Saturday, January 10, 2015

Waardenburg Syndrome Type 1.

WAARDENBURG SYNDROME. WS, 


described by the Dutch physician Petrus Waardenburg in 1951,104 is the prototypic congenital disorder of pigmentation. Although it was originally described as a syndrome combining pigmentary defects of the hair (poliosis or white forelock) and iris, congenital deafness, and developmental craniofacial abnormalities, it was subsequently realized that additional phenotypic manifestations could be part of the same syndrome. Four types of WS, WS1 through WS4. The discovery of molecular mutations accounting for the different types of WS has helped to explain its wide variety of manifestations as well as to illuminate the importance of specific genes for the development of different tissues and organs . While practically all cases of WS1 and WS3 show mutated PAX3,105,105,109,110 WS4 individuals either have homozygous mutations in EDN3 (the endothelin- 3 gene)111–113 or EDNRB (the endothelin-B receptor gene)114 or heterozygous mutations in SOX10.115 On the other hand, WS2 appears to arise more heterogeneously, as a mutation in MITF has been shown in only a small fraction of WS2 patients

Waardenburg Syndrome Type 1. 

Note poliosis (white forelock) and dystopia canthorum (lateral displacement of the medial canthi of the eyes).

Individuals

with WS1  are usually heterozygous for mutations in PAX3; hence, WS1 is autosomal dominant in inheritance. Although many different mutations in PAX3 have been associated with WS1, these mutations are thought either to be functionally null alleles or to abrogate the interactions of PAX3 with DNA.

Individuals with WS1 have pigmentation abnormalities associated with craniofacial abnormalities
(see Fig). Dystopia canthorum, which is lateral displacement of the medial canthi of the eyes, is the hallmark craniofacial defect found in virtually all cases of WS1. A broadening of the nasal root, the presence of hypoplastic alae nasi, and synophrys are other craniofacial abnormalities associated with WS1. Poliosis, such as the presence of a white forelock, is the most common pigmentation abnormality associated with WS1. Depigmented white spots on the skin occur less commonly, but are often located at the ventral midline reflecting the compromised migration of dysfunctional
melanocyte precursors from their origin in the dorsal neural crest. Pigmentary abnormalities of the iris, including complete heterochromia irides (differently colored irises), partial heterochromia irides (variations of color within an iris), or hypoplastic blue irides, can also be associated with WS1. Premature graying may also be observed in WS1. Congenital deafness is present in 57% of cases.117
The importance of PAX3 for the expression of MITF,118,119 with consequent effects upon melanocyte survival during development, is likely to account for the pigmentary defects of WS1. A role for PAX3 in governing the development of neural crest derivatives that contribute to bony and cartilaginous structures of the face,120 particularly those contributing to the formation of the frontal bone, explain the craniofacial anomalies observed in WS1. Sensorineural deafness, observed with
incomplete penetrance in WS1, results from the variable failure of melanoblasts to migrate to or to survive in the stria vascularis in the lateral wall of the cochlea.

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