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Greig cephalopolysyndactyly syndrome
A rare developmental defect during embryogenesis with digit duplication, polydactyly, syndactyly, and/or hyperphalangy characterized by multiple congenital anomaly syndrome.
ORPHA:380Classification level: Disorder
The precise estimates of birth prevalence are difficult to determine, as ascertainment is erratic (estimated range 1-9/1,000,000).
The primary findings include widely spaced eyes, macrocephaly with frontal bossing, and pre- or post-axial polydactyly and cutaneous syndactyly. The polydactyly is most commonly preaxial in the feet and postaxial in the hands, with variable cutaneous syndactyly, but the limb findings vary significantly. Other low frequency findings include central nervous system (CNS) anomalies, hernias, and cognitive impairment.
GCPS is caused by loss of function on chromosome 7p14.1 in the transcription factor gene GLI3.
Clinical diagnosis is challenging because the findings of GCPS are relatively non-specific, and no specific and sensitive clinical criteria have been delineated. A presumptive diagnosis of GCPS can be made if the patient has the classic triad of preaxial polydactyly with cutaneous syndactyly of at least one limb, hypertelorism, and macrocephaly. Individuals with a phenotype consistent with GCPS (but which may not manifest all three attributes listed above) and a GLI3 pathogenic variant may be diagnosed definitively with GCPS. In addition, individuals with a GCPS-consistent phenotype who are related to a definitively diagnosed family member in a pattern consistent with autosomal dominant inheritance may also be diagnosed definitively.
Differential diagnoses include preaxial polydactyly type 4, the GCPS contiguous gene syndrome, acrocallosal syndrome, Gorlin syndrome, Carpenter syndrome, and Teebi syndrome. The disorder is allelic to Pallister-Hall syndrome and one form of the acrocallosal syndrome.
Antenatal molecular diagnosis is technically feasible.
The disorder is inherited in an autosomal dominant manner. Genetic counseling should be proposed to individuals having the disease-causing mutation informing them that there is 50% risk of passing the pathogenic variant to offspring.
Management and treatment
Treatment of the disorder is symptomatic, with plastic or orthopedic surgery indicated for significant limb malformations.
The prognosis for is generally excellent. There may be a slight increase in the incidence of developmental delay or cognitive impairment. Patients with large deletions that include GLI3 may have a poorer prognosis.