Klein-Waardenburg syndrome

Waardenburg Syndrome, Type 3

Clinical Characteristics
Ocular Features: 

Type 3 Waardenburg syndrome has many of the features of other types but with the addition of upper limb anomalies.  Dystopia canthorum and a broad nasal root are characteristic.  Iris heterochromia is present in some patients.  Hypopigmentation may be seen in lashes and eyebrows.

Systemic Features: 

The upper limbs may appear underdeveloped with flexion contractures, fusion of the carpal bones and sometimes syndactyly.  A white forelock may or may not be present.  The cranial bones may be anomalous and rare patients can have microcephaly with significant mental retardation.  Mental function is usually normal though. Occasional patients have cleft palate and/or lip. Hearing loss is of the sensorineural type.  Hypopigmented skin patches are sometimes present but not all patients have them.

Genetics

The uniqueness of Waardenburg syndrome types 1 and 3 remains to be established.  Mutations in the PAX3 gene are responsible for both types and both have been found in the same family.  The phenotype is transmitted in an autosomal dominant pattern in either case but several families have been reported with type 1 WS in parents heterozygous for PAX3 mutations who had a homozygous child with the type 3 phenotype.  However, heterozygous individuals with type 3 have also been reported and the relationship of the two types remains unknown.

Craniofacial-deafness-hand syndrome(122880) with mutations in PAX3 has many features similar to those found in Waardenburg syndrome type 3 and may or may not be a unique disorder.

Pedigree: 
Autosomal dominant
Autosomal recessive
Treatment
Treatment Options: 

There is no treatment for the syndrome but cochlear implants might be helpful.

References
Article Title: 

Waardenburg Syndrome, Type 1

Clinical Characteristics
Ocular Features: 

Waardenburg syndrome is a disorder of pigmentation, sensorineural deafness, and a characteristic facial (nasal root) morphology.  Some have neural tube defects.  Based on clinical criteria, the syndrome has been divided into types 1, 2, 3, and 4, with subtypes of 2 and 4.  Types 1 and 3 are caused by mutations in the same gene.

Patients often have a white forelock and iris heterochromia.  The latter may be partial in individual irides, or the entire iris in one eye with the fundus hypopigmentation often matching the iris pattern.  The fundus may also have segmental areas of pigmentary changes corresponding to the iris heterochromia. The hypopigmented portion of the iris is often a brilliant blue.  Dystopia canthorum is a prominent and nearly constant (>95%) feature of type 1, and together with the prominent nasal root and increased intercanthal distance may suggest hypertelorism.  Synophrys is often present and the medial portions of the eyebrows can be exceptionally bushy.  Sometimes the poliosis involves the lashes and eyebrows.

Systemic Features: 

Congenital sensorineural deafness is an important feature.  Individuals with type 1 often have a white forelock (29%), premature graying (44%), and hypopigmented skin patches (55%).  A few patients have cleft palate and/or lip. Neural tube defects have also been reported. The considerably more rare type 3 is caused by mutations in the same gene as type 1, but it is claimed by some to be a separate disorder because of the association of limb anomalies. 

Genetics

Autosomal dominant inheritance is typical for the Waardenburg syndrome.  Types 1 and 3 are caused by mutations in the PAX3 gene (2q35) and, of these, type 1 is far more common.  Type 1 is caused by a heterozygous mutation whereas type 3 may result from either a heterozygous, compound heterozygous, or homozygous mutation.  Both types have been reported to occur in the same pedigree.  PAX genes act as transcription factors that attach to specific sections of DNA and regulate protein production.  PAX3 gene products, among other things, specifically influence neural crest cells important to the development of cranialfacial bones and melanocytes.  Paternal age plays a role in new mutations which probably account for many sporadic cases.

Waardenburg syndrome is an excellant example of genetic heterogeneity as types 1 (193500), 2 (193510), 3 (148820  and 4 (277580) can all result from mutations in different genes.  In addition, types 2 and 4 are each caused by mutations in several different genes. 

A child has been reported who was doubly heterozygous for mutations involving both MITF and PAX3. Hypopigmentation in the scalp hair, eyebrows and eyelashes was more severe than usually seen in patients with single mutations. In addition the face showed marked patchy pigmentation. One parent contributed the MITF mutation and the other added the mutation in PAX3.

 

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

No ocular treatment is necessary.  Patients may benefit from cochlear implants.

References
Article Title: 
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