Waardenburg Syndrome Type 1

A rare autosomal dominant syndrome caused by mutations in the PAX3 gene. It is characterized by hearing loss, dystopia canthorum (widely spaced inner corners of the eyes), and changes in the color of the skin, hair, and eyes.

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)/cCalculate Y = (2a-0.2479b-3.909)/bCalculate 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 mutation and was reclassified as having WS1 [ ]. Hence, the W index threshold was reduced to its current value of >1.95.

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).More than 90% of patients who meet the cardinal clinical diagnostic criteria for WS1 have identifiable mutations in [unpublished data].Multiple mutations, including missense, nonsense, and splice-site mutations, frameshifts, small deletions, and insertions, have been found throughout the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

Clinical Description
The phenotype of Waardenburg syndrome type 1 is variable even within a family.
( ) 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.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.

Hearing loss.
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 [ ].The white forelock is typically in the midline but the

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 [ ].

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

Mode of Inheritance
Waardenburg syndrome is inherited in an autosomal dominant manner.

Risk To Family Members
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 mutation.The mutation rate has been estimated at.4 per 100,000 [ ].
( ) 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.
Parents of a proband.

de novo
Waardenberg 1951 Jones et al 1975 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 [ ].
Sibs of a proband.

Kapur and Karam 1991
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.

Offspring 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.
Other family members of a proband.

Related Genetic Counseling Issues
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 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 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.

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

PAX3 PAX3
Molecular Genetics  ) have shown that an interaction occurs among , , and 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.

Normal product: Bondurand et al 2000
PAX3 SOX 10 MITF Mutations in have also been shown to cause the following: PAX3 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 [ mutation in the gene in patients with this disorder.This disorder is apparently distinct from both WS1 and WS3.Sommer et al 1983 Asher et al 1996 Asher et al 1996 PAX3

PAX3
2q35 Paired box protein Pax-3 is one of a family of nine human genes coding for DNA-binding transcription factors that are expressed in the early embryo.The genes are defined by the presence of a paired box (128 amino acid DNA-binding domain).In addition, the gene also contains a homeobox.The gene has ten exons [ ], 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 .Mutations within causing WS1 were first described in 1992 1992 Tassabehji et al 1992 Multiple abnormal allelic variants, including multiple mutations within the gene causing WS1, WS1 with spina bifida, WS3, and craniofacial-deafness-hand syndrome (CDHS) (OMIM 122880), have been described.The gene can fuse with the gene, this fusion creating a gain-of-function mechanism that results in alveolar rhabdomyosarcoma [].Individuals with alveolar rhabdomyosarcoma resulting from this mechanism do not have WS.

Table 3 . Comparison of Clinical Features in Waardenberg Syndrome Type 1 and Waardenburg Syndrome Type 2
11/10/01 13:15 patch of white hair may also be elsewhere.Red and black forelock have also been described [ ].The majority of individuals with WS1 have either a white forelock or early graying of scalp hair before age 30 years [ ].Congenital leukoderma (white skin patches) is frequently seen in WS1 on the face, trunk, or limbs [ ].These areas of hypopigmentation may be associated with an adjacent white forelock and frequently have hyperpigmented borders.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 gene being expressed in the neural crest.)foundthat 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.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 thanWS1 [].White forelock and leukoderma are both more common in WS1 than in WS2 (). (