Waardenburg Syndrome, Type 4c

A number sign (#) is used with this entry because Waardenburg syndrome type 4C (WS4C) is caused by heterozygous mutation in the SOX10 gene (602229) on chromosome 22q13.

Allelic disorders include Waardenburg syndrome type 2E (WS2E; 611584) and peripheral demyelinating neuropathy, central dysmyelination, Waardenburg syndrome, and Hirschsprung disease (PCWH; 609136).

Description

Waardenburg syndrome type 4 is an auditory-pigmentary syndrome characterized by pigmentary abnormalities of the eye, deafness, and Hirschsprung disease (review by Read and Newton, 1997). WS type 4C is caused by mutation in the SOX10 gene (602229). WS type 4 is genetically heterogeneous (see WS4A; 277580).

For a description of other clinical variants of Waardenburg syndrome, see WS1 (193500), WS2 (193510), and WS3 (148820).

Clinical Features

Pingault et al. (1998) reported 4 patients with Waardenburg syndrome type 4C. Clinical features included bilateral profound hearing loss, short segment Hirschsprung disease, and pigmentary abnormalities, including white hair, blue irides with gray speckles, and depigmented skin patches, all features consistent with WS4.

Southard-Smith et al. (1999) reported a patient with Waardenburg syndrome type 4C manifest as short segment Hirschsprung disease, profound sensorineural hearing loss, and hypopigmentation on the abdomen and neck. Both parents were phenotypically normal.

Elmaleh-Berges et al. (2013) retrospectively reviewed imaging studies from 14 Waardenburg probands who all had different mutations in the SOX10 gene, including 2 patients with WS2E; 6 with WS4C, 1 of whom was previously reported by Pingault et al. (2002); and 6 with PCWH, 2 of whom were previously reported by Pingault et al. (2002) and 1 by Bondurand et al. (2007). The patients, who had imaging for cochlear implant evaluation, a diagnosis of hearing loss, and/or evaluation of neurologic impairment, all had bilateral temporal bone abnormalities; the most frequent pattern consisted of agenesis or hypoplasia of one or more semicircular canals, an enlarged vestibule, and a cochlea with a reduced size and sometimes abnormal shape, but with normal partition. Three patients lacked a cochlear nerve, bilaterally in 2 patients with PCWH. Associated abnormalities observed when adequate MRI sequences were available included agenesis of the olfactory bulbs in 7 (88%) of 8 patients, hypoplastic or absent lacrimal glands in 11 (79%) of 14 patients, hypoplastic parotid glands in 12 (86%) of 14 patients, and white matter signal anomalies in 7 (54%) of 13 patients. These associated abnormalities were variably present in patients with all 3 SOX10-related Waardenburg diagnoses, except for the 2 patients with WS2E, who had normal lacrimal and parotid glands.

From a systematic literature search, Song et al. (2016) determined that the prevalence of hearing loss in patients with Waardenburg syndrome differed according to the genotype: the prevalence in those with WS4 due to SOX10 mutations was 92.9%.

Clinical Variability

Pingault et al. (2002) identified SOX10 mutations in patients with WS4 with Hirschsprung disease and in patients with WS and intestinal pseudoobstruction without frank aganglionosis. These results showed that chronic intestinal pseudoobstruction may be a manifestation associated with WS, and indicated that aganglionosis is not the only mechanism underlying the intestinal dysfunction of patients with SOX10 mutations.

Molecular Genetics

In 4 patients with Waardenburg-Shah syndrome, Pingault et al. (1998) identified 4 different heterozygous mutations in the SOX10 gene (602229.0001-602229.0004). Each mutation was predicted to result in loss of function, suggesting that the pathologic mechanism is haploinsufficiency.

In 2 patients with WS4, Southard-Smith et al. (1999) identified mutations in the SOX10 gene (602229.0009-602229.0010).

Bondurand et al. (2007) reported a 1-year-old boy with Waardenburg syndrome type 4C who had short-segment Hirschsprung disease, bilateral sensorineural deafness, hair and skin hypopigmentation, and bilateral cryptorchidism. Genetic analysis identified a de novo heterozygous deletion in the SOX10 gene (602229.0012).

Animal Model

Southard-Smith et al. (1998) identified Sox10 as the gene underlying the Dom Hirschsprung mouse model.