Popliteal Pterygium Syndrome Research Articles

Association and Mutation Analyses of the IRF6 Gene in Families with Nonsyndromic and Syndromic Cleft Lip and/or Cleft Palate

(1) To detect interferon regulatory factor 6 gene (IRF6) mutations in newly recruited Van der Woude syndrome (VWS) and popliteal pterygium syndrome (PPS) families. (2) To test for association, in nonsyndromic cleft lip and/or cleft palate (NSCL/P) and in VWS/PPS families, the single nucleotide polymorphism (SNP) rs642961, from the IRF6 enhancer AP-2α region, alone or as haplotype with rs2235371, a coding SNP (Val274Ile). IRF6 mutation screening was performed by direct sequencing and genotyping of rs642961 and rs2235371 by TaqMan technology. Seventy-one Swedish NSCL/P families, 24 Finnish cleft palate (CP) families, and 24 VWS/PPS families (seven newly recruited) were studied. Allelic and genotypic frequencies in each phenotype were compared to those of the controls, and no significant difference could be observed. IRF6 gene mutation was detected in six of the seven new VWS/PPS families. Association analysis of the entire VWS/PPS sample set revealed the A allele from rs642961 to be a risk allele. Significant association was detected in the Swedish CP subset of our NSCL/P collection where the G-C haplotype for rs642961-rs2235371 were at risk (P = .013). Our results do not support the previously reported association between the A allele of rs642961 and the NSCL phenotype. However, in the VWS/PPS families, the A allele was a risk allele and was, in a large majority (>80%), transmitted on the same chromosome as the IRF6 mutation.

Treatment Outcomes in Patients With Van der Woude and Popliteal Pterygium Syndromes Compared to Patients With Nonsyndromic Cleft Lip/Palate

Van der Woude syndrome (VWS) and popliteal pterygium syndrome (PPS) are allelic autosomal dominant disorders caused by mutations in interferon regulatory factor 6 (IRF6). They comprise the single most common syndromic cause of cleft lip and/or palate (CL/P), accounting for 2% of all cases. VWS is characterized by CL/P and lower lip sinuses; PPS has the same features as VWS plus popliteal webbing, genital malformations, and syngnathia. The aim of this study is to summarize the clinical characteristics and treatment outcomes for patients with VWS/PPS and compare them to those for patients with nonsyndromic CL/P.

Search for genetic modifiers of IRF6 and genotype–phenotype correlations in Van der Woude and popliteal pterygium syndromes

Van der Woude syndrome is the most common form of syndromic orofacial clefting, accounting for 1-2% of all patients with cleft lip and/or cleft palate. Van der Woude and popliteal pterygium syndromes are caused by mutations in IRF6, but phenotypic variability within and among families with either syndrome suggests that other genetic factors contribute to the phenotypes. The aim of this study was to identify common variants acting as genetic modifiers of IRF6 as well as genotype-phenotype correlations based on mutation type and location. We identified an association between mutations in the DNA-binding domain of IRF6 and limb defects (including pterygia). Although we did not detect formally significant associations with the genes tested, borderline associations suggest several genes that could modify the VWS phenotype, including FOXE1, TGFB3, and TFAP2A. Some of these genes are hypothesized to be part of the IRF6 gene regulatory network and may suggest additional genes for future study when larger sample sizes are also available. We also show that families with the Van de Woude phenotype but in whom no mutations have been identified have a lower frequency of cleft lip, suggesting there may be locus and/or mutation class differences in Van de Woude syndrome.

A combined targeted mutation analysis of IRF6 gene would be useful in the first screening of oral facial clefts

BackgroundInterferon Regulatory Factor 6 (IRF6) is a member of the IRF family of transcription factors. It has been suggested to be an important contributor to orofacial development since mutations of the IRF6 gene has been found in Van der Woude (VWS) and popliteal pterygium syndromes (PPS), two disorders that can present with isolated cleft lip and palate. The association between IRF6 gene and cleft lip and palate has also been independently replicated in many populations.MethodsWe screened a total of 155 Taiwanese patients with cleft lip with or without cleft palate (CL/P); 31 syndromic (including 19 VWS families), 44 non-syndromic families with at least two affected members, and 80 non-syndromic patients through a combined targeted, polymerase chain reaction (PCR)-based mutation analysis for the entire coding regions of IRF6 gene.ResultsWe found 11 mutations in 57.89% (11/19) of the VWS patients and no IRF6 mutation in 44 of the non-syndromic multiplex families and 80 non-syndromic oral cleft patients. In this IRF6 gene screening, five of these mutations (c.290 A>G, p.Tyr97Cys; c.360-375 16 bp deletion, p.Gln120HisfsX24; c.411_412 insA, p.Glu136fsX3; c.871 A>C, p.Thr291Pro; c.969 G>A, and p.Trp323X) have not been reported in the literature previously. Exon deletion was not detected in this series of IRF6 gene screening.ConclusionsOur results confirm the crucial role of IRF6 in the VWS patients and further work is needed to explore for its function in the non-syndromic oral cleft with vary clinical features.

Smad4-Irf6 genetic interaction and TGFβ-mediated IRF6 signaling cascade are crucial for palatal fusion in mice

Cleft palate is one of the most common human birth defects and is associated with multiple genetic and environmental risk factors. Although mutations in the genes encoding transforming growth factor beta (TGFβ) signaling molecules and interferon regulatory factor 6 (Irf6) have been identified as genetic risk factors for cleft palate, little is known about the relationship between TGFβ signaling and IRF6 activity during palate formation. Here, we show that TGFβ signaling regulates expression of Irf6 and the fate of the medial edge epithelium (MEE) during palatal fusion in mice. Haploinsufficiency of Irf6 in mice with basal epithelial-specific deletion of the TGFβ signaling mediator Smad4 (Smad4(fl/fl);K14-Cre;Irf6(+/R84C)) results in compromised p21 expression and MEE persistence, similar to observations in Tgfbr2(fl/fl);K14-Cre mice, although the secondary palate of Irf6(+/R84C) and Smad4(fl/fl);K14-Cre mice form normally. Furthermore, Smad4(fl/fl);K14-Cre;Irf6(+/R84C) mice show extra digits that are consistent with abnormal toe and nail phenotypes in individuals with Van der Woude and popliteal pterygium syndromes, suggesting that the TGFβ/SMAD4/IRF6 signaling cascade might be a well-conserved mechanism in regulating multiple organogenesis. Strikingly, overexpression of Irf6 rescued p21 expression and MEE degeneration in Tgfbr2(fl/fl);K14-Cre mice. Thus, IRF6 and SMAD4 synergistically regulate the fate of the MEE, and TGFβ-mediated Irf6 activity is responsible for MEE degeneration during palatal fusion in mice.

Comparative analysis of IRF6 variants in families with Van der Woude syndrome and popliteal pterygium syndrome using public whole-exome databases

Purpose:Mutations in the transcription factor IRF6 cause allelic autosomal dominant clefting syndromes, Van der Woude syndrome, and popliteal pterygium syndrome. We compared the distribution of IRF6 coding and splice-site mutations from 549 families with Van der Woude syndrome or popliteal pterygium syndrome with that of variants from the 1000 Genomes and National Heart, Lung, and Blood Institute Exome Sequencing Projects.Methods:We compiled all published pathogenic IRF6 mutations and performed direct sequencing of IRF6 in families with Van der Woude syndrome or popliteal pterygium syndrome.Results:Although mutations causing Van der Woude syndrome or popliteal pterygium syndrome were nonrandomly distributed with significantly increased frequencies in the DNA-binding domain (P = 0.0001), variants found in controls were rare and evenly distributed in IRF6. Of 194 different missense or nonsense variants described as potentially pathogenic, we identified only two in more than 6,000 controls. PolyPhen and SIFT (sorting intolerant from tolerant) reported 5.9% of missense mutations in patients as benign, suggesting that use of current in silico prediction models to determine function can have significant false negatives.Conclusion:Mutation of IRF6 occurs infrequently in controls, suggesting that for IRF6 there is a high probability that disruption of the coding sequence, particularly the DNA-binding domain, will result in syndromic features. Prior associations of coding sequence variants in IRF6 with clefting syndromes have had few false positives.

Síndrome do pterígio poplíteo: relato de caso e revisão da literatura

A síndrome do pterígio poplíteo é uma condição congênita rara, que envolve anomalias craniofaciais, geniturinárias e de extremidades. As características mais marcantes dessa síndrome são o pterígio poplíteo e uma dobra de pele triangular sobre a unha do hálux. Neste trabalho, é apresentado o caso de um paciente do sexo masculino, com um mês de idade, apresentando fendas labiais superiores e inferiores, fenda palatal, bolsa escrotal bífida, sindactilia de pododáctilos, pterígio poplíteo e dobra de pele sobre a unha do hálux. O paciente foi submetido a diversas intervenções cirúrgicas, visando à correção das anomalias. Dentre as malformações, a mais difícil de ser corrigida é a relacionada aos membros inferiores, sendo necessária abordagem conjunta com a equipe de ortopedia, na tentativa de evitar enxertos nervosos e déficits funcionais. A síndrome do pterígio poplíteo, quando tratada no momento apropriado e por equipe multidisciplinar, apresenta bom prognóstico.

A comprehensive review of the genetic basis of cleft lip and palate

Cleft lip and palate (CLP) are birth defects that affect the upper lip and the roof of the mouth. CLP has a multifactorial etiology, comprising both genetic and environmental factors. In this review we discuss the recent data on the etiology of cleft lip and palate. We conducted a search of the MEDLINE database (Entrez PubMed) from January 1986 to December 2010 using the key words: ‘cleft lip,’ ‘cleft palate,’ ‘etiology,’ and ‘genetics.’ The etiology of CLP seems complex, with genetics playing a major role. Several genes causing syndromic CLP have been discovered. Three of them—T-box transcription factor-22 (TBX22), poliovirus receptor-like-1 (PVRL1), and interferon regulatory factor-6 (IRF6)—are responsible for causing X-linked cleft palate, cleft lip/palate–ectodermal dysplasia syndrome, and Van der Woude and popliteal pterygium syndromes, respectively; they are also implicated in nonsyndromic CLP. The nature and functions of these genes vary widely, illustrating the high vulnerability within the craniofacial developmental pathways. The etiological complexity of nonsyndromic cleft lip and palate is also exemplified by the large number of candidate genes and loci. To conclude, although the etiology of nonsyndromic CLP is still largely unknown, mutations in candidate genes have been identified in a small proportion of cases. Determining the relative risk of CLP on the basis of genetic background and environmental influence (including smoking, alcohol use, and dietary factors) will be useful for genetic counseling and the development of future preventive measures.

Mutations in RIPK4 Cause the Autosomal-Recessive Form of Popliteal Pterygium Syndrome

The autosomal-recessive form of popliteal pterygium syndrome, also known as Bartsocas-Papas syndrome, is a rare, but frequently lethal disorder characterized by marked popliteal pterygium associated with multiple congenital malformations. Using Affymetrix 250K SNP array genotyping and homozygosity mapping, we mapped this malformation syndrome to chromosomal region 21q22.3. Direct sequencing of RIPK4 (receptor-interacting serine/threonine kinase protein 4) showed a homozygous transversion (c.362T>A) that causes substitution of a conserved isoleucine with asparagine at amino acid position 121 (p.Ile121Asn) in the serine/threonine kinase domain of the protein. Additional pathogenic mutations-a homozygous transition (c.551C>T) that leads to a missense substitution (p.Thr184Ile) at a conserved position and a homozygous one base-pair insertion mutation (c.777_778insA) predicted to lead to a premature stop codon (p.Arg260ThrfsX14) within the kinase domain-were observed in two families. Molecular modeling of the kinase domain showed that both the Ile121 and Thr184 positions are critical for the protein's stability and kinase activity. Luciferase reporter assays also demonstrated that these mutations are critical for the catalytic activity of RIPK4. RIPK4 mediates activation of the nuclear factor-κB (NF-κB) signaling pathway and is required for keratinocyte differentiation and craniofacial and limb development. The phenotype of Ripk4(-/-) mice is consistent with the human phenotype presented herein. Additionally, the spectrum of malformations observed in the presented families is similar, but less severe than the conserved helix-loop-helix ubiquitous kinase (CHUK)-deficient human fetus phenotype; known as Cocoon syndrome; this similarity indicates that RIPK4 and CHUK might function via closely related pathways to promote keratinocyte differentiation and epithelial growth.

Popliteal pterygium syndrome: Orofacial and general features

This report describes the case of a 13-year-old Indian boy with popliteal pterygium syndrome. The popliteal pterygium syndrome is an extremely rare hereditary disorder thought to occur with an incidence of approximately 1 in 300000 live births. It is a congenital malformation syndrome affecting the face, limbs, and genitalia with highly characteristic features, including popliteal webbing, cleft palate (with or without cleft lip), lower lip pits, syndactyly, and genital and nail anomalies. This patient was referred to our department because of complaints of pain in the mouth and poor oral health. The orofacial findings included cleft lip, cleft palate, lower lip pits, a few missing teeth, and severely decayed teeth. In this syndrome, the orodental problems are overshadowed by the major syndromic manifestations but nevertheless need appropriate management. These patients have special dental needs and early diagnosis of the affected children is therefore important in order to initiate preventive dental care and carry out appropriate dental treatment at the optimal time.

Two missense mutations of the IRF6 gene in two Japanese families with popliteal pterygium syndrome

Mutations in the interferon regulatory factor 6 gene (IRF6) cause either popliteal pterygium syndrome (PPS) or Van der Woude syndrome (VWS), allelic autosomal dominant orofacial clefting conditions. To further investigate the IRF6 mutation profile in PPS, we performed mutation analysis of patients from two unrelated Japanese families with PPS and identified mutations in IRF6: c.251G>T (R84L) and c.1271C>T (S424L). We also found R84L, which together with previous reports on R84 mutations, provided another line of evidence that both syndromes could result from the same mutation probably under an influence of a modifier gene(s). This supports the idea that the R84 residue in the DNA binding domain of IRF6 is a mutational hot spot for PPS. A luciferase assay of the S424L protein in the other family demonstrated that the mutation decreased the IRF6 transcriptional activity significantly to 6% of that of the wild-type. This finding suggests that the C-terminus region of IRF6 could have an important function in phosphorylation or protein interaction. To our knowledge, this is the first report of mutations observed in Japanese PPS patients.

Identification of a Van der Woude syndrome mutation in the cleft palate 1 mutant mouse

Mutations in Interferon Regulatory Factor 6 (IRF6) have been identified in two human allelic syndromes with cleft lip and/or palate: Van der Woude (VWS) and Popliteal Pterygium syndromes (PPS). Furthermore, common IRF6 haplotypes and single nucleotide polymorphisms (SNP) alleles are strongly associated with nonsyndromic clefting defects in multiple ethnic populations. Mutations in the mouse often provide good models for the study of human diseases and developmental processes. We identified the cleft palate 1 (clft1) mouse mutant in a forward genetic screen for phenotypes modeling human congenital disease. In the clft1 mutant, we have identified a novel missense point mutation in the mouse Irf6 gene, which confers an amino acid alteration that has been found in a VWS family. Phenotypic comparison of clft1 mutants to previously reported Irf6 mutant alleles demonstrates the Irf6(clft1) allele is a hypomorphic allele. The cleft palate seen in these mutants appears to be due to abnormal adhesion between the palate and tongue. The Irf6(clft1) allele provides the first mouse model for the study of an etiologic IRF6 missense mutation observed in a human VWS family.

Congenital unilateral maxillo-mandibulo-zygomatic fusion (syngnathia): A case report in an 8-year-old boy

Congenital causes of limited mouth opening involving fusion of maxilla and mandible (syngnathia) are rare anomalies that often present as part of syndromes such as Van der Woude and popliteal pterygium syndrome. Surgical management involves division of the bony fusion or breakdown of the adhesions in the first few days of life. The authors present a case of maxillo-mandibulo-zygomatic fusion (syngnathia) in an 8-year-old boy, who underwent surgical intervention to achieve adequate jaw function.

Variable phenotypic manifestation of IRF6 mutations in the Van der Woude syndrome and popliteal pterygium syndrome: implications for genetic counseling

Variable phenotypic manifestation of IRF6 mutations in the Van der Woude syndrome and popliteal pterygium syndrome: implications for genetic counseling

Integration of IRF6 and Jagged2 signalling is essential for controlling palatal adhesion and fusion competence

In mammals, adhesion and fusion of the palatal shelves are essential mechanisms during the development of the secondary palate; failure of these processes leads to the congenital anomaly, cleft palate. The mechanisms that prevent pathological adhesion between the oral and palatal epithelia while permitting adhesion and subsequent fusion of the palatal shelves via their medial edge epithelia remain obscure. In humans, mutations in the transcription factor interferon regulatory factor 6 (IRF6) underlie Van der Woude syndrome and popliteal pterygium syndrome. Recently, we have demonstrated that mice homozygous for a mutation in Irf6 exhibit abnormalities of epithelial differentiation that results in cleft palate as a consequence of adhesion between the palatal shelves and the tongue. In the current paper, we demonstrate that Irf6 is essential for oral epithelial differentiation and that IRF6 and the Notch ligand Jagged2 function in convergent molecular pathways during this process. We further demonstrate that IRF6 plays a key role in the formation and maintenance of the oral periderm, spatio-temporal regulation of which is essential for ensuring appropriate palatal adhesion.

Popliteal pterygium knee contracture: Treatment with the Ilizarov technique

Various treatment options are in use to address severe knee flexion contractures in children. Their success depends on an adequate selection of the proper one applying to each individual anatomical situation. Applied to limb deformity, the Ilizarov technique combines progressive correction, to joint structures flexibility restitution in case of severe knee flexion contracture. We review a continuous series of popliteal pterygium syndrome patients managed with this technique. Medical records of eight children (11 knees), consecutively treated between 1986 and 2007, were reviewed. Knee flexion ranged from 40 to 120 degrees. Contracture (> 90 degrees) was extremely severe in 10 cases. Progressive correction was gained by Ilizarov external fixation. Complications during and following articular chain distraction-lengthening were noted. Follow-up ranged from 1 to 21 years. Surgical realignment was rendered particularly complex by the popliteal cutaneous band itself, partly responsible of the joint stiffness and sciatic nerve shortening. Deformities were corrected by the Ilizarov technique. Complete extension was obtained in all cases. In six cases, flexion contracture reccurrence required to repeat the correction, using the same technique, at a mean interval of 3-4 years. During follow-up, four evolutive partial posterior tibial dislocations and one complete dislocation were diagnosed, all associated with recurrence of the flexion contracture. Level IV. Therapeutic Study.

Prevalence and nonrandom distribution of exonic mutations in interferon regulatory factor 6 in 307 families with Van der Woude syndrome and 37 families with popliteal pterygium syndrome

PurposeInterferon regulatory factor 6 encodes a member of the IRF family of transcription factors. Mutations in interferon regulatory factor 6 cause Van der Woude and popliteal pterygium syndrome, two related orofacial clefting disorders. Here, we compared and contrasted the frequency and distribution of exonic mutations in interferon regulatory factor 6 between two large geographically distinct collections of families with Van der Woude and between one collection of families with popliteal pterygium syndrome. MethodsWe performed direct sequence analysis of interferon regulatory factor 6 exons on samples from three collections, two with Van der Woude and one with popliteal pterygium syndrome. ResultsWe identified mutations in interferon regulatory factor 6 exons in 68% of families in both Van der Woude collections and in 97% of families with popliteal pterygium syndrome. In sum, 106 novel disease-causing variants were found. The distribution of mutations in the interferon regulatory factor 6 exons in each collection was not random; exons 3, 4, 7, and 9 accounted for 80%. In the Van der Woude collections, the mutations were evenly divided between protein truncation and missense, whereas most mutations identified in the popliteal pterygium syndrome collection were missense. Further, the missense mutations associated with popliteal pterygium syndrome were localized significantly to exon 4, at residues that are predicted to bind directly to DNA. ConclusionThe nonrandom distribution of mutations in the interferon regulatory factor 6 exons suggests a two-tier approach for efficient mutation screens for interferon regulatory factor 6. The type and distribution of mutations are consistent with the hypothesis that Van der Woude is caused by haploinsufficiency of interferon regulatory factor 6. On the other hand, the distribution of popliteal pterygium syndrome-associated mutations suggests a different, though not mutually exclusive, effect on interferon regulatory factor 6 function.

Congenital maxillomandibular syngnathia: Case report

Congenital maxillomandibular fusion is a very rare condition with few cases reported. Cases of combinations of bony or soft tissue adhesions between the mandible and maxilla with cleft of the lip or palate, aglossia, popliteal pterygium and van der Woude syndrome have been reported. The aim of this paper is to report a case of fibrous maxillomandibular fusion of the jaws, with synechiae of buccal mucosa and the gingivae, which was referred to the Oral and Maxillofacial team of the Korle-Bu Teaching Hospital, Accra, Ghana soon after delivery. Separation of the fusion was done under nitrous oxide/oxygen sedation. Cleft of the hard palate was discovered during surgery. Maxillomandibular syngnathia is considered rare and synechiae with other maxillofacial abnormalities without syngnathia could exist and should not be ruled out. This report adds more information to the literature, by reporting a baby with synechiae and a cleft of the palate. Prompt, definitive diagnosis and management of other abnormalities in the baby could only be done under deep sedation. This was necessary to avoid deformity and early death.

Missense mutations that cause Van der Woude syndrome and popliteal pterygium syndrome affect the DNA-binding and transcriptional activation functions of IRF6

Missense mutations that cause Van der Woude syndrome and popliteal pterygium syndrome affect the DNA-binding and transcriptional activation functions of IRF6

Atuação fonoaudiológica na Unidade De Terapia Intensiva em bebê com síndrome de pterígeo poplíteo

O objetivo deste estudo foi descrever a intervenção fonoaudiológica para a adequação da função alimentar por meio da avaliação e tratamento do sistema estomatognático e suas funções. O estudo foi feito a partir do relato de caso de um recém-nascido portador da Síndrome de Pterígio Poplíteo, que foi alimentado por sonda, atendido na Unidade de Tratamento Intensivo Neonatal. A avaliação fonoaudiológica apresentou os seguintes resultados: mandíbula retraída com pouca abertura, gengivas superiores e inferiores hipertróficas, palato com fissura pós-forame incisivo incompleta, reflexos orais de alimentação (busca, sucção, deglutição) presentes e adequados; reflexos de defesa (mordida, gag) anteriorizados e exacerbados. Apresentou pouca tolerância ao toque intra-oral. A sucção não nutritiva teve como resultado um número de sucções/pausas de 3:1, com ritmo presente, com força débil. Na sucção nutritiva, por meio da mamadeira, apresentou sucções/pausa de 5:1, com pausas longas. Foram observados sinais de estresse de alteração respiratória, estridor inspiratório leve, um episódio de engasgo e reflexo de gag anteriorizado e exacerbado, demonstrando hipersensibilidade oral em resposta ao bico convencional da mamadeira. Foram realizadas cinco sessões de intervenção fonoaudiológica, com orientações para a mãe e a equipe de enfermagem sobre postura, estimulação oral e uso de bico ortodôntico. O recém-nascido teve alta com via oral plena e com bom ganho de peso.