General description

Peripheral demyelinating neuropathy, central dysmyelinating leukodystrophy, Waardenburg syndrome, and Hirschsprung disease (PCWH) is a rare genetic disorder caused by mutations in the SOX10 gene. This disease is characterized by abnormalities in the development of oligodendrocytes, Schwann cells, melanocytes, and gastrointestinal ganglion cells, leading to a combination of four major syndromes: peripheral demyelinating neuropathy, central dysmyelinating leukodystrophy, Waardenburg syndrome (WS), and Hirschsprung disease. However, not all patients exhibit all four conditions. The disease follows an autosomal dominant inheritance pattern, with most cases arising from sporadic de novo mutations.

The SOX10 gene encodes a transcription factor expressed in neural crest-derived cells, playing a crucial role in their early development and differentiation. Its expression in melanocytes, Schwann cells, and gastrointestinal ganglion cells is associated with the respective symptoms of WS, peripheral neuropathy, and Hirschsprung disease. Additionally, its presence in oligodendrocyte lineage cells contributes to central dysmyelination.

Clinically, PCWH varies in severity. Severe cases show minimal myelination in both the central and peripheral nervous systems from birth, often leading to early mortality. Moderate cases present with developmental delays, hypotonia, and spastic quadriplegia in about half of the affected individuals, frequently accompanied by demyelinating neuropathy. Mild cases manifest with slight motor developmental delay and demyelinating neuropathy. WS symptoms include pigmentary abnormalities such as white forelock and heterochromia, along with sensorineural hearing loss. In cases with hearing impairment, inner ear malformations, including cochlear and semicircular canal abnormalities, may be observed, necessitating morphological evaluation. Many affected infants require early surgical intervention for Hirschsprung disease.