Andrea Palermo1, Ettore Capoluongo2, Rossella Del Toro1, Silvia Manfrini1, Paolo Pozzilli1, Daria Maggi1, Giuseppe Defeudis3,4,5, Francesco Pantano6, Roberto Coppola7, Francesco Maria Di Matteo8, Marco Raffaelli9, Paola Concolino2, Alberto Falchetti10. 1. Unit of Endocrinology and Diabetes, Department of Medicine, Campus Bio-Medico University of Rome, Rome, Italy. 2. Laboratory of Molecular Biology, Institute of Biochemistry and Clinical Biochemistry, Catholic University, Rome, Italy. 3. Unit of Endocrinology and Diabetes, Department of Medicine, Campus Bio-Medico University of Rome, Rome, Italy. g.defeudis@unicampus.it. 4. Department of Experimental Medicine, Sapienza University of Rome, Rome, Italy. g.defeudis@unicampus.it. 5. Unit of Endocrinology and Diabetes, Department of Medicine, University Campus Bio Medico di Roma, Via Alvaro del Portillo 21, Rome, Italy. g.defeudis@unicampus.it. 6. Medical Oncology Department, Campus Bio-Medico University of Rome, Rome, Italy. 7. Department of General Surgery, Campus Bio-Medico University of Rome, Rome, Italy. 8. Digestive Endoscopy Unit, Campus Bio-Medico University of Rome, Rome, Italy. 9. Unit of Endocrine and Metabolic Surgery, Catholic University, Rome, Italy. 10. EndOsmet Unit, Villa Donatello Private Hospital, Florence and Villalba Hospital, Bologna, Italy.
Abstract
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.
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 MEN1patients (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.