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.