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
Inheritance
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 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
Autosomal recessive
In order for autosomal recessive disorders to be expressed, offspring generally must inherit two mutations, one from each carrier parent. Carriers with only one mutation, such as the parents, do not have clinical disease. Note that carrier parents can expect that 1 in 4 children (25%) will inherit both mutations and have the disorder, 2 in 4 children (50%) will be carriers like their parents, while 1 in 4 children (25%) inherit neither mutation.
In order for autosomal recessive disorders to be expressed, offspring generally must inherit two mutations, one from each carrier parent. Carriers with only one mutation, such as the parents, do not have clinical disease. Note that carrier parents can expect that 1 in 4 children (25%) will inherit both mutations and have the disorder, 2 in 4 children (50%) will be carriers like their parents, while 1 in 4 children (25%) inherit neither mutation.