BES2003 Poster Presentations Endocrine Tumours and Neoplasia (47 abstracts)
Familial isolated primary hyperparathyroidism due to germline multiple endocrine neoplasia Type 1 (MEN1) mutations
JJO Turner 1 , AAJ Pannett 1,2 , AM Kennedy 1 , SA Forbes 2 , BM Cavaco 1,2 , JHD Bassett 2 , L Cianferotti 2 , B Harding 1,2 , B Shine 3 , F Flinter 4 , CGH Maidment 5 , R Trembath 6 & RV Thakker 1,2
1Molecular Endocrinology Group, University of Oxford, Nuffield Department of Medicine, Botnar Research Centre, Nuffield Orthopaedic Centre, Oxford, UK; 2MRC Molecular Endocrinology Group, MRC Clinical Sciences Centre, Imperial College School of Medicine, Hammersmith Hospital, London UK; 3Department of Clinical Biochemistry, John Radcliffe Hospital, Headington, Oxford, UK; 4Clinical Genetics Department, New Guy's House, Guy's Hospital, London, UK; 5Wexham Park Hospital, Slough, UK; 6Department of Genetics, Leicestershire Genetics Service, Leicester Royal Infirmary, Leicester, UK
Primary hyperparathyroidism (HPT) is most frequently encountered as a non-familial disorder, but 10% of patients with primary HPT will have a hereditary form, which may occur as an isolated endocrinopathy or as part of a complex tumour syndrome such as multiple endocrine neoplasia type 1 (MEN 1) or type 2 (MEN 2), or the hereditary hyperparathyroidism-jaw tumour syndrome (HPT-JT). Familial isolated hyperparathyroidism (FIHP) is an autosomal dominant disorder characterised by uniglandular or multiglandular parathyroid tumours that occur in the absence of other endocrine tumours. The disorder may represent either an early stage of multiple endocrine neoplasia type 1 (MEN1), or an allelic variant of MEN1, or a distinct entity involving another locus. We have explored these possibilities in 7 families in whom primary hyperparathyroidism occurred as the sole endocrinopathy in 17 available members (9 males and 8 females), over a mean (+/- SD) follow up period of 15.06 (+/- 8.83) years. We searched for germline mutations by using leukocyte DNA and 15 pairs of primers to amplify by PCR the coding region of the MEN1 gene. DNA sequence analysis of the PCR products identified 4 heterozygous mutations. These consisted of two 4bp intragenic deletions that would result in prematurely truncated proteins, and 2 missense (Asp153Val and Ala411Pro) mutations. Furthermore, analysis of parathyroid tumour DNA from one case revealed a loss of the wild type allele and retention of the mutant allele, consistent with Knudson's 'two-hit' model of hereditary cancer and a tumour suppressor role for MEN1 in FIHP. Thus, our results provide further support for FIHP being a distinct allelic variant of MEN1 and an analysis of the sixteen germline MEN1 mutations reported to date in FIHP and of the >230 germline mutations reported in MEN1 indicate that FIHP is associated with a higher frequency of missense MEN1 mutations.
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Endocrine Abstracts
ISSN 1470-3947 (print) | ISSN 1479-6848 (online)
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