Waardenburg syndrome type 4 (WS4), also known as Waardenburg-Shah syndrome, is an auditory-pigmentary syndrome characterized by pigmentary abnormalities of the hair, skin, and eyes, congenital sensorineural hearing loss, and Hirschsprung disease (reviews by Read and Newton, 1997 and ... Waardenburg syndrome type 4 (WS4), also known as Waardenburg-Shah syndrome, is an auditory-pigmentary syndrome characterized by pigmentary abnormalities of the hair, skin, and eyes, congenital sensorineural hearing loss, and Hirschsprung disease (reviews by Read and Newton, 1997 and Pingault et al., 2010). WS type 4A is caused by mutation in the EDNRB gene (131244). - Clinical Variability of Waardenburg Syndrome Types 1-4 Waardenburg syndrome has been classified into 4 main phenotypes. Type I Waardenburg syndrome (WS1; 193500) is characterized by pigmentary abnormalities of the hair, including a white forelock and premature graying; pigmentary changes of the iris, such as heterochromia iridis and brilliant blue eyes; congenital sensorineural hearing loss; and 'dystopia canthorum.' WS type II (WS2) is distinguished from type I by the absence of dystopia canthorum. WS type III (WS3; 148820) has dystopia canthorum and is distinguished by the presence of upper limb abnormalities. WS type 4 has the additional feature of Hirschsprung disease (reviews by Read and Newton, 1997 and Pingault et al., 2010). - Genetic Heterogeneity of Waardenburg Syndrome Type 4 Waardenburg syndrome type 4 is genetically heterogeneous. WS4B (613265) is caused by mutation in the EDN3 gene (131242) on chromosome 20q13, and WS4C (613266) is caused by mutation in the SOX10 gene (602229) on chromosome 22q13.
McKusick (1973); Lowry (1975), and Omenn and McKusick (1979) noted the frequent occurrence of Hirschsprung disease (aganglionic megacolon; 142623) in patients with Waardenburg syndrome. Fraser (1976) described a deaf male with no family history of deafness, complete blue-green ... McKusick (1973); Lowry (1975), and Omenn and McKusick (1979) noted the frequent occurrence of Hirschsprung disease (aganglionic megacolon; 142623) in patients with Waardenburg syndrome. Fraser (1976) described a deaf male with no family history of deafness, complete blue-green heterochromia with hypoplastic stroma in the blue iris, and Hirschsprung disease. Kelley and Zackai (1981) reported father and son with aganglionic megacolon and Waardenburg syndrome without dystopia canthorum. Shah et al. (1981) reported studies of 5 families in which a total of 12 babies (7 male; 5 female) with white forelock and white eyebrows and eyelashes presented in the neonatal period with intestinal obstruction. Eight patients had isochromia irides (light brown irides with mosaic pattern); in the other 4, information was not recorded. In 6 patients in whom the observations were recorded, no dystopia canthorum, broad nasal root, or white skin patches were found. Deafness could not be detected in any of the patients. Microcolon was noted in patients in whom contrast enemas were done. At operation, the proximal ileum was dilated with collapse of the distal ileum and colon in 8; operative notes were not available on the other 4. The 12 infants died 3 to 38 days after birth because of failure of the ileostomy to function. This disorder appeared to be clinically and genetically distinct from Waardenburg syndrome, which has a different pigmentary anomaly of the eye and usually does not have associated Hirschsprung disease, although the short segment type may rarely occur in WS. In 3 of 6 Mexican sibs, Liang et al. (1983) observed Hirschsprung disease in association with 'bicolored' irides. They used the term bicolored rather than heterochromia to emphasize that 2 distinct colors were present in the same iris. The unaffected parents were related, suggesting autosomal recessive inheritance. Liang et al. (1983) suggested a defect in the neural crest. Meire et al. (1987) reported Hirschsprung megacolon associated with Waardenburg syndrome without dystopia canthorum. The affected girl, 1 of 3 affected persons in her family, also showed unilateral ptosis with the Marcus Gunn phenomenon; the ptosis decreased on opening the mouth. In a patient with piebaldism and deafness, Kaplan and de Chaderevian (1988) found megacolon, left pulmonic artery stenosis, ocular ptosis, and unilateral duplication of the renal collecting system. Histologically, hypoganglionosis, hyperganglionosis, and ectopic ganglia were found in the lamina propria of the rectum (neuronal colonic dysplasia). The hypopigmented skin was found to be devoid of melanocytes, with no melanin in adjacent basal cells. Because of the absence of dystopia canthorum, the patient can be said to have had type II Waardenburg syndrome. (The name is spelled de Chadarevian in at least 4 other publications cited in Mendelian Inheritance in Man.) Kulkarni et al. (1989) described 3 sibs derived from an uncle-niece marriage who had white forelock, light-colored irides, white eyelashes, multiple hypopigmented skin patches, and obstructive ileal lesions. Syrris et al. (1999) reported a family with Waardenburg-Shah syndrome due to a heterozygous mutation in the EDNRB gene (R253X; 131244.0007). The family was of Afro-Caribbean origin and had variable manifestations of sensorineural deafness, heterochromia iridis, and Hirschsprung disease. Synophrys, hair or skin hypopigmentation, and dystopia canthorum were absent in this family. The data confirmed the role of EDNRB as the cause of Waardenburg-Shah disease and demonstrated that these is a variable expression of disease even within the same family.
In individuals with Hirschsprung disease as well as bicolored irides (6.3%), hypopigmentation (2.5%), sensorineural hearing loss (5.1%), and white forelock (7.6%) suggestive of WS4, Puffenberger et al. (1994) identified a mutation in the EDNRB gene (131244.0001). The mutation ... In individuals with Hirschsprung disease as well as bicolored irides (6.3%), hypopigmentation (2.5%), sensorineural hearing loss (5.1%), and white forelock (7.6%) suggestive of WS4, Puffenberger et al. (1994) identified a mutation in the EDNRB gene (131244.0001). The mutation was found to be dose sensitive, in that the homozygotes and heterozygotes had a 74% and a 21% risk, respectively, of developing Hirschsprung disease. Attie et al. (1995) identified a homozygous mutation in the EDNRB gene (A183G; 131244.0002) in 2 sisters with WS type IVA who were born of consanguineous Tunisian parents. Although neither affected sister had dystopia canthorum, both had deafness, white forelock, heterochromia iridis, and Hirschsprung disease. Inheritance in this family was autosomal recessive.