van der Woude Syndrome

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 a mutation in the interferon regulatory factor-6 (IRF6) gene can be helpful when distinguishing between uncomplicated cleft lip and/or cleft palate and van der Woude syndrome.[3] A wide variety of chromosomal mutations that cause van der Woude syndrome and are associated with IRF6 gene mutations have been described.[4] A potential modifying gene has been identified at 17p11.2-p11.1.

A study by Manjegowda et al found copy number variations affecting IRF6 in members of an Indian family with van der Woude syndrome, suggesting that such variations are involved in the development of the syndrome in the Indian population.[5]

In a study on monozygotic twins with van der Woude syndrome, Petrin et al found evidence that differences in DNA methylation can produce variations in phenotype even in persons with the same mutation for the syndrome. The DNA methylation levels significantly differed between twins at sites in or near the TP63 gene, which works with IRF6 in the palatal fusion process.[6]

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 findings, 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.[7]

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• 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.

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• 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 anomalies 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 abnormality.

• 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.[8] Dental fusion has also been reported.[9]

• 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). A patient without lip pits, oral clefts, or hypodontia but with a heart-shaped mass of the lower lip has been described.[10]

• 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.

  • Signs 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; some have described these entities as being part of a van der Woude syndrome–popliteal pterygium syndrome (VWS–PPS) spectrum.[11]

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• van der Woude syndrome is transmitted in autosomal dominant fashion.

• Penetrance has been reported to be 75% but is likely closer to 100% if appropriate family members 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 (IRF6) gene has been identified as the specific gene usually responsible for van der Woude syndrome[12] ; this gene has been shown to regulate fetal craniofacial development in mice.

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• Although diagnosis of van der Woude syndrome is primarily clinical, chromosomal analysis may be appropriate. This technology is rapidly improving and may be noninvasively performed using tissue that is easily obtained, transported, and stored, such as a piece of fingernail.

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• When planning surgical intervention, imaging studies of affected areas, such as CT scanning of the oropharynx, may be appropriate. Fistulography of lip pits may help to determine their depth and course.

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• Intelligence and cognitive testing may demonstrate abnormalities; these have been shown in one study to affect males more than females.[7]

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• Along with a thorough orofacial examination, a thorough general physical examination helps to determine if other associated anomalies of the cardiovascular system, genitourinary system, limbs, or other organ systems are present.

• Examination and genetic counseling by a pediatric geneticist (dysmorphologist) is suggested for families that may be affected by van der Woude syndrome. This should include an examination of as many potentially affected family members as possible.

• The American Academy of Pediatric Dentistry have released guidelines for the treatment of persons with special health care needs.[13]

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• Surgical repair of cleft lip and cleft palate or other anomalies may be required.

• Reconstruction of the lower lip may involve dermal allograft reconstruction.[1]

• Even in less severely affected individuals, surgical excision of lip pits is often performed, either to alleviate discomfort or for cosmetic reasons (eg, improving the appearance of lip pits or reducing mucous discharge).[2] Surgical removal of salivary tracts associated with lip pits may be challenging because they may be quite long, extending into other oral structures.[14]

• Infectious complications of cleft repairs are reportedly more common in patients with van der Woude syndrome than with other children undergoing similar surgery.[15]

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• Treatment of children with cleft palate is often best undertaken by a multidisciplinary team of pediatric plastic surgeons; dentists; otolaryngologists; geneticists; genetic counselors; social workers; and occupational, speech, and physical therapists.

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• Drug therapy currently is not a component of the standard of care for van der Woude syndrome. See Treatment.

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• Although van der Woude syndrome is transmitted by an autosomal dominant inheritance pattern, the degree of expression in affected families widely varies. Even monozygotic twins may be affected to markedly different degrees.[16]

• Because the expressivity of the phenotype varies, the potential effects on unborn children are difficult to predict and may be of particular concern to parents. High-resolution ultrasonography and fetal echocardiography may be of some use in prenatally characterizing the severity of the phenotype.

• Genetic counseling is recommended.

• As genetic diagnostic and therapeutic methods advance, the principal syndromic form involving cleft lip and cleft palate may prove amenable to early detection and even preventive therapy.

Cleft palate may be associated with feeding difficulties, voice disorders, frequent otitis media, and hearing loss. A study by Silvestre et al of pediatric patients with syndromic cleft lip and/or palate found that nearly a third tested positive for obstructive sleep apnea on the Pediatric Sleep Questionnaire. The study involved 178 patients, including those with isolated Pierre Robin sequence (29.8%), 22q11.2 deletion syndrome (14.6%), and van der Woude syndrome (6.7%).[17]

Lip pits may be associated with other disorders, including popliteal pterygium syndrome and orodigitofacial dysostosis.