Waardenburg Syndrome, Type 4a

A number sign (#) is used with this entry because Waardenburg syndrome type 4A (WS4A) is caused by heterozygous or homozygous mutation in the endothelin-B receptor gene (EDNRB; 131244) on chromosome 13q22.

The ABCD syndrome (600501), which can also be caused by mutation in the EDNRB gene, has a similar phenotype and may be considered an expression of Waardenburg syndrome 4A (Verheij et al., 2002).

Description

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.

Clinical Features

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.

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 EDNRB mutations was 53.3%.

Inheritance

Shah et al. (1981) reported parental consanguinity in 2 of 5 affected families as well as multiple affected sibs of both sexes in families, suggesting autosomal recessive inheritance. One family was ascertained through a first cousin of a patient with WS4; this proband had white forelock and heterochromia iridis, but no dystopia canthorum or deafness.

Badner and Chakravarti (1990) analyzed the 5 families reported by Shah et al. (1981) and Ambani (1983). Because 2 of the families demonstrated parental consanguinity, autosomal recessive inheritance had been suggested. Badner and Chakravarti (1990) concluded, however, that a single dominant gene with pleiotropic effects, with a more severe phenotype in homozygotes, was more plausible.

WS type 4A showed autosomal dominant inheritance in the family reported by Syrris et al. (1999).

Cytogenetics

Tuysuz et al. (2009) reported 3 unrelated patients with variable features of WS4A associated with de novo heterozygous deletions involving chromosome 13q and including the EDNRB gene. Two patients carried deletions of chromosome 13q22.1-q31.3 and had hypopigmentation of irides and HSCR and mild unilateral hearing loss, respectively. One patient carried a slightly larger deletion of chromosome 13q21.1-q31.3. and had prominent bicolored irides, ganglionic megacolon, and mild bilateral hearing loss, as well as severe short stature, scoliosis, and motor retardation. In addition, all 3 patients had mild developmental delay and dysmorphic facial features, including hypertelorism, broad nasal bridge, epicanthal folds, short philtrum, and low-set ears, consistent with the so-called 'proximal 13q deletion syndrome' (Brown et al., 1993). The data confirmed the variable phenotype observed in patients with heterozygous loss of function of EDNRB.

Mapping

By linkage analysis in a family in which 2 sibs had Waardenburg syndrome and Hirschsprung disease, Van Camp et al. (1995) found evidence for the disease locus on chromosome 13q.

Molecular Genetics

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.

Animal Model

In the mouse, at least 3 megacolon genes are associated with pigmentary abnormalities (Lane (1966, 1984)).

Matsushima et al. (2002) described a novel mutant mouse with a mutation in the Ednrb gene and proposed the mouse as an animal model of Waardenburg syndrome type IV. These mutants had a mixed genetic background and extensive white spotting. They died between 2 and 7 weeks after birth owing to megacolon; their colon distal to the megacolon lacked Auerbach plexus cells. These mutants did not respond to sound, and the stria vascularis of their cochleae lacked intermediate cells, i.e., neural crest-derived melanocytes. The inheritance was autosomal recessive as in human WS4. Breeding analysis revealed that WS4 mice are allelic with piebald-lethal and JF1 mice, which are also mutated in the Ednrb gene. Mutation analysis showed that the Ednrb gene lacked 318 nucleotides encoding transmembrane domains owing to deletion of exons 2 and 3.