Van der Woude syndrome (VWS) is a rare congenital genetic dysmorphic syndrome characterized by paramedian lower-lip fistulae, cleft lip with or without cleft palate, or isolated cleft palate.
The disorder represents the most common single-gene cause of cleft lip/cleft palate, i.e. 2% of all individuals with cleft lip/palate. Estimated incidence at birth is between 1/35,000 and 1/100,000 in the European and Asian populations. Males and females are affected equally.
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 (see this term).Whole-gene deletions are a very rare cause of VWS and the frequency of partial-gene deletions is not currently known.
The diagnosis is suspected on the basis of the clinical findings and can be confirmed by molecular genetic testing of IRF6. The presence of isolated lip pits, submucous cleft palate, and hypodontia in a parent of a patient with suspected VWS is highly indicative of the diagnosis.
The main differential diagnosis is AD popliteal pterygium syndrome (PPS; see this term). VWS has a milder phenotype; PPS includes popliteal pterygia, syndactyly, and abnormal external genitalia. There is significant overlap in the craniofacial features of the two syndromes. Other conditions to consider include isolated cleft lip, Kabuki syndrome and Hirschsprung disease (see these terms).
Prenatal diagnosis for at-risk pregnancies is possible provided that the disease-causing allele has been identified in the family. Cleft lip can be identified late in pregnancy on prenatal ultrasound.
VWS is inherited in an autosomal dominant manner. However, penetrance is incomplete and de novo mutations have been reported. Genetic counseling is recommended for affected families.
In the neonatal period, patients with cleft lip/palate should be monitored for nutritional intake and weight gain. Cleft lip and/or palate should then be managed by a multidisciplinary team with surgical and orthodontic treatment as needed. Speech therapy and audiological evaluation may also be required. Lip pits may be treated surgically for cosmetic purposes and/or to ensure proper lip function.
Successful correction of the congenital malformations is the main prognostic factor.
Last update: November 2013
- Dr Olivier ABBO
- Pr Philippe GALINIER