PMID- 29036195 OWN - NLM STAT- MEDLINE DCOM- 20171106 LR - 20230411 IS - 1932-6203 (Electronic) IS - 1932-6203 (Linking) VI - 12 IP - 10 DP - 2017 TI - Mutational and large deletion study of genes implicated in hereditary forms of primary hyperparathyroidism and correlation with clinical features. PG - e0186485 LID - 10.1371/journal.pone.0186485 [doi] LID - e0186485 AB - 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. FAU - Pardi, Elena AU - Pardi E AD - Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy. FAU - Borsari, Simona AU - Borsari S AD - Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy. FAU - Saponaro, Federica AU - Saponaro F AD - Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy. FAU - Bogazzi, Fausto AU - Bogazzi F AD - Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy. FAU - Urbani, Claudio AU - Urbani C AD - Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy. FAU - Mariotti, Stefano AU - Mariotti S AD - Endocrinology Unit, Department of Medical Sciences and Public Health, University of Cagliari, Cagliari, Italy. FAU - Pigliaru, Francesca AU - Pigliaru F AD - Endocrinology Unit, Department of Medical Sciences and Public Health, University of Cagliari, Cagliari, Italy. FAU - Satta, Chiara AU - Satta C AD - Endocrinology Unit, Department of Medical Sciences and Public Health, University of Cagliari, Cagliari, Italy. FAU - Pani, Fabiana AU - Pani F AD - Endocrinology Unit, Department of Medical Sciences and Public Health, University of Cagliari, Cagliari, Italy. FAU - Materazzi, Gabriele AU - Materazzi G AD - Department of Surgical, Medical and Molecular Pathology and Critical Area, University of Pisa, Pisa, Italy. FAU - Miccoli, Paolo AU - Miccoli P AD - Department of Surgical, Medical and Molecular Pathology and Critical Area, University of Pisa, Pisa, Italy. FAU - Grantaliano, Lorena AU - Grantaliano L AD - Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy. AD - Department of Medical Sciences, Hospital Villa Albani, Anzio (RM), Italy. FAU - Marcocci, Claudio AU - Marcocci C AD - Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy. AD - University Hospital of Pisa, Endocrine Unit 2, Pisa, Italy. FAU - Cetani, Filomena AU - Cetani F AUID- ORCID: 0000-0003-2558-9547 AD - University Hospital of Pisa, Endocrine Unit 2, Pisa, Italy. LA - eng PT - Journal Article DEP - 20171016 PL - United States TA - PLoS One JT - PloS one JID - 101285081 SB - IM MH - Adolescent MH - Adult MH - Aged MH - Female MH - *Gene Deletion MH - Genotype MH - Humans MH - Hyperparathyroidism, Primary/*genetics MH - Male MH - Middle Aged MH - *Phenotype MH - Young Adult PMC - PMC5643132 COIS- Competing Interests: The authors have declared that no competing interests exist. EDAT- 2017/10/17 06:00 MHDA- 2017/11/07 06:00 PMCR- 2017/10/16 CRDT- 2017/10/17 06:00 PHST- 2017/04/03 00:00 [received] PHST- 2017/10/01 00:00 [accepted] PHST- 2017/10/17 06:00 [entrez] PHST- 2017/10/17 06:00 [pubmed] PHST- 2017/11/07 06:00 [medline] PHST- 2017/10/16 00:00 [pmc-release] AID - PONE-D-17-12981 [pii] AID - 10.1371/journal.pone.0186485 [doi] PST - epublish SO - PLoS One. 2017 Oct 16;12(10):e0186485. doi: 10.1371/journal.pone.0186485. eCollection 2017.