Van der Woude syndrome (VDWS) is a genetic disorder characterized by the combination of lower lip pits, cleft lip with or without cleft palate (CL/P), and cleft palate only (CPO). The frequency of orofacial clefts ranges from 1:1000 to 1:500 births worldwide, and there are more than 400 syndromes that involve CL/P. VWS is distinct from other clefting syndromes due to the combination of cleft lip and palate (CLP) and CPO within the same family. Other features frequently associated with VWS include hypodontia in 10-81% of cases, narrow arched palate, congenital heart disease, heart murmur and cerebral abnormalities, syndactyly of the hands, polythelia, ankyloglossia, and adhesions between the upper and lower gum pads.
The association between lower lip pits and cleft lip and/or palate was first described by Anne Van der Woude in 1954. The worldwide disease incidence ranges from 1:100,000 to 1:40,000.
Genetics
Van der Woude syndrome is inherited as an autosomal dominant disease caused by a mutation in a single gene with equal distribution between the sexes. The disease has high penetrance at about 96% but the phenotypic expression varies from lower lip pits with cleft lip and cleft palate to no visible abnormalities. IRF6 contains two non-coding and seven coding exons and is part of a family of nine transcription factors with a highly conserved helix-turn-helix DNA binding domain called the Smad-interferon regulatory factor binding domain (SMIR). Mutations in coding or non-coding IRF6 exons can result in Van der Woude syndrome.
Pathophysiology
Lip pits were first reported in 1845 by Demarquay who thought they were indentations made by the upper incisors. Today it is known that they occur during embryogenesis due to IRF6 mutations. On day 32 of embryonic development there are four growth centers of the lower lip divided by two lateral grooves and one median. By day 38 of normal development, the grooves have disappeared. However, when growth of the mandibular process is impeded, a lip pit occurs. Lip pits begin to develop on day 36. Cleft lip begins to develop on day 40, and cleft palate emerges on day 50 of development. Therefore, it is very important to closely examine these patients as well as their relatives for lip pits, especially when there is a family history of mixed clefting, in order to make the VWS diagnosis.