True MEN1 or phenocopy? Evidence for geno-phenotypic correlations in MEN1 syndrome
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 mutat...
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Published in | Endocrine Vol. 65; no. 2; pp. 451 - 459 |
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Main Authors | , , , , , , , , , , , , , , , , , , |
Format | Journal Article |
Language | English |
Published |
New York
Springer US
01.08.2019
Springer Nature B.V |
Subjects | |
Online Access | Get full text |
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Summary: | 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. |
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Bibliography: | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 |
ISSN: | 1355-008X 1559-0100 |
DOI: | 10.1007/s12020-019-01932-x |