# Handbook of Genetic Counseling/Waardenburg Syndrome

Waardenburg Syndrome

## Contracting

* Introductions, acknowledge any prior contact
* Assess main concerns of patient
** Why are they visiting Genetics today?
** What do they hope to gain from the session?
** Assess knowledge of diagnosis -- any questions?
** How has *** been since his last hospital visit?
* Overview of today's session
** Restate patient's concerns
** Medical history, family history, physical exam, genetics, recurrence risk, testing options and limitations

## Pediatric Intake

* Pregnancy and Medical History
* Developmental History
* Family History
** cousin and uncle with white forelocks?
** premature greying
** different colored eyes

## Etiology

* WT1: PAX3 gene on chromosome 2 (2q35)
** codes for DNA binding transcription factors expressed in the early embryo
* WS2: MITF gene mutations (3p14.1-p12.3) have been described in 10-20%
** MITF gene mutations have also been identified in patients with the Tietz syndrome (deafness with uniform hypopigmentation)
* WT3: caused by mutations in the PAX3 gene (2q35)
* WT4: caused by mutations in the endothelin-3 gene (20q13.2-q13.3), endothelin receptor B gene (13q22), and SOX10 gene (22q13)

## Incidence and Carrier Frequency

* autosomal dominant inheritance
** majority of probands have an affected parent, though may be undiagnosed
** minority of probands do not have an affected parent and are assumed to have a de novo mutation
* risk to siblings of proband = 50% if parent affected
* risk to offspring of proband = 50%
* Type I incidence: 1:20,000 to 1:40,000
** comprises about 3% of congenitally deaf children
* Type IV has autosomal recessive inheritance

## Clinical Features

| Feature | %WT1 | %WT2 |
| 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 | 3-36% | 5-12% |
| high nasal root | 52-100% | 0-14% |
| medial eyebrow flare | 63-70% | 7% |
* Type I
** variable phenotype
** sesorineural hearing loss
*** congenital, non-progressive, uni- or bilateral
*** most common type is profound bilateral
** white forelock
*** may be present at birth or appear later
*** may become normally pigmented over time
** eyebrows and eyelashes may also be hypopigmented
** leukoderma
*** white skin patches, frequently on the face, trunk, or limbs
*** often have hyperpigmented borders
** spina bifida and cleft lip and palate have been described in multiple families
* Type 2
** 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
* Type 3 (Klein-Waardenburg Syndrome)
** individuals have a combination of typical WS1 features and hypoplasia or contractures of the limb muscles or joints, carpal bone fusion, or syndactyly
* Type 4
** Individuals having a rare combination of pigmentary abnormalities, hearing loss, and Hirschsprung disease

## Natural History

* does not affect lifespan or intelligence

## Testing

* Clinical Diagnosis
** An individual must have two major or one major plus two minor criteria to be considered affected by WT1**
** 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
*** 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.
* When ICD (a) and OCD (c) are the only measurements available, IPD (b) can be calculated according to the formula: [(c - a)/2] + a. This can be used when IPD (b) is already known to compare measured and calculated values.
* Molecular genetic testing
** available by sequencing the PAX3 gene (chromosomal locus 2q35)
** can be used to confirm the diagnosis in atypical cases
** primarily used for genetic counseling of at-risk family members
** detects over 90% of disease-causing mutations
*** most mutations are unique
** available clinically
* Prenatal testing
** available for pregnancies at 50% risk in which a parent has been identified as having a PAX3 mutation
** performed on fetal cells obtained by CVS or amniocentesis
** can determine whether or not the fetus has inherited the PAX3 mutation, but it cannot determine the clinical manifestations nor their severity
** not available for families who have not had molecular genetic testing of the PAX3 gene or do not have a PAX3 gene mutation

## Management and Treatment

* folic acid supplementation in pregnancy is 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
* congenital hearing loss can be identified through universal screening of newborns
* management of hearing loss
** as a minimum, all children with a risk for hereditary hearing loss should receive screening audiometry
** the team evaluating and treating the deaf individual should consist of an otolaryngologist with expertise in the management of early childhood otologic disorders, an audiologist experienced in the assessment of hearing loss in children, a clinical geneticist, and a pediatrician
** the expertise of an educator of the Deaf, a neurologist, and a pediatric ophthalmologist may also be required
** sequential audiologic examinations are essential to document the stability or progression of the hearing loss and to identify and treat superimposed hearing losses, such as middle ear effusion
*** an important part of the evaluation is determining the appropriate habilitation option
**** possibilities include hearing aids, vibrotactile devices, and cochlear implantation
**** cochlear implantation can be considered in children over 12 months of age with severe-to-profound hearing loss

## Psychosocial Issues

* guilt issues with the affected parent
* individual education plan
** school support/signer

## Support Groups and Resources

* 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: ASDC1@aol.com
    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: NADinfo@nad.org
    www.nad.org
* National Vitiligo Foundation
    611 S Fleishel Ave
    Tyler, TX 75701
    Phone: 903-531-0074
    Email: vitiligo@Trimofran.org
    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: noah@albinism.org
    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

* www.geneclinics.org
* Smith's Recognizable Patterns of Human Malformation
* OMIM #193500, #193510, #600193, #148820
* An Atlas of Characteristic Syndromes by Wiedemann, Grosse, and Dibbern
* Arias, S. and Mota, M. (1978). Apparent Non-Penetrance for Dystopia in Waardenburg Syndrome Type I, With Some Hints on the Diagnosis of Dystopia Canthorum. J. Genet Hum, Vol 26, No. 2, pp 103-131.

## Notes

The information in this outline was last updated in 2002.