Clinical characteristics: Typical Greig cephalopolysyndactyly syndrome (GCPS) is characterized by macrocephaly, widely spaced eyes associated with increased interpupillary distance, preaxial polydactyly with or without postaxial polydactyly, and cutaneous syndactyly. Developmental delay, intellectual disability, or seizures appear to be uncommon manifestations (~<10%) of GCPS and may be more common in individuals with large (>300-kb) deletions that encompass GLI3. Approximately 20% of individuals with GCPS have hypoplasia or agenesis of the corpus callosum.
Diagnosis/testing: The diagnosis of GCPS is established in a proband who has typical clinical findings and either a heterozygous pathogenic variant of GLI3 or a deletion of chromosome 7p14.1 involving GLI3.
Management: Treatment of manifestations: Elective surgical repair of polydactyly with greatest priority given to correction of preaxial polydactyly of the hands; for polydactyly of the feet, the cosmetic benefits and easier fitting of shoes can be outweighed by potential orthopedic complications. Syndactyly which is more than minimal is typically repaired surgically.
Surveillance: Monitoring for evidence of increased rate of head growth or neurologic concerns and the need of brain MRI.
Genetic counseling: GCPS is inherited in an autosomal dominant manner and is caused by either a pathogenic variant involving GLI3 or a deletion of chromosome 7p14.1 involving GLI3. The proportion of individuals with GCPS caused by de novo genetic alteration is unknown. If the causative genetic alteration in the proband is a deletion of chromosome 7p14.1, the parents of the proband are at risk of having a balanced chromosome rearrangement; if a parent has a balanced structural chromosome rearrangement, the risk to sibs of a proband depends on the specific chromosome rearrangement and the possibility of other variables. Each child of an individual with GCPS has a 50% chance of inheriting the GCPS-causing genetic alteration. Prenatal testing for pregnancies at increased risk is possible if the GCPS-causing genetic alteration has been identified in an affected family member or a parent is known to have a balanced structural chromosome rearrangement involving 7p14.1. The reliability of ultrasound examination for prenatal diagnosis is unknown.
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