OMIM ID:
Waardenburg Syndrome, Type 1
Alternate Names
Defective Genes
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
Inheritance
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
Autosomal dominant disorders require only one mutation for the disease to be expressed. Since an affected parent has two chromosomes, only one of which has the mutant gene, parents can expect that half (50%) of their children will receive that one and inherit the disease. It is common for individuals that inherit the mutation, however, to not have evidence of the disease (nonpenetrance).
Autosomal dominant inheritance leads to a vertical pattern of transmission