IRF6-Related Disorders

IRF6-Related Disorders

National Organization for Rare Disorders, Inc.

Important

It is possible that the main title of the report IRF6-Related Disorders is not the name you expected. Please check the synonyms listing to find the alternate name(s) and disorder subdivision(s) covered by this report.

Synonyms

  • popliteal pterygium syndrome
  • Van der Woude syndrome

Disorder Subdivisions

  • None

General Discussion

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.

Symptoms

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.

Causes

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.

Affected Populations

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.

Standard Therapies

Diagnosis

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.



Treatment

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

Investigational Therapies

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

Email: prpl@cc.nih.gov



For information about clinical trials sponsored by private sources, contact:

www.centerwatch.com



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

Email: jeff-murray@uiowa.edu

Lab website: http://genetics.uiowa.edu



and



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

Email: jennifer-rigdon@uiowa.edu



Mailing address:

University of Iowa, Murray Lab

Department of Pediatrics

500 Newton Road, 2182 ML

Iowa City, Iowa 52242-1081

References

TEXTBOOKS

Gorlin RJ, Cohen MM JR, Levin LS. Popliteal pterygium syndrome (facio-genito-popliteal syndrome). In: Syndromes of the head and neck. Oxford, UK: Oxford University Press; 1990:629-631.



JOURNAL ARTICLES

Mitchell K, O'Sullivan J, Missero C, et al. Exome sequence identifies RIPK4 as the Bartsocas-Papas syndrome locus. Am J Hum Genet. 2012;90(1):69-75.



Kalay E, Sezgin O, Chellappa V, dt al. Mutations in RIPK4 cause the autosomal-recessive form of popliteal pterygium syndrome. Am J Hum Genet. 2012;90(1):76-85.



Desmyter L, Ghassibe M, Revencu N, et al. IRF6 Screening of Syndromic and a priori Non-Syndromic Cleft Lip and Palate Patients: Identification of a New Type of Minor VWS Sign. Mol Syndromol. 2010:1(2):67-74.



Jones JLP, Canady JW, Brookes JT, et al. Wound Complications after cleft repair in children with Van der Woude syndrome. J Craniofac Surg. 2010;21:1350-3.



de Lima RL, Hoper SA, Ghassibe M, et al. 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. Genet Med. 2009;11(4):241-7.



Houweling AC, Gille JJP, Baart JA, van Hagen JM, Lachmeijer AM. Variable phenotypic manifestation of IRF6 mutations in the Van der Woude syndrome and popliteal pterygium syndrome: implications for genetic counseling. Clin Dysmorphol. 2009;18:225-227.



Yeetong P, Mahatumarat C, Siriwan P, Rojvachiranonda N, Suphapeetiporn K, Shotelersuk V. Three novel mutations of the IRF6 gene with one associated with an unusual feature in Van der Woude syndrome. Am J Med Genet A. 2009;149A:2489-2492.



Osoegawa K, Vessere GM, Utami KH, et al. Identification of novel candidate genes associated with cleft lip and palate using array comparative genomic hybridization. J Med Genet. 2008;45(2):81-6.



Tan EC, Lim EC, Yap SH, et al. Identification of IRF6 gene variants in three families with Van der Woude syndrome. Int J Mol Med. 2008; 21:747-751.



Pegelow M, Peyrard-Janvid M, Zucchelli M, et al. Familial non-syndromic cleft lip and palate - Analysis of the IRF6 gene and clinical phenotypes. Eur J Orthod. 2008;30:169-175.



Brosch S, Baur M, Blin N, Reinert S, Pfister M. A novel IRF6 nonsense mutation (Y67X) in a German family with Van der Woude syndrome. Int J Mol Med. 2007:20:85-89.



Zechi-Ceide RM, Guion-Almeida ML, de Oliveira Rodini ES, Jesus Oliveira NA, Passos-Bueno MR. Hydrocephalus and moderate mental retardation in a boy with Van der Woude phenotype and IRF6 gene mutation. Clin Dysmorphol. 2007;16(3):163-6.



Du XY, Tang W, Tian WD, Li XY, Liu L, Zheng XH. [Identification of three novel mutations of IRF6 in Chinese families with Van der Woude syndrome]. Zhonghua Yi Xue Yi Chuan Xue Za Zhi. 2006;23(1):82-83.



Matsuzawa N, Kondo S, Shimozato K, et al. Two missense mutations of the IRF6 gene in two Japanese families with popliteal pterygium syndrome. Am J Med Genet A. 2006;152A(9):2262-2267.



Richardson RJ, Dixon J, Malhotra S, et al. Irf6 is a key determinant of the keratinocyte proliferation-differentiation switch. Nat Genet. 2006;38:1329-1334.



Ingraham CR, Kinoshita A, Kondo S, et al. Abnormal skin, limb and craniofacial morphogenesis in mice deficient for interferon regulatory factor 6 (Irf6). Nat Genet. 2006;38:1335-1340.



Peyrard-Janvid M, Pegelow M, Koillinen H, et al. Novel and de novo mutations of the IRF6 gene detected in patients with Van der Woude or popliteal pterygium syndrome. Eur J Hum Genet. 2005;13:1261-1267.



Kantaputra PN, Limwongse C, Assawamakin A, et al. A Novel Mutation in IRF6 Underlies Hearing Loss, Pulp Stones, Large Craniofacial Sinuses, and Limb Anomalies in Van der Woude Syndrome Patients. Oral Biosci Med. 2004;1:1-6.



Kondo S, Schutte BC, Richardson RJ, et al. Mutations in IRF6 cause Van der Woude and popliteal pterygium syndromes. Nat Genet. 2002;32:285-9.



Taniguchi T, Ogasawara K, Takaoka A, et al. IRF family of transcription factors as regulators of host defense. Annu Rev Immunol. 2001;19:623-55.



Wong FK, Koillinen H, Rautio J, et al. Genetic heterogeneity and exclusion of a modifying locus at 17p11.2-p11.1 in Finnish families with Van der Woude syndrome. J Med Genet. 2001;38:198-202.



Lees MM, Winter RM, Malcolm S, et al. Popliteal pterygium syndrome: a clinical study of three families and report of linkage to the Vander Woude syndrome locus on 1q32. J Med Genet. 1999;36:888-92.



Froster-Iskenius UG. Popliteal pterygium syndrome. J Med Genet. 1990;27:320-6.



Bixler D, Poland C, Nance WE. Phenotypic variation in the popliteal pterygium syndrome. Clin Genet. 1973;4:220-8.



INTERNET

Durda KM, Schutte BC, Murray JC. (Updated March 1, 2011). IRF6-Related Disorders. In: GeneReviews at GeneTests: Medical Genetics Information Resource (database online). Copyright, University of Washington, Seattle. 1993-2012. Available at http://www.genetests.org. Accessed March 9, 2012.



Online Mendelian Inheritance in Man (OMIM). The Johns Hopkins University. Van Der Woude Syndrome 1; VWS1. Entry No: 119300. Last Edited October 14, 2011. Available at: http://www.ncbi.nlm.nih.gov/omim/. Accessed March 9, 2012.



Online Mendelian Inheritance in Man (OMIM). The Johns Hopkins University. Popliteal Pterygium Syndrome; PPS. Entry No: 119500. Last Edited July 22, 2011. Available at: http://www.ncbi.nlm.nih.gov/omim/. Accessed March 9, 2012.



Online Mendelian Inheritance in Man (OMIM). The Johns Hopkins University. Interferon Regulatory Factor 6; IRF6 . Entry No: 607199. Last Edited July 6, 2011. Available at: http://www.ncbi.nlm.nih.gov/omim/. Accessed March 9, 2012.

Resources

Children's Craniofacial Association

13140 Coit Road

Suite 517

Dallas, TX 75240

USA

Tel: (214)570-9099

Fax: (214)570-8811

Tel: (800)535-3643

Email: contactCCA@ccakids.com

Internet: http://www.ccakids.com



AmeriFace

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USA

Tel: (702)769-9264

Fax: (702)341-5351

Tel: (888)486-1209

Email: info@ameriface.org

Internet: http://www.ameriface.org



Cleft Palate Foundation

1504 East Franklin Street

Suite 102

Chapel Hill, NC 27514-2820

USA

Tel: (919)933-9044

Fax: (919)933-9604

Tel: (800)242-5338

Email: info@cleftline.org

Internet: http://www.cleftline.org



NIH/National Institute of Arthritis and Musculoskeletal and Skin Diseases

Information Clearinghouse

One AMS Circle

Bethesda, MD 20892-3675

USA

Tel: (301)495-4484

Fax: (301)718-6366

Tel: (877)226-4267

TDD: (301)565-2966

Email: NIAMSinfo@mail.nih.gov

Internet: http://www.niams.nih.gov/



Wide Smiles

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USA

Tel: (209)942-2812

Fax: (209)464-1497

Email: josmiles@yahoo.com

Internet: http://www.widesmiles2.org/



Genetic and Rare Diseases (GARD) Information Center

PO Box 8126

Gaithersburg, MD 20898-8126

Tel: (301)251-4925

Fax: (301)251-4911

Tel: (888)205-2311

TDD: (888)205-3223

Internet: http://rarediseases.info.nih.gov/GARD/



For a Complete Report

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