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.     

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: 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.     

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。     

Congenital lower lip pits (Van der Woude syndrome): report of a case

Van der Woude syndrome (VWS) is a rare autosomal dominant disorder that is characterized by a cleft lip and palate with congenital lip pits. This is a report of a case of VWS with sinuses in the lower lip, a cleft in the upper lip, and a supernumerary tooth in the maxilla. The main characteristics of this disorder are discussed. Dental treatment of the patient was performed, but the surgical removal of the sinus was rejected by the parents. This case report brings this condition to the attention of dentists and surgeons and emphasizes lip pits may not always be identical in appearance.     

Popliteal pterygium syndrome in a Swedish family-clinical findings and genetic analysis with the van der Woude syndrome locus at 1q32-q41

The present study describes a Swedish family in which the mother and her son were affected with signs of popliteal pterygium syndrome (PPS, OMIM 119500). Both individuals had bilateral complete cleft lip and palate, oral synechiae, paramedian pits on the lower lip, toe syndactyly and a piece of triangular skin overgrowth on the great toes. The son also presented with soft tissue syndactyly of the 2nd and 3rd fingers. Although popliteal pterygium was not found, the above clinical features were diagnostic for PPS. Chromosomal abnormalities were not revealed in either case by cytogenetic analyses. A test for microdeletion in the VWS region at 1q32-q41 was performed in the family using 5 polymorphic microsatellite markers from the region. The affected son was found to be heterozygous for all 5 markers, suggesting that microdeletion at the VWS region was unlikely. The VWS locus, however, was not excluded by haplotype analysis of the family.     

Popliteal pterygium syndrome in a Swedish family--clinical findings and genetic analysis with the van der Woude syndrome locus at 1q32-q41

The present study describes a Swedish family in which the mother and her son were affected with signs of popliteal pterygium syndrome (PPS, OMIM 119500). Both individuals had bilateral complete cleft lip and palate, oral synechiae, paramedian pits on the lower lip, toe syndactyly and a piece of triangular skin overgrowth on the great toes. The son also presented with soft tissue syndactyly of the 2nd and 3rd fingers. Although popliteal pterygium was not found, the above clinical features were diagnostic for PPS. Chromosomal abnormalities were not revealed in either case by cytogenetic analyses. A test for microdeletion in the VWS region at 1q32-q41 was performed in the family using 5 polymorphic microsatellite markers from the region. The affected son was found to be heterozygous for all 5 markers, suggesting that microdeletion at the VWS region was unlikely. The VWS locus, however, was not excluded by haplotype analysis of the family.     

Genetic association studies of cleft lip and/or palate with hypodontia outside the cleft region.

OBJECTIVE: The purpose of this study was to determine whether the candidate genes previously studied in subjects with cleft lip, cleft palate, or both are associated with hypodontia outside the region of the cleft. SUBJECTS: One hundred twenty subjects from the Iowa Craniofacial Anomalies Research Center were selected based on the availability of both dental records and genotype information. METHOD: The type of orofacial clefting and type and location of dental anomalies (missing teeth, supernumerary teeth, or peg laterals) were assessed by dental chart review and radiographic examination. Genotype analysis of candidate genes was performed using polymerase chain reaction/single-strand conformation polymorphism analysis. RESULTS: The prevalence of hypodontia in this sample was 47.5%, with 30.0% of subjects having missing teeth outside the cleft. There was a positive association between subjects with cleft lip or cleft lip and palate who had hypodontia outside the cleft region (compared with noncleft controls) and both muscle segment homeo box homolog 1 (MSX1) (p =.029) and transforming growth factor beta 3 (TGFB3) (p =.024). It was not possible in this analysis to determine whether this association was specifically associated with orofacial clefting combined with hypodontia or whether it was due primarily to the clefting phenotype. CONCLUSIONS: In this sample, there was a significantly greater incidence of hypodontia outside the cleft region in subjects with cleft lip and palate, compared with cleft lip only or cleft palate only. Cleft lip and/or palate with hypodontia outside the cleft region was positively associated with both TGFB3 and MSX1, compared with noncleft controls.     

Left-sided predominance of hypodontia irrespective of cleft sidedness in a French population

Objective : Individuals with oral clefts exhibit considerably more dental anomalies than do individuals without clefts. Our aim was to evaluate the prevalence of tooth agenesis in a sample composed of 124 children (81 boys and 43 girls, mean age 12.5?years) with clefts registered with the Cleft Palate Center in Strasbourg (France). Design : Cleft types and dental agenesis were assessed by clinical and radiographic examination. Cleft types were divided into four groups according to the clinical extent of the cleft (cleft lip only [CL, 12.9%], cleft lip and alveolus [CLA, 4%], cleft lip and palate [CLP, 49.2%], and cleft palate only [CP, 33.9%]). Results : Of the subjects 63% had evidence of hypodontia: maxillary lateral incisors (54%) and upper and lower premolars (32%) were the most common missing teeth. The number of dental ageneses associated with CP (54%) and CLP (79%) was significantly higher than that with CL (33%). All these anomalies were found in proportionately higher frequencies as the severity of the cleft increased, and we found left side predominance for hypodontia (p < .01) irrespective of cleft sidedness. Conclusions : Both right-sided and left-sided clefts were more frequently correlated with left-sided dental agenesis. This left-sided prevalence suggests that common signaling malfunctions might be involved, both in dental development anomalies and cleft genesis.     

Familial non-syndromic cleft lip and palate--analysis of the IRF6 gene and clinical phenotypes

The aim of this study was to characterize Swedish families with non-syndromic cleft lip and/or palate (NSCL/P) for mutations or other sequence variants in the interferon regulatory factor 6 (IRF6) gene, as well as to describe their cleft phenotypes and hypodontia. Seventeen Swedish families with at least two family members with NSCL/P were identified and clinically evaluated. Extracted DNA from blood samples was used for IRF6 mutation screening. Exonic fragments of the IRF6 gene were sequenced and chromatograms were inspected. Statistical analysis was undertaken with marker- and haplotype association tests. No disease-associated IRF6 mutation could be determined in the families analyzed. One new and seven known single nucleotide polymorphisms (SNPs) were detected. The A allele of SNP rs861019 in exon 2 and the G allele of SNP rs7552506 in intron 3 showed association with cleft lip and palate (CLP; odds ratios of 3.1 and 5.45, respectively). Hypodontia was observed more commonly in individuals affected with CL/P as compared with family members without a cleft (P < 0.01). The hypodontia most often affected the cleft area, possibly representing a secondary effect. The distribution of cleft phenotypes in 15 of the 17 families with NSCL/P differed from the mixed cleft types seen in Van der Woude syndrome (VWS), in that CLP did not occur together with an isolated cleft palate within the same family. It was concluded that mutations of the IRF6 gene are not a common cause for cleft predisposition in Swedish NSCL/P families.     

Tooth agenesis patterns in bilateral cleft lip and palate

Bartzela TN, Carels CEL, Bronkhorst EM, Rønning E, Rizell S, Kuijpers-Jagtman AM. Tooth agenesis patterns in bilateral cleft lip and palate. Eur J Oral Sci 2010; 118: 47–52. © 2010 The Authors. Journal compilation © 2010 Eur J Oral Sci
Individuals with cleft lip and palate present significantly more dental anomalies, even outside the cleft area, than do individuals without clefts. Our aim was to evaluate the prevalence of tooth agenesis and patterns of hypodontia in a large sample of patients with complete bilateral cleft lip and palate (BCLP). Serial panoramic radiographs (the first radiograph was taken at 10.5–13.5 yr of age) of 240 patients with BCLP (172 male patients, 68 female patients) were examined. Third molars were not included in the evaluation. Agenesis of at least one tooth was present in 59.8% of patients. Upper laterals and upper and lower second premolars were missing most frequently. Using the tooth agenesis code (TAC), 52 different agenesis patterns were identified, of which simultaneous agenesis of 12, 22, 15, 25, 35, and 45 was the most frequent pattern. Nine of the 240 patients showed combined BCLP and oligodontia.     

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。     

Novel IRF6 mutations in Chinese patients with Van der Woude syndrome

Van der Woude syndrome (VWS) (OMIM 119300) is a dominantly inherited, developmental disorder that is characterized by pits and/or sinuses of the lower lip and a cleft lip and/or cleft palate. Mutations in the interferon regulatory factor 6 gene (IRF6) have been recently identified in patients with VWS, with more than 60 mutations reported. However, the VWS phenotype, IRF6 mutation genotypes, and their interrelationships in Chinese VWS patients have not been studied. Here, we report 11 Chinese families with variable clinical phenotypes of VWS and identified mutations in all patients. Of the 11 mutations, 8 appeared to be novel: CC5.6GT, T342A, 566delA, C748T, C756A, C989A, C1209G, and 1316delT. Seven mutations caused a change or loss of the IRF6 domain. The marked phenotypic variation may be caused by the action of certain modifier genes on IRF6 function.     

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.     

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.     

The relationship between hypodontia in the second premolar region and heredity of cleft, lip and palate in children with isolated cleft palate

The aim of the investigation was to study the relationship between hypodontia in the second premolar region and heredity of cleft lip and palate (CLP) in children with isolated cleft palate (CP). The following null-hypothesis was tested: The heredity for CLP will not give rise to higher prevalence of hypodontia in the second premolar region of the maxilla and the mandible in CP-patients. The material consisted of 188 children born with non-syndromic CP (77 boys and 111 girls). Surgical files initiated at birth and panoramic radiographs at ten years of age have been studied concerning heredity for CLP and hypodontia of second premolars. For all CP-children, irrespective of hereditary background the prevalence of second premolar hypodontia did not differ significantly. However, there was a tendency to higher prevalence of hypodontia of the lower second premolars. The null-hypothesis: The heredity for CLP will not give rise to higher prevalence of hypodontia in the second premolar region of the maxilla and the mandible in CP-patients was not rejected.     

Dental anomalies of number in the permanent dentition of patients with bilateral cleft lip: radiographic study

Objective: To radiographically evaluate the prevalence of dental anomalies in patients with complete and incomplete bilateral cleft lip, comparing the prevalence of anomalies between genders and cleft types. Setting: Hospital for Rehabilitation of Craniofacial Anomalies, University of S?o Paulo (HRAC/USP), Bauru, S?o Paulo, Brazil. Participants: 150 randomly selected panoramic radiographs of individuals with complete or incomplete bilateral cleft lip; patient age 12 to 25 years (mean age 13.8 years). Results: Data were statistically analyzed to compare the possible association between presence of hypodontia and supernumerary teeth, according to gender and cleft type. Among the 150 patients evaluated, 80 (53.3%) were male and 70 (46.6%) were female. Since no statistically significant difference was found in hypodontia between genders, data were grouped for analysis, revealing prevalence of 31.6% for complete clefts and 26.8% for incomplete clefts. Concerning supernumerary teeth, the prevalence for the male patients was 28.2% for complete cleft lip and 29.2% for incomplete cleft lip. For female patients, the prevalence was significantly (p = .006) lower for complete cleft lip (17.5%) than for incomplete cleft lip (46.6%). Conclusions: The present results suggest that the prevalence of hypodontia was higher in patients with complete cleft lip, and the prevalence of supernumerary teeth was higher in patients with incomplete cleft lip, in agreement with previous studies.     

A review of tooth formation in children with cleft lip/palate

The literature on tooth formation in children with cleft lip and/or palate is reviewed. The main focus of interest is the association of cleft type and dental abnormalities in number, size, shape, timing of formation, and eruption and cause of the abnormalities. The upper lateral incisor is the most susceptible to injury in the area of cleft in both deciduous and permanent dentitions. This tooth is affected in most instances, even in the cases of microforms of the cleft lip. The prevalence of hypodontia increases strongly with the severity of cleft. More teeth are congenitally missing from the upper jaw than from the lower jaw; however, in the permanent dentition both jaws are affected. Very high prevalence of hypodontia are observed in connection with the Van der Woude syndrome associated with cleft and with the Pierre Robin anomaly. Hypodontia is similarly prevalent in subjects with isolated cleft palate with and without a positive family history of clefts. The prevalence of hypodontia varies largely in different populations. Asymmetric formation of the contralateral teeth is a milder form of hypodontia. The prevalence of asymmetrically developing pairs of teeth is far more common in children with clefts than in children with normal palates or lips. In the permanent dentition the timing of tooth formation is delayed in children from all cleft groups compared to noncleft children. The delay lengthens (with increasing severity of cleft) from 0.3 to 0.7 years and is similar in all permanent teeth in both jaws. In children with hypodontia, the delay is still more severe. As the child becomes older, the delay may increase.(ABSTRACT TRUNCATED AT 250 WORDS)     

Isolated soft tissue cleft lip: epidemiology and associated dental anomalies

Oral Diseases (2011) 17 , 221–231 Objectives: The aim of this investigation was to study the epidemiology of the isolated soft tissue cleft lip (ICL) population and to evaluate the dental anomalies associated with permanent dentition. Methods: The study included 19 children aged 9–13 years presenting ICL selected from 657 cleft lip‐affected patients treated during the last 10 years in two craniofacial centers. Only 17 patients could be included for dental anomaly evaluation: Hyperdontia, Hypodontia, Gemination, Talon tooth, Microdontia, and Macrodontia. These were compared with cleft lip and palate (CLP) and cleft lip and alveolus (CLA)‐affected populations and with normal populations. Results: The prevalence of ICL was 2.8%. All types of tooth abnormalities were found to be higher and mainly significant for the cleft side of ICL compared with the normal population. On the side opposite the cleft, the prevalence of dental anomalies reduced toward the normal individuals and was not significantly different. The significant differences found between CLP, CLA, and ICL‐affected populations were mostly depicted by lateral incisors and second pre‐molar hypodontia. Conclusions: Isolated cleft lip is a rare phenomenon among the spectrum of the cleft‐affected population. The prevalence of the dental anomalies in ICL maintains the proportional trend according to clefting severity.     

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?