Popliteal Pterygium Syndrome Research Articles

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

Cleft lip and cleft palate (CLP) are common disorders that occur either as part of a syndrome, where structures other than the lip and palate are affected, or in the absence of other anomalies. Van der Woude syndrome (VWS) and popliteal pterygium syndrome (PPS) are autosomal dominant disorders characterized by combinations of cleft lip, CLP, lip pits, skin-folds, syndactyly and oral adhesions which arise as the result of mutations in interferon regulatory factor 6 (IRF6). IRF6 belongs to a family of transcription factors that share a highly conserved N-terminal, DNA-binding domain and a less well-conserved protein-binding domain. To date, mutation analyses have suggested a broad genotype–phenotype correlation in which missense and nonsense mutations occurring throughout IRF6 may cause VWS; in contrast, PPS-causing mutations are highly associated with the DNA-binding domain, and appear to preferentially affect residues that are predicted to interact directly with the DNA. Nevertheless, this genotype–phenotype correlation is based on the analysis of structural models rather than on the investigation of the DNA-binding properties of IRF6. Moreover, the effects of mutations in the protein interaction domain have not been analysed. In the current investigation, we have determined the sequence to which IRF6 binds and used this sequence to analyse the effect of VWS- and PPS-associated mutations in the DNA-binding domain of IRF6. In addition, we have demonstrated that IRF6 functions as a co-operative transcriptional activator and that mutations in the protein interaction domain of IRF6 disrupt this activity.

A novel mutation in IRF6 resulting in VWS–PPS spectrum disorder with renal aplasia

Popliteal pterygium syndrome (PPS) and Van der Woude syndrome (VWS) are caused by mutations in the gene interferon regulatory factor 6 (IRF6). Skeletal, genital malformations and involvement of the skin occur in PPS and orofacial clefting and lip pits occur in both. We report on a patient with unilateral cleft lip and palate, ankyloblepharon, paramedian lip pits, unilateral renal aplasia, and a coronal hypospadias. By sequencing IRF6, we detected a novel missense mutation (Arg339Ile). The other family members were unaffected and had no IRF6 mutations, including the patient's brother who was also born with hypospadias. The patient and his brother were both conceived by in vitro fertilization (IVF). It is discussed whether the renal malformation in the patient is related to the IVF procedure or to the IRF6 mutation.

The Shikani Optical Stylet: a useful adjunct to airway management in a neonate with popliteal pterygium syndrome

The craniofacial abnormalities of popliteal pterygium syndrome present unique challenges to the pediatric anesthetist. Congenital fibrous bands between the maxilla and mandible limit mouth opening and the tongue may be fused to the palate. We describe the use of the Shikani Optical Stylet, a novel fiberoptic endoscope, in the airway management of a neonate with popliteal pterygium syndrome and syngnathia.

Poster 091: Two Missense Mutations of the IRF6 Gene in 2 Japanese Families With Popliteal Pterygium Syndrome

Mutations in the interferon regulatory factor 6 gene (IRF6) cause popliteal pterygium syndrome (PPS), a rare autosomal dominant orofacial clefting syndrome accompanied by skin and genital anomalies. We encountered two Japanese familes in which several members were affected with PPS. Here we report results of mutation analysis and functional study of mutated alleles identified in the families.

Popliteal pterygium syndrome (PPS) with intra-alveolar syngnathia: A discussion of anesthetic and surgical considerations

Popliteal pterygium syndrome (PPS) is a rare genetic disorder that involves the association of a popliteal web with a combination of craniofacial, genitourinary and extremity malformations. In this article, we describe a patient with PPS complicated with multiple intra-alveolar syngnathia. We discuss the anesthetic and the surgical management of this case and review the literature regarding PPS and intra-alveolar syngnathia.

PR38 PTERYGIUM SYNDROME: A SPECTRUM OF FEATURES

Pterygium Syndrome is an extremely rare and complex congenital disorder consisting of severe contractures involving multiple flexural surfaces and associated craniofacial abnormalities, including mandibular hypoplasia and epicanthic folds. It is also often associated with other congenital abnormalities of the cardiovascular, respiratory and genitourinary systems. It may present in different forms including multiple Pterygium Syndrome of Escobar, lethal multiple Pterygium Syndrome, Popliteal Pterygium Syndrome and Arthrogryposis Multiplex Congenita. The incidence is unknown, a mutation in the IRF6 gene has been found in the Popliteal varient and it is postulated that the pterygia result from the embryonic onset of foetal akinesia. The clinical presentation, multidisciplinary management and longterm outcome of three patients with this condition, managed in the Australian CranioFacial Unit will be presented.

Interferon regulatory factor 6 (IRF6) and fibroblast growth factor receptor 1 (FGFR1) contribute to human tooth agenesis

Phenotypic characteristics expressed in syndromes give clues to the factors involved in the cause of isolated forms of the same defects. We investigated two genes responsible for craniofacial syndromes, FGFR1 and IRF6, in a collection of families with isolated tooth agenesis. Cheek swab samples were obtained for DNA analysis from 116 case/parent trios. Probands had at least one developmentally missing tooth, excluding third molars. In addition, we studied 89 cases and 50 controls from Ohio to replicate any positive findings. Genotyping was performed by kinetic polymerase chain-reaction or TaqMan assays. Linkage disequilibrium analysis and transmission distortion of the marker alleles were performed. The same variants in the IRF6 gene that are associated with isolated orofacial clefts are also associated with human tooth agenesis (rs861019, P = 0.058; rs17015215-V274I, P = 0.0006; rs7802, P = 0.004). Mutations in IRF6 cause Van der Woude and popliteal pterygium syndromes. The craniofacial phenotypic characteristics of these syndromes include oral clefts and preferential tooth agenesis of incisors and premolars, besides pits on the lower lips. Also it appears that preferential premolar agenesis is associated with FGFR1 (P = 0.014) and IRF6 (P = 0.002) markers. There were statistically significant data suggesting that IRF6 interacts not only with MSX1 (P = 0.001), but also with TGFA (P = 0.03).

Syngnathia Without Any Other Associated Anomaly: A Very Rare Case Report

Congenital bony fusion of the mandible and maxilla (syngnathia) without any other oral anomalies is a very rare condition. Numerous cases with other anomalies like cleft lip, cleft palate, aglossia have been described. Syngnathia can also occur with Vander Woude syndrome and popliteal pterygium syndrome. This report presents a very rare case of syngnathia with true bony fusion between mandible and maxilla, unusually with no other intra-oral or systemic anomalies, of which only a few cases exist in the world literature.

Irf6 is a key determinant of the keratinocyte proliferation-differentiation switch

The epidermis is a highly organized structure, the integrity of which is central to the protection of an organism. Development and subsequent maintenance of this tissue depends critically on the intricate balance between proliferation and differentiation of a resident stem cell population; however, the signals controlling the proliferation-differentiation switch in vivo remain elusive. Here, we show that mice carrying a homozygous missense mutation in interferon regulatory factor 6 (Irf6), the homolog of the gene mutated in the human congenital disorders Van der Woude syndrome and popliteal pterygium syndrome, have a hyperproliferative epidermis that fails to undergo terminal differentiation, resulting in soft tissue fusions. We further demonstrate that mice that are compound heterozygotes for mutations in Irf6 and the gene encoding the cell cycle regulator protein stratifin (Sfn; also known as 14-3-3sigma) show similar defects of keratinizing epithelia. Our results indicate that Irf6 is a key determinant of the keratinocyte proliferation-differentiation switch and that Irf6 and Sfn interact genetically in this process.

Spectrum of Features in Pterygium Syndrome

Pterygium syndrome is a complex and rare congenital deformity that consists of contractures involving multiple flexural surfaces and associated craniofacial anomalies. It often has associated conditions, including anomalies of the cardiovascular, respiratory, gastrointestinal and genitourinary systems. It may present in different forms, including multiple pterygium syndrome of Escobar, lethal multiple pterygium syndrome, popliteal pterygium syndrome, lethal popliteal syndrome (Bartsocas-Papas syndrome) and arthrogryposis multiplex congenita. The clinical presentation, multidisciplinary management and the long-term outcome in three patients with this condition are presented.

Novel and de novo mutations of the IRF6 gene detected in patients with Van der Woude or popliteal pterygium syndrome

The interferon regulatory factor 6 gene (IRF6) has been identified as the major Van der Woude (VWS) syndrome and popliteal pterygium (PPS) syndrome gene with mutations in the majority of the kindreds. We have studied altogether 17 kindreds from Sweden, Finland, Norway, Thailand and Singapore, and report here 10 mutations, six of them previously unseen. In two kindreds, we could document de novo mutations, both of them changing a codon for a glutamine residue to a stop. No mutation could be detected in the four VWS kindreds from Finland, suggesting a founder effect for a mutation in an atypical noncoding position. Our findings demonstrate that several distinct mutations occur in the Swedish population, and confirm the general notion of a broad spectrum of IRF6 mutations underlying the VWS/PPS phenotypes.

Genomic, cDNA and embryonic expression analysis of zebrafish IRF6, the gene mutated in the human oral clefting disorders Van der Woude and popliteal pterygium syndromes

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.

Novel mutations in the IRF6 gene for Van der Woude syndrome.

Van der Woude syndrome (VWS, OMIM 119300) is an autosomal dominant craniofacial disorder characterized by pits of the lower lip, hypodontia, and cleft lip and/or cleft palate. It is the most common form of syndromic orofacial clefting and has very high penetrance with varied expressivity. The disease locus for VWS has been mapped to a 1.6-cM region on 1q32-41 between D1S205 and D1S491. Recently, mutations have been found in the interferon regulatory factor 6 ( IRF6) gene in patients with VWS and popliteal pterygium syndrome. To identify novel mutations of IRF6 in VWS patients, we screened four Chinese VWS families in all nine exons and their flanking splice junctions by direct sequencing. We identified three missense mutations and one nonsense mutation in IRF6. Our study further confirmed that IRF6 is essential for craniofacial development.

Mutations in IRF6 cause Van der Woude and popliteal pterygium syndromes.

Interferon regulatory factor 6 (IRF6) belongs to a family of nine 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-alpha and -beta after viral infection, but the function of IRF6 is unknown. The gene encoding IRF6 is located in the critical region for the Van der Woude syndrome (VWS; OMIM 119300) locus at chromosome 1q32-q41 (refs 2,3). The disorder is an autosomal dominant form of cleft lip and palate with lip pits, and is the most common syndromic form of cleft lip or palate. Popliteal pterygium syndrome (PPS; OMIM 119500) is a disorder with a similar orofacial phenotype that also includes skin and genital anomalies. Phenotypic overlap and linkage data suggest that these two disorders are allelic. We found a nonsense mutation in IRF6 in the affected twin of a pair of monozygotic twins who were discordant for VWS. Subsequently, we identified mutations in IRF6 in 45 additional unrelated families affected with VWS and distinct mutations in 13 families affected with PPS. Expression analyses showed high levels of Irf6 mRNA along the medial edge of the fusing palate, tooth buds, hair follicles, genitalia and skin. Our observations demonstrate that haploinsufficiency of IRF6 disrupts orofacial development and are consistent with dominant-negative mutations disturbing development of the skin and genitalia.

Mixed clefting type in Rapp‐Hodgkin syndrome

Mixed clefting type (MCT) is the rare occurrence of cleft lip, with or without cleft palate, and cleft palate alone in the same pedigree. Here we present a family with Rapp-Hodgkin syndrome (RHS) that manifests MCT, and use this rare finding to suggest that RHS may be related not only to phenotypically similar syndromes, but seemingly dissimilar ones as well. RHS has obvious phenotypic overlap with other ectodermal dysplasia-clefting syndromes (EDCS), such as ectrodactyly-ectodermal dysplasia-clefting syndrome (EEC) and ankyloblepharon-ectodermal dysplasia-clefting syndrome (AEC), all of which show MCT. MCT is also found in the allelic disorders van der Woude syndrome (VDW) and popliteal-pterygium syndrome (PPS). Therefore, while VDW and PPS have little clinical overlap with the EDCS, the common finding of MCT may indicate closer relationships at the developmental or genetic level.

A Case of a New Syndrome or a Variant of the Rare Popliteal Pterygium Syndrome

The popliteal pterygium syndrome is very rare, and is characterized by a congenital popliteal web accompanying the genitourinary, craniofacial, and musculoskeletal anomalies. We described a case of presumably popliteal pterygium syndrome with severe right popliteal web, right renal agenesis, left bifurcated ninth rib, urethral orifice in the vagina, right presacral discoloration resembling A-V malformation, imperforate anus, skin dimple in the left gluteal region, right calcaneovalgus foot with supernumerary digits and aberrant profunda femoris artery. This is the first report of this combination in the pertinent literature.

A CASE OF A NEW SYNDROME OR A VARIANT OF THE RARE POPLITEAL PTERYGIUM SYNDROME

The popliteal pterygium syndrome is very rare, and is characterized by a congenital popliteal web accompanying the genitourinary, craniofacial, and musculoskeletal anomalies. We described a case of presumably popliteal pterygium syndrome with severe right popliteal web, right renal agenesis, left bifurcated ninth rib, urethral orifice in the vagina, right presacral discoloration resembling A-V malformation, imperforate anus, skin dimple in the left gluteal region, right calcaneovalgus foot with supernumerary digits and aberrant profunda femoris artery. This is the first report of this combination in the pertinent literature.

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.

A case of popliteal pterygium syndrome

Popliteal pterygium syndrome is a rare disorder, usually showing autosomal dominant inheritance. A four-year-old girl presented with a popliteal web on the left extending from the buttock to the heel. She also had an incomplete cleft lip, hypoplastic labia majora and foot/digit/nail anomalies. The popliteal web was released by Z-plasty procedures. However, the patient dropped out of further treatment. Ten years later she was brought again with severe deformity in her left lower extremity, tibial shortening of approximately 15 cm and foot deformity. Nearly-full knee extension was obtained and below-knee amputation was performed at the patient’s request. Plans of inserting a prosthesis was prevented by the loss of contact with the patient and her family.

Popliteal pterygium syndrome: a clinical study of three families and report of linkage to the Van der Woude syndrome locus on 1q32

Popliteal pterygium syndrome (PPS) is a rare autosomal dominant disorder, thought to occur with an incidence of approximately 1 in 300 000 live births. The main clinical manifestations are popliteal...