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NORD is grateful 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 assistance in the preparation of this report.
IRF6-related disorders include a spectrum of disorders caused by abnormalities in the interferon regulatory factor 6 (IRF6) gene. Van der Woude syndrome (VWS) is at the mild end of the spectrum and popliteal pterygium syndrome (PPS) is at the severe end of the spectrum. Individuals with VWS can have lip pits alone, cleft lip or cleft palate alone, or a combination of these anomalies.
The physical features associated with PPS include cleft lip and/or cleft palate, lower lip pits, webbed skin (pterygium) on the backs of both legs (popliteal) and between the legs (intercrural), malformation and/or underdevelopment of the genitals, 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 very distinctive finding in this condition.
The symptoms of IRF6-related disorders vary greatly from case to case. Some affected individuals may have mild symptoms, 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 a combination of these anomalies. Lip pits are usually on both lips. More rarely, VWS can include conical elevation 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 a few cases, 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 cases, webbed skin may also be present between the legs in the area of the upper inner thighs (intercrural pterygium). In addition, 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). In some cases, infants may have a triangular (pyramidal) fold of skin that covers the toenails. Dimples in the skin of the elbows and knees may also be present.
Individuals with PPS may also have several abnormalities of the face. Most infants have incomplete closure of the roof of mouth (cleft palate) and/or a vertical groove in the upper lip (cleft lip). In rare cases, hearing impairment, secondary to cleft palate, may also be present. Children with cleft palate may also be prone to repeated infections of the middle ear (otitis media). Many affected individuals also have depressions (pits), fluid filled sacs (cysts), or hollows (fistulae) near the center (paramedian) of the lower lip. 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). In some cases, affected individuals may exhibit restricted movement of the tongue (ankyloglossia). Many of these facial abnormalities may 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 vagina, 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 cases, the clitoris may be underdeveloped. In some males with this disorder, the scrotum may be abnormally divided (bifid). In other rare cases, the scrotum may be absent and, as a result, the testes may remain in the abdomen. In approximately 40 percent of affected males who do 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 normal in IRF6-related disorders except when there is a large deletion of the IRF6 gene.
IRF6-related disorders are inherited as autosomal dominant genetic traits. Dominant genetic disorders occur when only a single copy of an abnormal gene is necessary for the appearance of the disease. 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 an IRF6-related disorder have an affected parent. The risk of an affected parent passing the abnormal gene to offspring is 50% for each pregnancy, regardless of the sex of the resulting child.
Mutations in the interferon regulatory factor 6 (IRF6) gene are associated with IRF6-related disorders. The IRF6 gene has been mapped to chromosome 1q32-q41.
Chromosomes, which are present in the nucleus of human cells, carry the genetic information for each individual. Human body cells normally have 46 chromosomes. Pairs of human chromosomes are numbered from 1 through 22 and the sex chromosomes are designated X and Y. Males have one X and one Y chromosome and females have two X chromosomes. Each chromosome has a short arm designated "p" and a long arm designated "q". Chromosomes are further sub-divided into many bands that are numbered. For example, "chromosome1q32" refers to band 32 on the long arm of chromosome 1. The numbered bands specify the location of the thousands of genes that are present on each chromosome.
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.
Symptoms of the following disorders can be similar to those of IRF6-related disorders. Comparisons may be useful for a differential diagnosis:
Kabuki syndrome is a rare disorder characterized by mental retardation, short stature, unusual facial features, abnormalities of the skeleton and unusual skin ridge patterns on the fingers, toes, palms of the hands and soles of the feet. (For more information choose "Kabuki" as your search term in the Rare Disease Database.)
Branchio-oculo-facial syndrome (BOFS) is a very rare genetic disorder that is apparent at birth (congenital). The disorder may be characterized by low birth weight; presence of an abnormal pit, opening (cleft), or tumor-like skin abnormality (hemangiomatous or atrophic skin lesion) behind both ears (postauricular area); distinctive malformations of the head and facial (craniofacial) area; abnormalities of the eyes; premature graying of the scalp hair during adolescence; and/or other abnormalities. Some individuals with BOFS have cleft lip and/or cleft palate while others may have an unusually wide, prominent ridge of the upper lip (philtrum) that resembles a surgically repaired cleft lip (pseudocleft). Additional craniofacial abnormalities may include a broad, misshapen (dysplastic) nose and malformed ears. In individuals with the disorder, characteristic eye (ocular) abnormalities may include unusually small eyes (microphthalmia); clouding of the lenses of the eyes (cataracts); crossing of the eyes at birth (congenital strabismus); widely spaced eyes (ocular hypertelorism); and/or absence of tissue (coloboma) from the colored portion of the eyes (iris), giving the iris a "keyhole" appearance. BOFS is inherited as an autosomal dominant genetic trait. (For more information choose "branchio-oculo-facial syndrome" as your search term in the Rare Disease Database.)
Bartsocas-Papas syndrome is a disorder that can also include clefts of the lip or palate and pterygia similar to what are seen in PPS. It has a more severe phenotype and can be lethal in some, but not all, cases. It is inherited as an autosomal recessive and has recently been found to have mutations in the RIPK4 gene in at least some cases.
The diagnosis of IRF6-related disorders is based on physical features and 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.
Molecular genetic testing can be used to confirm a diagnosis based on physical features. Approximately 70% of individuals with VWS have a detectable mutation in the IRF6 gene. Approximately 74% of individuals with PPS have a detectable mutation in the IRF6 gene.
If a diagnosis of an IRF6-related disorder is confirmed, the affected person's parents should receive a careful physical examination to determine if they have a very mild form of the disorder.
Prenatal diagnosis for IRF6-related disorders is available if a specific IRF6 mutation is identified in a family member. 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.
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 treated surgically 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 some cases, surgery may 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, etc.). 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.
A supportive apparatus that initiates movement (dynamic splint) and/or surgery may be used to treat 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.
Genetic counseling will be of benefit for affected individuals and their families
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:
Contact for additional information about IRF6-related disorders:
Jeff Murray, MD
University of Iowa
Division of Neonatology
Department of Pediatrics
Iowa City, IA 52242
Phone: (319) 335-6897
Fax: (319) 335-6970
Lab website: http://genetics.uiowa.edu
Jennifer Rigdon, MSN-CNL, RN
Research Study Coordinator
Department of Pediatrics
Murray & Lidral Craniofacial Genetics Labs &
The National Children's Study
Phone: (319) 335-6741
Toll-Free: (866) 520-8982
Fax: (319) 335-6848
University of Iowa, Murray Lab
Department of Pediatrics
500 Newton Road, 2182 ML
Iowa City, Iowa 52242-1081
(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.].)
(To become a member of NORD, an organization must meet established criteria and be approved by the NORD Board of Directors. If you're interested in becoming a member, please contact Susan Olivo, Membership Manager, at email@example.com.)
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Report last updated: 2012/03/15 00:00:00 GMT+0