Autosomal dominant popliteal pterygium syndrome (ORPHA:1300)
A rare genetic, multiple congenital anomalies syndrome characterized by cleft lip, with or without cleft palate, pits in the lower lip, contractures of the lower extremities, abnormal external genitalia, syndactyly of fingers and/or toes, and a pyramidal skin fold over the hallux nail.
Epidemiology
The prevalence of autosomal-dominant-popliteal pterygium syndrome (AD-PPS) is unknown. However, based on the occurence of cleft lip/palate in the general population, the prevalence at birth of popliteal pterygium syndrome (PPS) has been suggested at 1/300,000 with more than 200 cases of AD-PPS being reported worldwide.
Clinical description
Presentation may be as early as the first trimester, with detection of cleft lip and/or palate on ultrasound. In addition to facial clefts (91%-97%), patients may have 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), spina bifida occulta, retrognathia, accessory medial meniscus, and talipes. Growth and intellectual development are normal in patients with AD-PPS although there are some reports of delayed language acquisition and learning disabilities.
Etiology
AD-PPS is associated with mutations in the IRF6 gene (1q32.2-q32.3), involved in the formation of epithelial tissues, especially the periderm. Almost all affected patients harbor mutations in IRF6.
Diagnostic methods
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 in the DNA Binding Domain of IRF6(encoded in exons 3 and 4) that alter residues that are predicted to interact directly with DNA.
Differential diagnosis
Mildly affected AD-PPS patients have significant clinical overlap with Van der Woude syndrome (VWS), a disorder caused by deletions and mutations in the same gene (IRF6). In fact, affected individuals in the same family, having the same mutation in IRF6, have been diagnosed with AD-PPS and with VWS. The cause of this variable expressivity is not known. Bartsocas-Papas syndrome, CHAND syndrome and multiple pterygium syndrome should also be considered.
Antenatal diagnosis
If the disease-causing mutation has been identified in the family, prenatal diagnosis for at-risk pregnancies is possible through molecular analysis following amniocentesis or chorionic villus sampling.
Genetic counseling
The pattern of inheritance is autosomal dominant with a 50% risk of disease transmission to offspring. 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 AD-PPS is generally supportive and symptomatic.
Prognosis
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.

                            Last update: 
                            August 2019


                            - Expert reviewer(s): 
                            Dr Elizabeth LESLIE  - Dr Brian SCHUTTE