Submucosal dissection to close wide cleft palate with folded mucoperiosteum for bilateral cleft lip and palate with popliteal pterygium syndrome.

Characteristic features of popliteal pterygium syndrome (PPS) associated with the craniofacial region include cleft palate, syngnathia, and difficulty with reconstruction. We developed a new procedure of submucosal dissection with periosteotomy to close the folded mucosa in bilateral cleft lip and palate patients with PPS. This technique could be applicable for patients with wide cleft palate.

Congenital Maxillomandibular Synechia with Multiple Malformations in a Very-Low-Birth-Weight Infant: A Case Report.

Congenital maxillomandibular synechia is a rare malformation that is characterized by a fusion of the maxilla and mandible. The fusion is fibrous or bony and prevents mouth opening, which causes difficulties in feeding and occasionally in breathing. Although extremely rare, neonatologists must understand the disease because it can be fatal and require emergency treatment after birth. We report the case of a very-low-birth-weight (VLBW) infant with congenital maxillomandibular synechia and other malformations, including cleft palate, syndactyly, and cryptorchidism. The patient presented with extremely limited mouth opening, and endotracheal intubation seemed impossible; fortunately, the patient did not have respiratory distress syndrome. The patient underwent surgical release of the fibrous bands on days 10 and 17, and good mouth opening was achieved. The patient was able to consume breast milk orally and was discharged home at a corrected gestational age of 1 month without recurrence of difficulty in mouth opening or any sequelae. This is the first reported case of a VLBW infant with congenital maxillomandibular synechia who required more complicated management of feeding, surgical intervention, and anesthesia.

Orthopedic Surgical Management of Complicated Congenital Popliteal Pterygium Syndrome: A Case Report.

Introduction: Popliteal pterygium syndrome (PPS) is a rare autosomal-dominant condition that causes fixed flexion deformity of the knee. The popliteal webbing and shortening of the surrounding soft tissue could limit the functionality of the affected limb unless it is surgically corrected. We reported a case of PPS in a pediatric patient encountered in our hospital. Case: A 10-month-old boy came with a congenital abnormally flexed left knee with bilateral undescended testis and syndactyly of the left foot. The left popliteal pterygium extending from the buttock to the calcaneus was observed, with an associated fixed flexion contracture of the knee and equine position of the ankle. Normal vascular anatomy was seen in the angiographic CT scan; therefore, multiple Z-plasty and fibrotic band excision were performed. The sciatic trunk was exposed on the popliteal level, and the fascicular segment was excised from the distal stump and sutured to the proximal stump under the microscope to extend the sciatic nerve for approximately 7 cm. No postoperative complications were reported. Multiple tendons and soft tissue reconstruction were performed when the patient was 2-year-old to correct the adductus and equine deformity of the left foot. Discussion: Surgical correction for popliteal pterygium demands staged techniques to deal with the shortened structure. In our case, multiple Z-plasty were performed, and the fibrotic band was excised until its base with meticulous consideration of the underlying neurovascular bundle. Fascicular shifting technique for sciatic nerve lengthening can be considered in unilateral popliteal pterygium with difficulty extending the knee due to shortened sciatic nerve. The unfavorable outcome of nerve conduction disturbance resulting from the procedure may be multifactorial. Still, the existing foot deformity, including a certain degree of pes equinovarus could be treated by multiple soft tissue reconstructions and adequate rehabilitation to achieve the desired outcome. Conclusion: Multiple soft tissue procedures resulted in acceptable functional outcomes. However, the nerve grafting procedure is still a challenging task. Further study is required to explore the technique in optimizing the nerve grafting procedure for popliteal pterygium.

A Complex Intrachromosomal Rearrangement Disrupting IRF6 in a Family with Popliteal Pterygium and Van der Woude Syndromes.

Clefts of the lip and/or palate (CL/P) are considered the most common form of congenital anomalies occurring either in isolation or in association with other clinical features. Van der woude syndrome (VWS) is associated with about 2% of all CL/P cases and is further characterized by having lower lip pits. Popliteal pterygium syndrome (PPS) is a more severe form of VWS, normally characterized by orofacial clefts, lower lip pits, skin webbing, skeletal anomalies and syndactyly of toes and fingers. Both syndromes are inherited in an autosomal dominant manner, usually caused by heterozygous mutations in the Interferon Regulatory Factor 6 (IRF6) gene. Here we report the case of a two-generation family where the index presented with popliteal pterygium syndrome while both the father and sister had clinical features of van der woude syndrome, but without any point mutations detected by re-sequencing of known gene panels or microarray testing. Using whole genome sequencing (WGS) followed by local de novo assembly, we discover and validate a copy-neutral, 429 kb complex intra-chromosomal rearrangement in the long arm of chromosome 1, disrupting the IRF6 gene. This variant is copy-neutral, novel against publicly available databases, and segregates in the family in an autosomal dominant pattern. This finding suggests that missing heritability in rare diseases may be due to complex genomic rearrangements that can be resolved by WGS and de novo assembly, helping deliver answers to patients where no genetic etiology was identified by other means.

Novel IRF6 variant in orofacial cleft patients from Durban, South Africa.

BACKGROUND: To date, there are over 320 variants identified in the IRF6 gene that cause Van der Woude syndrome or popliteal pterygium syndrome. We sequenced this gene in a South African orofacial cleft cohort to identify the causal IRF6 variants in our population. METHOD: Saliva samples from 100 patients with syndromic and non-syndromic CL ± P were collected. Patients were recruited from the cleft clinics at two public, tertiary hospitals in Durban, South Africa (SA), namely Inkosi Albert Luthuli Central Hospital (IALCH) and KwaZulu-Natal Children's Hospital (KZNCH). We prospectively sequenced the exons of IRF6 in 100 orofacial cleft cases, and where possible, we also sequenced the parents of the individuals to determine the segregation pattern. RESULTS: Two variants were identified; one novel (p.Cys114Tyr) and one known (p.Arg84His) missense variant in IRF6 gene were identified. The patient with the p.Cys114Tyr variant was non-syndromic with no clinical VWS phenotype expected of individuals with IRF6 coding variants, and the patient with the p.Arg84His had phenotypic features of popliteal pterygium syndrome. The p.Arg84His variant segregated in the family, with the father also being affected. CONCLUSIONS: This study provides evidence that IRF6 variants are found in the South African population. Genetic counselling is essential for affected families, particularly in the absence of a known clinical phenotype since it helps with the plans for future pregnancies.

Novel de novo missense mutation in the interferon regulatory factor 6 gene in an Italian infant with IRF6-related disorder.

BACKGROUND: Congenital maxillomandibular syngnathia is a rare craniofacial anomaly leading to difficulties in feeding, breathing and ability to thrive. The fusion may consist of soft tissue union (synechiae) to hard tissue union. Isolated cases of maxillomandibular fusion are extremely rare, it is most often syndromic in etiology. CASE PRESENTATION: Clinical management of a female newborn with oromaxillofacial abnormities (synechiae, cleft palate, craniofacial dysmorphisms, dental anomaly) and extraoral malformations (skinfold overlying the nails of both halluces, syndactyly, abnormal external genitalia) is presented. The associated malformations addressed to molecular genetic investigations revealing an interferon regulatory factor 6 (IRF6)-related disorder (van der Woude syndrome/popliteal pterygium syndrome). A novel de novo heterozygous mutation in exon 4 of IRF6 gene on chromosome 1q32.2, precisely c.262A > G (p.Asn88Asp), was found. Similarities are discussed with known asparagine missense mutations in the same codon, which may alter IRF6 gene function by reduced DNA-binding ability. A concomitant maternal Xp11.22 duplication involving two microRNA genes could contribute to possible epigenetic effects. CONCLUSIONS: Our reported case carrying a novel mutation can contribute to expand understandings of molecular mechanisms underlying synechiae and orofacial clefting and to correct diagnosing of incomplete or overlapping features in IRF6-related disorders. Additional multidisciplinary evaluations to establish the phenotypical extent of the IRF6-related disorder and to address family counseling should not only be focused on the surgical corrections of syngnathia and cleft palate, but also involve comprehensive otolaryngologic, audiologic, logopedic, dental, orthopedic, urological and psychological evaluations.

A new surgical approach to treatment of bilateral syngnathia in a patient with popliteal pterygium-syndrome.

This case describes the treatment of syngnathia with a popliteal-pterygium syndrome. Although short-term successful surgical treatment has been described in literature, long-term follow up is essential, as the mouth opening limitations can be repetitively reoccurring. This requires new, individual treatment strategies as demonstrated in this case. A young patient is shown, who is successfully undergoing an alloplastic temporomandibular joint replacement to improve mouth opening, increasing the posterior airway space and facilitating the food intake.

Síndrome de pterigium poplíteo: abordaje desde la cirugía maxilofacial pediátrica

RESUMEN Introducción: El síndrome de pterigium poplíteo es una enfermedad autosómica dominante poco frecuente que resulta de una mutación en el gen IRF6 (1q32.2-q32.3). Objetivo: Notificar a la comunidad médica sobre el diagnóstico de una paciente con el síndrome de pterigium poplíteo. Presentación del caso: Se presenta el caso de una niña de 4 meses de edad atendida en el Hospital Pediátrico Universitario de Cienfuegos "Paquito González Cueto", con solución de continuidad que se extiende desde el labio superior hasta el paladar blando, así como otras alteraciones a nivel genital, con ausencia de labios mayores y menores y una banda fibrótica (pterigium) en el miembro inferior izquierdo que da la impresión de un miembro corto en comparación con el derecho. Desde la especialidad de cirugía maxilofacial pediátrica, tras haber diagnosticado una fisura de labio y paladar bilateral completa, se realizaron los procederes protocolizados para este tipo de pacientes, que incluyen correcciones quirúrgicas de las malformaciones bucofaciales. Conclusiones: En esta ocasión, se pudo corroborar que por muy rara que puedan ser algunas entidades, las mismas pueden presentarse, por lo que debemos tenerlas presentes al plantear los diferentes diagnósticos diferenciales, para así, tratarlas adecuadamente.

ABSTRACT Introduction: Popliteal pterygium syndrome is a rare autosomal dominant disease resulting from a mutation in the IRF6 gene (1q32.2-q32.3). Objective: Inform the medical community about the diagnosis of a patient with popliteal pterygium syndrome. Case Presentation: The case of a 4-month-old girl treated at "Paquito González Cueto" University Pediatric Hospital of Cienfuegos is presented, with continuity solution that extends from the upper lip to the soft palate, as well as other alterations at the genital level, with the absence of labia majora and minora and a fibrotic band (pterygium) in the left lower limb that gives the impression of a short limb in comparison with the right. From the specialty of pediatric maxillofacial surgery, after having diagnosed a fissure of the lip and complete bilateral palate, the protocolized procedures were carried out for this type of patients, which include surgical corrections of orofacial malformations. Conclusions: On this occasion, it was possible to corroborate that no matter how rare some entities may be, they can be presented, so we must keep them in mind when raising the different differential diagnoses, in order to treat them properly.

Prenatal Sonographic and Molecular Genetic Diagnosis of Popliteal Pterygium Syndrome.

Popliteal pterygium syndrome (PPS) is an extremely rare autosomal dominant disorder, characterized by the cleft palate with or without cleft lip, limbs abnormalities with highly characteristic features of popliteal webbing, syndactyly, and genital abnormalities and nail anomalies. Prenatal diagnosis of PPS has been extremely rare. We describe a unique case of fetal PPS at 20 weeks of gestation. The diagnosis of PPS was based on the ultrasound findings of bilateral popliteal webbings, extending from posterior aspects of the upper thighs through the lower legs, resulting in restriction in knee extension, bilateral equinovarus feet with syndactyly, ambiguous genitalia and the grooved lip. Anatomical structures were otherwise normal. Trio whole-exome sequencing revealed a de novo heterozygous IRF6 gene mutation in the fetus, confirming the diagnosis with PPS. In conclusion, popliteal webbing or combination of facial cleft or cleft variants and bilateral abnormal postures of the lower limbs is suggestive of PPS and genetic diagnosis should be warranted.

Popliteal Pterygium With Van Der Woude Syndrome.

Van der Woude syndrome (VWS) is an autosomal dominant syndrome due to mutation of a gene located in the long arm of chromosome 1 (1q32.3-q4) called the interferon regulatory factor-6 (IRF6) gene. VW syndrome-affected children are born with a cleft lip or palate, hypodontia (absent teeth), and bilateral paramedian lower-lip pits, which are usually moist because they are often associated with accessory salivary glands and mucous glands that empty into the pits. Popliteal pterygium syndrome (PPS), also known as a fasciogenito-popliteal syndrome or popliteal web syndrome is a rare autosomal dominant disorder with an incidence of approximately 1 in 300,000 live births. The most common clinical manifestations are popliteal webbing, cleft palate, cleft lip, syndactyly, and genital and nail anomalies. This report describes the clinical features in one case with positive family history, showing the range of anomalies found in popliteal pterygium with VWS.

Bartsocas-Papas syndrome: The first case report of severe autosomal recessive form from Indonesia.

INTRODUCTION: Bartsocas-Papas syndrome (BPS) is an autosomal recessive form of Popliteal Pterygium syndrome (PPS). It is a very rare disease characterized by congenital craniofacial anomalies, popliteal webbing, and genitourinary and musculoskeletal anomalies. Almost all of the cases were reported in dead intrauterine pregnancies. PRESENTATION OF CASE: We present a 10-month-old boy with bilateral complete cleft lip and palate, abnormal scalp hair, an absence of both upper eyelids, choanal atresia, syndactyly of the third and fourth fingers of the right hand, agenesis fingers on the left hand, bilateral popliteal pterygia, bilateral talipes equinovarus, agenesis of the toes of both lower extremities, intercrural webbing, an absence of testis, and scrotal anomaly. Multistage surgical correction was performed for the multiple congenital malformations. CONCLUSION: We report the first case of BPS from Indonesia. Gradual management should be performed according to the patient's age and available facilities.

Non-random distribution of deleterious mutations in the DNA and protein-binding domains of IRF6 are associated with Van Der Woude syndrome.

BACKGROUND: The development of the face occurs during the early days of intrauterine life by the formation of facial processes from the first Pharyngeal arch. Derangement in these well-organized fusion events results in Orofacial clefts (OFC). Van der Woude syndrome (VWS) is one of the most common causes of syndromic cleft lip and/or palate accounting for 2% of all cases. Mutations in the IRF6 gene account for 70% of cases with the majority of these mutations located in the DNA-binding (exon 3, 4) or protein-binding domains (exon 7-9). The current study was designed to update the list of IRF6 variants reported for VWS by compiling all the published mutations from 2013 to date as well as including the previously unreported VWS cases from Africa and Puerto Rico. METHODS: We used PubMed with the search terms; "Van der Woude syndrome," "Popliteal pterygium syndrome," "IRF6," and "Orofacial cleft" to identify eligible studies. We compiled the CADD score for all the mutations to determine the percentage of deleterious variants. RESULTS: Twenty-one new mutations were identified from nine papers. The majority of these mutations were in exon 4. Mutations in exon 3 and 4 had CADD scores between 20 and 30 and mutations in exon 7-9 had CADD scores between 30 and 40. The presence of higher CADD scores in the protein-binding domain (exon 7-9) further confirms the crucial role played by this domain in the function of IRF6. In the new cases, we identified five IRF6 mutations, three novel missense mutations (p.Phe36Tyr, p.Lys109Thr, and p.Gln438Leu), and two previously reported nonsense mutations (p.Ser424*and p.Arg250*). CONCLUSION: Mutations in the protein and DNA-binding domains of IRF6 ranked among the top 0.1% and 1% most deleterious genetic mutations, respectively. Overall, these findings expand the range of VWS mutations and are important for diagnostic and counseling purposes.

IRF6 and SPRY4 Signaling Interact in Periderm Development.

Rare mutations in IRF6 and GRHL3 cause Van der Woude syndrome, an autosomal dominant orofacial clefting disorder. Common variants in IRF6 and GRHL3 also contribute risk for isolated orofacial clefting. Similarly, variants within genes that encode receptor tyrosine kinase (RTK) signaling components, including members of the FGF pathway, EPHA3 and SPRY2, also contribute risk for isolated orofacial clefting. In the mouse, loss of Irf6 or perturbation of Fgf signaling leads to abnormal oral epithelial adhesions and cleft palate. Oral adhesions can result from a disruption of periderm formation. Here, we find that IRF6 and SPRY4 signaling interact in periderm function. We crossed Irf6 heterozygous ( Irf6+/-) mice with transgenic mice that express Spry4 in the basal epithelial layer ( TgKRT14::Spry4). While embryos with either of these mutations can have abnormal oral adhesions, using a new quantitative assay, we observed a nonadditive effect of abnormal oral epithelial adhesions in the most severely affected double mutant embryos ( Irf6+/-;TgKRT14::Spry4). At the molecular level, the sites of abnormal oral adhesions maintained periderm-like cells that express keratin 6, but we observed abnormal expression of GRHL3. Together, these data suggest that Irf6 and RTK signaling interact in regulating periderm differentiation and function, as well as provide a rationale to screen for epistatic interactions between variants in IRF6 and RTK signaling pathway genes in human orofacial clefting populations.

IRF6 expression in basal epithelium partially rescues Irf6 knockout mice.

BACKGROUND: Mutations in IRF6, CHUK (IKKA), and RIPK4 can lead to a disease spectrum that includes cutaneous, limb, and craniofacial malformations. Loss of these alleles in the mouse leads to perinatal lethality and severe cutaneous, limb, and craniofacial defects also. Genetic rescue in the mouse has been shown for Ikka and Ripk4. RESULTS: Here, we show partial genetic rescue of Irf6 knockout embryos using the KRT14 promoter to drive Irf6 expression in the basal epithelium. In contrast to Irf6 knockout embryos, rescue embryos survive the immediate perinatal period. Macroscopic examination reveals rescue of skin adhesions between the axial and appendicular skeleton. Unexpectedly, KRT14-driven Irf6 expression does not completely rescue orofacial clefting and adhesions between the palate and tongue, suggesting the importance of cell-autonomous IRF6 expression in periderm. Like knockout embryos, Irf6 rescue embryos also have persistent esophageal adhesions, which likely contribute to postnatal demise. CONCLUSIONS: Together, these data suggest that targeted expression of IRF6 can significantly reduce disease severity, but that a minimum level of Irf6 in both periderm and basal epithelial cells is necessary for orofacial development. Therefore, homologous human and mouse phenotypes are observed for IRF6, IKKA, and RIPK4. In this work, we show that altering the expression level of IRF6 dramatically modified this phenotype in utero. Developmental Dynamics 246:670-681, 2017. © 2017 Wiley Periodicals, Inc.

Shared molecular networks in orofacial and neural tube development.

BACKGROUND: Single genetic variants can affect multiple tissues during development. Thus it is possible that disruption of shared gene regulatory networks might underlie syndromic presentations. In this study, we explore this idea through examination of two critical developmental programs that control orofacial and neural tube development and identify shared regulatory factors and networks. Identification of these networks has the potential to yield additional candidate genes for poorly understood developmental disorders and assist in modeling and perhaps managing risk factors to prevent morbidly and mortality. METHODS: We reviewed the literature to identify genes common between orofacial and neural tube defects and development. We then conducted a bioinformatic analysis to identify shared molecular targets and pathways in the development of these tissues. Finally, we examine publicly available RNA-Seq data to identify which of these genes are expressed in both tissues during development. RESULTS: We identify common regulatory factors in orofacial and neural tube development. Pathway enrichment analysis shows that folate, cancer and hedgehog signaling pathways are shared in neural tube and orofacial development. Developing neural tissues differentially express mouse exencephaly and cleft palate genes, whereas developing orofacial tissues were enriched for both clefting and neural tube defect genes. CONCLUSION: These data suggest that key developmental factors and pathways are shared between orofacial and neural tube defects. We conclude that it might be most beneficial to focus on common regulatory factors and pathways to better understand pathology and develop preventative measures for these birth defects. Birth Defects Research 109:169-179, 2017. © 2016 Wiley Periodicals, Inc.

O impacto da intervenção fisioterapêutica sobre o desempenho motor e equilíbrio de uma criança com diagnóstico de síndrome do pterígio poplíteo: estudo de caso / The impact of physical therapy intervention on motor performance and balance of a child diagnosed with popliteal pterygium syndrome: case report

A síndrome do pterígio poplíteo (SPP) é uma doença congênita rara cujo tratamento fisioterapêutico visa independência funcional. O objetivo deste estudo foi verificar o efeito de um plano fisioterapêutico sobre a amplitude de movimento, o desempenho motor e o equilíbrio de uma criança com SPP. Menina de 4 anos realizou um programa interventivo com 20 sessões de fisioterapia de 40 minutos cada, uma vez por semana. Para avaliação dos resultados do programa, foram utilizados a Escala de Desenvolvimento Motor, a Escala de Equilíbrio Pediátrica e o Teste de Goniometria Manual. Ao término do período interventivo, e após 1 mês, a criança foi reavaliada, constando-se incrementos no desempenho motor, no equilíbrio e na amplitude de movimento, principalmente na extensão de joelhos. Demais ganhos podem não ter sido alcançados devido à adaptação prévia da criança à sua condição. Os resultados apresentados evidenciam a contribuição da fisioterapia para a melhora da independência funcional e da qualidade de vida do paciente com SPP (AU)

Popliteal pterygium syndrome (PPS) is a rare congenital disease whose physical therapy (PT) treatment aims at functional independence. The objective of this study was to investigate the effect of a PT plan on range of motion, motor performance, and balance of a child with PPS. A 4-year-old girl underwent an interventional program with 20 PT sessions of 40 minutes each, once a week. The Motor Development Scale, the Pediatric Balance Scale, and the Manual Goniometry Test were used to evaluate the results of the program. At the end of the intervention period, and after 1 month, the child was reassessed, showing increases in motor performance, balance, and range of motion, especially in knee extension. Other gains may not have been achieved due to the child's prior adjustment to her condition. The results presented here emphasize the contribution of PT to the improvement of the functional independence and quality of life of patients with PPS (AU)

Van der Woude and Popliteal Pterygium Syndromes: Broad intrafamilial variability in a three generation family with mutation in IRF6.

Patients with Van der Woude syndrome typically present with cleft lip, cleft lip and palate, or with cleft palate only. In contrast to non-syndromic cleft lip and/or palate, Van der Woude syndrome typically is characterized by bilateral, paramedian lower-lip pits. Popliteal pterygium syndrome shares features with Van der Woude syndrome, but, in addition, is characterized by a popliteal pterygium, genital anomalies, cutaneous syndactyly of the fingers and the toes, and a characteristic pyramidal fold of skin overlying the nail of the hallux. In some patients oral synechiae or eyelid synechiae are present. Van der Woude Syndrome and Popliteal pterygium syndrome are autosomal dominantly inherited disorders caused by heterozygous mutations in IRF6. We present a three generation family with tremendous intrafamilial phenotypic variability. The newborn index patient had a diagnosis of Popliteal pterygium syndrome. The mother presented with a classic Van der Woude Syndrome, while the maternal grandfather had Van der Woude Syndrome as well as minor signs of Popliteal pterygium syndrome. In all three affecteds the known pathogenic mutation c.265A>G, p.Lys89Glu in IRF6 was identified. While inter- as well as intra-familial variability has been described in IRF6-related disorders, the occurrence of a typical Van der Woude Syndrome without any other anomalies as well as a diagnosis of Popliteal pterygium syndrome in the same family is rare. © 2016 Wiley Periodicals, Inc.

Toward an orofacial gene regulatory network.

Orofacial clefting is a common birth defect with significant morbidity. A panoply of candidate genes have been discovered through synergy of animal models and human genetics. Among these, variants in interferon regulatory factor 6 (IRF6) cause syndromic orofacial clefting and contribute risk toward isolated cleft lip and palate (1/700 live births). Rare variants in IRF6 can lead to Van der Woude syndrome (1/35,000 live births) and popliteal pterygium syndrome (1/300,000 live births). Furthermore, IRF6 regulates GRHL3 and rare variants in this downstream target can also lead to Van der Woude syndrome. In addition, a common variant (rs642961) in the IRF6 locus is found in 30% of the world's population and contributes risk for isolated orofacial clefting. Biochemical studies revealed that rs642961 abrogates one of four AP-2alpha binding sites. Like IRF6 and GRHL3, rare variants in TFAP2A can also lead to syndromic orofacial clefting with lip pits (branchio-oculo-facial syndrome). The literature suggests that AP-2alpha, IRF6 and GRHL3 are part of a pathway that is essential for lip and palate development. In addition to updating the pathways, players and pursuits, this review will highlight some of the current questions in the study of orofacial clefting.

A Japanese family with popliteal pterygium syndrome.

We investigated a family in which the mother and a daughter suffered from popliteal pterygium syndrome (PPS). Mutation in the interferon regulatory factor 6 (IRF6) gene was detected in the mother and daughter. This is the second report of a family case with mutation in the IRF6 gene in Japanese patients with PPS.

Anatomic Severity, Midfacial Growth, and Speech Outcomes in Van der Woude/Popliteal Pterygium Syndromes Compared to Nonsyndromic Cleft Lip/Palate.

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 CL/P 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.