Familial paragangliomas: The emerging impact of molecular genetics on evaluation and management

Hypothesis: Advancements in molecular genetics has direct impact on the eva luation and management of patients and family members with familial paragan gliomas (FP). Background: Familial paragangliomas, in contrast to sporadic cases, are com monly multiple, bilateral, and present at an earlier age. Familial tumors a re inherited in an autosomal dominant pat tern with genomic imprinting of t he paternal allele. Mapping studies have identified regions on chromosome 1 1q as harboring the genetic defect responsible for paraganglioma formation. Methods: A multigenerational family with five affected females with head an d neck paragangliomas underwent clinical and genetic evaluation. Genetic ma pping was performed with microsatellite markers from chromosome 11q13 and q 23. Nonaffected individuals were screened for carrying the affected haploty pe. In addition, by using DNA obtained from an amniotic fluid sample, in ut ero screening of a fetus was performed. Results: The most common complaints were hearing loss and neck masses that usually manifested by age 25. Genetic mapping identified loci 11q13 and q23 as sites likely responsible for tumorogenesis. Three unaffected family mem bers, including a fetus, were identified as carriers of the affected haplot ype. The genetic findings were used to design a screening protocol for fami ly members at risk for developing glomus tumors. Conclusions: Genetic screening of unaffected family members can identify in dividuals harboring the mutated allele. Identification of family members at risk for developing FP by molecular genetic techniques may lead to early d etection of head and neck paragangliomas and may directly impact morbidity from glomus tumors and their treatment.