Congenital hypomyelinating neuropathy, central dysmyelination, and Waardenburg-Hirschsprung disease: phenotypes linked by SOX10 mutation.

A unique phenotype of Waardenburg-Hirschsprung disease (WS4) accompanied by peripheral neuropathy and central dysmyelination has been recognized recently in association with SOX10 mutations. We report an infant boy with lethal congenital hypomyelinating neuropathy and WS4 who had a heterozygous SOX10 mutation (Q250X). Histopathological studies showed an absence of peripheral nerve myelin despite normal numbers of Schwann cells and profound dysmyelination in the central nervous system. These observations suggest that some SOX10 mutations such as Q250X may allow Schwann cells and oligodendrocytes to proliferate but interfere with further differentiation to form myelin. In contrast with the SOX10 loss-of-function mutations causing only WS4, mutations associated with both peripheral and central dysmyelination may affect pathology through a dominant-negative mechanism.