Two missense mutations in the IRF6 gene in two Japanese families with Van der Woude syndrome

Van der Woude syndrome (VWS) is a common autosomal dominant disorder with cleft lip and/or palate and lower lip pits. Its prevalence is estimated to be 1/33,600 in the Finnish Population, and 1/47,813 in the Japanese. We performed mutation analysis of the IRF6 gene by direct sequencing in 2 unrelated Japanese families that consist of a total of 3 affected members with cleft lip and palate associated with lower lip pits. Consequently, we found novel base substitutions, 25C>T, in IRF6-exon 3 in a boy, his mother, and his phenotypically normal maternal grandmother in one of the families. A known mutation, 250C>T, was identified in exon 4 of a girl and her unaffected father in the other family. The same mutations were never observed among 190 healthy Japanese. The results indicate incomplete penetrance and variable expressivity in the families. Because 25C>T and 250C>T predict to lead to R9W and R84C substitutions, respectively, at the most conserved DNA binding domain of IRF6, and because arginine at positions 9 and 84 is highly conserved among IRFs, the 2 mutations may lead to abolish the DNA binding activity in the developing craniofacial region. To our knowledge, this is the first report of IRF6 mutations observed in Japanese VWS patients.     

福建范德伍兹综合征1例家系IRF6基因突变的检测

目的检测福建省一范德伍兹综合征(VWS)家系IRF6基因的突变。方法在IRF6(interferonregulatoryfactor6)基因内设计引物,经分段聚合酶链反应(PCR)和DNA测序进行突变检测,运用PIX-ProteinIdentification软件对检测结果进行蛋白二级结构分析。结果在所有患者IRF6基因的第379密码子发现TGG>TGA(r.1400g→a)的碱基变化,该突变引入终止码,引起IRF6蛋白转录提前终止。结论范德伍兹综合征由IRF6基因突变引起,IRF6基因与唇腭、牙齿发育密切相关。     

一例Van der Woude 综合征家系IRF6基因突变的检测

目的 :对一例河北峪金矿VanderWoude综合征 (VWS)家系进行IRF6基因突变的检测。方法 :在IRF6(interferonregulatoryfactor 6)基因内设计引物 ,经分段聚合酶链反应 (PCR)和DNA测序进行突变检测 ,运用PIX ProteinIdentification软件对检测结果进行蛋白质二级结构分析。结果 :在所有患者IRF6基因的第 40 0密码子发现与表型一致的CGG >TGG (r .14 61c→t)的突变 ,该突变引起IRF6蛋白质二级预测结构的改变。结论 :VanderWoude综合征由IRF6基因突变引起 ,IRF6基因与唇腭、牙齿发育密切相关。     

一个陕西汉族Van der Woude综合征家系IRF6基因的突变筛查

目的对一个陕西省汉族Van der Woude综合征(VWS)家系进行IRF6基因的突变筛查.方法在IRF6(interferon regulatory factor 6)基因内设计引物,经分段PCR(聚合酶链反应)包括剪切位点的9个外显子后DNA测序进行突变筛查,运用PIX-Protein Identification软件对检测结果进行蛋白二级结构分析.结果在所有患者IRF6基因的第2密码子发现与表型一致的GCC>GTC (r.268c→t NM 214278)的突变,该突变引起IRF6蛋白二级预测结构的改变.结论该家系Van der Woude综合征由IRF6基因突变引起,IRF6基因与唇腭、牙齿发育密切相关.     

Van der Woude syndrome in twins

This article discusses monozygotic twin patients with Van der Woude syndrome, the most common form of syndromic cleft lip and palate, who have concordant manifestations. The syndrome has an autosomal dominant hereditary pattern with variable expressivity and a high degree of penetrance with clinical features, including lower lip sinuses with a cleft lip, cleft palate, or both. Some mutations have been found to cause this disorder. Genetic counseling and informing patients about inheritance is crucial. The appearance, etiology, genetic aspects, differential diagnosis, and treatment modalities are discussed. To the authors' knowledge, this is the third report of monozygotic concordant twins with this syndrome in the literature.     

Van der Woude综合征家系先天缺牙患者MSX1基因突变的检测

目的探讨MSX1基因与Van der Woude综合征(VWS)家系中缺牙的关系。方法从VWS家系9中伴发缺牙患者2人及家系正常成员2人、60个牙列完整的健康者共64人的静脉血中提取DNA,设计MSX1基因引物,采用PCR方法扩增MSX1基因外显子1、2的编码区,而后对外显子1、2的PCR纯化产物测序,进行序列比对分析。结果 VWS家系9两个缺牙患者MSX1基因中有ivs2+68 C>T多态;伴IRF6基因突变的VWS患者缺牙较多。结论 VWS家系9中先天缺牙患者的牙先天缺失与MSX1基因的ivs2+68 C>T多态可能相关。     

Van der Woude syndrome: clinical presentation in 64 patients.

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.     

Hypoplasia and hypodontia in Van der Woude syndrome.

OBJECTIVE: The purpose of this study was (1) to assess maxillary development in cleft individuals with Van der Woude syndrome (VWS) and (2) to compare hypodontia in VWS and nonsyndromic cleft matched controls. DESIGN AND SETTING: Retrospective case-control study from the Center for Craniofacial Anomalies, University of California, San Francisco, California. PATIENTS AND PARTICIPANTS: The sample consisted of 15 individuals with Van der Woude syndrome and 15 nonsyndromic cleft lip and/or palate controls paired for age, gender, and cleft type in the age range of 5 to 13 years. MAIN OUTCOME MEASURES: Cephalograms were digitized, and 31 linear and angular measurements were made. Serial panoramic radiographs were used to assess the presence or absence of permanent teeth. RESULTS: The maxillary sagittal position represented by midface length (Co-A) was significantly shorter in the Van der Woude syndrome subjects than in the matched controls (p = .031), suggesting a trend towards greater maxillary hypoplasia, particularly in Van der Woude syndrome with bilateral cleft lip and/ or palate. Measurements indicating sagittal jaw relationship (ANB angle and the Wits) were significantly smaller in the children with Van der Woude syndrome than in matched controls (p = .008 and p = .006). A significantly larger number of individuals with Van der Woude syndrome than matched controls had missing teeth (p = .014). The mandibular second premolar was missing more frequently in children with Van der Woude syndrome than in the matched controls (p = .031). The differences concerning both maxillary hypoplasia and hypodontia were most marked in the more severe cleft type, represented by bilateral cleft lip and/or palate. CONCLUSIONS: Based on these findings, the expectation is that there will be maxillary hypoplasia and hypodontia of greater severity in Van der Woude syndrome than in nonsyndromic clefts.     

Van der Woude syndrome: a case report

Among the many disturbances of development and growth that involve the oral and perioral structures, cleft lip and palate is perhaps the commonest. Dental literature is replete with syndromes associated with cleft lip and palate, one of which is Van der Woude syndrome. The characteristics of Van der Woude syndrome is the association of cleft lip and/or palate with distinctive lower lip pits. A case of Van der Woude syndrome in an 11-year-old boy and his sister is presented.     

干扰素调节因子6基因致病的Van der Woude综合征的家系调查和遗传特点分析

目的 探讨中国人Van der Woude综合征（VWS）的临床表型及遗传学特点。方法 先证者法收集14个VWS家系并进行口腔专科检查、家系调查及基因突变分析,分析不同VWS家系个体或同一家系不同个体的临床表型,绘制家系图谱,明确遗传方式及致病基因,计算表型分布频率和表型基因频率。结果 VWS家系基本符合常染色体显性遗传特征,患者多数表现为典型的VWS,致病基因为干扰素调节因子6（IRF6）。VWS表型分布频率为：唇瘘91.9%,唇腭裂73.0%,牙畸形8.1%。不同家系个体和同一家系的不同个体临床表型存在明显差异。结论 收集的家系均为常染色体显性遗传,表现度变异大。中国人群VWS致病基因为IRF6,为Ⅰ型VWS。     

一个范德伍德综合征家系的IRF6基因突变检测

目的:对收集的1个湖北Van der Woude综合征(VWS)家系进行临床和遗传特点分析,并进行IRF6基因的突变检测。方法:通过先证者及现场家系调查、临床检查和系谱分析收集VWS家系。在IRF6基因的外显子-内含子接头及9个外显子编码区分别设计引物,经聚合酶链式反应扩增并纯化后直接测序。结果:收集的VWS家系符合常染色体显性遗传特征,家系受累患者共3名(1名男性和2名女性),患者表现为典型的下唇瘘管或凹陷,且合并有唇腭裂和先天缺牙。患者表型在同一家系内有明显差异,且呈逐代加重趋势。在所有患者IRF6基因第412位密码子发现与表型一致的CGA>TGA(c.1234C>T)改变,经查证为一个已知的无义突变。结论:该VWS家系疾病表现度极不一致,是由IRF6基因的1个已知无义突变导致,IRF6是参与颌面部发育的重要基因。     

Van der Woude syndrome: a report of two cases

Van der Woude syndrome is a rare autosomal dominant condition with high penetrance and variable expression. It consists of a cleft lip and/or palate pits on the vermilion of the lower lip, and hypodontia. Two cases of congenital lip pits with cleft lip and alveolus and an isolated cleft palate are described to illustrate the variable presentation of the clinical features and the importance of early recognition of Van der Woude syndrome because of the genetic implications.     

Clinical and genetic studies of Van der Woude syndrome in Sweden.

Van der Woude syndrome (VWS) is an autosomal dominant craniofacial disorder characterized by pits of the lower lip, hypodontia and cleft lip and/or cleft palate. It has been reported as the most common form of syndromic orofacial clefting with very high penetrance and varied expressivity. The disease locus for VWS has been mapped to chomosome 1q32, but the gene is yet to be cloned. Here we report a total of 11 Swedish VWS patients: 9 familial cases from two families and two isolated cases. Clinical examination of these patients showed phenotypic variability, even between patients from the same family. Genetic studies were performed using four microsatellite markers from chromosome 1q32. Constitutional deletion in this region was not demonstrated in any of the familial or isolated cases. However, in the two VWS families, linkage analysis using these markers showed positive LOD (logarithm of the odds) scores ranging from 2.56 to 2.88 to all individual markers. The highest LOD score of 3.75 was obtained with the combined haplotypes of D1S491 and D1S205, thus confirming linkage of VWS in these two families to 1q32. We conclude that there is varied expressivity but no evidence of genetic heterogeneity in VWS.     

Van der Woude syndrome: dentofacial features and implications for clinical practice

Background:  Van der Woude syndrome (VWS) is the most common clefting syndrome in humans. It is characterized by the association of congenital lower lip fistulae with cleft lip and/or cleft palate. VWS individuals have a high prevalence of hypodontia. Although caused by a single gene mutation, VWS has variable phenotypic expression. This study aimed to describe the range of clinical presentations in 22 individuals with VWS to facilitate its diagnosis.
Methods:  A retrospective study of 22 patients with a diagnosis of VWS was undertaken at the Australian Craniofacial Unit (ACFU) in Adelaide. Three extended families with affected members were included in the study cohort.
Results:  The overall prevalence of lip pits in this study cohort was 86%. Cleft phenotypes included bilateral cleft lip and palate (32%); unilateral cleft lip and palate (32%); submucous cleft palate (23%); and isolated cleft hard and soft palate (9%). Missing permanent teeth were reported in 86% of affected individuals.
Conclusions:  Submucous cleft palate in VWS may go undiagnosed if the lower lip pits are not detected. Associated hypodontia and resultant malocclusions will also require management by a dental team.     

Correlations between microforms of the Van der Woude syndrome and cleft palate

The lower lip was examined in 397 children with isolated cleft palate (CP), in 518 cleft lip children with or without cleft palate (CL(P)) and in 1000 noncleft children. Familial occurrence of clefts, other concomitant anomalies and the type and extension of the cleft were determined from the child's medical history. A total of 323 orthopantomograms, taken at the ages of 6-12 years, were available in the detection of hypodontia of the permanent teeth excluding the third molars in the CP group. The incidence of lower lip sinus and microforms (conical elevations, CE) was noted. The incidence of sinuses was 2.3% in the CP group, 2.5% in the CL(P) group and 0% in the noncleft group. The corresponding figures for CE were 39.3%, 0.8% and 0.7%, respectively. In the CP group with CE, the familial occurrence of clefts was statistically higher (30.0%) than in the group without CE (20.7%). The corresponding figures for hypodontia were 40.7% and 24.7%, respectively. Conical elevations are cleft palate related disturbances in the development of the lower lip. At least in certain cases the CE do represent microforms of the sinus syndrome. Thus the question arises: do the CE always represent microforms of the Van der Woude syndrome, or are they only pathogenic similarities of a variable etiology?     

Surgical correction of congenital lower lip sinuses in Van der Woude syndrome.

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.     

Treatment of lower lip pits in Van der Woude syndrome: a systematic review

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.