Introduction: Multiple endocrine neoplasia type 1 (MEN1) is a rare multitumour syndrome, characterized by the occurrence of parathyroid (PHPT), pituitary adenoma (PA) and pancreatic neuroendocrine tumors (pNETs). The gene responsible is MEN1 gene, however 10 to 20% of patients are not carriers of MEN1 mutation. Recently, a study has shown that these patients have less aggressive course of the disease, and more favorable life expectancy than their mutation-positive counterparts. Nevertheless, their clinical and histopathological features are still unknown.
Study design: Genetic, clinical and histopathological features were analyzed in a retrospective, single-center study of 102 consecutive patients with MEN1. Direct sequencing and MLPA of MEN1 gene were performed in all patients, and CDKN1b gene in MEN1 mutation-negative patients.
Results: We found 34% of mutation-negative cases among all patients, or 47% among index cases. None of these patients had gene alterations in CDKN1b gene. Women were more prevalent among all patients, but this was especially pronounced in mutation-negative patients (86% vs 59% in mutation-positive, P<0.01). All major MEN1 tumors appeared earlier in mutation carriers, and none of mutation-negative patients had more than two major MEN1-tumors. The most frequent phenotype was PA/PHPT in mutation-negative, and PA/PHPT/pNET in mutation-positive patients. PAs were more frequent in mutation-negative than in mutation-positive patients (83% vs 57% respectively, P<0.01). Acromegaly appeared almost exclusively in mutation-negative patients (41% vs 3% in mutation positive, P<0.001). Conversely, pNETs predominantly appeared in mutation-positive (45% vs 9% in mutation-negative, P<0.01), and majority of them were multiple (58%). PHPT was equally distributed, but the presence of polyglandular disease was a major feature of mutation carriers (77% vs none in mutation-negative). Bronchial NETs were more prevalent among mutation-negative patients (P<0.05), and adrenal tumors were equally distributed (P>0.05). There was no difference in age of death and OS between mutation-positive and mutation-negative patients (P>0.05).
Conclusion: MEN1 phenocopy differs from genetically confirmed MEN1 syndrome in several aspects: the presence of only two, solitary, coexisting major MEN1-tumors that develop later in life, marked female predominance, frequently occurring acromegaly, and rare pNETs. It appears that other, non-hereditary factors are involved in initiation and development of multiple-organ NETs in MEN1 phenocopy patients. However, the contribution of low-penetrant mutations in other genes cannot be entirely excluded.
19 - 22 May 2018
European Society of Endocrinology