Phenotypes Associated With MEN1 Syndrome: A Focus on Genotype-Phenotype Correlations.

Chiara Mele,Monica Mencarelli,Alberto Falchetti,Gianluca Aimaretti,Paolo Marzullo,Stefania Mai,Marina Caputo,Massimo Scacchi,Loredana Pagano

doi:10.3389/fendo.2020.591501

Abstract

Multiple endocrine neoplasia type 1 (MEN1) is a rare autosomal dominant inherited tumor syndrome, associated with parathyroid, pituitary, and gastro-entero-pancreatic (GEP) neuroendocrine tumors (NETs). MEN1 is usually consequent to different germline and somatic mutations of the MEN1 tumor suppressor gene, although phenocopies have also been reported. This review analyzed main biomedical databases searching for reports on MEN1 gene mutations and focused on aggressive and aberrant clinical manifestations to investigate the potential genotype-phenotype correlation. Despite efforts made by several groups, this link remains elusive to date and evidence that aggressive or aberrant clinical phenotypes may be related to specific mutations has been provided by case reports and small groups of MEN1 patients or families. In such context, a higher risk of aggressive tumor phenotypes has been described in relation to frameshift and non-sense mutations, and predominantly associated with aggressive GEP NETs, particularly pancreatic NETs. In our experience a novel heterozygous missense mutation at c.836C>A in exon 6 was noticed in a MEN1 patient operated for macro-prolactinoma, who progressively developed recurrent parathyroid adenomas, expanding gastrinomas and, long after the first MEN1 manifestation, a neuroendocrine uterine carcinoma. In conclusion, proof of genotype-phenotype correlation is limited but current evidence hints at the need for long-term interdisciplinary surveillance in patients with aggressive phenotypes and genetically confirmed MEN1.

Highlights

Multiple endocrine neoplasia type 1 (MEN1) syndrome (OMIM#131100) is a rare autosomal dominant inherited tumor syndrome with high penetrance, that is typically associated with parathyroid, pituitary, and gastro-entero-pancreatic (GEP) neuroendocrine tumors (NETs), either functioning or nonfunctioning [1, 2]
GEP NETs is clinically important for three main reasons: 1) these tumors could have a malignant course, which represent the most frequent cause of death in MEN1 patients; 2) several studies demonstrated that non-functioning GEP NETs are associated with a worse prognosis compared to other functioning tumors; 3) the absence of a clinical syndrome and specific biomarkers can result in delayed diagnosis, which increase the mortality rate [22, 59]
In the context of the potential genotype-phenotype correlation, we report on the case of a 69-year-old woman with a previously unrecognized long history of MEN1, who was referred to our

Summary

INTRODUCTION

Multiple endocrine neoplasia type 1 (MEN1) syndrome (OMIM#131100) is a rare autosomal dominant inherited tumor syndrome with high penetrance, that is typically associated with parathyroid, pituitary, and gastro-entero-pancreatic (GEP) neuroendocrine tumors (NETs), either functioning or nonfunctioning [1, 2]. A recent study on 189 patients with typical MEN1 phenotype described a higher prevalence (74%) of mutation-negative cases than previously reported [24]. Non-functioning GEP NETs are the most frequent tumor types They occur in approximately 55% of MEN1 subjects and are often multiple, asymptomatic or cause compressive symptoms [58]. GEP NETs is clinically important for three main reasons: 1) these tumors could have a malignant course, which represent the most frequent cause of death in MEN1 patients; 2) several studies demonstrated that non-functioning GEP NETs are associated with a worse prognosis compared to other functioning tumors; 3) the absence of a clinical syndrome and specific biomarkers can result in delayed diagnosis, which increase the mortality rate [22, 59].

A NOVEL MEN1 GENE MUTATION RELATED TO AGGRESSIVE PHENOTYPE

Findings

DISCUSSION

CONCLUSIONS