Van Der Woude Research Articles

Van der Woude syndrome: A rare case report

Van der Woude syndrome (VWS) is a rare autosomal dominant condition typically comprising the cleft lip or cleft palate and pits of the lower lips. The degree to which individuals carrying the gene are affected varies widely, even within families. The variable manifestations include lip pits alone, absent teeth, and isolated cleft lip and palate of varying degrees of severity, bifid uvula, ankyloglossia, and enamel hypoplasia. We report a case of VWS manifesting with bifid uvula, hypodontia, ankyloglossia, and enamel hypoplasia.

Rare presentation of Van der Woude syndrome in a mother and child: A case report from Sub-Saharan Africa

Van der Woude syndrome (VWS) is a very rare congenital abnormality with high degree of penetrance and variable phenotypic expression. Common phenotypic features reported in the literature include bifid uvula, submucous cleft palate, or cleft palate to incomplete and complete unilateral or bilateral cleft lip and palate with lower lip pits as cardinal feature. Bilateral, single median or paramedian pits have been reported. We present an unusual VWS in both mother and child with the mother presenting with double bilateral (four) lower lip pits.

Van der woude syndrome: A report of four cases

Van der Woude Syndrome (VWS) is a rare autosomal dominant disorder with high penetrance and variable expressivity. The condition occurs in about 1:100,000–1:40,000 stillborn or live births and is characterized by lower lip pits, cleft lip, and/or cleft palate. Associated features of VWS include ankyloglossia, high arched palate, limb anomalies, congenital heart defects bifid uvula and syngnathia. We report four interesting cases of VWS with orofacial features. None of the four patients had any family history of lip pits, cleft lip, and/or cleft palate. The first patient with VWS showed a fusion of primary mandibular anterior teeth and the fourth patient demonstrated a supernumerary mandibular incisor. These features are very unusual in patients with VWS.

Novel IRF6 Mutations Detected in Orofacial Cleft Patients by Targeted Massively Parallel Sequencing

Common variants in interferon regulatory factor 6 (IRF6) have been associated with nonsyndromic cleft lip with or without cleft palate (NSCL/P) as well as with tooth agenesis (TA). These variants contribute a small risk towards the 2 congenital conditions and explain only a small percentage of heritability. On the other hand, many IRF6 mutations are known to be a monogenic cause of disease for syndromic orofacial clefting (OFC). We hypothesize that IRF6 mutations in some rare instances could also cause nonsyndromic OFC. To find novel rare variants in IRF6 responsible for nonsyndromic OFC and TA, we performed targeted multiplex sequencing using molecular inversion probes (MIPs) in 1,072 OFC patients, 67 TA patients, and 706 controls. We identified 3 potentially pathogenic de novo mutations in OFC patients. In addition, 3 rare missense variants were identified, for which pathogenicity could not unequivocally be shown, as all variants were either inherited from an unaffected parent or the parental DNA was not available. Retrospective investigation of the patients with these variants revealed the presence of lip pits in one of the patients with a de novo mutation suggesting a Van der Woude syndrome (VWS) phenotype, whereas, in other patients, no lip pits were identified.

Lack of Association between Missense Variants in GRHL3 (rs2486668 and rs545809) and Susceptibility to Non-Syndromic Orofacial Clefts in a Han Chinese Population

BackgroundGrainyhead-like-3 (GRHL3) was recently identified as the second gene that, when mutated, can leads to Van der Woude syndrome, which is characterized by orofacial clefts (OFC) and lower lip pits. In addition, a missense variant (rs41268753) in GRHL3 confers risk for non-syndromic cleft palate cases of European ancestry. Together with interferon regulatory factor 6 (IRF6), GRHL3 may be associated with the risk of NSOFC which awaits for being verified across different ethnic populations.ObjectiveThe aim of this study was to investigate the possible relationship between common functional variants in GRHL3 and susceptibility to NSOFC, especially cleft palate cases, in a Han Chinese population, one of the ethnic groups with the highest birth prevalence of orofacial clefting.MethodsBecause the allele frequency for rs41268753 minor alleles was zero in our Chinese population, we selected functional single nucleotide polymorphisms (SNPs) spanning GRHL3 with minor allele frequencies (MAFs) > 5% in the Han Chinese population. Two SNPs which meet the above criteria were then genotyped in a case-control cohort comprising 1145 individuals using the TaqMan 5′-exonuclease allelic discrimination assay.ResultsSNPs rs2486668 and rs545809 were used in this study. Overall genotype and allele distributions of both SNPs in general and stratified genotyping analyses revealed no statistically significant differences between cases and controls. Further logistic regression analyses using different genetic models failed to reveal any evidence that these markers influence risk to NSOFC.ConclusionsThe variant rs41268753 in GRHL3 increases the risk for cleft palate in European population, but our findings failed to detect the link between two GRHL3 SNPs (rs2486668 and rs545809) and risk to NSOFC in the Han Chinese cohort. Although the present study did not provide any evidence that common functional variants in GRHL3 may contribute to NSOFC etiology in this Chinese population, further studies with a larger sample size, additional SNPs, and a more diverse ethnic cohort are still warranted.

Management of Lip Pits in Van der Woude Syndrome: A Clinical Classification With Difficulty Index

Numerous case reports have been published on lip pits in Van der Woude syndrome explaining the morphology and genetics in detail; however, thus far, no article has focused on the classification of lip pits as an aid in surgical management. Although the procedure for lip pits in Van der Woude syndrome appears straightforward, even in the best of hands, the excision can be very challenging with no guarantee of esthetically desirable results. Therefore, we have devised a classification based on a difficulty index in the management of lower lip pits to assist in predicting the treatment outcome before surgery, as well as to offer the choice of a particular technique in a specific situation. We reviewed 19 cases of Van der Woude syndrome having lower lip pits that were operated on at our unit from May 2005 to June 2015 with a minimum follow-up of at least 6months. The data analyzed included the patient's age and gender, location of the lip pits with regard to their proximity to the white skin roll, number of lip pits, presurgical depth of the lip pits, and discharge of mucous secretion from the pits, as well as timing of lip pit excision. Four techniques of excision were performed via routine excision, modified routine excision, vertical wedge excision, and inverted-T lip reduction. The data were tabulated and analyzed. On the basis of our experience in managing lip pits, a clinically relevant classification with a difficulty index was then proposed. Among the 12 patients having preoperative involvement of the white skin roll, 8 had distortion of the white skin roll when operated on by either routine excision (n= 2), modified routine excision (n=3), or inverted-T lip reduction (n= 3). The remaining 4 patients had no distortion of the white skin roll after surgery when the vertical wedge excision technique was performed. The 7 patients who had no distortion of the white skin roll preoperatively presented with esthetic results when operated on by either the routine excision, modified routine excision, or inverted-T lip reduction technique. In 2 patients with a presurgical pit depth greater than 6mm, mucocele formation was observed after surgery. Using the data obtained, we proposed a classification based on 2 parameters: involvement of the white skin roll and presurgical depth. A difficulty index also was proposed using these same variables. Classification and evaluation of the difficulty of lip pit excision are essential in planning the surgical treatment to give improved esthetic results. This proposed classification and difficulty index will provide the operating surgeon with a standardized scheme to evaluate the difficulty of the excision as well as to predict the overall outcome of the procedure before surgery.

Association study between Van der Woude Syndrome causative gene GRHL3 and nonsyndromic cleft lip with or without cleft palate in a Chinese cohort

Cleft lip with or without cleft palate (CL/P) is one of the most common birth defects worldwide and is characterized by abnormalities of the orofacial structure. Syndromic CL/P is mainly caused by Mendelian disorders such as Van der Woude Syndrome (VWS). However, >70% of CL/P cases are nonsyndromic, characterized by isolated orofacial cleft without any known syndrome. The etiology of nonsyndromic CL/P (NSCL/P) remains elusive, but it has been suggested that causative genes of syndromic CL/P might also contribute to NSCL/P. As such, the VWS causative gene IRF6 has been extensively studied in NSCL/P. Recently, GRHL3 was identified as another VWS causative gene. Thus, it may be a novel candidate gene for NSCL/P. In the present study, we genotyped 10 tag SNPs covering GRHL3 and performed association analysis with NSCL/P in 504 cases and 455 healthy controls. Our preliminary results identified rs10903078, rs4638975, and a haplotype rs10903078-rs6659209 of GRHL3 that exceeded the significance threshold (p<0.05), though none survived Bonferroni correction for multiple comparisons. As the first study between GRHL3 and NSCL/P, the contribution of this gene to NSCL/P etiology should be interpreted with caution based on existing evidence. Further, the robustness of association between GRHL3 and NSCL/P should be further validated in expanded cohorts.

Sequencing the GRHL3 Coding Region Reveals Rare Truncating Mutations and a Common Susceptibility Variant for Nonsyndromic Cleft Palate

Nonsyndromic cleft lip with/without cleft palate (nsCL/P) and nonsyndromic cleft palate only (nsCPO) are the most frequent subphenotypes of orofacial clefts. A common syndromic form of orofacial clefting is Van der Woude syndrome (VWS) where individuals have CL/P or CPO, often but not always associated with lower lip pits. Recently, ∼5% of VWS-affected individuals were identified with mutations in the grainy head-like 3 gene (GRHL3). To investigate GRHL3 in nonsyndromic clefting, we sequenced its coding region in 576 Europeans with nsCL/P and 96 with nsCPO. Most strikingly, nsCPO-affected individuals had a higher minor allele frequency for rs41268753 (0.099) than control subjects (0.049; p = 1.24× 10(-2)). This association was replicated in nsCPO/control cohorts from Latvia, Yemen, and the UK (pcombined = 2.63× 10(-5); ORallelic = 2.46 [95% CI 1.6-3.7]) and reached genome-wide significance in combination with imputed data from a GWAS in nsCPO triads (p = 2.73× 10(-9)). Notably, rs41268753 is not associated with nsCL/P (p = 0.45). rs41268753 encodes the highly conserved p.Thr454Met (c.1361C>T) (GERP = 5.3), which prediction programs denote as deleterious, has a CADD score of 29.6, and increases protein binding capacity insilico. Sequencing also revealed four novel truncating GRHL3 mutations including two that were de novo in four families, where all nine individuals harboring mutations had nsCPO. This is important for genetic counseling: given that VWS is rare compared to nsCPO, our data suggest that dominant GRHL3 mutations are more likely to cause nonsyndromic than syndromic CPO. Thus, with rare dominant mutations and a common risk variant in the coding region, we have identified an important contribution for GRHL3 in nsCPO.

Popliteal Pterygium Syndrome (Facio-Genito-Popliteal Syndrome)

Background: IRF6-related disorders span a spectrum from isolated cleft lip and palate and Van der Woude syndrome (VWS) at the mild end to popliteal pterygium syndrome (PPS) at the more severe end. Popliteal pterygia are found in popliteal pterygium syndrome, multiple pterygium syndrome and Arthrogryposis. The popliteal pterygium syndrome is a rare congenital condition, in which the patient has facial, genitourinary and skeletal anomalies along with popliteal pterygium. Autosomal dominant popliteal pterygium syndrome (AD-PPS) is a rare genetic malformation disorder characterized by cleft lip, with or without cleft palate, contractures of the lower extremities, abnormal external genitalia, syndactyly of fingers and/or toes, and a pyramidal skin fold over the hallux nail. AD-PPS is associated with mutations in the IRF6 gene (1q32.2-q32.3), involved in the formation of connective and epithelial tissues. Almost all affected patients harbor mutations in this gene. The word ‘pterygium’ is derived from the Greek word pterygion, which means wing. Pathologically it denotes a wing-like abnormal band of tissue. The most obvious characteristics of this syndrome are popliteal pterygium and a triangular crease of skin over the hallux. The orofacial findings include cleft lip, cleft palate, lower lip pits, a few missing teeth, and severely decayed teeth. The dental problems are overshadowed by the major syndromic manifestations. These patients have special dental needs and early preventive dental care and appropriate dental treatment at the optimal time is important. Diagnosis of pterygium syndrome is based on the clinical findings and confirmed by molecular genetic testing. AD-PPS is highly associated with missense mutations that alter residues that are predicted to interact directly with DNA in exons 3 and 4 of IRF6. Conclusion: An understanding of the molecular genetic basis of this syndrome is essential for prenatal diagnosis and also for genetic counseling of the parents. Keywords: Popliteal pterygium syndrome, Escobar syndrome, Magnetic resonance imaging, Congenital contractures, Genetic counseling.

口角瘻を合併した先天性下唇瘻の1例

Congenital lower lip pits often appear as one of the main features of Van der Woude syndrome (VWS), which is an autosomal dominant disorder syndrome. Although most cases are associated with cleft lip, cleft palate, or both, some cases are rarely accompanied by anomalies other than cleft lip and palate. Lower lip pits are usually excised for cosmesis, but some of them have mucocele as a complication. In this paper, we report a case of lower lip pits associated with commissural pits, which was complicated by a mucocele after excision.

Orthodontic management of displaced premaxilla in Van der Woude syndrome

Cleft lip and palate is the most common congenital disorder affecting facial region. Van der Woude syndrome is a rare autosomal dominant disorder characterized by varying degree of cleft lip and/or palate, distinctive pits on the lower lip and hypodontia. A case of Van der Woude syndrome treated successfully with fixed orthodontic treatment is presented. The main feature of treatment planning and execution included moving the premaxilla to midline with gentle orthodontic force.

Genetic Factors in Selected Complex Congenital Malformations with Cleft Defect.

Cleft lips, alveolar ridges and palates are among the most common birth defects. There are over 500 different complex genetic disorders that include cleft defects. The most common related defects include abnormalities of the skeleton, skull, cardiovascular and nervous system. The occurrence of a cleft results from the interplay of multiple genes and environmental factors. Several thousand different mutations responsible for these syndromes have been discovered, whereas there are still numerous phenotypic cases of unknown genetic origin. The aim of this study was to present various clinical aspects and the latest discoveries with regard to genetic research in complex malformations, such as Van der Woude syndrome, popliteal pterygium syndrome, EEC syndrome, Pierre Robin sequence, various forms of Stickler syndrome, and Treacher Collins syndrome. These complex syndromes have different incidences, and most of them also have allelic variants with characteristic severities that differ even among close relatives. Easier access to genetic counseling and the lower cost of DNA testing in recent years can lead to new findings on the causes of such syndromes.

Irf6 directly regulates Klf17 in zebrafish periderm and Klf4 in murine oral epithelium, and dominant-negative KLF4 variants are present in patients with cleft lip and palate.

Non-syndromic (NS) cleft lip with or without cleft palate (CL/P) is a common disorder with a strong genetic underpinning. Genome-wide association studies have detected common variants associated with this disorder, but a large portion of the genetic risk for NSCL/P is conferred by unidentified rare sequence variants. Mutations in IRF6 (Interferon Regulatory Factor 6) and GRHL3 (Grainyhead-like 3) cause Van der Woude syndrome, which includes CL/P. Both genes encode members of a regulatory network governing periderm differentiation in model organisms. Here, we report that Krüppel-like factor 17 (Klf17), like Grhl3, acts downstream of Irf6 in this network in zebrafish periderm. Although Klf17 expression is absent from mammalian oral epithelium, a close homologue, Klf4, is expressed in this tissue and is required for the differentiation of epidermis. Chromosome configuration capture and reporter assays indicated that IRF6 directly regulates an oral-epithelium enhancer of KLF4. To test whether rare missense variants of KLF4 contribute risk for NSCL/P, we sequenced KLF4 in approximately 1000 NSCL/P cases and 300 controls. By one statistical test, missense variants of KLF4 as a group were enriched in cases versus controls. Moreover, two patient-derived KLF4 variants disrupted periderm differentiation upon forced expression in zebrafish embryos, suggesting that they have dominant-negative effect. These results indicate that rare NSCL/P risk variants can be found in members of the gene regulatory network governing periderm differentiation.

IRF6 mutation screening in non-syndromic orofacial clefting: analysis of 1521 families.

Van der Woude syndrome (VWS) is an autosomal dominant malformation syndrome characterized by orofacial clefting (OFC) and lower lip pits. The clinical presentation of VWS is variable and can present as an isolated OFC, making it difficult to distinguish VWS cases from individuals with non-syndromic OFCs. About 70% of causal VWS mutations occur in IRF6, a gene that is also associated with non-syndromic OFCs. Screening for IRF6 mutations in apparently non-syndromic cases has been performed in several modestly sized cohorts with mixed results. In this study, we screened 1521 trios with presumed non-syndromic OFCs to determine the frequency of causal IRF6 mutations. We identified seven likely causal IRF6 mutations, although a posteriori review identified two misdiagnosed VWS families based on the presence of lip pits. We found no evidence for association between rare IRF6 polymorphisms and non-syndromic OFCs. We combined our results with other similar studies (totaling 2472 families) and conclude that causal IRF6 mutations are found in 0.24-0.44% of apparently non-syndromic OFC families. We suggest that clinical mutation screening for IRF6 be considered for certain family patterns such as families with mixed types of OFCs and/or autosomal dominant transmission.

Prenatal diagnosis and management of Van der Woude syndrome

Abstract We report the postnatal diagnosis of Van der Woude syndrome (VWS) in a foetus found to have an isolated right cleft lip and palate by ultrasound examination. After prenatal genetic counselling, the parents declined further evaluation by amniocentesis. At delivery, the infant was also found to have labial pits in the lower lip in addition to the cleft lip and palate identified by ultrasound consistent with VWS. Although VWS is rare, its autosomal dominant inheritance and variable penetrance should prompt additional modalities to more thoroughly evaluate the extent of other organ system and more extensive craniofacial anomalies.

Toward an orofacial gene regulatory network.

Orofacial clefting is a common birth defect with significant morbidity. A panoply of candidate genes have been discovered through synergy of animal models and human genetics. Among these, variants in interferon regulatory factor 6 (IRF6) cause syndromic orofacial clefting and contribute risk toward isolated cleft lip and palate (1/700 live births). Rare variants in IRF6 can lead to Van der Woude syndrome (1/35,000 live births) and popliteal pterygium syndrome (1/300,000 live births). Furthermore, IRF6 regulates GRHL3 and rare variants in this downstream target can also lead to Van der Woude syndrome. In addition, a common variant (rs642961) in the IRF6 locus is found in 30% of the world's population and contributes risk for isolated orofacial clefting. Biochemical studies revealed that rs642961 abrogates one of four AP-2alpha binding sites. Like IRF6 and GRHL3, rare variants in TFAP2A can also lead to syndromic orofacial clefting with lip pits (branchio-oculo-facial syndrome). The literature suggests that AP-2alpha, IRF6 and GRHL3 are part of a pathway that is essential for lip and palate development. In addition to updating the pathways, players and pursuits, this review will highlight some of the current questions in the study of orofacial clefting.

Novel Mutations in the IRF6 Gene on the Background of Known Polymorphisms in Polish Patients With Orofacial Clefting.

To examine the role of the IRF6 mutations in Polish families with Van der Woude syndrome and popliteal pterygium syndrome and to determine the effect of IRF6 single nucleotide polymorphisms (rs7552506, rs2013162, and rs2235375) on cleft lip and/or palate susceptibility. IRF6 mutation screening was performed by direct sequencing of all coding exons of the gene and their flanking intronic regions. Cosegregation analysis was performed to establish the relation of single nucleotide polymorphisms and cleft lip and/or palate phenotypes. We screened the IRF6 gene in eight families with clinical recognition of Van der Woude syndrome and popliteal pterygium syndrome. In five families we identified pathogenic mutations, all affecting the DNA-binding or the protein-binding domain of IRF6. Two of the mutations were novel-a missense mutation Arg31Thr and a small deletion Trp40Glyfs*23. In most cases we found also a haplotype of three single nucleotide polymorphisms-rs7552506, rs2013162, and rs2235375. The association of the single nucleotide polymorphisms and cleft lip and/or palate susceptibility has been previously published. The variants did not cosegregate with phenotype in examined families nor did they cosegregate with pathogenic mutations. The single nucleotide polymorphisms were deemed not causative, due to their presence in unaffected family members. Two novel mutations (Arg31Thr and Trp40Glyfs*23) in the IRF6 gene were identified to be causative for Van der Woude and popliteal pterygium syndromes. In the present study no association between the single nucleotide polymorphisms rs7552506, rs2013162, and rs2235375 and the cleft lip and/or palate phenotype was found. The hypothesis, whether the haplotype of the three single nucleotide polymorphisms was correlated with IRF6 expression level, demands further investigation.

A RETROSPECTIVE STUDY ON RECOGNIZABLE SYNDROMES ASSOCIATED WITH CRANIOFACIAL CLEFTS

Objective: There are about 300 to 600 syndromes associated with clefts in the craniofacial region. The cleft lip, cleft palate and cleft lip palate are the most common clefts seen in the craniofacial region. Sometimes these clefts are associated with other anomalies which are known as syndromic clefts. The objective of this study is to identify the syndromes associated with the clefts in the craniofacial region. Materials & methods: This retrospective study consists of 270 cases of clefts in the craniofacial region. The detailed case history including the maternal history, antenatal, natal, perinatal history and family history were taken from the patients and their parents. Based on the clinical examination, radiological findings and genetic analysis the different syndromes were identified. Results: 18 syndromic clefts were identified which belong to 10 different syndromes. It shows 6.67% of clefts are syndromic and remaining are nonsyndromic clefts. Conclusion: Median cleft face syndrome, Van der woude syndrome and Pierre Robin sequence are the common syndromes associated with the clefts in the craniofacial region.

Disease-associated mutations in IRF6 and RIPK4 dysregulate their signalling functions

IRF6 and RIPK4 are critical regulators of keratinocyte differentiation and their mutation cause the developmental syndromes Van der Woude syndrome (VWS) and Bartsocas-Papas syndrome (BPS), respectively. RIPK4 promotes keratinocyte differentiation, in part, by inducing IRF6 transactivator function through the phosphorylation of its C-terminal domain at Ser413 and Ser424. Although more than 200 IRF6 mutations have been identified in VWS, a p.Arg412X nonsense mutation is particularly prevalent. A RIPK4 p.Ser376X nonsense mutation in BPS was also recently identified. Here, we demonstrated for the first time that the truncation of IRF6 at Arg412 causes its rapid proteasome-dependent degradation. The truncation of IRF6 also prevented the induction of its transactivator function by RIPK4. Similarly, the p.Ser376X mutation in RIPK4 impaired its induction of IRF6 transactivator function. The mutation also inhibited the stabilisation of β-catenin by RIPK4, and thus may additionally impair Wnt signalling. Collectively, our findings provide important mechanistic insight into how the p.Arg412X and p.Ser376X mutations may cause VWS and BPS, respectively.

Crimmigration

This extended review of two 2013 publications, Guia, van der Woude, and van der Leun (eds.) Social Control and Justice: Crimmigration in the Age of Fear and Aas and Bosworth (eds.) The Borders of Punishment: Migration, Citizenship and Social Exclusion, critically engages with the potential for race scholarship in the paradigms utilized by the contributors. While acknowledging that these volumes represent an imaginative and significant recasting of criminology, raising as they do a number of useful theoretical issues, the author identifies a reluctance to frame any aspect of these studies in terms of racialization. While much of the substantive content might easily be examined using that concept, it is implicit rather than explicit in this scholarship. Sociologists interested in the racialization of immigration are urged to engage seriously with the work and ideas contained in these two volumes and to bring their insights to bear in complementing this emerging field.