# 193510

WAARDENBURG SYNDROME, TYPE 2A; WS2A


Alternative titles; symbols

WAARDENBURG SYNDROME, TYPE IIA
WAARDENBURG SYNDROME WITHOUT DYSTOPIA CANTHORUM
WS2


Phenotype-Gene Relationships

Location Phenotype Phenotype
MIM number
Inheritance Phenotype
mapping key
Gene/Locus Gene/Locus
MIM number
3p13 Waardenburg syndrome, type 2A 193510 AD 3 MITF 156845
Clinical Synopsis
 
Phenotypic Series
 

INHERITANCE
- Autosomal dominant
HEAD & NECK
Ears
- Deafness, congenital sensorineural
Eyes
- Dystopia canthorum absent
- Heterochromia iridis
- Hypoplastic iris stoma
- Synophrys
Nose
- Wide nasal bridge
- Hypoplastic alae nasi
SKIN, NAILS, & HAIR
Skin
- Congenital partial albinism (leukoderma) on face, trunk, or limbs
Hair
- White forelock
- White eyelashes and eyebrows
- Premature graying of hair
MISCELLANEOUS
- Variable expressivity of each feature
- Genetic heterogeneity of Waardenburg syndrome type 2
- Other variants of Waardenburg syndrome include Waardenburg syndrome type 1 (193500), Waardenburg syndrome type 3 (148820), and Waardenburg syndrome type 4 (277580)
MOLECULAR BASIS
- Caused by mutation in the microphthalmia-associated transcription factor gene (MITF, 156845.0001)

TEXT

A number sign (#) is used with this entry because of evidence that 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 (WS2) 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. WS2E (611584) is caused by mutation in the SOX10 gene (602229) on chromosome 22q13. WS2F (619947) is caused by mutation in the KITLG gene (184745) on chromosome 12q21.

A form of WS2, designated WS2D, was thought to be caused by deletion of the SNAI2 gene (602150.0001), but the deletion has been reclassified as a variant of unknown significance.


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%.

Waardenburg Syndrome Type 2 with Ocular Albinism

Lewis (1978) found 7 affected males and 5 affected females in 3 consecutive generations of a Caucasian kindred. As in the X-linked Nettleship-Falls form of ocular albinism (300500), the patients showed reduced visual acuity, photophobia, nystagmus, translucent irides, strabismus, hypermetropic refractive errors, and albinotic fundus with foveal hypoplasia. The skin lesions showed macromelanosomes as in X-linked ocular albinism. Deafness, which was accompanied by vestibular hypofunction, lentigines even in unexposed areas, optic nerve dysplasia, and dominant inheritance distinguished this form of ocular albinism. (In the LEOPARD syndrome (151100) vestibular function is normal.)

Bard (1978) described a kindred that was atypical of Waardenburg syndrome in several ways. Although the nasal root was prominent, one affected person had dystopia of the inner canthi or lower puncta. The face in some showed striking freckling of pale skin. Symptomatic vestibular disturbance was another unusual feature. Lewis (1989) expressed the opinion that the family reported by Bard (1978) as an instance of Waardenburg syndrome in fact had this disorder. Lewis (1989) had also been told of 2 other small families with the syndrome. Goldberg (1966) described a Waardenburg syndrome family with apparent ocular albinism.

Morell et al. (1997) presented an update of the clinical findings in the family of Bard (1978). The deafness was sensorineural and congenital. Heterochromia iridis was a prominent feature in 1 sibship in which both segmental iris bicolor and complete heterochromia occurred. Most of the affected individuals showed transillumination defects of the iris. Hypopigmentation of the fundus was mild in some, moderate in others, and severe in yet others. Almost all affected individuals had strabismus and visual acuity defects. One individual with a prominent white forelock, characteristic of Waardenburg syndrome, was pictured. In this family, Morell et al. (1997) identified digenic inheritance of Waardenburg syndrome and oculocutaneous albinism; see MOLECULAR GENETICS.


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).

Waardenburg Syndrome, Type 2A, with Ocular Albinism, Digenic

Studying the family reported by Bard (1978), Morell et al. (1997) demonstrated apparent digenic inheritance resulting from a combination of heterozygosity for a 1-bp deletion in exon 8 of the MITF gene (156845.0005) and homozygosity or heterozygosity for the R402Q polymorphism of the tyrosinase gene (TYR; 606933.0009), a functionally significant polymorphism that is associated with moderately reduced tyrosinase catalytic activity, and also heterozygous for the 1-bp deletion in MITF. Morell et al. (1997) proposed that the WS2-OA phenotype results from digenic interaction between a gene for a transcription factor, MITF, and a gene that it regulates, TYR.

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.


See Also:

REFERENCES

  1. Arias, S. Genetic heterogeneity in the Waardenburg syndrome. Birth Defects Orig. Art. Ser. VII(4): 87-101, 1971.

  2. Arias, S. Waardenburg syndrome--two distinct types. (Letter) Am. J. Med. Genet. 6: 99-100, 1980. [PubMed: 7187610, related citations] [Full Text]

  3. Asher, J. H., Jr., Friedman, T. B. Mouse and hamster mutants as models for Waardenburg syndromes in humans. J. Med. Genet. 27: 618-626, 1990. [PubMed: 2246770, related citations] [Full Text]

  4. Bard, L. A. Heterogeneity in Waardenburg's syndrome: report of a family with ocular albinism. Arch. Ophthal. 96: 1193-1198, 1978. [PubMed: 666627, related citations] [Full Text]

  5. Farrer, L. A., Arnos, K. S., Asher, J. H., Jr., Baldwin, C. T., Diehl, S. R., Friedman, T. B., Greenberg, J., Grundfast, K. M., Hoth, C., Lalwani, A. K., Landa, B., Leverton, K., Milunsky, A., Morell, R., Nance, W. E., Newton, V., Ramesar, R., Rao, V. S., Reynolds, J. E., San Agustin, T. B., Wilcox, E. R., Winship, I., Read, A. P. Locus heterogeneity for Waardenburg syndrome is predictive of clinical subtypes. Am. J. Hum. Genet. 55: 728-737, 1994. [PubMed: 7942851, related citations]

  6. Farrer, L. A., Grundfast, K. M., Amos, J., Arnos, K. S., Asher, J. H., Jr., Beighton, P., Diehl, S. R., Fex, J., Foy, C., Friedman, T. B., Greenberg, J., Hoth, C., Marazita, M., Milunsky, A., Morell, R., Nance, W., Newton, V., Ramesar, R., San Agustin, T. B., Skare, J., Stevens, C. A., Wagner, R. G., Jr., Wilcox, E. R., Winship, I., Read, A. P. Waardenburg syndrome (WS) type I is caused by defects at multiple loci, one of which is near ALPP on chromosome 2: first report of the WS Consortium. Am. J. Hum. Genet. 50: 902-913, 1992. [PubMed: 1349198, related citations]

  7. George, A., Zand, D. J., Hufnagel, R. B., Sharma, R., Sergeev, Y. V., Legare, J. M., Rice, G. M., Scott Schwoerer, J. A., Rius, M., Tetri, L., Gamm, D. M., Bharti, K., Brooks, B. P. Biallelic mutations in MITF cause coloboma, osteopetrosis, microphthalmia, macrocephaly, albinism, and deafness. Am. J. Hum. Genet. 99: 1388-1394, 2016. [PubMed: 27889061, images, related citations] [Full Text]

  8. Goldberg, M. F. Waardenburg's syndrome with fundus and other anomalies. Arch. Ophthal. 76: 797-810, 1966. [PubMed: 4958935, related citations] [Full Text]

  9. Hageman, M. J., Delleman, J. W. Heterogeneity in Waardenburg syndrome. Am. J. Hum. Genet. 29: 468-485, 1977. [PubMed: 331943, related citations]

  10. Hughes, A. E., Newton, V. E., Liu, X. Z., Read, A. P. A gene for Waardenburg syndrome type 2 maps close to the human homologue of the microphthalmia gene at chromosome 3p12-p14.1. Nature Genet. 7: 509-512, 1994. [PubMed: 7951321, related citations] [Full Text]

  11. Lalwani, A. K., Attaie, A., Randolph, F. T., Deshmukh, D., Wang, C., Mhatre, A., Wilcox, E. Point mutation in the MITF gene causing Waardenburg syndrome type II in a three-generation Indian family. Am. J. Med. Genet. 80: 406-409, 1998. [PubMed: 9856573, related citations]

  12. Lewis, R. A. Ocular albinism and deafness. (Abstract) Am. J. Hum. Genet. 30: 57A only, 1978.

  13. Lewis, R. A. Personal Communication. Houston, Tex. 9/1989.

  14. Liu, X.-Z., Newton, V. E., Read, A. P. Waardenburg syndrome type II: phenotypic findings and diagnostic criteria. Am. J. Med. Genet. 55: 95-100, 1995. [PubMed: 7702105, related citations] [Full Text]

  15. Morell, R., Spritz, R. A., Ho, L., Pierpont, J., Guo, W., Friedman, T. B., Asher, J. H., Jr. Apparent digenic inheritance of Waardenburg syndrome type 2 (WS2) and autosomal recessive ocular albinism (AROA). Hum. Molec. Genet. 6: 659-664, 1997. [PubMed: 9158138, related citations] [Full Text]

  16. Nobukuni, Y., Watanabe, A., Takeda, K., Skarka, H., Tachibana, M. Analyses of loss-of-function mutations of the MITF gene suggest that haploinsufficiency is a cause of Waardenburg syndrome type 2A. Am. J. Hum. Genet. 59: 76-83, 1996. [PubMed: 8659547, related citations]

  17. Pingault, V., Ente, D., Dastot-Le Moal, F., Goossens, M., Marlin, S., Bondurand, N. Review and update of mutations causing Waardenburg syndrome. Hum. Mutat. 31: 391-406, 2010. [PubMed: 20127975, related citations] [Full Text]

  18. Read, A. P., Newton, V. E. Waardenburg syndrome. J. Med. Genet. 34: 656-665, 1997. [PubMed: 9279758, related citations] [Full Text]

  19. Reynolds, J. E., Meyer, J. M., Landa, B., Stevens, C. A., Arnos, K. S., Israel, J., Marazita, M. L., Bodurtha, J., Nance, W. E., Diehl, S. R. Analysis of variability of clinical manifestations in Waardenburg syndrome. Am. J. Med. Genet. 57: 540-547, 1995. [PubMed: 7573125, related citations] [Full Text]

  20. Song, J., Feng, Y., Acke, F. R., Coucke, P., Vleminckx, K., Dhooge, I. J. Hearing loss in Waardenburg syndrome: a systematic review. Clin. Genet. 89: 416-425, 2016. [PubMed: 26100139, related citations] [Full Text]

  21. Tachibana, M., Takeda, K., Nobukuni, Y., Urabe, K., Long, J. E., Meyers, K. A., Aaronson, S. A., Miki, T. Ectopic expression of MITF, a gene for Waardenburg syndrome type 2, converts fibroblasts to cells with melanocytes characteristics. Nature Genet. 14: 50-54, 1996. [PubMed: 8782819, related citations] [Full Text]

  22. Tassabehji, M., Newton, V. E., Liu, X.-Z., Brady, A., Donnai, D., Krajewska-Walasek, M., Murday, V., Norman, A., Obersztyn, E., Reardon, W., Rice, J. C., Trembath, R., Wieacker, P., Whiteford, M., Winter, R., Read, A. P. The mutational spectrum in Waardenburg syndrome. Hum. Molec. Genet. 4: 2131-2137, 1995. [PubMed: 8589691, related citations] [Full Text]

  23. Tassabehji, M., Newton, V. E., Read, A. P. Waardenburg syndrome type 2 caused by mutations in the human microphthalmia (MITF) gene. Nature Genet. 8: 251-255, 1994. [PubMed: 7874167, related citations] [Full Text]

  24. Tassabehji, M., Read, A. P., Newton, V. E., Patton, M., Gruss, P., Harris, R., Strachan, T. Mutations in the PAX3 gene causing Waardenburg syndrome type 1 and type 2. Nature Genet. 3: 26-30, 1993. [PubMed: 8490648, related citations] [Full Text]


Marla J. F. O'Neill - updated : 01/23/2017
Cassandra L. Kniffin - updated : 5/24/2016
Cassandra L. Kniffin - updated : 3/15/2010
Cassandra L. Kniffin - updated : 3/8/2010
Victor A. McKusick - updated : 11/28/2007
Victor A. McKusick - updated : 6/23/1997
Creation Date:
Victor A. McKusick : 6/2/1986
carol : 05/15/2023
carol : 07/06/2022
alopez : 07/05/2022
carol : 08/06/2020
alopez : 02/03/2020
carol : 11/07/2017
carol : 01/23/2017
carol : 09/08/2016
carol : 09/07/2016
carol : 05/24/2016
ckniffin : 5/24/2016
alopez : 12/29/2015
ckniffin : 3/15/2010
ckniffin : 3/8/2010
alopez : 12/10/2007
terry : 11/28/2007
carol : 8/31/2004
carol : 1/30/2002
carol : 1/8/2002
carol : 4/2/1999
carol : 6/18/1998
carol : 6/18/1998
mark : 6/23/1997
terry : 6/23/1997
terry : 6/19/1997
mimadm : 9/11/1995
mark : 8/1/1995
carol : 2/6/1995
terry : 11/15/1994
warfield : 4/14/1994
carol : 6/17/1993

# 193510

WAARDENBURG SYNDROME, TYPE 2A; WS2A


Alternative titles; symbols

WAARDENBURG SYNDROME, TYPE IIA
WAARDENBURG SYNDROME WITHOUT DYSTOPIA CANTHORUM
WS2


ORPHA: 3440, 895;   DO: 0110950;  


Phenotype-Gene Relationships

Location Phenotype Phenotype
MIM number
Inheritance Phenotype
mapping key
Gene/Locus Gene/Locus
MIM number
3p13 Waardenburg syndrome, type 2A 193510 Autosomal dominant 3 MITF 156845

TEXT

A number sign (#) is used with this entry because of evidence that 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 (WS2) 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. WS2E (611584) is caused by mutation in the SOX10 gene (602229) on chromosome 22q13. WS2F (619947) is caused by mutation in the KITLG gene (184745) on chromosome 12q21.

A form of WS2, designated WS2D, was thought to be caused by deletion of the SNAI2 gene (602150.0001), but the deletion has been reclassified as a variant of unknown significance.


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%.

Waardenburg Syndrome Type 2 with Ocular Albinism

Lewis (1978) found 7 affected males and 5 affected females in 3 consecutive generations of a Caucasian kindred. As in the X-linked Nettleship-Falls form of ocular albinism (300500), the patients showed reduced visual acuity, photophobia, nystagmus, translucent irides, strabismus, hypermetropic refractive errors, and albinotic fundus with foveal hypoplasia. The skin lesions showed macromelanosomes as in X-linked ocular albinism. Deafness, which was accompanied by vestibular hypofunction, lentigines even in unexposed areas, optic nerve dysplasia, and dominant inheritance distinguished this form of ocular albinism. (In the LEOPARD syndrome (151100) vestibular function is normal.)

Bard (1978) described a kindred that was atypical of Waardenburg syndrome in several ways. Although the nasal root was prominent, one affected person had dystopia of the inner canthi or lower puncta. The face in some showed striking freckling of pale skin. Symptomatic vestibular disturbance was another unusual feature. Lewis (1989) expressed the opinion that the family reported by Bard (1978) as an instance of Waardenburg syndrome in fact had this disorder. Lewis (1989) had also been told of 2 other small families with the syndrome. Goldberg (1966) described a Waardenburg syndrome family with apparent ocular albinism.

Morell et al. (1997) presented an update of the clinical findings in the family of Bard (1978). The deafness was sensorineural and congenital. Heterochromia iridis was a prominent feature in 1 sibship in which both segmental iris bicolor and complete heterochromia occurred. Most of the affected individuals showed transillumination defects of the iris. Hypopigmentation of the fundus was mild in some, moderate in others, and severe in yet others. Almost all affected individuals had strabismus and visual acuity defects. One individual with a prominent white forelock, characteristic of Waardenburg syndrome, was pictured. In this family, Morell et al. (1997) identified digenic inheritance of Waardenburg syndrome and oculocutaneous albinism; see MOLECULAR GENETICS.


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).

Waardenburg Syndrome, Type 2A, with Ocular Albinism, Digenic

Studying the family reported by Bard (1978), Morell et al. (1997) demonstrated apparent digenic inheritance resulting from a combination of heterozygosity for a 1-bp deletion in exon 8 of the MITF gene (156845.0005) and homozygosity or heterozygosity for the R402Q polymorphism of the tyrosinase gene (TYR; 606933.0009), a functionally significant polymorphism that is associated with moderately reduced tyrosinase catalytic activity, and also heterozygous for the 1-bp deletion in MITF. Morell et al. (1997) proposed that the WS2-OA phenotype results from digenic interaction between a gene for a transcription factor, MITF, and a gene that it regulates, TYR.

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.


See Also:

Arias (1980)

REFERENCES

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Contributors:
Marla J. F. O'Neill - updated : 01/23/2017
Cassandra L. Kniffin - updated : 5/24/2016
Cassandra L. Kniffin - updated : 3/15/2010
Cassandra L. Kniffin - updated : 3/8/2010
Victor A. McKusick - updated : 11/28/2007
Victor A. McKusick - updated : 6/23/1997

Creation Date:
Victor A. McKusick : 6/2/1986

Edit History:
carol : 05/15/2023
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warfield : 4/14/1994
carol : 6/17/1993