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Background Genome-wide linkage analysis and whole genome sequencing in a Van der Woude syndrome (VWS) family revealed that the SNP, rs539075, within intron 2 of the cadherin 2 gene ( CDH2 ) co-segregated with the disease phenotype. Results A study with nonsyndromic cleft lip with or without cleft palate (NSCL ± P) cases (N = 292) and controls (N = 287) established association of this SNP with NSCL ± P as a risk factor. RT-PCR based expression analysis of the SNP-harbouring region of intron 2 of CDH2 in the clefted lip and/or palate tissues of 16 patients revealed that the mutant allele expressed in all those individuals having it (hetero-/homozygous), whereas the wild type allele expressed in <50% of the samples in which it was present. The intronic transcript was also present in the prospective lip and palate region of 13.5 dpc mouse embryo, detected by RNA in situ hybridization and RT-PCR. Conclusions These results including the in silico , characterization of the ~200 nt-intronic transcript showed that conformationally it fits best with noncoding small RNA, possibly a precursor of miRNA. Its function in the orofacial organogenesis remains to be elucidated which will enable us to define the role of this mutant ncRNA in the clefting of lip and palate. [ABSTRACT FROM AUTHOR]

The presence of lower lip pits in individuals with Van der Woude syndrome (VWS) may cause discomfort due to saliva secretion. Furthermore, one of the main complaints in relation to lip pits is poor aesthetics, which often affects quality of life. The aim of this systematic review was to identify the best technique for the surgical removal of lower lip pits in terms of aesthetic and functional characteristics. A search of the PubMed, Embase, Web of Science, Science Direct, and Scopus databases was performed on December 27, 2016, which retrieved 88 records without duplicates. Among these papers, three ultimately met all eligibility criteria. The three studies included a total of 61 individuals, with follow-up ranging from 6 months to 10 years and sample collection from 10 to 24 years. The findings demonstrated that the outcome of surgical removal of lower lip pits was better with the use of vertical wedge excision, inverted-T lip reduction, Mutaf–Goldstein technique and modified simple excision than with simple excision. Simple excision may result in postoperative complications, such as mucocele and pit recurrence. [ABSTRACT FROM AUTHOR]

Introduction Van der Woude syndrome (VWS) is the most frequent form of syndromic cleft lip and palate (SCLP) accounting for 2% of all patients with CLP. Case presentation We describe the orthodontic treatment of a girl diagnosed with VWS referred by her family dentist for her cosmetic concerns. Discussion Comprehensive orthodontic treatment, secondary bone graft, distraction osteogenesis (for a deficient maxilla), secondary palatoplasty and excision of lower lip pits, as well as orthodontic and prosthetic procedures may provide a satisfactory outcome. Genetic testing showed a known putative splice site mutation (c.174 + 1 G/A) as the prime cause of VWS in our patient and her family. Conclusion SCLP has significant effects on facial aesthetics and the psychosocial status. Parents should be assessed and counseled appropriately. This condition is treatable in the absence of life threatening systemic anomalies. An interdisciplinary team approach is advocated. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Résumé: Le syndrome de Van der Woude (SVDW) représente la première cause de fente labio-alvéolopalatine d’origine syndromique. Il associe à ces fentes, des fistules de la lèvre inférieure et parfois des hypodonties. Des découvertes récentes ont permis de mettre en évidence des mutations du gène de l’IRF6 dans ce syndrome et, ainsi, de mieux comprendre les variabilités cliniques de ce syndrome. À la lumière des cas pris en charge récemment dans notre institution et d’une revue de la littérature, nous tentons de faire le point sur cette association syndromique. [ABSTRACT FROM AUTHOR]

Abstract: Elimination of cosmetic deformity of lower lip pits and lower lip protrusion is the most common indication for lower lip repair in Van der Woude syndrome. 34 patients with lower lip pits that were operated on between 1982 and 2006 were reviewed. Surgical correction was performed with one of three different techniques: simple excision, vertical wedge resection, or inverted-T lip reduction. The aesthetic results were evaluated by two groups of raters. One group consisted of 10 medical professionals, and the other 10 lay people. A rating scheme was utilized, with a score of 3 for good, 2 for fair, and 1 for poor results. The final results were compared based on the mean score for each patient and inter-rater reliability was assessed using a weighted kappa coefficient. There was a fair agreement on the ratings between raters within groups. Inverted-T lip reduction received the best aesthetic result score from both groups of evaluators, with a mean score of 2.38±0.30 in the professional group, and 2.43±0.29 in the lay group. The results conclude that inverted-T lip reduction is a simple, safe and effective technique that achieves a better aesthetic result in lower lip repair of Van der Woude syndrome. [Copyright &y& Elsevier]

Abstract: Non-syndromic oral clefts share the main clinical features of Van der Woude Syndrome (VWS), with the exception of the lower lip pit. Thus, about 15% of VWS cases are indistinguishable from cases with non-syndromic oral clefts. IRF6 mutations are the major cause of VWS; however, variants in this gene show strong association with non-syndromic oral clefts, with a higher increased risk among cases with cleft lip only (CLO). A total of 39 individuals, including 16 patients with CLO and 23 patients with a family history of cleft, were examined for IRF6 mutations in the present study. Seven variants, including five known (c.-75-4 A>; G, c.-73T>; C, c.459G>; T 5, c.820G>; A, and c.1060 + 37C>; T) and two novel (c.-75-23G>; C and c.1380G>; T), were found. Both novel variants were inherited from non-affected parents and we did not find also in the 120 control chromosomes. In silico analysis revealed that both c.1380G>; T and c.-75-23G>; C variants may disrupts a putative exonic splicing enhancer and intronic splicing binding site for SC35, respectively. Taken together, the presence of deleterious IRF6 variants in patients with non-syndromic oral clefts could be most likely an evidence for VWS. While, IRF6 variants could, at best, contribute to clefting as part of a complex inheritance pattern, with both additional genes and environmental factors having a role. [Copyright &y& Elsevier]

Abstract: Van der Woude syndrome (VWS) and popliteal pterygium syndrome (PPS) are autosomal dominant clefting disorders recently discovered to be caused by mutations in the IRF6 (Interferon Regulatory Factor 6) gene. The IRF gene family consists of nine members encoding transcription factors that share a highly conserved helix-turn-helix DNA-binding domain and a less conserved protein-binding domain. Most IRFs regulate the expression of interferon-α and -β after viral infection, but the function of IRF6 remains unknown. We have isolated a full-length zebrafish irf6 cDNA, which encodes a 492 amino acid protein that contains a Smad-IRF interaction motif and a DNA-binding domain. The zebrafish irf6 gene consists of eight exons and maps to linkage group 22 closest to marker unp1375. By in situ hybridization analysis of embryo whole-mounts and cryosections, we demonstrate that irf6 is first expressed as a maternal transcript. During gastrulation, irf6 expression was concentrated in the forerunner cells. From the bud stage to the 3-somite stage, irf6 expression was observed in the Kupffer''s vesicle. No expression could be detected at the 6-somite and 10-somite stages. At the 14-somite stage, expression was detected in the otic placode. At the 17-somite stage, strong expression was also observed in the cloaca. During the pharyngula, hatch and larva periods up to 5 days post-fertilization, irf6 was expressed in the pharyngeal arches, olfactory and otic placodes, and in the epithelial cells of endoderm derived tissues. The latter tissues include the mouth, pharynx, esophagus, endodermal lining of swim bladder, liver, exocrine pancreas, and associated ducts. Overall, the zebrafish expression data are consistent with the observations of lip pits in VWS patients, as well as more recent reports of alae nasi, otitis media and sensorineural hearing loss documented in some patients. [Copyright &y& Elsevier]

Van der Woude syndrome (VWS) is the most common type of syndromic orofacial cleft, being characterised by variable association of lower lip pits, cleft lip and cleft palate. VWS is transmitted in an autosomal dominant manner, with high penetrance and variable expressivity, and a gene for this disease has been mapped in 1q32-q41. Very recently, mutations of the interferon regulatory factor 6 (IRF6) gene have been found in VWS patients, suggesting that this gene plays an important role in the orofacial development. We report a novel mutation of the IRF6 in an Italian family with six members affected by VWS with different expression. This mutation, the W217X, produces a stop codon within exon 6 of the IRF6 gene, with loss of the SMIR domain of the IRF6 protein. [Copyright &y& Elsevier]

The fusion of digits or toes, syndactyly, can be part of complex syndromes, including van der Woude syndrome. A subset of van der Woude cases is caused by dominant-negative mutations in the epithelial transcription factor Grainyhead like-3 (GRHL3), and Grhl3 −/− mice have soft-tissue syndactyly. Although impaired interdigital cell death of mesenchymal cells causes syndactyly in multiple genetic mutants, Grhl3 −/− embryos had normal interdigital cell death, suggesting alternative mechanisms for syndactyly. We found that in digit separation, the overlying epidermis forms a migrating interdigital epithelial tongue (IET) when the epithelium invaginates to separate the digits. Normally, the non-adhesive surface periderm allows the IET to bifurcate as the digits separate. In contrast, in Grhl3 −/− embryos, the IET moves normally between the digits but fails to bifurcate because of abnormal adhesion of the periderm. Our study identifies epidermal developmental processes required for digit separation. • Epidermal cells actively migrate into the interdigital mesenchyme • Active migration of epidermal cells is required for digit separation • Non-adhesive property of periderm cells prevents epithelial fusion between the digits • GRHL3 is required for normal periderm development and function Kashgari et al. identify an epidermal developmental process required for digit separation. During this process, epidermal cells actively migrate downward into the underlying mesenchyme, forming an interdigital epithelial tongue (IET). Fusion of the digits is prevented by the non-adhesive periderm cells on the epithelial surface. [ABSTRACT FROM AUTHOR]

Background Midfacial growth retardation in cleft lip and palate (CLP) cases, is seen in all the three dimensions. Conventionally these cases are managed by orthographic surgery which has a high rate of relapse. The application of the distraction osteogenesis (DO) has revolutionized the management protocol. The aim of the study was to evaluate the efficacy of rigid external distractor (RED) in management of cleft induced maxillary hypoplasia. Methods Ten cases of unilateral CLP between 11 and 20 years of age having gross midfacial deficiency and those who have undergone presurgical orthodontic treatment were included in the study. The cases were operated for Le Fort 1 osteotomy and application of RED. DO was carried out through transnasal traction wires. Clinico-radiological evaluation of presurgical and 1, 6 and 12 months post distraction parameters were statistically analysed by application of paired ' t '-test. Result There were 4 males and 6 females with a mean age of 15.1 years. The mean distraction carried out was 14.95 mm. There was a significant improvement in all the hard and soft tissue parameters except SNB. Facial profile improvement and stable occlusion was achieved in all the cases. Conclusion Midfacial DO using RED is a versatile procedure where the maxilla can be moved in multiple planes to achieve a functional, aesthetic and occlusal balance. Keeping in view of the significant relapse rate the clinicians are required to plan 15–20% excess amount of distraction. [ABSTRACT FROM AUTHOR]