Clinical Significance

Nearly 50% of patients with MEN1 will die as a result of their disease; thus, genetic screening to identify family members with germline MEN1 mutations may lead to closer monitoring, earlier identification of tumors, improved outcomes, and longer survival. Primary hyper-parathyroidism is present in more than 90% of patients with MEN1, but parathyroid carcinomas are rarely seen. In addition, pancreatic tumors may be observed in about 60% of MEN1 patients. These most commonly are classified as gastrinomas or insulinomas. Pituitary adenomas also occur in about 30% of MEN1 patients, but pituitary carcinomas are not usually detected. Variable expressivity and reduced penetrance also have been reported in many MEN1 families, making distinction of a familial condition difficult to discern from sporadic tumor occurrence. Absence of a detectable mutation does not exclude the diagnosis of MEN1. Genetic variability in other genes with which the menin protein interacts also may contribute to variable phe-notypes of family members with the same MEN1 allele.

Identification of carriers of MEN1 gene mutations has not been very successful in either predicting or preventing the course of MEN1. The utility of MEN1 mutation detection in directing patient care is limited by the absence of very sensitive imaging methods for early detection and treatment of MEN1-associated tumors, coupled with the lack of adequate treatment options for the types of tumors observed in MEN1.10 Knowledge of the carrier status is not an indicator for prophylactic surgery as in MEN2; thus, mutation screening in MEN1 patients does not avoid or cure the malignancy but may assist in clinical monitoring and lifestyle decisions. When a family-specific mutation can be identified, the clinical significance of a subsequent negative genetic analysis in an at-risk relative can aid the genetic counselor in reassuring that family member. Targeting therapy to the menin protein has not been attempted because its function and the protein domains required for tumorigenesis have not been identified.11

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