A novel germline mutation at exon 10 of MEN1 gene: a clinical survey and positive genotype-phenotype analysis of a MEN1 Italian family, including monozygotic twins

Context: Clinical phenotype variability in MEN1 syndrome exists and evidence for an established genotype-phenotype is lacking. However, a higher aggressiveness of MEN1-associated gastro-entero-pancreatic (GEP) (neuro)endocrine tumours (NETs) tumours has been reported when MEN1 gene truncating mutations are detected. We found a novel germline truncating mutation of MEN1 gene at exon 10 in a subject with an aggressive clinical behavior of GEP-NETs. Successively, other two mutant-affected familial members have been identified. Objective: The aim of this observational study was to investigate genotype-phenotype correlation in these three members, with attention to GPE-NETs behavior over the years. Design: The genetic and clinical data obtained and the follow-up screening program (2012–2016) were according to the International Guidelines in a multidisciplinary academic reference center. The familial history collected strongly suggested MEN1 GEP-NETs in at least other four members from different generations. Patients: Three MEN1 patients (aged 30–69 years at MEN1 diagnosis) were clinically screened for MEN1 GEP-NETs, both functioning and nonfunctioning. Methods: Biochemical, imaging, and nuclear medicine tests and fine-needle agobiopsy were performed, depending on found/emerging clinical symptoms/biochemical abnormalities, and made when necessary. Results: Our clinical survey found strong genotype-phenotype correlation with aggressive MEN1 GEP-NETs (G1, G2-NETs, and multiple ZES/gastrinomas) over the years. The familial history strongly suggested ZES/gastrinoma in progenitors from previous generations. Conclusions: This novel MEN1 truncating mutation correlates with an aggressive evolution and behavior of MEN1 GEP-NETs in studied affected subjects, confirming the need for MEN1 individuals to be evaluated by a skilled multidisciplinary team, as also stated by International Guidelines.