Endocrine Abstracts (2019) 65 CMW2.2 | DOI: 10.1530/endoabs.65.CMW2.2

Genetic testing in hyperparathyroidism - who to test and why

Sashi Mariathasan1, Katrina Andrews2, Edward Thompson2, Ruth Armstrong2, Helen Simpson3, Ruth Casey4,2 & Soo-Mi Park2


1Univeristy of Cambridge Medical School, Cambridge, UK; 2East Anglian Medical Genetics Service, Cambridge University Hospital NHS Foundation Trust, Cambridge, UK; 3Department of Endocrinology, University College London Hospitals NHS Foundation Trust, London, UK; 4Department of Endocrinology, Cambridge University Hospital NHS Foundation Trust, Cambridge, UK


Primary hyperparathyroidism (PHPT) is a common endocrine disorder with a prevalence of 0.86% in Europe. Approximately 10% of cases are hereditary. Syndromic PHPT occurs as part of multiple endocrine neoplasia (MEN)1, MEN4, MEN2A and hyperparathyroidism jaw tumour syndrome. Non-syndromic causes include familial hypocalciuric hypercalcaemia. Establishing the underlying genetic cause allows for targeted, cost effective management. Current guidelines recommend that genetic testing is considered in PHPT with i) age <40y, ii) multi-glandular/ recurrent disease, iii) with a personal or family history (FH) suggestive of an endocrine neoplasia syndrome or iv) a FH of PHPT. We reviewed 100 PHPT patients seen in the Cambridge Endocrine Genetics clinic over a 4y period who were referred for multi-glandular disease, relevant FH, Ca:Creatinine clearance ratio (CaCrR) <0.01, age <50y, or >1 risk factor. We offered NGS panel gene testing, including genes MEN1, CDC73, CASR, CDKN1A, CDKN1B, CDKN2A, CDKN2B, CDKN2C, RET, GCM2, GNA11, and AP2S1. Of the 100 patients, (26 male, 74 female), the mean age was 41.6y (S.D. 17.1). A pathogenic germline variant was identified in 18% (11 CASR, 5 MEN1, 1 CDC73, 1 AP2S1) and a variant of uncertain significance (VUS) was identified in 3 patients (all in RET). The mean CaCrR was 0.008 in those with a pathogenic variant in CASR vs 0.016 in mutation negative group (P 0.003). A CaCrR <0.01 had a sensitivity of 95% but poor specificity of 52%. In isolation, age at diagnosis, multi-glandular disease and gender were not predictive of a pathogenic variant whereas a positive FH was a strong predictor of hereditary PHPT. The diagnostic rate was 10.5% in those >50 y compared to 18% in those <50y. In summary, genetic testing is recommended in PHPT at any age with i) syndromic PHPT, ii) FH of PHPT or related endocrinopathy, iii) a CaCrR <0.01 and iv) multiple risk factors.

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