Waardenburg Syndrome, Type 4b

A number sign (#) is used with this entry because Waardenburg syndrome type 4B (WS4B) is caused by homozygous and heterozygous mutation in the endothelin-3 gene (EDN3; 131242) on chromosome 20q13.

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 4B is caused by mutation in the EDN3 gene (131242). 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

Edery et al. (1996) reported a 4-year-old girl with Waardenburg-Shah syndrome. She had colonic aganglionosis, bilateral sensorineural hearing loss, and pigmentary anomalies, including achromic patches of the skin, white eyelashes, pale blue retina, but absence of dystopia canthorum found in Waardenburg syndrome type 1 (193500).

Hofstra et al. (1996) reported a patient, born of consanguineous parents, with WS4B. A previous child in this family had been diagnosed with a similar combination of Hirschsprung disease, depigmentation, and deafness. Depigmentation and deafness were present in other relatives. Molecular analysis identified a homozygous mutation in the EDN3 gene (C159F; 131242.0002)

Vinuela et al. (2009) reported a Spanish boy, born of consanguineous parents, with Waardenburg syndrome type 4B. The patient had pale blue irides, white forelock, depigmented skin patches, total colonic aganglionosis, and profound sensorineural hearing loss treated successfully with a cochlear implant.

Shamseldin et al. (2010) reported an 8-year-old Egyptian boy with WS4B confirmed by genetic analysis (R93G; 131242.0009). He was noted to have a white forelock, grayish blue eyes, hypoplastic ears, and intrauterine growth retardation at birth. Hirschsprung disease was diagnosed soon after. He also had mixed hearing loss with absence of brainstem auditory-evoked response. Family history revealed 2 sibs who died as neonates from complications related to Hirschsprung disease. At age of 8 years, the proband was doing well at a school for the deaf, but no formal IQ testing had been done. He still showed poor physical growth.

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 EDN3 mutations was 75.0%.

Molecular Genetics

In a patient with WS4, Edery et al. (1996) identified a homozygous substitution/deletion mutation of the EDN3 gene (131242.0001).

In a child with WS4, Pingault et al. (2001) identified a heterozygous nonsense mutation in the EDN3 gene (C169X; 131242.0007). Three unaffected relatives and a fetus terminated at 29 weeks' gestation because of intestinal obstruction also had the mutation. The fetus was found to have Hirschsprung disease affecting the ileum and colon, but no features of Waardenburg syndrome.

In a Spanish boy with WS4B, Vinuela et al. (2009) identified a homozygous mutation in the EDN3 gene (H112R; 131242.0008). The patient's father and paternal grandmother, who were each heterozygous for the mutation, had white forelocks. Vinuela et al. (2009) were not able to distinguish whether the mild manifestations in the heterozygous carriers were due to haploinsufficiency or a mild dominant-negative effect.

Animal Model

Baynash et al. (1994) found that targeted disruption of the mouse endothelin-B ligand (Edn3) gene produces a recessive phenotype of megacolon and coat color spotting.