Endocrine Abstracts (2017) 49 EP348 | DOI: 10.1530/endoabs.49.EP348

Exome analysis of a large family with familial isolated primary hyperparathyroidism (FIHP) and multiple cancers

Filomena Cetani1, Elena Pardi2, Simona Borsari2, Federica Saponaro2, Liborio Torregrossa3, Chiara Mazzanti4, Paolo Aretini4, Marco La Ferla4, Sara Franceschi4, Francesca Lessi4, Prospero Civita4 & Claudio Marcocci4

1University Hospital of Pisa, Endocrinology Unit, Pisa, Italy; 2Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy; 3Department of Surgical, Medical and Molecular Pathology and Critical Area, University of Pisa, Pisa, Italy; 4Fondazione Pisana Per La Scienza Onlus, Pisa, Italy.

Familial Isolated Hyperparathyroidism (FIHP) is a hereditary disorder characterized by primary hyperparathyroidism (PHPT) with no evidence of other endocrine disorders. Germline MEN1, CDC73 and CASR mutations have been identified, but the majority of FIHP has still unrecognized causes. The aim of this study was to identify, by whole-exome sequencing, novel gene alterations in a large FIHP kindred. The family’s proband, her sister, brother and niece were affected by PHPT. The proband was negative at MEN1, CDC73 and CASR gene mutations by Sanger analysis. The proband, her sister and niece were also affected by papillary thyroid carcinoma, the brother had Non-Hodgkin Lymphoma and bladder cancer. The proband had also a moderate colorectal polyposis and the niece a renal angiomyolipoma. We analyzed the proband, two affected and two healthy family’s members with the Illumina NextSeq550 platform. The raw data were converted using Bcl2toFastq tools. Data analysis was performed by the SeqMule pipeline. The three affected individuals, but not the healthy relatives, shared 57 rare genetic variants. A more stringent filter related to genes involved in hereditary cancer detected one missense variant in the APC gene (V530A) in the three affected patients, subsequently confirmed by Sanger analysis. Moreover, the other affected relative and 2/15 healthy members carried the variant. The APC gene is involved in familial polyposis (FAP), an inherited disease marked by thousands colorectal polyps. The APC variant was predicted deleterious by three statistic model. Although the affected individuals don’t have classical FAP features, the proband had the excision of two colonic polyps. We might speculate that the presence of non-truncating mutation could lead to a mild colonic phenotype, as showed in the attenuated FAP, characterized by the presence of <100 polyps. FAP tumor spectra is highly various, in about 2% of cases papillary thyroid carcinoma and bladder cancer have been reported.