iris heterochromia

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: 

Waardenburg Syndrome, Type 2

Clinical Characteristics
Ocular Features: 

This type of Waardenburg syndrome is distinguished from type 1 and 3 (193500) by the fact that it is caused by mutations in a different gene and in the absence of dystopia canthorum.  It has been claimed that hearing loss is more common and severe in type 2 (77%) as is heterochromia of the iris (47%) while skin and hair hypopigmentation are less common.

Families with WS2A may have the full spectrum of eye findings seen in X-linked ocular albinism I (300500) including decreased acuity, photophobia, nystagmus, translucent irides, hypermetropia, and albinotic fundi with foveal hypoplasia.  Indeed, such families have been considered to have 'albinism, ocular, with sensorineural deafness' (103470).  Such families might be considered to have an autosomal dominant form of ocular albinism.

Systemic Features: 

Congenital sensorineural hearing loss is an important and common feature.  Also characteristic are the white forelock, poliosis, and hypopigmented skin patches.

Genetics

Waardenburg syndrome is an excellent example of genetic heterogeneity as types 1 and 3 (193500, 148820), 2 (193510), and 4 (277580) are all caused by mutations in different genes. 

Type 2 described here is a genetically heterogeneous autosomal dominant disorder.  WS2A is caused by a mutation in MITF (microphthalmia-associated transcription factor) (3p14.1-p12.3).  This is the same disorder described as 'Albinism, ocular, with sensorineural deafness' in OMIM (103470)  (WS2-OA).

A locus at 1p21-p13.3 is associated with WS2B (600193) and WS2C (606662) maps to 8p23.  In addition, homozygous SNAI2 mutations at 8q11 have been found in several patients with WS2D (608890) suggesting autosomal recessive inheritance but the normal parents were not studied.  Recent evidence suggests that SOX10 mutations can also play a role via MITF promoter modulation (WS2E) (611584).

Type 4 is also the result of mutations in at last three 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 but assistive hearing devices can be helpful.

References
Article Title: 

Waardenburg Syndrome, Type 4

Clinical Characteristics
Ocular Features: 

The skin and ocular pigmentary changes and the sensorineural hearing loss in type 4 Waardenburg syndrome resembles that of other types.  Patients, however, usually lack synophrys and dystopia canthorum.

Systemic Features: 

Type 4 Waardenburg syndrome is largely similar to other types except that many patients also have Hirschsprung disease.

Genetics

Both autosomal dominant and recessive inheritance have been reported for type 4 Waardenburg syndrome.  Both heterozygous and homozygous mutations in the EDNRB (endothelin-B receptor) gene (13q22) occur in patients.  The aganglionic megacolon feature may be dose sensitive since homozygotes have been reported to have a 74% chance of developing Hirschsprung disease while only 21% of heterozygotes do so.

Types 4A (277580) and 4B (613265) are both caused by mutations in the EDNRB gene, and type 4C (613266) results from a mutation in the SOX10 gene.  Waardenburg syndrome WS2E is allelic to type 4C.  This is an example of genetic heterogeneity both within the main types and within the subtypes.

Pedigree: 
Autosomal dominant
Autosomal recessive
Treatment
Treatment Options: 

No ocular treatment is necessary but assistive hearing devices can be beneficial.

References
Article Title: 

Waardenburg syndrome

Read AP, Newton VE. Waardenburg syndrome. J Med Genet. 1997 Aug;34(8):656-65. Review.

PubMed ID: 
9279758
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