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Objective: The purpose of this study is to analyze the clinical characteristics of patients with Van der Woude syndrome (VWS) and to detect variations in each patient. Finally, the combination of genotype and phenotype can make a clear diagnosis of VWS patients with different phenotype penetrance. Methods: Five Chinese VWS pedigree were enrolled. Whole exome sequencing of the proband was performed, and the potential pathogenic variation was further verified by Sanger sequencing in the patient and their parents. The human mutant IRF6 coding sequence was generated from the human full-length IRF6 plasmid by site-directed mutagenesis and cloned into the GV658 vector, RT-qPCR and Western blot were used to detect the expression of IRF6. Results: We found one de novo nonsense variation (p. Gln118Ter) and three novel missense variations (p. Gly301Glu, p. Gly267Ala, and p. Glu404Gly) co-segregated with VWS. RT-qPCR analysis revealed that p. Glu404Gly significantly reduced the expression level of IRF6 mRNA. Western blot of cell lysates confirmed that IRF6 p. Glu404Gly abundance levels were lower than those for IRF6 wild type. Conclusions: This discovery of the novel variation (IRF6 p. Glu404Gly) expands the spectrum of known variations in VWS in Chinese humans. Genetic results combined with clinical phenotypes and differential diagnosis points from other diseases can make a definitive diagnosis and provide genetic counseling for families. [ABSTRACT FROM AUTHOR]

Van der Woude syndrome (VWS) is a rare syndrome of genetic etiology, commonly occasioned by mutations in the IRF6 gene and that causes disorders in craniofacial development. VWS is characterized by the presence of paramedian fistulas in the lower lip and cleft lip and / or cleft palate. Although some dental phenotypes have been reported in this syndrome, multiple and rare hypodontias were not described. Through this case report, we present a case of Van der Woude Syndrome (VWS) with rare and multiple hypodontia in which clinical data and radiographic exams were evaluated. The patient presented hypodontia of eight permanent teeth (lateral incisors, second premolars and second molars). So, when the dentist recognizes multiple and/or rare hypodontias, for an accurate diagnosis, detailed examination of the lower lip is indicated, as well as a survey of the family history and referral for genetic counseling, since the syndrome presents high penetrance. The patient is expected to be rehabilitated to have a good quality of life. Rehabilitation in these cases requires alveolar bone graft, orthodontics and prosthesis to replace missing teeth. [ABSTRACT FROM AUTHOR]

Aims: Van der Woude syndrome (VWS) is one of the most common craniofacial anomalies, causing significant functional and psychological burden to the patients. This study aimed to identify the genetic cause of VWS in a Chinese family. Methods: Whole genome sequencing (WGS) was performed to screen for pathogenic mutations. Various Bioinformatics tools were used to assess the pathogenicity of the variants. Cosegregation analysis of the candidate variant was carried out. Interpretation of variants was performed according to the American College of Medical Genetics and Genomics guidelines. Results: A novel frameshift duplication c.373_374dupAA (p.Asn125Lys fs*43) was identified in exon 4 of the interferon regulatory factor 6 (IRF6) gene in all 3 affected members, which were not found in unaffected family members. The novel mutation leads to a frameshift and a premature stop codon which caused putative truncated protein. Protein alignment indicated high evolutionary conservation of the p.N125 residue, and this mutation was predicted by online tools to be damaging and deleterious. Conclusions: This study demonstrates that the novel mutation c.373_374dupAA (p.Asn125Lysfs*43) in the IRF6 gene corresponds to the VWS in this family. The discovery of this pathogenic variant enriches the genotypic spectrum of IRF6 gene and contributes to genetic diagnosis and counseling of families with VWS. [ABSTRACT FROM AUTHOR]

Objective: To screen for interferon regulatory factor 6 (IRF6) pathogenic variants in patients clinically diagnosed with nonsyndromic cleft lip palate (NSCL/P) and establish the proportion of misdiagnosed Van der Woude syndrome (VWS) cases, which could have biased previous NSCL/P case–control association studies. Design: Retrospective case series. Setting: Tertiary care children's hospital. Participants: One hundred seventy-two unrelated Mexican patients with NSCL/P, 128 of whom had previously been included in a NSCL/P case–control association study. Main Outcomes Measurements: Sanger sequencing of the 9 IRF6 exons were performed, all variants respect with sequence reference were reported and classified for their pathogenic significance according to the American College of Medical Genetics and Genomics guidelines. Results: Seven percent of cases were familial. No pathogenic variant was identified in IRF6. We identified 12 previously reported benign variants; their frequencies did not significantly differ from those reported for individuals of Mexican ancestry. Three of them were uncommon intronic variants not reported in ClinVar. The rs2235371 and rs2235375 variants, which were previously analyzed in a NSCL/P case–control association study (containing 132 patients, 128 of whom were analyzed herein) did not show discordant association results comparing to the 370 controls from the previous study. Conclusions: The misdiagnosis of IRF6 -related VWS as NSCL/P appears to be infrequent in our sample, suggesting that mutational screening of IRF6 would have a low diagnostic yield in patients with NSCL/P. The absence of IRF6 pathogenic alleles could be related to the application of an exhaustive clinical evaluation that discarded the syndromic forms and/or the low proportion of familial cases included. [ABSTRACT FROM AUTHOR]

In rare instances, cleft lip and palate occur in association with synechia, intraoral fibrous bands connecting the maxilla and mandible. The main concern in synechia is a restricted mouth opening that leads to airway and feeding problems. This study reports our experience in the treatment of 3 cases and includes a review of the literature. Three patients with intraoral fibrous bands received treatment and follow-ups in our center. Division of the bands and reconstruction of the lip and palate were successfully performed. All reported cases in the literature were collected for a summary of clinical presentations and as references for management. Early management of the synechia improves the mouth opening and facilitates the treatment of associated anomalies. [ABSTRACT FROM AUTHOR]

This report describes the presentation of a newborn male with circumferential tongue-palate fusion associated with cleft palate and alveolar bands. After intraoral adhesions lysis, the patient was diagnosed with Pierre Robin sequence. A family history of cleft lip and palate was noted, and interferon regulatory factor 6 (IRF6) sequencing revealed a heterozygous variant, confirming the diagnosis of van der Woude syndrome. The disruption of IRF6 resulted in abnormal orofacial development including micrognathia and intraoral adhesions as well as tongue-palate fusion, then resulting in glossoptosis with airway obstruction and cleft palate. [ABSTRACT FROM AUTHOR]

Van der Woude syndrome (VWS) is a rare autosomal dominant genetic disorder characterized by orofacial clefting and lip pits. Mutations in the transcription factor interferon regulatory factor 6 gene (IRF6) have been identified in individuals with VWS. We performed direct sequencing of the gene for molecular investigation of a proband with Bangladeshi-Malay ancestry. A novel transition mutation (c.113T>C), which resulted in an amino acid substitution (p.Ile38Thr) in the deoxyribonucleic acid-binding domain was detected. Testing of family members showed that the mutation segregated with the VWS phenotype for members of her immediate family. Although there is some phenotypic variability, all of the affected members are of the female gender [ABSTRACT FROM AUTHOR]

The article presents study to characterize the skin of patients with Van der Woude Syndrome (VWS). It mentions collection of discarded tissue from a hip during surgical alveolar bone graft and comparison of samples from children with VWS harbouring Interferon Regulatory Factor 6 (IRF6) mutations with samples from children with nonsyndromic cleft lip and palate (NSCLP). It reveals hip skin from children with VWS showed a thicker epidermis as compared to that of children with NSCLP.

Objective: To summarize the clinical characteristics and surgical and speech outcomes for patients with Van der Woude/popliteal pterygium syndromes (VWS/PPS) and to compare them with a historic cohort of patients with nonsyndromic cleft lip/cleft palate (CL/P). Design: Retrospective chart review. Setting: Tertiary care center. Patients: All patients with VWS/PPS seen at Boston Children's Hospital from 1979 to 2012: 28 patients with VWS (n = 21)/PPS (n = 7) whose mean age was 17.3 ± 10.4 years, including 18 females (64%) and 10 males (36%); 18 patients (64%) had a family history of VWS/PPS. Main Outcome Measures: Cleft type, operative procedures, speech, and midfacial growth. Data were compared with historic cohorts of patients with nonsyndromic CUP treated at one tertiary care center. Results: There were 24 patients (86%) with CP± L, Veau types I (n = 4,17%), II (n = 4,17%), III (n = 5, 21%), and IV (n = 11, 46%). Nine patients (38%) had palatal fistula after palatoplasty. Fourteen of 23 (61%) patients with CL/P age 5 years or older had midfacial retrusion, and 10 (43%) required a pharyngeal flap for velopharyngeal insufficiency. Fisher's exact test demonstrated higher frequencies of Veau type IV CP±L (P= .0016), bilateral CL±P (P= .0001), and complete CL±P (P < .0001) in VWS/PPS compared with nonsyndromic patients. Incidences of midfacial retrusion (P= .0001), palatal fistula (P < .0001), and need for pharyngeal flap (P= .0014) were significantly greater in patients with VWS/PPS. Conclusions: Patients with VWS/PPS have more severe forms of labiopalatal clefting and higher incidences of midfacial retrusion, palatal fistula, and velopharyngeal insufficiency following primary repair as compared with nonsyndromic CL/P. [ABSTRACT FROM AUTHOR]

Kabuki syndrome (KS) is a multiple congenital anomaly/mental retardation syndrome with characteristic facial features. Despite more than 350 documented cases and recent correlation of MLL2 mutations as a genetic cause, its full clinical spectrum is still being defined. This report describes two patients who were initially diagnosed with Van der Woude syndrome (VWS) based on the presence of lower lip pits. However, this finding can occur with KS, albeit infrequently. For patients with lower lip pits, a thorough evaluation should be made to distinguish between VWS and KS, as there are differences in long-term prognosis. [ABSTRACT FROM AUTHOR]

Objective: Evaluation of the IRF6 gene in Van der Woude syndrome cases from an Indian population. Subjects: Nine affected and four unaffected individuals from seven families with Van der Woude syndrome as well as five normal controls (with no history of Van der Woude or any other congenital malformation and belonging to the same geographical area as the families with Van der Woude syndrome). Method: Direct sequencing of all coding regions and exon-intron boundaries of the IRF6 gene. Results: Five novel variants: IVS1+3900 A.G, 191 T.C, IVS4+775 C.T, IVS8+218 C.T, 1511 T.A (Ser 416 Arg) and two known variants: IVS6+27 C.G, 1083 G.A (V274I) were detected. Except for one, all were in noncoding regions either in 39UTR or in introns. There was only one mutation in the coding region, detected in a normal control. Conclusion: The present report indicates that point mutations in the coding region of the IRF6 gene may not be a major cause of Van der Woude syndrome in Indian populations. [ABSTRACT FROM AUTHOR]

Objective: Van der Woude syndrome, characterized by lip pits and cleft lip! palate, presents with variable expressions. This retrospective study was designed to obtain a better understanding of its clinical pattern in Taiwanese patients. Materials and Methods: Of 13,147 cleft patients treated at the Chang Gung Craniofacial Center from 1976 to 2004, there were 64 with Van der Woude syndrome. Clinical expressions and family histories were collected and analyzed. Results: The male to female ratio was 1:1. The majority had complete cleft types. Severe cleft was found among the patients, with 52% having bilateral cleft lip and palate, 31% having unilateral cleft lip and palate, and 17% having isolated cleft palate. A positive family history was found in 53.1% of the patients. The size, shape, location, and depth of the pits varied among patients. Conclusion: Clinical presentations did not always parallel those reported in the literatures. These differences warrant further investigation. [ABSTRACT FROM AUTHOR]

Objective: This report describes the clinical and genetic features of two large and unrelated families with Van der Woude syndrome in Brazil, emphasizing the range of anomalies found within and between the families. Patients: Family 1 included 54 descendants spanning five generations, with 12 (22.23%) individuals manifesting Van der Woude syndrome. In family 2, examinations comprised 17 descendants distributed over tour generations, and 8 (47.06%) people presented features of Van der Woude syndrome. Results: In family 1, the first two generations were not affected, but the other three generations had affected members showing a unique association of lip pits and cleft lip/palate with equilibrated gender distribution. In family 2, all generations were affected, and the clinical expression of disease was heterogeneous, including members with isolated clefts, isolated lip pits, and association of cleft lip/palate with lip pits. In both families, affected members transmitted their traits to descendants in an autosomal dominant mode of inheritance with apparent low penetrance in family 1, but high penetrance in family 2. Patients were treated surgically by cheiloplasty and/or palatoplasty with satisfactory results. Conclusions: Van der Woude syndrome was transmitted by an autosomal dominant pattern with variable expressivity and penetrance and equilibrated gender distribution. Physicians should be aware of the variety of malformations that can be associated with Van der Woude syndrome. Genetic counseling in Van der Woude syndrome affected families is important, because a high percentage of descendants can have some kind of clefting. [ABSTRACT FROM AUTHOR]

Objective: To review the clinical outcome for patients with Van der Woude syndrome undergoing surgical excision of congenital lip sinuses. Design: Retrospective chart review. Setting: Multidisciplinary cleft-craniofacial team within a tertiary care hospital. Patients, Participants: Seventeen patients with Van der Woude syndrome were identified from hospital records as having cleft lip and/or palate surgery performed at the University of Iowa, and six of these patients underwent simple surgical excision of lower lip sinuses. Main outcome measures: Incidence of postoperative complications and number of surgeries required per patient for correction of lower lip defect. Results: All six patients undergoing surgical excision of lip sinuses had postoperative mucocele formation. These uniformly required one or two further surgeries for correction. There were no other complications associated with the procedures and no patient had a pre- or postoperative whistling deformity. Cosmetic outcome was thought to be satisfactory in all cases. Conclusions: Despite the overall improvement in cosmetic appearance following simple surgical excision of congenital lower lip sinuses, the high rate of mucocele formation and repeat surgery has led to cautious preoperative counseling regarding the risks and benefits of the procedure. [ABSTRACT FROM AUTHOR]