Waardenburg Syndrome Type 1 11/10/01 13:15

Funded by the NIH • Developed at the University of Washington, Seattle

Waardenburg Syndrome Type 1

[WS1]

Author: Jeff Milunsky, MD Boston University School of Medicine

Posted: 30 July 2001

Summary

Disease characteristics. Waardenburg syndrome type 1 (WS1) is an auditory-pigmentary disorder comprising congenital sensorineural hearing loss and pigmentary disturbances of the iris, hair, and skin, along with dystopia canthorum (lateral displacement of the inner canthi). The hearing loss in WS1 observed in ~57% of patients is congenital, typically nonprogressive, either unilateral or bilateral, and of the sensorineural type. The most common type of hearing loss in WS1 is profound bilateral loss (>100dB). The classic white forelock observed in ~45% of patients is the most common hair pigmentation anomaly seen in WS. The majority of individuals with WS1 have either a white forelock or early graying of the scalp hair before age 30 years. Patients may have complete heterochromia iridium, partial/segmental heterochromia, or hypoplastic or brilliant blue irides.

Diagnosis/testing. The diagnosis is established by clinical findings in most patients. Diagnostic criteria rely upon the presence of sensorineural hearing loss, pigmentary changes, and calculation of the W index to identify dystopia canthorum. Molecular genetic testing by sequencing of the PAX3 gene (chromosomal locus 2q35) detects over 90% of disease-causing mutations. Such testing is available clinically. Molecular genetic testing can be used to confirm the diagnosis in atypical cases; however, it is primarily used for genetic counseling of at-risk family members.

Genetic counseling. Waardenburg syndrome is inherited in an autosomal dominant manner. The majority of probands have an affected parent. A minority of probands do not have an affected parent and are presumed to have a de novo mutation. The risk to the sibs of the proband depends upon the status of the parents. If a parent is affected, the risk is 50%. Offspring of an individual with WS1 have a 50% chance of inheriting the disease-causing mutation. Prenatal testing is available for pregnancies at 50% risk in which a parent has been identified as having a PAX3 mutation.

Diagnosis

Waardenburg syndrome type 1 is an auditory-pigmentary disorder comprising congenital sensorineural hearing loss and pigmentary disturbances of the iris, hair, and skin, along with dystopia canthorum (lateral displacement of the inner canthi). The diagnosis is established by clinical findings in most patients. Molecular genetic testing is available by sequencing the PAX3 gene (chromosomal locus 2q35). Molecular genetic testing can be used to confirm the diagnosis in atypical cases; however, it is primarily used for genetic counseling of at-risk family members.

Clinical Diagnosis

Diagnostic criteria for Waardenburg syndrome type 1 (WS1) have been proposed by the Waardenburg Consortium [Farrer et al 1992]. An individual must have two major or one major plus two minor criteria to be considered affected.

Major Criteria

Congenital sensorineural hearing loss White forelock, hair hypopigmentation Pigmentation abnormality of the iris

Complete heterochromia iridum (eyes of different color) Partial/segmental heterochromia (two different colors in same iris, typically brown and blue) Hypoplastic blue irides, or brilliant blue irides

Dystopia canthorum, W index >1.95* Affected first-degree relative

Minor Criteria

Skin hypopigmentation (congenital leukoderma) Synophyrys/medial eyebrow flare

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Broad/high nasal root, prominent columella Hypoplastic alae nasi Premature gray hair (before age 30 years)

* W index: The measurements necessary to calculate the W index (in mm) are as follows: inner canthal distance(a), interpupillary distance(b), and outer canthal distance(c).

Calculate X = (2a-0.2119c-3.909)/c Calculate Y = (2a-0.2479b-3.909)/b Calculate W = X + Y + a/b

An abnormal W index result is >1.95. Previously, a W index of greater than 2.07 was necessary to diagnose WS1 in an individual meeting all of the other diagnostic criteria. With molecular analysis, a family previously clinically classified as having WS2 based on the W index was found to have a PAX3 mutation and was reclassified as having WS1 [Tassabehji et al 1993]. Hence, the W index threshold was reduced to its current value of >1.95.

Molecular Genetic Testing

Clinical molecular diagnostic testing by sequencing the PAX3 gene is available (Table 1). More than 90% of patients who meet the cardinal clinical diagnostic criteria for WS1 have identifiable mutations in PAX3 [unpublished data]. Multiple mutations, including missense, nonsense, and splice-site mutations, frameshifts, small deletions, and insertions, have been found throughout the PAX3 gene. Complete deletion of the PAX3 gene has also been described in several patients. Although several families share some mutations, most mutations are private. Genotype/phenotype correlations in the PAX3 gene are not well established except for the N47H mutation in WS3 [Hoth et al 1993] and the N47K mutation described in craniofacial-deafness-hand syndrome [Asher et al 1996].

Table 1. Molecular Genetic Testing Used in Waardenburg Syndrome Type 1 % of Patients Genetic Mechanism Test Type Test Availability >90% Mutations in PAX3 DNA Clinical

Genetically Related Disorders

Mutations in PAX3 have also been shown to cause the following:

WS3 (Klein-Waardenburg Syndrome), in which individuals have a combination of typical WS1 features and hypoplasia or contractures of the limb muscles or joints, carpal bone fusion, or syndactyly [Hoth et al 1993] Craniofacial-deafness-hand syndrome (CDHS) (OMIM 122880), in which patients have a flat facial profile, ocular hypertelorism, hypoplastic nose with slit-like nares, and sensorineural hearing loss. X-ray findings include a small maxilla, absent or small nasal bones, and ulnar deviation of the hands [Sommer et al 1983, Asher et al 1996]. Asher et al (1996) identified a missense mutation in the PAX3 gene in patients with this disorder. This disorder is apparently distinct from both WS1 and WS3. Clinical Description

The phenotype of Waardenburg syndrome type 1 is variable even within a family. Liu et al (1995) summarized the penetrance (percentage) of clinical features of WS1 (Table 2). These figures were based on Lui's study of 60 individuals with WS1 and reports in the literature of 210 individuals with WS1.

Table 2. Penetrance of Clinical Features of Waardenberg Syndrome Type 1 Clinical Finding % of Patients Sensorineural hearing loss 57-58% Heterochromia irides 15-31% Hypoplastic blue eyes 15-18% White forelock 43-48% Early graying 23-38% Leukoderma 30-36% High nasal root 52-100% Medial eyebrow flare 63-70%

Hearing loss. The hearing loss in WS1 is congenital, typically nonprogressive, either unilateral or bilateral, and of the sensorineural type. The most common type in WS1 is profound bilateral hearing loss (>100dB). The laterality of the hearing loss is variable among and within families.

Hair color. The classic white forelock is the most common hair pigmentation anomaly seen in WS. The forelock may be present at birth, or appear later, typically in the teen years. The white forelock may become normally pigmented over time. In evaluating a patient with suspected WS1 without a white forelock, the individual should be asked whether the hair has been dyed. The hypopigmentation can also involve the eyebrows and eyelashes [Fraser 1976]. The white forelock is typically in the midline but the http://www.geneclinics.org/servlet/access?db=geneclinics&id=8888889&key=hTAmeSXYiaUo1&gry=INSERTGRY&fcn=y&fw=3B0P&filename=/profiles/ws1/details.html Page 2 of 7 Waardenburg Syndrome Type 1 11/10/01 13:15

patch of white hair may also be elsewhere. Red and black forelock have also been described [Reed et al 1967]. The majority of individuals with WS1 have either a white forelock or early graying of scalp hair before age 30 years [Farrer et al 1992].

Skin pigmentation. Congenital leukoderma (white skin patches) is frequently seen in WS1 on the face, trunk, or limbs [Read and Newton 1997]. These areas of hypopigmentation may be associated with an adjacent white forelock and frequently have hyperpigmented borders.

Occasional findings. Other findings have been associated with WS1 [da-Silva 1991]. Spina bifida [da-Silva 1991, Pantke et al 1971] and cleft lip and palate [Giacola et al 1969] have been described in multiple families. The finding of spina bifida in several families with WS1 is not surprising given that WS is considered a neurocristopathy with the PAX3 gene being expressed in the neural crest.

Genotype-Phenotype Correlations

DeStefano et al (1998) found that the presence of pigmentary disturbances correlated more with mutations that delete the homeodomain than with missence mutations or deletions that include the paired domain. No genotype-phenotype correlation for the hearing loss in WS1 has been found.

Prevalence

It is difficult to quote an exact figure for the prevalence of WS1 without population-based molecular analysis. The prevalence figures vary from 1:20,000 to 1:40,000, comprising about 3% of congenitally deaf children [Waardenburg 1951, Fraser 1976]. Differential Diagnosis

Waardenburg syndrome type 2 (WS2). WS1 is distinguished from WS2 by the presence in WS1 of lateral displacement of the inner canthi (dystopia canthorum) [Arias 1971, Arias and Mota 1978]. If the average W index across a family is less than 1.95, the diagnosis is WS2. Sensorineural hearing loss and heterochromia iridum are the two most characteristic features of WS2. Both are more common in WS2 than WS1 [Liu et al 1995]. White forelock and leukoderma are both more common in WS1 than in WS2 (Table 3).

MITF gene mutations [Tassabehji et al 1994, Nobokuni et al 1996, Morel et al 1997] have been described in 10-20% of patients with WS2. MITF gene mutations have also been identified in patients with the Tietz syndrome (deafness with uniform hypopigmentation) [Tassabehji et al 1995].

Table 3. Comparison of Clinical Features in Waardenberg Syndrome Type 1 and Waardenburg Syndrome Type 2 % of Patients Clinical Finding WS1 WS2 Sensorineural hearing loss 57-58% 77-78% Heterochromia irides 15-31% 42-54% Hypoplastic blue eyes 15-18% 3-23% White forelock 43-48% 16-23% Early graying 23-38% 14-30% Leukoderma 30-36% 5-12% High nasal root 52-100% 0-14% Medial eyebrow flare 63-70% 7%

Waardenburg syndrome type 4 (WS4). Individuals having a rare combination of pigmentary abnormalities, hearing loss, and Hirschsprung disease have WS4 caused by mutations in the endothelin-3 gene [Edery et al 1996, Hofstra et al 1996], endothelin receptor B gene [Puffenberger et al 1994], and SOX10 gene [Kuhlbrodt et al 1998, Pingault et al 1998]. Management

Management of the hearing loss associated with WS1 depends on its severity (see Hereditary Deafness and Hearing Loss Overview).

Folic acid supplementation in pregnancy has been recommended for women at increased risk of having a child with WS1, given the possibly increased risk of neural tube defects in association with WS1 [Fleming and Copp 1998]. Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal or cultural issues that individuals may face or to substitute for consultation with a

genetics professional. To find a genetics or prenatal diagnosis clinic, see . -ED.

Mode of Inheritance

Waardenburg syndrome is inherited in an autosomal dominant manner.

Risk To Family Members

Parents of a proband. The majority of probands have an affected parent. It is appropriate to examine the parents of a proband for clinical manifestations of WS1 by evaluating the facial features, calculating the W index, examining the skin and hair for hypopigmentation, and obtaining an audiogram. A minority of probands do not have an affected parent and are presumed to have a de novo mutation. The mutation rate has been estimated at.4 per 100,000 [Waardenberg 1951]. Jones et al (1975) found evidence of advanced paternal age effect in new mutations for WS1. In addition, the family history may appear to be negative because of failure to recognize the disorder in family members.

Sibs of a proband. The risk to the sibs of the proband depends upon the status of the parents. If a parent is affected, the risk is 50%. If neither parent has clinical findings of WS1, the risk to sibs of a proband is low. Germline mosaicism has been postulated [Kapur and Karam 1991].

Offspring of a proband. Offspring of an individual with WS1 have a 50% chance of inheriting the disease-causing mutation. The clinical manifestations in the offspring cannot be predicted and range from mild or sub-clinical features through the classic phenotype of WS1, including deafness.

Other family members of a proband. The risk to other family members depends upon the status of the proband's parents. If a parent is found to be affected, the family members of that parent are at risk.

Related Genetic Counseling Issues

DNA Banking. DNA banking is the storage of DNA that has been extracted from white blood cells for possible future use. Since it is likely that testing methodologies and our understanding of genes, mutations, and diseases will improve in the future, consideration should be given to banking DNA particularly when the sensitivity of currently available testing is less than 100%. For laboratories offering DNA banking, see .

Prenatal Testing

Prenatal testing is available for pregnancies at 50% risk in which a parent has been identified as having a PAX3 mutation. Prenatal testing is performed on fetal cells obtained by chorionic villus sampling (CVS) at 10-12 weeks' gestation or amniocentesis at 15-18 weeks' gestation. Although this testing can determine whether or not the fetus has inherited the PAX3 mutation, it cannot determine the clinical manifestations nor their severity. Prenatal testing is rarely requested, given the clinical variability even within families. In addition, prenatal testing for conditions associated with a good prognosis and not affecting intellect or lifespan is not common. Although most centers would consider prenatal testing to be the choice of the parents, careful discussion and examination of these issues are appropriate.

Prenatal diagnosis is not available for families who have not had molecular genetic testing of the PAX3 gene or do not have a PAX3 gene mutation. Molecular Genetics

Table 4. Molecular Genetics of Waardenburg Syndrome Type 1 Gene Symbol Locus Normal Gene Product Genomic Databases PAX3 2q35 Paired box protein Pax-3

Molecular Genetic Pathogenesis

PAX3 is one of a family of nine human PAX genes coding for DNA-binding transcription factors that are expressed in the early embryo. The PAX genes are defined by the presence of a paired box (128 amino acid DNA-binding domain). In addition, the PAX3 gene also contains a homeobox. The PAX3 gene has ten exons [Read 2001], with the paired box in exons 2-4 and the homeobox in exons 5 and 6. Mutations within the gene or of the entire gene result in a haploinsufficiency of PAX3. Mutations within PAX3 causing WS1 were first described in 1992 [Baldwin et al 1992, Tassabehji et al 1992].

Pathologic variants: Multiple abnormal allelic variants, including multiple mutations within the PAX3 gene causing WS1, WS1 with spina bifida, WS3, and craniofacial-deafness-hand syndrome (CDHS) (OMIM 122880), have been described. The PAX3 gene can fuse with the FKHR gene, this fusion creating a gain-of-function mechanism that results in alveolar rhabdomyosarcoma [Galili et al 1993]. Individuals with alveolar rhabdomyosarcoma resulting from this mechanism do not have WS.

Normal product: Bondurand et al (2000) have shown that an interaction occurs among PAX3, SOX 10, and MITF in the regulation of melanocyte development that affects a molecular pathway leading to the auditory-pigmentary abnormalities seen in WS. Given the marked variability in penetrance of phenotypic features among family members having the same mutation, the potential role of modifier genes may be significant. http://www.geneclinics.org/servlet/access?db=geneclinics&id=8888889&key=hTAmeSXYiaUo1&gry=INSERTGRY&fcn=y&fw=3B0P&filename=/profiles/ws1/details.html Page 4 of 7 Waardenburg Syndrome Type 1 11/10/01 13:15

Resources

GeneClinics provides information about selected national organizations and resources for the benefit of the reader. GeneClinics is not responsible for information provided by other organizations. -ED.

American Society for Deaf Children PO Box 3355 Gettysburg, PA 17325 Phone: 717-334-7922 (business V/TTY); 800-942-ASDC (parent hotline) Fax: 717-334-8808 Email: [email protected] www.deafchildren.org

National Association of the Deaf 814 Thayer Silver Spring, MD 20910-4500 Phone: 301-587-1788 (voice); 301-587-1789 (TTY) Fax: 301-587-1791 Email: [email protected] www.nad.org

National Vitiligo Foundation 611 S Fleishel Ave Tyler, TX 75701 Phone: 903-531-0074 Email: [email protected] www.vitiligofoundation.org

National Organization for Albinism and Hypopigmentation PO Box 959 East Hempstead, NH 03826-0959 Phone: 603-887-2310; 800-473-2310 Email: [email protected] www.albinism.org

NCBI Genes and Disease Webpage www.ncbi.nlm.nih.gov/disease/Waard.html

Hereditary Hearing Loss Home Page Additional information on Waardenburg syndrome www.uia.ac.be/dnalab/hhh References

Articles on Waardenburg Syndrome Type 1

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Literature Cited

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Profile History

Author

Jeff Milunsky, MD Director of Clinical Genetics and Associate Director of Molecular Genetics Center for Human Genetics Boston University School of Medicine

Dr. Milunsky is an Assistant Professor in the Department of Pediatrics at Boston University School of Medicine. He has directed a deafness clinic in conjunction with Otolaryngology at Boston University for several years. His interest in Waardenburg syndrome predates the identification of PAX3, when he was involved in gene mapping of several families with WS1.

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Last Update/Revision

30 July 2001

Revision History

08 Aug 2001: PB copyedits (me) 30 Jul 2001: Au final revisions (me) 23 Jul 2001: RP edits, summary added (tk) 14 May 2001: RP and Au edits (tk) 19 Apr 2001: RP edits (tk) 31 Mar 2001: RP edits (tk) 16 Mar 2001: CD edits (tk) 08 Mar 2001: RP edits (tk) 06 Mar 2001: RP edits (tk) 21 Feb 2001: CN edits (tk) 12 Feb 2001: Original submission

Funded by National Library of Medicine, National Human Genome Research Institute, National Cancer Institute, and Office of Rare Diseases of the NIH Administrative support from University of Washington, Seattle

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