ABSTRACT Objective: (1) To study seven unrelated Spanish fam- ilies with multiple endocrine neoplasia type I (MEN I), describing clinical features and investigating the presence of germline mutations in the MEN1 gene, and (2) to estab- lish reference values for pancreatic polypeptide and gas- trin after a standardized test meal in a healthy control group, analyzing the usefulness of this test for detecting neuroendocrine gastroenteropancreatic tumors in subjects with MEN I. Methods: Two or three generations of 7 kindreds with MEN I, consisting of a total of 39 individual family mem- bers, were investigated. Three of the families were sub- jected only to genetic analysis, and the other four families were also assessed clinically. A group of 23 healthy con- trol subjects were also studied. Results: Mutations in the MEN1 gene were found in six of the seven families studied. Of the 4 families studied clinically, 12 family members were genetically affected. In these study subjects, hyperparathyroidism, adrenal ade- nomas, neuroendocrine gastroenteropancreatic tumors, and pituitary adenomas developed in 100%, 50%, 16%, and 12%, respectively. All demonstrated pancreatic tumors were associated with abnormal results after a test meal, but 75% of them also showed high basal hormonal measurements. Conclusion: Analysis of the MEN1 gene decreases the total number of subjects who need to undergo repeat- ed clinical and biochemical studies, but genetic mutations are not detected in all families with MEN I. Hyperparathyroidism is the most common manifestation of the syndrome, but the presence of adrenal adenomas has probably been underestimated. Ingestion of a standardized test meal for stimulation of gastrin and pancreatic polypeptide could be a complementary proce- dure for diagnosing gastroenteropancreatic tumors in selected patients with MEN I in whom basal gastrin and pancreatic polypeptide levels are normal. (Endocr Pract. 2000;6:13-19) INTRODUCTION Multiple endocrine neoplasia type I (MEN I) is an autosomal dominant disease characterized by the presence of tumors affecting the parathyroid glands, anterior pitu- itary, and gastroenteropancreatic (GEP) tissues (1). Other manifestations include thyroid and adrenal adenomas, car- cinoid tumors, and lipomas. Periodic screening of family members is recommended to facilitate early diagnosis and to decrease the morbidity and mortality associated with this syndrome (2,3). Recently, the MEN1 gene was identi- fied in chromosome 11q13 (4,5). The presence of germline mutations in the MEN1 gene allows the detection of gene carriers and reduces the need for periodic bio- chemical, radiologic, and clinical screenings. In the cur- rent investigation, we studied seven unrelated Spanish families, searching for mutations in the MEN1 gene and characterizing their disease phenotypes. The usefulness of a standardized test meal measuring gastrin and pancreatic polypeptide (PP) for the detection of endocrine pancreatic tumors was assessed, and reference values for the test were established. SUBJECTS AND METHODS Patient Cohort Two or three generations of 7 families, consisting of 39 individual members (22 women and 17 men; mean age, 38 ± 16 years) were studied (Fig. 1). Informed consent was obtained from all patients, and the protocol was GENETIC, CLINICAL, AND BIOCHEMICAL ANALYSIS OF UNRELATED SPANISH FAMILIES WITH MULTIPLE ENDOCRINE NEOPLASIA TYPE I Ana Chico, PhD, 1 Lluis Gallart, PhD, 1 Jesús M. Martín-Campos, MD, 1 Lluis Catasús, MD, 1 Carmen Mayoral, 1 Eugenia Mato, MD, 1 Federico Tortosa, MD, 1 Lluis Bernà, MD, 1 José Rodríguez-Espinosa, MD, 1 Francisco Blanco-Vaca, MD, 1 Xavier Matías-Guiu, MD, 1 Alberto de Leiva, MD, PhD, 1 and Dídac Mauricio, MD 2 Submitted for publication March 18, 1999 Accepted for publication August 20, 1999 From the 1 Departments of Endocrinology, Biochemistry, Pathology, and Nuclear Medicine, Hospital Santa Creu i Sant Pau, Autonomous University, Barcelona, Spain, and 2 Endocrinology Unit, Hospital Parc Taulí, Sabadell, Spain. Address correspondence and reprint requests to Dr. Ana Chico, Department of Endocrinology, Hospital de la Santa Creu i Sant Pau, Av. Sant Antoni M a Claret 167, 08025 Barcelona, Spain. © 2000 AACE. ENDOCRINE PRACTICE Vol. 6 No. 1 January/February 2000 13 Original Article Abbreviations: CT = computed tomographic; GEP = gastroenteropan- creatic; MEN I = multiple endocrine neoplasia type I; MRI = magnetic resonance imaging; PCR = poly- merase chain reaction; PP = pancreatic polypeptide