NORD gratefully acknowledges Brian C. Schutte, PhD, Departments of Microbiology & Molecular Genetics and Pediatrics & Human Development, Michigan State University; Elizabeth J. Leslie, PhD, Center for Craniofacial and Dental Genetics, Department of Oral Biology, School of Dental Medicine, University of Pittsburgh; and Howard M. Saal, MD, FACMG, Division of Human Genetics, Department of Pediatrics, Cincinnati Children's Hospital Medical Center and University of Cincinnati College of Medicine, for assistance in the preparation of this report.
A special thank you to Jeff Murray, MD, Division of Neonatology, Department of Pediatrics, University of Iowa, and Jennifer Rigdon, MSN-CNL, RN, Research Study Coordinator, Department of Pediatrics, Murray & Lidral Craniofacial Genetics Labs & The National Children’s Study, University of Iowa, for their contribution in 2012.
IRF6-related disorders are a group of orofacial clefting disorders including Van der Woude syndrome (VWS) and popliteal pterygium syndrome (PPS). These conditions are caused by mutations in the interferon regulatory factor 6 (IRF6) gene.
Individuals with VWS are at the least severe end of the spectrum. They can have lip pits or cleft lip or cleft palate, or any combination of these anomalies. Individuals with PPS usually have the lip pits, cleft lip and/or cleft palate, with additional skin and limb abnormalities including webbed skin (pterygium) on the backs of both legs (popliteal) and between the legs (intercrural), malformation and/or genital anomalies, webbing or fusion of the fingers and/or toes (syndactyly), adhesion of upper and lower jaw (intraoral adhesions), and adhesion of upper and lower eyelids (ankyloblepharon). A cone-shaped fold of skin on the nail of the big toe is a characteristic finding in PPS.
The symptoms of IRF6-related disorders vary greatly from person to person. Some affected individuals may have mild clinical signs, while others may exhibit a more severe form of the disease (variable expressivity).
Individuals with VWS can have lip pits alone, cleft lip or cleft palate alone, or any combination of these anomalies. Lip pits usually occur on the lower lip as paired depressions. Less commonly in VWS, one will see conical elevations of the lip, a single lip pit, partial absence of the teeth, incomplete cleft palate, and restricted movement of the tongue (ankyloglossia).
Individuals with PPS typically have a thick web of skin (pterygium) on the backs of both legs (popliteal), extending from the hip (ischial tuberosity) to the heel (calcaneus). In some patients, this abnormal webbing may be present on one leg (unilateral). Such webbing may lead to difficulty walking since full extension of the legs may be limited or the legs may be abnormally rotated (inward or outward).
In most patients, webbed skin may also be present between the legs in the area of the upper inner thighs (intercrural pterygium). Certain joints may be permanently fixed in a flexed position (joint contractures), particularly the knees. Infants with PPS may also exhibit webbing or fusion of one or more fingers and/or toes (syndactyly) and some children may have a triangular (pyramidal) fold of skin that covers the toenails, especially of the big toe. Dimples in the skin of the elbows and knees may also be present.
PPS may also be associated with abnormalities of the face. Most infants have incomplete closure of the roof of mouth (cleft palate) and/or in the upper lip (cleft lip). Children with cleft palate may also be prone to repeated infections of the middle ear (otitis media). Children with PPS may also have abnormal bands of fibrous tissue on the gums (gingival synechiae) and/or between the upper (maxilla) and lower (mandible) bones of the jaws (syngnathia), causing difficulties in opening the mouth. In addition, some affected individuals may have abnormal fibrous tissue connecting the edges of the eyelids (ankyloblepharon filiform) and may exhibit restricted movement of the tongue (ankyloglossia). Many of these facial abnormalities, especially the presence of a cleft palate, can contribute to feeding problems, breathing difficulties, and/or speech impairment.
Individuals affected with PPS may also have abnormalities of the sexual organs (genitalia). In some females, the two long folds of skin on either side of the vaginal opening (labia majora), and/or the uterus may be underdeveloped (hypoplastic). In some patients, the clitoris may be underdeveloped. In some males with this disorder, the scrotum may be abnormally divided (bifid). Rarely, the scrotum may be small (hypoplastic) or absent and, as a result, the testes may remain in the abdomen (undescended testicles). In approximately 40% of affected males who have a scrotum, the testes may also fail to descend from the abdomen into the scrotum (cryptorchidism).
In severe cases of PPS, malformations of the arms and legs (extremities) may be present including absence (agenesis) or underdevelopment (hypoplasia) of the fingers and/or toes, abnormal outward (valgus) or inward (varus) bending of the feet, and/or malformation (dysplasia) of the nails.
Growth and intelligence are usually normal in IRF6-related disorders. Exceptions would be if the IRF6 genetic change is related to a chromosome change or rearrangement involving the IRF6 gene and other genes.
Mutations in the interferon regulatory factor 6 (IRF6) gene are associated with IRF6-related disorders.
IRF6-related disorders are inherited as autosomal dominant genetic conditions. The autosomes are the 22 pairs of chromosomes similar in both males and females. All autosomal genes are paired with one copy from each parent. Autosomal dominant genetic disorders occur when only one copy of an autosomal gene pair is abnormal and causes the appearance of the disorder. The abnormal gene can be inherited from either parent, or can be the result of a new mutation (gene change) in the affected individual. Most individuals with IRF6-related disorders have an affected parent. The risk of an affected parent passing the abnormal gene to offspring is about 50% for each pregnancy, with children of both sexes being at equal risk.
VWS is the most common single gene cause of cleft lip and palate. The prevalence is in the range of 1/35,000-1/100,000 in Europe and Asia. The prevalence of PPS is approximately 1/300,000.
The diagnosis of IRF6-related disorders is based on physical features with confirmation by molecular genetic testing.
A diagnosis of VWS should be considered if a child is born with cleft lip and/or cleft palate, even if lip pits are not present. However, current practice does not include IRF6 sequencing for such individuals because the cost is too high and the yield is too low (<0.5%). Molecular genetic testing can be used to confirm a diagnosis based on physical features. Traditionally, molecular genetic testing used the Sanger method to sequence each of the 9 exons of IRF6. For VWS, more mutations were identified in exons 3, 4, 7 and 9, suggesting a two-tiered approach for optimal screening. For PPS, nearly all mutations were identified in exons 3, 4 and 9, providing a strong rationale for a two-tiered screening approach. In addition, a mutation was found in MCS9.7 in a family with VWS. MCS9.7 is a 600 bp sequence located 9.7 kb upstream of the IRF6 gene. Studies showed that MCS9.7 is an enhancer element, a DNA sequence that functions as a regulatory switch for producing IRF6 gene products. The mutation identified in this VWS family reduced the activity of the MCS9.7 enhancer, suggesting that it is likely the cause of the phenotype in the affected individuals. Thus, recent molecular genetic testing protocols also include the MCS9.7 region.
To date, approximately 70% of individuals with VWS have a detectable mutation in the IRF6 gene. Approximately 97% of individuals with PPS have a detectable mutation in the IRF6 gene.
If a diagnosis of a suspected IRF6-related disorder is not molecularly confirmed, at least two hypotheses exist for the inability to find all mutations. First, traditional methods for molecular genetic testing did not screen the entire IRF6 and surrounding region for mutations in potential regulatory sequences. In support of this hypothesis, a highly penetrant mutation in the MCS9.7 enhancer of IRF6 was identified in a family with VWS. Second, mutations in other genes may account for the IRF6-related phenotypes in some families; this includes the 5% of VWS families that have mutations at the VWS2 locus in GRHL3 and 2-3% of PPS cases with mutations in RIPK4 or other genes in related pterygium syndromes (e.g., SFN and IKKA). With time, molecular genetic screens are converting to next generation sequencing platforms that allow whole exomes (all exons in the genome) and whole genomes to be sequenced. These platforms will provide a more complete assessment of the IRF6 gene and regulatory elements in order to find all mutations in IRF6-related disorders.
If a diagnosis of an IRF6-related disorder is confirmed, the parents of the affected individual should have a careful physical examination to determine if they have any signs of the disorder. For example, the presence of an abnormality in the lower lip or the presence of the pyramidal skin fold on the nail of the big toe.
Prenatal diagnosis and preimplantation genetic diagnosis for IRF6-related disorders is available if a specific IRF6 mutation has been identified. Molecular genetic testing for the specific IRF6 mutation can be performed on fetal cells obtained by amniocentesis at 16-18 weeks gestation or chorionic villus sampling at 10-12 weeks gestation. Preimplantation genetic diagnosis involves in vitro fertilization and testing for a gene mutation in cells taken from a blastocyst. Only those embryos which do not have the mutation will be implanted.
Genetic counseling is an important intervention for affected individuals and their families. The recurrence risk for IRF6-related disorders is as high as 50%, as expected for autosomal dominant inheritance with high penetrance. In addition, a specific set of mutations in IRF6 (missense mutations that alter amino acids predicted to interact directly with the DNA) are associated with, but not determinate for, PPS. In other words, individuals with VWS who carry one of these PPS-associated mutations, are potentially at risk for having a child with the more severe PPS phenotype. Conversely, individuals with PPS can have a child with the less severe VWS phenotype. At this time, the factors that modify the phenotype in either direction are unknown. Thus, while the risk for having a child with an IRF6-related disorder is predictable, the severity of the phenotype for the at-risk offspring is not predictable.
Cleft lip and cleft palate are treated with surgery and orthodontics. Individuals with cleft palate usually also need speech therapy and hearing testing. Lip pits can be surgically excised for cosmetic reasons or for lip function.
The treatment of PPS is directed toward the specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists. Pediatricians; plastic, orthopedic, and maxillofacial surgeons; speech pathologists; and specialists who treat the ears, nose, and throat (otolaryngologists) may need to systematically and comprehensively plan an affected child’s diagnosis and treatment.
The webs of skin (pterygium) behind the legs (popliteal) may be surgically removed. Corrective surgery should be performed as early as possible since the webs of skin (pterygium) may limit an affected individual’s ability to extend the legs and may inhibit normal walking. However, in many cases, surgery can be complicated, since the bundle of nerves (e.g., sciatic nerve and its branches) and blood vessels that extend down through the legs (neurovascular bundle) may be embedded within the web of skin. In these cases, surgeons must remove the nerves and blood vessels from the extra skin and attempt to place them in their normal location within the legs.
The web of skin between the legs (intercrural pterygium) may also be surgically removed, since it may limit the individual’s ability to open, close, and independently move the legs, interfering with normal walking. Webbing or fusion of one or more fingers or toes (syndactyly) may also be corrected surgically.
Abnormal fibrous strands in the mouth (oral synechiae), such as those connecting the jaws (syngnathia) or gums (gingival synechiae), and abnormal fibrous tissue connecting the edges of the eyelids (ankyloblepharon filiform) may also be surgically corrected.
Surgery may also be performed to correct genital abnormalities that may be associated with PPS but may result in infertility. In females, plastic surgery may help to reconstruct the vagina and associated structures (labia majora, clitoris). In males, surgery may be performed to move undescended testes into the scrotum and attach them so that they will not retract (orchiopexy). Plastic surgery may also be performed to correct abnormal division of the scrotum. Treatment with an endocrinologist may be necessary to address the small penis (micropenis) which may also be present.
A supportive apparatus that initiates movement (dynamic splint) and/or surgery may be used to treat joint contractures. Physical therapy is also helpful for children who have joint contractures.
A team approach for infants with this disorder may be of benefit and may include special social support, speech therapy, physical therapy, and other medical services. Other treatment is symptomatic and supportive. All children born with cleft lip and or cleft palate are best managed by a cleft palate or craniofacial team.
Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov
All studies receiving U.S. government funding, and some supported by private industry, are posted on this government web site.
For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:
Tollfree: (800) 411-1222
TTY: (866) 411-1010
For information about clinical trials sponsored by private sources, contact:
For information about clinical trials conducted in Europe, contact:
Contact for additional information about IRF6-related disorders:
Brian C. Schutte, Ph.D.
Department of Microbiology and Molecular Genetics
Department of Pediatrics and Human Development
567 Wilson Drive; Room 5162 BPS
Michigan State University
TEL: 517 884 5346
Elizabeth J. Leslie, Ph.D.
Center for Craniofacial and Dental Genetics
Dept. of Oral Biology, School of Dental Medicine
University of Pittsburgh
office: (412) 648-1488
Howard Saal, MD, FACMG
Division of Human Genetics
Cincinnati Children’s Hospital Medical Center
3333 Burnet Ave.
Cincinnati, OH 45229
University of Cincinnati College of Medicine
phone: (513) 636-4760
(Please note that some of these organizations may provide information concerning certain conditions potentially associated with this disorder [e.g., cleft palate, speech impairment, etc.].)
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