Original article
Shah-Waardenburg syndrome and PCWH associated with SOX10 mutations: A case report and review of the literature

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Summary

Shah-Waardenburg syndrome is a rare congenital disorder with variable clinical expression, characterised by aganglionosis of the rectosigmoïd (Hirschsprung disease), and abnormal melanocyte migration, resulting in pigmentary abnormalities and sensorineural deafness (Waardenburg syndrome). Mutations in the EDN, EDNRB and SOX10 genes can be found in patients with this syndrome. SOX10 mutations are specifically associated with a more severe phenotype called PCWH: peripheral demyelinating neuropathy, central dysmyelinating leukodystrophy, Waardenburg syndrome, and Hirschsprung disease. Neuronal expression of SOX10 occurs in neural crest cells during early embryonic development and in glial cells of the peripheral and central nervous systems during late embryonic development and in adults. We present a 4-year-old girl with the PCWH phenotype associated with a de novo nonsense mutation (S384X) in SOX10. Main clinical features were mental retardation, peripheral neuropathy, deafness, Hirschsprung disease, distal arthrogryposis, white hairlock, and growth retardation. She presented with hypotonia, developmental delay, reduced peripheral nerve conduction velocities, and radiologically assessed central hypomyelination. Subsequently, the formation of abnormal myelin within the central and peripheral nervous system was functionally and radiologically assessed.

Children presenting with features of Waardenburg syndrome and neurological dysfunction should be tested for mutations in the SOX10 gene to enable diagnosis and counselling.

Introduction

Shah-Waardenburg syndrome is a rare congenital disorder characterised by aganglionosis of the rectosigmoid (Hirschsprung disease) and abnormal melanocyte migration (or differentiation) resulting in sensorineural deafness and pigmentary abnormalities (Waardenburg syndrome).1 The pathogenesis of Shah-Waardenburg syndrome involves abnormal migration and/or differentiation of neural crest cells during embryonic development. Neural crest cells originate from the neuroepithelium of the folding neural tube and migrate into various locations, such as the nervous system, skin, colon and inner ear. Pre-migratory cells are pluripotent cells. After migration, various genes induce differentiation into several cell types such as neurons and glial cells, melanocytes, epinephrin producing cells of the adrenal gland, and many of the skeletal and cranial connective tissue components.2

Mutations in at least three different genes have been reported to cause Shah-Waardenburg syndrome: the endothelin-B receptor gene (EDNRB), encoding an endothelin receptor; the endothelin 3 gene (EDN3), encoding one of the ligands of the endothelin receptor, and the SOX10 gene, which encodes a transcription factor Sox 10.

The SOX10 gene is located on chromosome 22q13. SOX10 is essential for the development of cells in the neural crest lineage, including melanocytes and enteric ganglia.3, 4 Later on, it controls the proliferation and differentiation of Schwann cells and oligodendrocytes.5, 6, 7 Truncating mutations of SOX10 cause either Shah-Waardenburg syndrome or a more complex neurocristopathy designated PCWH (peripheral demyelinating neuropathy, central dysmyelinating leukodystrophy, Waardenburg syndrome, and Hirschsprung disease).8

Currently, clinical data of patients with PCWH caused by mutations in SOX10 are scarce and follow-up data are lacking. In the present report, we describe the evolution of clinical and radiological findings in a 4-year-old girl with PCWH associated with a SOX10 mutation and we review the literature.

Section snippets

Clinical report

This female infant was born after an uneventful pregnancy and delivery as the second child of healthy, nonconsanguineous parents. Family history was negative for congenital or neurological disorders. Home delivery had been uneventful with optimal Apgar scores. Nine days after birth, the girl was admitted to our hospital because of feeding difficulties and vomiting. Physical examination at admission showed an alert infant with length, birth weight and head circumference normal for its age (all 0

Discussion

SOX10 is a member of the SOX gene family of transcriptional regulators and is selectively expressed in neural crest cells during early stages of development. During late embryonic development and in the adult expression in glial cells of the peripheral and central nervous system ensues.11 In contrast to mutations in the genes EDNRB and EDN3 related to Shah-Waardenburg syndromes, only children with SOX10 mutations have neurological symptoms. However, data on the natural history of patients with

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