic temporal bone malformations, which, in association with other radiological abnormalities, represent highly specific diagnostic markers. The constellation of findings reflects the shared neural crest origin of the affected tissues and should always be investigated to support appropriate genetic testing. Early identification of these features via MRI can aid diagnosis, especially in children without classic syndromic signs, and support the patients' management.