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 http://www.geneclinics.org/servlet/access?db=geneclinics&id=8888889&key=hTAmeSXYiaUo1&gry=INSERTGRY&fcn=y&fw=3B0P&filename=/profiles/ws1/details.html Page 1 of 7 Waardenburg Syndrome Type 1 11/10/01 13:15 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.