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 autosomal dominant disorder characterized by tumors of thyroid C cells and pheochromocytoma. Recently, germline mutations in the RET proto-oncogene have been identified in patients with MEN-II. The aims of this study were (1) to define the mutations in clinically diagnosed MEN-II families, (2) to compare the results of genetic and biochemical testing, and (3) to evaluate the impact of mutation analyses for the members of these families.

DESIGN

Register-based survey study of clinically affected and unaffected members of MEN-II families.

SETTING

Register of families from Germany and Spain with pheochromocytomas. Two research laboratories 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 families, 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 syndrome, von Hippel-Lindau disease.

RESULTS

In eight of these families, RET mutations were identified. The specific mutations were detected in all affected members. The remaining two families without RET mutations were 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, premorbid genetic testing was performed in all MEN-II and VHL families, resulting in detection of asymptomatic carriers in the MEN-II families. Clinically, 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 family and extra-adrenal pheochromocytoma in three of nine affected individuals in the two families combined.

CONCLUSIONS

The diagnosis of MEN-II should be confirmed by molecular genetic analysis and the diagnosis of VHL syndrome should be considered for families with an absence of RET mutations and a preponderance of pheochromocytomas.