Van Der Woude Syndrome 1

A number sign (#) is used with this entry because van der Woude syndrome-1 (VWS1) is caused by heterozygous mutation in the gene encoding interferon regulatory factor-6 (IRF6; 607199) on chromosome 1q32.

Description

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

Also see VWS2 (606713), caused by mutation in the GRHL3 gene (608317) on chromosome 1p36.

Clinical Features

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.

Other Features

Nopoulos et al. (2007) reported brain MRI results in 7 adult men and 7 adult women with VWS. Seven of the affected patients belonged to a single large kindred; the remaining patients each came from a different family. Individuals with VWS had markedly larger gray matter volumes of the anterior cerebrum compared to controls, and there was a negative correlation between anterior gray matter volume and IQ, indicating that the changes had functional significance. Men with VWS also had decreased volumes of the posterior cerebrum. Nopoulos et al. (2007) concluded that brain structure is altered in individuals with VWS, similar to that observed in patients with isolated cleft lip/palate (see 119530 and Nopoulos et al., 2002), suggesting that both disorders reflect abnormal brain development.

Cytogenetics

Bocian and Walker (1987) described a patient with an interstitial deletion of chromosome 1q, del(1q32-q41). Among other anomalies, the patient had congenital lower lip pits similar to those found in association with the van der Woude syndrome and with the popliteal pterygium syndrome. Bocian and Walker (1987) suggested that the van der Woude syndrome may be due to a submicroscopic deletion of chromosome 1q in the area stated. A tentative assignment of the locus, symbolized PIT, to 1q32-q41 was made on the basis of this report. Sander et al. (1994) reported a microdeletion involving 1q32-q41 in a family with VWS. They found allelic loss of the stable and highly polymorphic microsatellite D1S205. They estimated that the upper bound of the size of the deletion was 4 Mb.

Schutte et al. (1999) screened a panel of 37 VWS families for loss of transmission of an allele using a highly polymorphic marker (D1S3753) from the VWS critical region. Allele loss, indicating the presence of a deletion, was identified in 1 family. In this family, the phenotype in 3 generations of affected individuals was confined to the cardinal signs of VWS, in contrast to previously reported deletions in which developmental delay and other anomalies accompanied features of VWS (Bocian and Walker, 1987; Sander et al., 1994). Houdayer et al. (2000) performed a microsatellite-based screening test for 1q32-q41 haploinsufficiency on 14 family triads with VWS and identified no additional microdeletions.

Mapping

Wienker et al. (1987) excluded linkage of VDWS with a considerable number of marker loci in studies of a kindred segregating for the disorder through 5 generations. Only linkage with Duffy blood group (110700) showed a uniformly positive lod score (lod = 1.31 at theta = 0.0). Murray et al. (1988) found linkage of LPS to the renin gene (REN; 179820); lod = 4.62 at theta = 0.04. Studies by Nishimura et al. (1989) raised the maximum lod score to 8.62 at theta = 0.02 for linkage of LPS and REN. Murray et al. (1988) and Nishimura et al. (1989) also adopted a candidate gene approach and investigated whether the laminin B2 (150290) gene might be the site of the mutation in VDWS. The finding of several recombinants ruled out this possibility. Nishimura et al. (1989) used the same approach to investigate decay accelerating factor (125240) as the site of the mutation and found no recombinants (lod = 2.22). Murray et al. (1990) reported a multipoint linkage analysis that indicated flanking of the VDWS locus by REN and D1S65 at a lod score of 10.83.

Schutte et al. (1996) constructed a 3.5-Mb YAC contig and sequence tagged site (STS) map extending from D1S245 to D1S414 in the region containing the VWS locus. They also carried out deletion mapping on a somatic cell hybrid derived from a patient with VWS due to a microdeletion. Analysis of this hybrid and genetic analysis in an additional family narrowed the VWS critical region to a 1.6-cM region flanked by D1S491 and D1S205. The authors noted that the STS markers that flank this critical region and the proximal and distal ends of the microdeletion are present in a single 850-kb YAC.

Houdayer et al. (1999) studied the linkage of 6 microsatellite markers in the 1q32-q41 region to the disease phenotype in 5 Caucasian VWS kindreds. A maximum cumulative lod score of 3.27 at a recombination fraction of 0.00 was obtained with marker D1S245. The inner 4 markers were found to be tightly linked to one another without recombination. The authors concluded that the results favored locus homogeneity.

In studies of 4 multiplex Caucasian VWS families that had been recruited at 3 different locations in the U.S., Beiraghi et al. (1999) found positive lod scores without any recombination in the candidate region of 1q. The largest 2-point lod score was 5.87. They used an assay method for short tandem repeat (STR) markers that provided highly accurate size estimation of marker allele fragment sizes, enabling them to determine the specific alleles segregating with the VWS gene in each of the 4 families. They observed a striking pattern of STR allele sharing at several closely linked loci among the 4 VWS families. These results suggested the possibility of a unique (i.e., single) origin for the mutation responsible for many or most cases of VWS.

Lees et al. (1999) reported clinical features and linkage analysis in 3 families with popliteal pterygium syndrome. Linkage analysis showed a multipoint lod score of 2.7 with no evidence of recombination using the markers D1S205, D1S491, and D1S3753 in the critical region for VWS on chromosome 1q32, supporting the hypothesis that these 2 conditions are allelic.

The cardinal features of van der Woude syndrome are lip pits and cleft lip with or without cleft palate or cleft palate (alone) (119540). Since none of these traits is present in all mutation carriers, some individuals or familial VWS cases, especially those lacking lip pits, are indiscernible from nonsyndromic CL/P (119530), raising the question of whether allelic variation at the VWS locus could underlie nonsyndromic CL/P. Houdayer et al. (2001) addressed this question using parametric linkage (lod score) analysis in 21 multiplex nonsyndromic CL/P families based on a tightly linked microsatellite marker (D1S3753) and nonparametric analysis using the transmission/disequilibrium test in 106 nonsyndromic CL/P triads (2 parents and an offspring) and 3 selecting markers on chromosome 1. No evidence for linkage of nonsyndromic CL/P to VWS was found on the 21 families using the lod score approach. In contrast, the transmission/disequilibrium test yielded a significant P value of 0.04 for D1S205, supporting involvement of VWS in nonsyndromic CL/P in a complex, modifying/polygenic manner rather than as a monogenic/major disease locus.

Wong et al. (2001) performed linkage analysis in 5 Finnish families with VWS. Three of these families were linked to the 1q32-q41 region. A recombination in an unaffected individual reduced the critical region to a 200-kb interval bounded by the markers at D1S491 and D1S3753. The authors expressed caution about the use of apparently unaffected individuals in a condition with low expressivity. Linkage disequilibrium suggested that the critical region was 130 kb bounded by the markers at D1S491 and D1S2136.

Modifier Loci

The expression of VWS, which has incomplete penetrance, is highly variable. Both the occurrence of cleft lip/palate and cleft palate within the same kindred and a recurrence risk of less than 40% for cleft palate among descendants with VWS suggested that the development of clefts in this syndrome is influenced by modifying genes at other loci. To test this hypothesis, Sertie et al. (1999) conducted linkage analysis in a large Brazilian kindred with VWS, considering as affected the individuals with CP, regardless of whether it was associated with other clinical signs of VWS. The results suggested that a gene at 17p11.2-p11.1 (604547), together with the VWS gene at 1q32, enhances the probability of CP in an individual carrying the 2 at-risk genes. Sertie et al. (1999) stated that if this hypothesis is confirmed in other VWS pedigrees, it will represent one of the first examples of a gene, mapped through linkage analysis, that modifies the expression of a major gene.

Molecular Genetics

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.

Malik et al. (2010) identified 16 Pakistani probands with VWS from more than 1,200 individuals with CL/P, for a frequency of approximately 1% in Pakistan. Analysis of IRF6 in the 16 VWS probands identified mutations in 12 of them (see, e.g., 607199.0009 and 607199.0018), including 2 missense mutations that previously had been identified in patients with popliteal pterygium syndrome (PPS). While no clinical signs of PPS were identified or reported by these patients or their families, Malik et al. (2010) noted that subtler signs of PPS such as genital hypoplasia may have been present but were not evaluated in this study.

To test whether DNA variants in regulatory elements cause VWS, Fakhouri et al. (2014) sequenced 3 conserved elements near IRF6 in 70 VWS families who were negative for mutations with IRF6 exons and identified a duplication (350dupA) within a highly conserved sequence in the MCS9.7 enhancer element in a 3-generation Brazilian family. The duplication was present in 3 affected individuals as well as in 2 unaffected family members, but it was not found in 100 unaffected controls or in 1,092 genomes from 14 populations in the NHLBI Exome Sequencing Project database. Functional analysis demonstrated that the 350dupA mutation disrupted MCS9.7 enhancer activity in 2 different cell lines as well as in vivo in a transgenic mouse embryo assay.

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.