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True MEN1 or phenocopy? Evidence for geno-phenotypic correlations in MEN1 syndrome.

Abstract：

PURPOSE:Multiple endocrine neoplasia type 1 is a rare tumor syndrome caused by germline mutations of MEN1 gene. Phenotype varies widely, and no definitive correlation with the genotype has been observed. Mutation-negative patients with MEN1-associated tumors represent phenocopies. By comparing mutation-positive and mutation-negative patients, we aimed to identify phenotype features predictive for a positive genetic test and to evaluate the role of MEN1 mutations in phenotype modulation. METHODS:Mutation screeening of MEN1 gene by Sanger sequencing and assessment of clinical data of 189 consecutively enrolled probands and relatives were performed at our national and European Reference Center. Multiple ligation probe amplification analysis of MEN1 gene and Sanger sequencing of CDKN1B were carried out in clinically suspicious but MEN1-negative cases. RESULTS:Twenty-seven probands and twenty family members carried MEN1 mutations. Five mutations have not been described earlier. Pronouncedly high number of phenocopies (>70%) was observed. Clinical suspicion of MEN1 syndrome emerged at significantly earlier age in MEN1-positive compared to MEN1-negative probands. Gastroenteropancreatic neuroendocrine tumors developed significantly earlier and more frequently in carriers compared to non-carriers. Probands with high-impact (frameshift, nonsense, large deletions) mutations, predicted to affect menin function significantly, developed GEP-NETs more frequently compared to low-impact (inframe and missense) mutation carriers. CONCLUSIONS:MEN1 phenocopy is common and represents a significant confounder for the genetic testing. GEP-NET under 30 years best predicted a MEN1 mutation. The present study thus confirmed a previous proposal and suggested that GEP-NET under 30 years should be considered as a part of the indication criteria for MEN1 mutational analysis.

journal_name

Endocrine

journal_title

Endocrine

authors

Kövesdi A,Tóth M,Butz H,Szücs N,Sármán B,Pusztai P,Tőke J,Reismann P,Fáklya M,Tóth G,Somogyi A,Borka K,Erdei A,Nagy EV,Deák V,Valkusz Z,Igaz P,Patócs A,Grolmusz VK

doi

10.1007/s12020-019-01932-x

subject

Has Abstract

pub_date

2019-08-01 00:00:00

pages

451-459

issue

eissn

1355-008X

issn

1559-0100

pii

10.1007/s12020-019-01932-x

journal_volume

pub_type

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True MEN1 or phenocopy? Evidence for geno-phenotypic correlations in MEN1 syndrome.