eMedicine Specialties > Pediatrics: Genetics and Metabolic Disease > Genetics
van der Woude Syndrome
Updated: Apr 16, 2009
Introduction
Background
van der Woude syndrome is an autosomal dominant syndrome characterized by a cleft lip or cleft palate, distinctive pits of the lower lips, or both. It is the most common syndrome associated with cleft lip or cleft palate. The degree to which individuals who carry the gene are affected widely varies, even within families. These variable manifestations include lower lip pits alone, absent teeth, or isolated cleft lip and cleft palate of varying severity. Hypodontia (absent teeth) has been increasingly recognized as a frequently associated anomaly. Many other associated anomalies have also been described.
Cleft lip and cleft palate in an infant with van der Woude syndrome. (Photo courtesy of Mary J. Hauk, DDS.)
Closer view of cleft lip and cleft palate in an infant with van der Woude syndrome, showing raised pits of lower lip. (Photo courtesy of Mary J. Hauk, DDS.)
Intraoral view of cleft lip and cleft palate in an infant with van der Woude syndrome. (Photo courtesy of Mary J. Hauk, DDS.)
Pathophysiology
The most prominent and consistent features of van der Woude syndrome are orofacial anomalies caused by an abnormal fusion of the palate and lips at 30-50 days postconception. Most cases of van der Woude syndrome have been linked to a deletion in chromosome 1q32-q41; however, a second chromosomal locus at 1p34 has also been identified. The responsible mutation has been identified in the interferon regulatory factor-6 (IRF -6) gene, but the exact mechanism of this mutation on craniofacial development is uncertain.
Demonstrating the presence or absence of an IRF-6 mutation can be helpful when distinguishing between uncomplicated cleft lip and/or cleft palate and van der Woude syndrome. A wide variety of chromosomal mutations that cause van der Woude syndrome and are associated with IRF-6 gene mutations have been described. A potential modifying gene has been identified at 17p11.2-p11.1.
Frequency
International
In general, van der Woude syndrome affects about 1 in 100,000-200,000 individuals. About 1-2% of patients with cleft lip or cleft palate have van der Woude syndrome.
Mortality/Morbidity
The severity of van der Woude syndrome widely varies, even within families. Approximately 25% of individuals with van der Woude syndrome are asymptomatic or have minimal symptoms, such as absent teeth or trivial indentations in the lower lips. Others have severe clefting in the lip or palate. Lip pits are often associated with accessory salivary glands that empty into the pits, which occasionally leads to embarrassing visible discharge. Hypodontia is present in 10-81% of affected individuals. Most upper and/or lower second premolars are frequently absent.
Race
Differences among races have not been described.
Sex
van der Woude syndrome equally affects both sexes. A single, small study has suggested that males with the syndrome may have poorer cognitive function than females.1
Clinical
History
- Because of its variability, obtaining a detailed family history is important in diagnosing van der Woude syndrome. However, approximately 30-50% of all cases of van der Woude syndrome arise as a de novo mutation.
- The pedigree should suggest an autosomal dominant inheritance pattern, unless the phenotype is the result of a de novo mutation in the affected individual. Expressivity also widely varies, and careful clinical examination of parents and relatives may be necessary.
- Physical examination of relatives, close examination of family photos, or interviews of older relatives may be necessary to identify minimally affected family members.
Physical
- Orofacial manifestations
- van der Woude syndrome is characterized by cleft lip and/or cleft palate and distinctive lower lip pits. This combination is present in approximately 70% of overtly affected individuals but is present in less than one half of those who carry the gene.
- Severity may widely vary, even in members of the same family.
- Cleft lip and cleft palate
- The cleft lip and cleft palate may be isolated.
- The severity of these symptoms widely varies and may be unilateral or bilateral.
- Submucous cleft palate is common and may be easily missed during physical examination.
- Hypernasal voice and cleft or bifid uvula may be present. A bifid uvula is also a possible isolated finding in certain individuals with van der Woude syndrome.
- Lip pits
- Lower lip pits are fairly distinctive. The pits are usually medial, often (but not always) on the vermilion portion of the lower lip. They tend to be centered on small elevations in infancy but become simple depressions by adulthood; however, the presentation varies. They are usually bilateral but are occasionally median or paramedian or unilateral and are most often found on the left side.
- Visible or expressible saliva may be present in the lip pits because of an association with the accessory salivary glands. Pits may lead to tracts that are surprisingly long, making surgical removal challenging.
- Lip pits may be the only symptom.
- Teeth: Hypodontia may be observed and most commonly presents as missing maxillary or mandibular second premolars or maxillary lateral incisors. This may be the only symptom. An association of van der Woude syndrome and taurodontism (teeth with greatly enlarged pulp chambers) has been reported.2
- Other oral manifestations: Although infrequently reported, other symptoms include syngnathia (congenital adhesion of the jaws); narrow, high, arched palate; and ankyloglossia (short glossal frenulum or tongue-tie).
- Extraoral manifestations
- Extraoral manifestations are rare but include limb anomalies, popliteal webs, and brain abnormalities.
- Accessory nipples, congenital heart defects, and Hirschsprung disease have been reported.
- Extraoral manifestations may be unassociated additional anomalies or infrequently expressed aspects of van der Woude syndrome.
- Symptoms of van der Woude syndrome have been seen in individuals with popliteal pterygium syndrome, which has also been linked to mutations in the same gene. These 2 entities are believed to be allelic variants of the same condition.
Causes
- van der Woude syndrome is transmitted in autosomal dominant fashion.
- Penetrance has been reported to be 75% but is likely closer to 100% if supposedly unaffected carriers are closely examined for minor expressions of the syndrome.
- The gene for van der Woude syndrome has been localized to chromosome 1q32-q41. Intriguing linkage studies have suggested that a second modifying gene mapped to chromosome 17p11.2-p11.1 may influence the degree of phenotypic expression of a gene defect at this locus. A second chromosome locus for van der Woude syndrome has been mapped to 1p34.
- The interferon regulatory factor-6 (IRF-6) gene has been tentatively identified as the specific gene responsible for van der Woude syndrome; this gene has been shown to regulate fetal craniofacial development in mice.
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| References |
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References
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Further Reading
Keywords
van der Woude syndrome, VWS, VDWS, cleft lip syndrome, lip pit syndrome, cleft palate, dimpled papillae of the lip, cleft lip, lip pits, hypodontia, hypernasal voice, cleft uvula, bifid uvula, syngnathia, ankyloglossia, congenital heart defect, Hirschsprung disease, popliteal pterygium syndrome, congenital heart defects
