Waardenburg Syndrome, Type 2a

A number sign (#) is used with this entry because Waardenburg syndrome type 2A (WS2A) is caused by heterozygous mutation in the gene encoding microphthalmia-associated transcription factor (MITF; 156845) on chromosome 3p13.

A highly overlapping disorder, Tietz albinism-deafness syndrome (TADS; 103500), is also caused by heterozygous mutation in the MITF gene.

Description

Waardenburg syndrome type 2 is an autosomal dominant auditory-pigmentary syndrome characterized by pigmentary abnormalities of the hair, skin, and eyes; congenital sensorineural hearing loss; and the absence of 'dystopia canthorum,' the lateral displacement of the ocular inner canthi, which is seen in some other forms of WS (reviews by Read and Newton, 1997 and Pingault et al., 2010).

Clinical Variability of Waardenburg Syndrome Types 1-4

Waardenburg syndrome has been classified into 4 main phenotypes. Waardenburg syndrome type 1 (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 2 (WS2) is distinguished from type 1 by the absence of dystopia canthorum. WS type 3 (WS3; 148820) has dystopia canthorum and is distinguished by the presence of upper limb abnormalities. WS type 4 (WS4; 277580), also known as Waardenburg-Shah syndrome, has the additional feature of Hirschsprung disease (reviews by Read and Newton, 1997 and Pingault et al., 2010).

Genetic Heterogeneity of Waardenburg Syndrome Type 2

Waardenburg syndrome type 2 is a genetically heterogeneous disorder. WS2B (600193) has been mapped to chromosome 1p, WS2C (606662) has been mapped to chromosome 8p23, WS2D (608890) is caused by mutation in the SNAI2 gene (602150) on chromosome 8q11, and WS2E (611584) is caused by mutation in the SOX10 gene (602229) on chromosome 22q13.

Clinical Features

Arias (1971) suggested the existence of 2 types of Waardenburg syndrome based in the presence or absence of dystopia canthorum. Hageman and Delleman (1977) presented family data supporting delineation of 2 types: type I, with dystopia canthorum; and type II, without dystopia canthorum. The frequency of deafness was higher in type II.

In a personally studied series of 81 individuals from 21 families with WS type II in comparison with 60 personally studied patients from 8 families with type I, Liu et al. (1995) concluded that sensorineural hearing loss (77%) and heterochromia iridum (47%) were more common in WS type II than in type I. On the other hand, white forelock and skin patches were more frequent in type I.

Reynolds et al. (1995) reviewed their collection of 26 WS1 and 8 WS2 families. Deafness was more frequent and more severe in the WS2-affected individuals than had been found previously. No one in either group had neural tube defects or cleft lip and/or palate. However, 12 individuals in 5 families had some signs or symptoms of Hirschsprung megacolon (WS4). Their data led Reynolds et al. (1995) to conclude that use of the W-index to discriminate between affected WS1 and WS2 individuals may be problematic since (1) ranges of W-index scores of affected and unaffected individuals overlapped considerably within both WS1 and WS2 families, and (2) a considerable number of both affected and unaffected WS2 individuals exhibited W-index scores consistent with dystopia canthorum.

Tassabehji et al. (1994) reported 2 unrelated families with WS type 2. Both had typical WS2, with various combinations of hearing loss, heterochromia irides, white forelock, skin hypopigmentation, and premature graying. Neither had dystopia canthorum.

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 WS2 due to MITF mutations was 89.6%.

Mapping

Studies of a few families with WS type II failed to show linkage to ALPP (171800) and/or the PAX3 gene (606597) on chromosome 2q37, where WS type 1 had been mapped (Farrer et al., 1992; Tassabehji et al., 1993).

In a study of 2 families with WS type II, Hughes et al. (1994) demonstrated linkage to a group of microsatellite markers located on chromosome 3p14.1-p12. D3S1261 gave a maximum lod score of 6.5 at 0.0 recombination in 1 large type II family. In a second, smaller family, the adjacent marker D3S1210 gave a lod score of 2.05 at 0.0 recombination. The human homolog of the mouse microphthalmia gene (MITF; 156845) maps to the same region. Asher and Friedman (1990) had pointed out that because of phenotypic similarities, microphthalmia (mi) is a possible model for Waardenburg syndrome; there are many mi alleles, some dominant and others recessive, which interact and complement in various ways, giving a range of phenotypes that can include white coat, premature graying, unpigmented eyes, and hearing loss.

Molecular Genetics

Tassabehji et al. (1994) demonstrated heterozygous mutations in the MITF gene (156845.0001 and 156845.0002) in affected members of 2 families with Waardenburg syndrome type 2A. One of the families had been reported by Hughes et al. (1994). Inheritance was autosomal dominant.

In a study of 134 probands with auditory-pigmentary syndromes, Tassabehji et al. (1995) detected MITF mutations in 7 families (see, e.g., 156845.0004 and 156845.0008), of which 5 had definite WS2. The authors concluded that WS2 is heterogeneous, and that about 20% of cases are caused by mutation in the MITF gene.

In affected individuals from a 3-generation Indian family with WS2A, Lalwani et al. (1998) identified heterozygosity for an R214X mutation in the MITF gene (156845.0007). The authors noted that the mutation had been reported earlier in a northern European family by Nobukuni et al. (1996). In both families, hearing loss was the most common finding, followed by ocular pigmentary disturbance. The latter was significantly different between the 2 families, with heterochromia iridis occurring in 8 of 11 affected members of the Indian family and in 4 of 14 affected members of the European family.

George et al. (2016) studied 2 unrelated families in which the parents had features of WS2A and carried heterozygous mutations in MITF (156845.0003 and 156845.0010-156845.0012). In each family, there was also 1 affected child who inherited both parental mutations; the 2 compound heterozygous children exhibited coloboma, osteopetrosis, microphthalmia, macrocephaly, albinism, and deafness (COMMAD; 617306).

Associations Pending Confirmation

For discussion of a possible role of variation in the KITLG gene in Waardenburg syndrome type 2, see 184745.0008.

Exclusion Studies

Farrer et al. (1994) typed microsatellite markers within and flanking the PAX3 gene (606597) on chromosome 2q35 in 41 WS1 kindreds and 26 WS2 kindreds defined on the basis of presence or absence of dystopia canthorum according to the W index of patients. Evaluation of heterogeneity in location scores obtained by multilocus analysis indicated that in 60% of all WS families and in 100% of WS1 families, the phenotype was linked to PAX3. None of the WS2 families were linked to the PAX3 gene.

Pathogenesis

Tachibana et al. (1996) showed that MITF transactivates the gene for tyrosinase (TYR; 606933), a key enzyme for melanogenesis, and is critically involved in melanocyte differentiation. Absence of melanocytes affects pigmentation in the skin, hair, and eyes, and hearing function in the cochlea. Therefore, hypopigmentation and hearing loss in WS2 are likely to be the results of an anomaly of melanocyte differentiation caused by MITF mutations.

Nomenclature

Hughes et al. (1994) found that WS2 is heterogeneous, with mutations at different loci in different families. They suggested that the type II Waardenburg syndrome mapping to 3p13 be named WS2A and the unlinked form(s) provisionally designated 'WS2B.' WS2B (600193) is used here to designate a locus on chromosome 1p.

History

Bard (1978) described a kindred that was atypical in several ways. Lewis (1989) suggested that Bard's patients in fact had the disorder discussed in entry 103470. Genetic studies by Morell et al. (1997) showed that the family of Bard (1978) had digenic inheritance of type II Waardenburg syndrome and autosomal recessive ocular albinism.