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IRF6-Related Disorders.

Source

GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2019.
2003 Oct 30 [updated 2014 Jul 3].

Author information

1
Department of Microbiology and Molecular Genetics, Department of Pediatrics and Human Development, Michigan State University, East Lansing, Michigan
2
Division of Human Genetics, Cincinnati Children’s Hospital Medical Center, Department of Pediatrics, University of Cincinnati, Cincinnati, Ohio
3
Department of Otolaryngology, Vanderbilt University, Nashville, Tennessee
4
Department of Oral Biology, School of Dental Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania

Excerpt

CLINICAL CHARACTERISTICS:

IRF6-related disorders span a spectrum from isolated cleft lip and palate and Van der Woude syndrome (VWS) at the mild end to popliteal pterygium syndrome (PPS) at the more severe end. Individuals with VWS show one or more of the following anomalies: Congenital, usually bilateral, paramedian lower-lip fistulae (pits) or sometimes small mounds with a sinus tract leading from a mucous gland of the lip. Cleft lip (CL). Cleft palate (CP). Note: Cleft lip with or without cleft palate (CL±P) is observed about twice as often as CP only. Submucous cleft palate (SMCP). The PPS phenotype includes the following: CL±P. Fistulae of the lower lip. Webbing of the skin extending from the ischial tuberosities to the heels. In males: bifid scrotum and cryptorchidism. In females: hypoplasia of the labia majora. Syndactyly of fingers and/or toes. Anomalies of the skin around the nails. A characteristic pyramidal fold of skin overlying the nail of the hallux (almost pathognomonic). In some non-classic forms of PPS: filiform synechiae connecting the upper and lower jaws (syngnathia) or the upper and lower eyelids (ankyloblepharon). In both VWS and PPS, growth and intelligence are normal.

DIAGNOSIS/TESTING:

Diagnosis of VWS and PPS is based on clinical findings. Detection of a heterozygous pathogenic variant in IRF6 confirms the diagnosis in approximately 72% of individuals with the Van der Woude syndrome phenotype and approximately 97% of individuals with the popliteal pterygium syndrome phenotype.

MANAGEMENT:

Treatment of manifestations: Supportive/symptomatic treatment may include surgery, pediatric dentistry, orthodontia, speech therapy, feeding and hearing evaluation, physical therapy, and orthopedic care. Prevention of secondary complications: Timely treatment of otitis media due to eustachian tube dysfunction to prevent secondary hearing loss; evaluations by a speech-language pathologist can aid in determining if speech therapy or other interventions are appropriate for a child with secondary hearing loss. Surveillance: Parameters for surveillance for cleft lip and/or cleft palate have been published by the American Cleft Palate-Craniofacial Association.

GENETIC COUNSELING:

IRF6-related disorders are inherited in an autosomal dominant manner. Most individuals diagnosed with an IRF6-related disorder have an affected parent; however, penetrance is incomplete and de novo mutation has been reported. The risk to the sibs of the proband depends on the genetic status of the proband's parents. If a parent of the proband is affected or has an IRF6 pathogenic variant, the risk to the sibs of inheriting the pathogenic variant is 50%. Prenatal diagnosis for pregnancies at increased risk is possible using molecular genetic testing if the pathogenic variant has been identified in an affected family member. Prenatal ultrasound examination may detect a cleft lip with/without cleft palate in some fetuses later in the second trimester, but it is much less likely to detect an isolated cleft palate or lip pits.

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