CONSEQUENCES OF DIRECT GENETIC TESTING FOR GERMLINE MUTATIONS IN THE CLINICAL MANAGEMENT OF FAMILIES WITH MULTIPLE ENDOCRINE NEOPLASIA, TYPE-II

Objective.-Multiple endocrine neoplasia, type II (MEN-II) is an autoso mal dominant disorder characterized by tumors of thyroid C cells and p heochromocytoma. Recently, germline mutations in the RET proto-oncogen e have been identified in patients with MEN-II. The aims of this study were (1) to define the mutations in clinically diagnosed MEN-II famil ies, (2) to compare the results of genetic and biochemical testing, an d (3) to evaluate the impact of mutation analyses for the members of t hese families. Design.-Register-based survey study of clinically affec ted and unaffected members of MEN-II families. Setting.-Register of fa milies from Germany and Spain with pheochromocytomas. Two research lab oratories at Cambridge University in the United Kingdom. Patients.-We investigated consenting affected and unaffected members belonging to a series of 10 families who met the clinical criteria for MEN-II. Main Outcome Measures.-(1) Presence or absence of germline mutation in the RET proto-oncogene in affected and unaffected members of the 10 famili es, and (2) in the absence of RET mutation in a given family, presence or absence of germline mutation in the von Hippel-Lindau (VHL) gene, which is the susceptibility gene involved in a closely related syndrom e, von Hippel-Lindau disease. Results.-In eight of these families, RET mutations were identified. The specific mutations were detected in al l affected members. The remaining two families without RET mutations w ere subsequently shown to have a mutation within the VHL gene. The VHL mutations were identified in both families and represent a previously undescribed base change, After identification of the mutation, premor bid genetic testing was performed in all MEN-II and VHL families, resu lting in detection of asymptomatic carriers in the MEN-II families. Cl inically, the two VHL families differed from the eight MEN-II families by the presence of a C-cell tumor in only one individual from each fa mily and extra-adrenal pheochromocytoma in three of nine affected indi viduals in the two families combined. Conclusions.-The diagnosis of ME N-II should be confirmed by molecular genetic analysis and the diagnos is of VHL syndrome should be considered for families with an absence o f RET mutations and a preponderance of pheochromocytomas.