Predictive genetic screening and clinical findings in multiple endocrine neoplasia type I families

Germline mutations of the MEN1 gene have been identified as the causative g enetic defect of multiple endocrine neoplasia type I (MENI), an autosomal d ominantly inherited condition. To establish the basis for predictive family screening we evaluated the spectrum of MEN1 gene mutations in MEN-I patien ts treated at our institution. Relatives at risk were subjected to predicti ve genetic screening after genetic counseling. Gene carriers were subjected to extensive clinical screening for MEN-I, including biochemical tests for basal hormone concentrations in blood and urine, a standardized meal stimu lation test and imaging procedures (ultrasonography, computed tomography, m agnetic resonance imaging). Among index patients of 15 independent MEN-I ki ndreds, 14 heterozygous MENI germline mutations were identified by single-s trand conformational variant analysis (SSCV) and direct DNA sequence analys is. Of 51 individuals at risk, 26 predictively tested relatives with the wi ld-type MEN1 gene could be excluded from further screening procedures becau se they had not inherited the disease. In all previously presumed unaffecte d relatives with the mutant gene, our extensive clinical screening program revealed at least one manifestation of MEN-I. Furthermore, 22 additional di agnoses could be established in identified MEN-I patients. We show that mut ation analysis enables predictive genetic screening for MEN-I families, pro viding a valuable tool for genetic counseling and clinical management. An e xtensive clinical screening program focusing on genetically proven individu als at risk allows detection of MEN-I manifestations at an early, asymptoma tic stage of the disease. Controlled, prospective studies are now required to prove whether timely appropriate treatment on the basis of predictive sc reening might help improve disease-related quality of life and prolong life expectancy in MEN-I kindreds.