Mutational and large deletion study of genes implicated in hereditary forms of primary hyperparathyroidism and correlation with clinical features

Abstract

The aim of this study was to carry out genetic screening of the MEN1, CDKN1B and AIP genes, both by direct sequencing of the coding region and multiplex ligation-dependent probe amplification (MLPA) assay in the largest monocentric series of Italian patients with Multiple Endocrine Neoplasia type 1 syndrome (MEN1) and Familial Isolated Hyperparathyroidism (FIHP). The study also aimed to describe and compare the clinical features of MEN1 mutation-negative and mutation-positive patients during long-term follow-up and to correlate the specific types and locations of MEN1 gene mutations with onset and aggressiveness of the main MEN1 manifestations. A total of 69 index cases followed at the Endocrinology Unit in Pisa over a period of 19 years, including 54 MEN1 and 15 FIHP kindreds were enrolled. Seven index cases with MEN1 but MEN1 mutation-negative, followed at the University Hospital of Cagliari, were also investigated. FIHP were also tested for CDC73 and CaSR gene alterations. MEN1 germline mutations were identified in 90% of the index cases of familial MEN1 (F-MEN1) and in 23% of sporadic cases (S-MEN1). MEN1 and CDC73 mutations accounted for 13% and 7% of the FIHP cohort, respectively. A CDKN1B mutation was identified in one F-MEN1. Two AIP variants of unknown significance were detected in two MEN1-negative S-MEN1. A MEN1 positive test best predicted the onset of all three major MEN1-related manifestations or parathyroid and gastro-entero-pancreatic tumors during follow-up. A comparison between the clinical characteristics of F and S-MEN1 showed a higher prevalence of a single parathyroid disease and pituitary tumors in sporadic compared to familial MEN1 patients. No significant correlation was found between the type and location of MEN1 mutations and the clinical phenotype. Since all MEN1 mutation-positive sporadic patients had a phenotype resembling that of familial MEN1 (multiglandular parathyroid hyperplasia, a prevalence of gastro-entero-pancreatic tumors and/or the classic triad) we might hypothesize that a subset of the sporadic MEN1 mutation-negative patients could represent an incidental coexistence of sporadic primary hyperparathyroidism and pituitary tumors or a MEN1 phenocopy, in our cohort, as in most cases described in the literature.

Multiple endocrine neoplasia type 1: analysis of germline MEN1 mutations in the Italian multicenter MEN1 patient database

“…Recently, also another study failed to find a significant direct correlation between the type and location of MEN1 mutations and Truncating mutations include frameshift, nonsense, splicing and large intra-genic deletions; non-truncating mutations include missense and in-frame deletions. Results of Student's t-test: frameshift vs. nonsense p = 0.36; frameshift vs. missense p = 0.71; frameshift vs. splicing site mutations p = 0.25; splicing site mutations vs. nonsense p = 0.66; splicing site mutations vs. missense p = 0.38; missense vs. nonsense p = 0.60; truncating mutations vs. non-truncating mutations p = 0.87; Exon 2 vs. Exon 3 p = 0.60; Exon 2 vs. Exon 9 p = 0.64; Exon 2 vs. Exon 10 p = 0.76; Exon 3 vs. Exon 9 p = 0.83; Exon 3 vs. Exon 10 p = 0.44; Exon 9 vs. Exon 10 p = 0.41 SD standard deviation, NA non-applicable Endocrine (2018) 62:215-233 clinical phenotypes in 54 MEN1 patients with Italian ancestry [12]. Our series of patients also included a pair of monozygous twins; at the time of the study (age under 35 years), they manifested PHPT only, being inconclusive for the study of genotype-phenotype correlation.…”

Genetic predictors of insulin-producing pancreatic tumor

“…Так, E. Pardi и соавт. [15] обнаружили вариант Arg16His гена AIP у пациента с инсулиномой и первичным гиперпаратиреозом. Авторы считают данный вариант полиморфизмом, так как он выявлен и у ряда здоровых индивидуумов [15].…”

“…[15] обнаружили вариант Arg16His гена AIP у пациента с инсулиномой и первичным гиперпаратиреозом. Авторы считают данный вариант полиморфизмом, так как он выявлен и у ряда здоровых индивидуумов [15]. Как известно, в отличие от мутаций, приводящих к патогенным вариантам генов, полиморфизмы обычно вызывают изменения, не влекущие за собой значимые изменения генов (непатогенные варианты), но в действительности различие между мутацией и полиморфизмом не всегда четкое.…”

Multiple Endocrine Neoplasia Type 1 (MEN1) Phenocopy Due to a Cell Cycle Division 73 (CDC73) Variant

“…In > 75% of patients, MEN1 is caused by mutations, including whole or partial gene deletions, in-frame and frameshift deletions or insertions, splice site, nonsense and missense mutations, of the tumor suppressor gene MEN1 , which encodes the protein menin [ 8 , 9 ]. The remaining < 25% of patients, may have mutations in as-yet unidentified genes, or may represent phenocopies [ 3 , 10 ]. Phenocopies, which refer to genetic disease manifestations without the specific gene mutation, can confound clinical diagnosis of hereditary disorders and therefore have implications for the management and treatment of both the patient and their relatives [ 3 , 10 ].…”

“…The remaining < 25% of patients, may have mutations in as-yet unidentified genes, or may represent phenocopies [ 3 , 10 ]. Phenocopies, which refer to genetic disease manifestations without the specific gene mutation, can confound clinical diagnosis of hereditary disorders and therefore have implications for the management and treatment of both the patient and their relatives [ 3 , 10 ]. Furthermore, it has been reported that mutations in genes, for example, the cell cycle division 73 ( CDC73 ), calcium sensing receptor ( CASR ), and cyclin dependent kinase inhibitor 1B ( CDKN1B ), can result in MEN1 phenocopies [ 3 , 10 ].…”