Clinical characteristics: Most commonly, 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. In rare instances, IRF6 pathogenic variants have also been reported in individuals with nonsyndromic orofacial cleft (18/3,811; 0.47%) and in individuals with spina bifida (2/192).
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:
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 nonclassic forms of PPS: filiform synechiae connecting the upper and lower jaws (syngnathia) or the upper and lower eyelids (ankyloblepharon)
Other musculoskeletal anomalies may include spina bifida occulta, talipes equinovarus, digital reduction, bifid ribs, and short sternum.
In VWS, PPS, IRF6-related neural tube defect, and IRF6-related orofacial cleft, growth and intelligence are typical.
Diagnosis/testing: Diagnosis of an IRF6-related disorder is established in a proband with suggestive findings and a heterozygous pathogenic variant in IRF6 identified by molecular genetic testing. A heterozygous pathogenic variant in IRF6 is identified in approximately 72% of individuals with the VWS phenotype, approximately 97% of individuals with the PPS phenotype, and fewer than 1% of individuals with a neural tube defect or orofacial cleft.
Management: Treatment of manifestations: Supportive/symptomatic treatment of VWS and PPS may include surgical treatment of lip pits and cleft lip and palate pediatric dentistry, orthodontia, speech therapy, feeding therapy, timely treatment of otitis media due to eustachian tube dysfunction to prevent secondary hearing loss, physical therapy, orthopedic care, and surgical treatment for cryptorchidism. Surgical treatment may be needed for those with oral and/or eyelid synechiae. IRF6-related neural tube defects are treated in a standard manner as per neurosurgeon. IRF6-related orofacial clefts are treated in a standard manner.
Surveillance: Surveillance for those with cleft lip and/or cleft palate includes weekly assessment of nutritional intake and weight gain during the first month of life; otolaryngologic evaluation within the first six months of life and continued throughout adolescence; audiologic evaluation with infant's first visit to cleft clinic, with the frequency of subsequent evaluations based on the history of ear disease or hearing loss; speech-language pathology evaluation by age six months, twice during the first two years of life, at least annually until age six years, at least annually until after adenoid involution, and at least every two years until dental and skeletal maturity; dental evaluation within six months of the first tooth erupting and no later than age 12 months, and routine dental evaluation continued throughout life. In individuals with myelomeningocele, assessment of walking and mobility and bowel and bladder management with each visit throughout life.
Genetic counseling: IRF6-related disorders are inherited in an autosomal dominant manner. Most individuals diagnosed with an IRF6-related clefting disorder (e.g., VWS or PPS) inherited an IRF6 pathogenic variant from a heterozygous parent who may or may not have manifestations of the disorder. 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 and/or has an IRF6 pathogenic variant, the risk to the sibs of inheriting the pathogenic variant is 50%. Once an IRF6 pathogenic variant has been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic testing are possible. 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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