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Autosomal dominant popliteal pterygium syndrome
Autosomal dominant popliteal pterygium syndrome (AD-PPS) is a rare genetic malformative disorder characterized by cleft lip, with or without cleft palate, contractures of the lower extremities, abnormal external genitalia, syndactyly of fingers and/or toes, and a pyramidal skin fold over the hallux nail.
Exact prevalence and annual incidence are not known but a prevalence of about 1/300,000 has been suggested for PPS. More than 200 cases of AD-PPS have been reported.
Patients with AD-PPS have cleft lip and/or palate (91%-97%), lower lip pits or sinuses (45%), webbing of the skin extending from the ischial tuberosities to the heels (popliteal pterygium with contractures possibly impairing mobility) (58%), bifid scrotum and cryptorchidism in affected males and hypoplasia of the labia majora in females, finger and/or toe syndactyly, and skin abnormalities around the nails. Almost all patients have a pyramidal fold of skin overlying the nail of the hallux. Some may have missing teeth. Other occasional features include filiform synechiae connecting the upper and lower jaws (syngnathia) or the upper and lower eyelids (ankyloblepharon) and talipes. Growth and intellectual development are normal in patients with PPS although there are some reports of delayed language acquisition and learning disabilities.
AD-PPS is associated with mutations in the IRF6 gene (1q32.2-q32.3), involved in the formation of connective and epithelial tissues. Almost all affected patients harbor mutations in this gene.
Diagnosis is based on the presence of the characteristic range of clinical findings (cleft lip with or without cleft palate, popliteal pterygium, genital and nail anomalies), and can be confirmed by molecular genetic testing. AD-PPS is highly associated with missense mutations that alter residues that are predicted to interact directly with DNA in exons 3 and 4 of IRF6.
Mildly affected AD-PPS patients have significant clinical overlap with van der Woude syndrome (see this term), a disorder caused by deletions and mutations in the same gene. In fact, affected individuals in the same family, having the same mutation in IRF6, have been diagnosed with PPS and with VWS. Multiple pterygium syndrome and Bartsocas-Papas syndrome should also be considered (see these terms).
Prenatal diagnosis for at-risk pregnancies is possible through molecular analysis following amniocentesis or chorionic villus sampling, if the disease-causing mutation has been identified in the family.
AD-PPS follows an autosomal dominant pattern of inheritance. However, penetrance is incomplete and expressivity is variable. De novo mutations have also been reported. Genetic counseling should be provided to affected families.
Management and treatment
In infants, nutritional intake and weight gain should be monitored. Cleft lip and/or palate should be treated surgically at an early stage and orthodontically by a specialized multidisciplinary team. Speech therapy as well as audiological and dental assessments should also be provided. Surgery may also be required for lip pits, popliteal pterygium, syndactyly and ankyloblepharon. Rarely, surgical correction of abnormal genitalia may be considered. Management of the other manifestations of PPS is generally supportive and symptomatic.
Overall prognosis is good. Growth and intelligence are expected to be normal, and corrective surgeries are available, especially for orofacial clefts. However, the prognosis for physical activity depends on the severity of the pterygium and the success of corrective surgery. Genital anomalies may cause infertility.