At birth, patients with VWS have one or more of the following dysmorphic features: paramedian lower-lip pits (fistulae, usually bilateral), small mounds with a sinus tract leading from a mucous gland of the lip, or cleft lip/cleft palate. Lip pits are the most common sign (>80%) and are mostly asymptomatic although dribbling and infection is possible. The second most frequent sign is cleft lip, followed by cleft palate, with variable clinical repercussions depending on severity. Some patients have cleft lip with or without cleft palate, while others have cleft palate only. Hypodontia and dental hypoplasia are also common. Other non-classic signs include single unilateral lip pits, submucous cleft, bifid uvula, ankyloglossia, limb abnormalities (skin folds, syndactyly), and sensorineural hearing loss. Growth, development and intellectual abilities are normal in VWS patients.
Mutations in the IRF6 gene (1q32.2-q32.3), involved in epidermal development and in regulation of craniofacial development, are found in over 70% of patients with VWS.IRF6 mutations are also causal for popliteal pterygium syndrome .Whole-gene deletions are a very rare cause of VWS and the frequency of partial-gene deletions is not currently known. Recently, mutations in the gene GRHL3 (1p36), coding for a Grainyhead-like protein 3 homolog, was found in eight families with VWS with no causative mutations in IRF6.
