Endocrine Abstracts

Primary hyperparathyroidism (PHPTH) is a common endocrine disorder and it is estimated that 10% of cases are hereditary, related to syndromes including; multiple endocrine neoplasia (MEN) type 1, MEN type 4, MEN2A and hereditary hyperparathyroidism jaw tumour syndrome. Further hereditary cases can occur in the absence of syndromic features such as familial hypercalcemia hypocalcuria. Identifying cases of hereditary PHPTH enables a personalised medicine approach. Current guidelines recommend that genetic testing is considered for patients i) presenting with PHPTH <40 years of age, ii) with multi-glandular/ recurrent disease, iii) with a personal or family history suggestive of an endocrine neoplasia syndrome or iv) a family history of PHPTH.

Aims and methods: A retrospective review of patients referred for genetic testing for suspected hereditary HPTH over a 4 year period at Cambridge University Hospital NHS Foundation Trust was performed. Genetic analysis was performed by next generation sequencing of a gene panel including; MEN1, RET, CDC73, CDKN1A, CDKN2B, CDKN2C, CaSR, AP2S1, GNA11. Aims of this study were to better define testing criteria for suspected hereditary PHPTH in a UK cohort.

Results: 75 patients were included in this study (54 female) with a mean age of 40 (SD 16.4). A pathogenic germline variant was identified in 17.3% (n=13) and a variant of uncertain significance was identified in 5 patients (6.7%). A pathogenic variant was identified in CDC73 in a single patient, MEN1 in 3, CaSR in 8 patients and AP2S1 in a single paediatric case. Five of the eight patients with a CaSR mutation had a calcium creatinine ratio (CaCrR) <0.01 and there was a significant difference in the mean CaCrR in those patients with an identified CaSR mutation versus those without (P=0.0078). Age at diagnosis, histology showing hyperplasia and gender were not predictive of a pathogenic germline variant (P=0.28) (P=0.57) and (P=0.31) but a positive family history was (P=6.4e−05). 20 patients were > 50 years of age and the diagnostic rate of a pathogenic variant was 10% in those patients > 50 years compared to 19% in those < 50 years. Two patients > 50 years were diagnosed with a pathogenic variant in MEN1 and CaSR but both patients had at least one risk factor for genetic testing. Family history was a strong predictor of hereditary PHPTH in this cohort. Pathogenic variants can be identified in older patients particularly those with additional risk factors. Such patients should therefore should be considered for genetic testing.