OR15-3 Extreme Phenotypic Variability of a Novel Mutation of MEN1 Gene in a Family with 14 Carriers across 3 Generations

Multiple endocrine neoplasia type 1 (MEN1) is an autosomal dominant disease characterized by the development of tumoral lesions usually benign in different glands. The most common tumors involve the parathyroid, pituitary and endocrine pancreas. Over 1300 mutations of MEN1 gene have been identified in approximately 4000 patients. Attempts to identify a correlation between genotype and phenotype have been unsuccessful as symptoms can vary among families and even among relatives that share the same mutation. The aim of this work is to characterize a family with a new mutation of MEN1 gene, through clinical findings, biochemical tests, and morphologic exams. The index case is a 38 years-old man with recurrent renal lithiasis during the last 20-years. In addition to the primary hyperparathyroidism, the patient also presented a pituitary microadenoma with hyperprolactinemia. The coexistence of these two manifestations suggested the diagnosis of MEN1. Genetic tests detected a new heterozygous germinal mutation in the exon 9 of the gene MEN1: c.1321_1323 dup TGG, which is expected to lead to a duplication of the tryptophan (p.Trp 441dup) of the MENIN protein. This variant is not described in the available databases (1000 Genomes e ExAC) nor in the ClinVar (online public archive). The analysis in silico performed with the software Mutation Taster classified this variant as the “pathogenic.” The family history of the patient was collected and a genealogical tree of the family was made. Written informed consent was obtained. The genetic diagnosis proposed to the members of this family identified 14 carriers of the mutation across 3 generations (including the index case), aged between 5 and 71 years old. A screening program to search for alterations in MEN1 positive carriers showed that primary hyperparathyroidism was the most common manifestation involving 6 patients. However, only 50% (2/4) of the subjects above 60 years-old were affected what is in favor of a low penetrance of this mutation. In three adult carriers, the only clinical manifestation was the presence of non-functional pancreatic (3) and lung (1) neuroendocrine tumors; Cushing's disease was the first and so far unique manifestation of the disorder in an 18-year-old girl. Despite sharing the same mutation and being exposed to similar environmental conditions as they all live on the same island, carriers of the mutation in this family presented variable phenotypes. This finding suggests that the nature and effect of the second hit that triggers the tumoral lesion in patients that carry the genomic mutation are mainly unknown. On the other side, this phenotypic variability demands the definition of a screening protocol, to correctly value the clinical manifestations and biochemical tests with implication in the prognosis of these patients.