Van der Woude syndrome (VWS) is a dominantly inherited developmental disorder characterized by pits and/or sinuses of the lower lip, and cleft lip and/or cleft palate (CL/P, CP). It is the most common cleft syndrome.
- ... Van der Woude syndrome (VWS) is a dominantly inherited developmental disorder characterized by pits and/or sinuses of the lower lip, and cleft lip and/or cleft palate (CL/P, CP). It is the most common cleft syndrome. - Genetic Heterogeneity of van der Woude Syndrome Most reported cases of VWS have been linked to chromosome 1q32-q41 (VWS1) and are due to mutation in the IRF6 gene. VWS2 (606713) has been mapped to chromosome 1p34 and a mutation identified in the WDR65 gene (614259).
In 3 generations of a family, Levy (1962) found malformations of the lower lip consisting of symmetrical lumps. Two sibs had cleft palate in addition to the lip anomaly. The literature on this syndrome was analyzed by van ... In 3 generations of a family, Levy (1962) found malformations of the lower lip consisting of symmetrical lumps. Two sibs had cleft palate in addition to the lip anomaly. The literature on this syndrome was analyzed by van der Woude (1954), who found confirmation for the autosomal dominant mode of inheritance. It is possible that in some affected families, because of the variable expressivity of the gene, the syndrome is expressed only as pits. Baker (1964) reported such a pedigree with affected members in 3 generations showing pits as the only malformation. On the other hand, only harelip and/or cleft palate without pits could segregate in families as a dominant trait. Test and Falls (1947) described the condition transmitted through 5 generations. The rule that cleft palate alone and cleft lip with or without cleft palate behave differently does not hold in this disorder, in which either type of cleft alone or the 2 in combination may occur. Janku et al. (1980) traced the van der Woude syndrome through 7 generations. Lip pits, the most common manifestation, were present in 88% of the affected and were the only manifestation in 64%. Clefts of lip and palate occurred in 21%. Penetrance was 96.7%. Ranta and Rintala (1983) analyzed the 'microforms' of the van der Woude syndrome in cases of cleft palate. Conical elevations (CE) on the lower lip at the site of sinuses were present in 39.3% of cleft palate cases, 0.8% of cleft lip with or without cleft palate cases, and 0.7% of noncleft cases. In CP cases with CE, the familial occurrence of clefts was statistically higher (30%) than in CP cases without CE. The corresponding figures for hypodontia were 40.7% and 24.7%, respectively. See review by Schinzel and Klausler (1986). Burdick et al. (1987) reported 2 unrelated families from the area of Beijing, China. Ankyloglossia was found in the proband in each family. Sorricelli et al. (1966) also described this association. Kocer et al. (2001) described a child with symmetrical lower lip pits and cleft palate whose mother had only a single lower lip pit in the right paramedian region. (The possibility of mosaicism in the mother might be raised. VAM) Birnbaum et al. (2008) analyzed the IRF6 gene in 63 families with what was believed to be isolated CL/P or CP and identified a deletion/insertion and duplication in 2 families, respectively. Despite 'credible denials' of a history of lip pits in family members, upon reinterviewing and retrieval of preoperative photographs, the presence of lip pits in both families confirmed the diagnosis of VWS. Birnbaum et al. (2008) noted that this is important for genetic counseling, because the recurrence risk of VWS is higher than the recurrence risk for nonsyndromic clefts.
In efforts to clone the VWS gene, Watanabe et al. (2001) analyzed 900 kb of genomic sequence from the critical region of 1q32-q41. They found a polymorphism within a polymorphism that is a deletion/insertion (del/ins) polymorphism with a ... In efforts to clone the VWS gene, Watanabe et al. (2001) analyzed 900 kb of genomic sequence from the critical region of 1q32-q41. They found a polymorphism within a polymorphism that is a deletion/insertion (del/ins) polymorphism with a TTCC short tandem repeat (STR) embedded within it. They suggested that this be called a 'matroshka' polymorphism, after the Russian doll that has additional dolls nested inside. Kondo et al. (2002) performed direct sequence analysis of genes and presumptive transcripts in the 350-kb VWS critical region identified by linkage analysis and identified mutations in the IRF6 gene, encoding interferon regulatory factor-6. They found a nonsense mutation in exon 4 of the IRF6 gene (607199.0001) in the affected twin of a pair of monozygotic twins who were discordant for VWS. Subsequently, they identified mutations in 45 additional unrelated families with VWS and distinct mutations in 13 families with popliteal pterygium syndrome (119500). In a family whose affected members showed cleft lip with or without cleft palate and isolated cleft palate, Kondo et al. (2002) found that all affected members regardless of phenotype shared the 18-bp deletion (607199.0002) found in the proband. The authors hypothesized that marked phenotypic variation in their cohort strongly implicated the action of stochastic factors or modifier genes on IRF6 function. Ghassibe et al. (2004) screened the IRF6 gene in 6 families with VWS and identified 6 heterozygous missense mutations, respectively, all affecting either the DNA-binding or the protein-binding domain. In a 4-generation VWS family in which affected individuals carried an L22P mutation (607199.0014), 2 of the patients displayed additional features: 1 had finger syndactyly, and the other had toe syndactyly and oral synechiae. Ghassibe et al. (2004) stated that because syndactyly and synechiae are major signs for PPS, these 2 patients were considered to have PPS, whereas the 6 other affected family members were classified as VWS, thus demonstrating that a single mutation could be responsible for both syndromes. Yeetong et al. (2009) reported 3 female patients with lower lip anomalies, all of whom had heterozygous mutations in the IRF6 gene. One patient was a 16-year-old girl with bilateral conical elevations without pits, joining at the midline of the lower lip, giving the appearance of a heart-shaped mass; she was heterozygous for a nonsense mutation (Q49X; 607199.0017). Her mother and other relatives were reported to have similar findings, but were unavailable for evaluation. - Van der Woude Syndrome-Popliteal Pterygium Syndrome Spectrum In a patient with overlapping features of VWS and PPS (unilateral cleft lip and palate, ankyloblepharon, paramedian lip pits) as well as unilateral renal aplasia and coronal hypospadias, de Medeiros et al. (2008) identified a novel heterozygous mutation in the IRF6 gene (607199.0013). The patient and his brother, who had hypospadias and nephrocalcinosis but no IRF6 mutation, were both conceived by in vitro fertilization. De Medeiros et al. (2008) suggested that the hypospadias and renal aplasia may have been due to the method of fertilization rather than the IRF6 mutation. They noted that a lethal PPS syndrome (263650) has renal aplasia as a feature.