World J. Surg. 25, 610 – 616, 2001 DOI: 10.1007/s002680020170 WORLD Journal of SURGERY © 2001 by the Socie ´te ´ Internationale de Chirurgie Predictive Genetic Screening and Clinical Findings in Multiple Endocrine Neoplasia Type I Families Ina Kopp, M.D., 1 Detlef Bartsch, M.D., 1 Anja Wild, Ph.D., 1 Thomas Schilling, M.D., 1 Christoph Nies, M.D., 1 Anders Bergenfelz, M.D., 2 Harald Rieder, M.D., 3 Babette Simon, M.D., 2 Matthias Rothmund, M.D. 1 1 Department of Surgery, Philipps-University Marburg, 35033 Marburg, Germany 2 Department of Internal Medicine, Philipps-University Marburg, 35033 Marburg, Germany 3 Human Genetics, Division of Clinical Genetics, Philipps-University Marburg, 35033 Marburg, Germany Abstract. Germline mutations of the MEN1 gene have been identified as the causative genetic defect of multiple endocrine neoplasia type I (MEN- I), an autosomal dominantly inherited condition. To establish the basis for predictive family screening we evaluated the spectrum of MEN1 gene mutations in MEN-I patients treated at our institution. Relatives at risk were subjected to predictive 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 stimulation test and imaging procedures (ultrasonography, computed tomography, magnetic resonance imaging). Among index patients of 15 independent MEN-I kindreds, 14 heterozy- gous MEN1 germline mutations were identified by single-strand confor- mational variant analysis (SSCV) and direct DNA sequence analysis. Of 51 individuals at risk, 26 predictively tested relatives with the wild-type MEN1 gene could be excluded from further screening procedures because they had not inherited the disease. In all previously presumed unaffected relatives with the mutant gene, our extensive clinical screening program revealed at least one manifestation of MEN-I. Furthermore, 22 additional diagnoses could be established in identified MEN-I patients. We show that mutation analysis enables predictive genetic screening for MEN-I families, providing a valuable tool for genetic counseling and clinical management. An extensive clinical screening program focusing on genet- ically proven individuals at risk allows detection of MEN-I manifestations at an early, asymptomatic stage of the disease. Controlled, prospective studies are now required to prove whether timely appropriate treatment on the basis of predictive screening might help improve disease-related quality of life and prolong life expectancy in MEN-I kindreds. Multiple endocrine neoplasia type I (MEN-I) is a syndrome char- acterized by the combined occurrence of parathyroid, endocrine, pancreatic, and anterior pituitary tumors. Various other tumors may occur in association with MEN-I, including neuroendocrine tumors of the lung, gut, and thymus (NET), adrenocortical tu- mors, lipoma, malignant melanoma, angiofibroma, collagenoma, ependymoma, pheochromocytoma, and carcinoma of the thyroid [1– 6]. Because germline mutations of the MEN1 gene have been identified as the causative genetic defect of the autosomal domi- nantly inherited MEN-I syndrome [7], mutation analysis may now provide the basis for predictive family screening to detect relatives at risk in a presymptomatic stage of the disease. For carriers of the mutant MEN1 gene, extensive clinical screening seems to be indicated in respect of the high penetrance [1, 3], a lack of genotype-phenotype correlation [8 –10], multiplic- ity of organ involvement, and multicentricity of tumors in the affected organs [3, 4, 11]. The pattern of clinical signs and hor- mone secretion is complex [4, 11, 12], and the profile of hormone secretion is temporally variable [13]. Patients are threatened by morbidity due to hormone excess and the possible development of malignancy [4, 5, 11, 14]. By means of an extensive screening program the MEN-I trait is biochemically detectable two decades prior to clinically overt disease [13]. Although extensive screening of an individual is cost-intensive, predictive genetic screening of families could prove cost-effective by excluding kindred members without mutation from further clinical investigations. In addition, extensive clinical assessment might help improve the quality of life and prolong the life expect- ancy of carriers of a mutant MEN1 gene by allowing early detec- tion of MEN-I-associated tumors and appropriate therapeutic intervention. Here we present preliminary results of predictive family screening using mutation analysis in 15 independent MEN-I kindreds. Patients and Methods A series of 24 MEN-I patients were treated surgically at the Philipps-University of Marburg between 1990 and 1998. Twenty patients from 15 independent kindreds were included in the study. MEN-I was defined by the presence of endocrine tumors in two of the three principal MEN-I-related tissues. Peripheral blood was obtained for mutation analysis of the MEN1 gene after genetic counseling and informed consent from the 15 index patients and 5 relatives previously affected by MEN-I included in the study. Results were explained to the patients by a geneticist and a This International Association of Endocrine Surgeons (IAES) article was presented at the 38th World Congress of Surgery International Sur- gical Week (ISW99), Vienna, Austria, August 15–20, 1999. A. Bergenfelz, M.D. is now at Department of Surgery, University Hospital, Lund, Sweden. Correspondence to: I. Kopp, M.D., e-mail: kopp@mailer.uni-marburg.de