Presentation: Patient with possible familial hyperparathyroidism

A 31-year-old man is referred to the endocrine clinic with raised serum calcium levels on biochemical testing for irritable bowel-like symptoms. Although his symptoms have now resolved and he is otherwise well, his biochemistry confirms hypercalcaemia (corrected calcium 2.74mmol/l (2.15mmol/l to 2.55mmol/l)) with raised parathyroid hormone (PTH) 8.0pmol/l (NR 1.6mol/l to 6.9pmol/l)). His urinary calcium-to-creatinine clearance ratio is 0.06. He is not aware of any family history of primary hyperparathyroidism (PHPT). A Tc-99m sestamibi scan indicates a left superior parathyroid adenoma.

• Constitutional (germline) genomic testing should be considered if a patient presents with PHPT (unexplained hypercalcaemia with PTH levels that are high or in the upper normal range, and a calcium-to-creatinine clearance ratio of more than 0.02) meeting one of the following criteria:
  • presenting before the age of 50 years; or
  • presenting at any age with one of the following:
    • a confirmed or relevant family history;
    • multi-glandular disease or hyperplasia on histology in the presence of a relevant family history;
    • parathyroid carcinoma or atypical or cystic adenoma; or
    • ossifying fibroma(s) of the maxilla and/or mandible.
• Patients with biochemistry suggestive of PHPT (raised serum calcium and PTH) who are vitamin D replete but show signs of hypocalciuria (having a urinary calcium clearance-to-creatine ratio of less than 0.02) may have familial hypocalciuric hypercalcaemia (FHH) and may be suitable for constitutional genomic testing, irrespective of age.
• Patients with clinical features of endocrine neoplasia syndromes, including hyperparathyroidism, may be suitable for genomic testing under a different clinical indication.

• Consult the National Genomic Test Directory. From here you can access the rare and inherited disease eligibility criteria for information about individual tests and their associated eligibility criteria. You can also access a spreadsheet of all available tests.
  • For information about how to arrange testing in Wales, Scotland or Northern Ireland, see our dedicated Knowledge Hub resource.
• To find out which genes are included on different gene panels, see the NHS Genomic Medicine Service (GMS) Signed Off Panels Resource.
• For patients who meet test directory eligibility criteria and do not have a personal or family history of a genetic variant in a familial hyperparathyroid or FHH gene, select the following:
  • R151 Familial hyperparathyroidism or FHH test panel. This panel currently comprises the following genes: AP2S1, CASR, CDC73, CDKN1B, GCM2, GNA11, MEN1 and RET. The test detects small variants and copy number variation (CNV) by small gene panel sequencing.
  • R226 Inherited parathyroid cancer panel for patients with parathyroid carcinoma. This involves CDC73 single gene testing. For more information, see Presentation: Patient with parathyroid carcinoma.
  • R319 Calcium-sensing receptor phenotypes. This involves CASR single gene testing and should be considered in neonatal hyperparathyroidism.
  • R217 and R218: These are multiple endocrine neoplasia panels, to be requested when there are clinical features of a wider multiple endocrine neoplasia syndrome, including hypercalcaemia (for example, multiple endocrine neoplasia types 1, 2 and 4 (MEN1, MEN2 and MEN4, respectively) and hyperparathyroidism jaw tumour syndrome).
    • The R217 panel currently comprises the following genes: AIP, CDC73, CDKN1B, MEN1, PRKAR1A, RET and VHL. The test involves small gene panel sequencing.
    • The R218 panel involves RET single gene testing.
• For patients presenting with PHPT or FHH in whom a genetic diagnosis in a relevant PHPT or FHH predisposition gene has been established in another family member, single gene testing for that specific variant should be considered. R240 Diagnostic testing for known mutation(s) could be selected, if the pathogenic variant report about the close family member is available and testing was performed in an accredited laboratory.
• None of the tests described above include whole genome sequencing, so you should use your local Genomic Laboratory Hub test order and consent (record of discussion) forms.
• The majority of tests are DNA based, and an EDTA sample (purple-topped tube) is required. The sample is best stored at four degrees Celsius until it can be posted to the genomic laboratory.
• Information about patient eligibility and test indications was correct at the time of writing. When requesting a test, please refer to the National Genomic Test Directory to confirm the right test for your patient.

For clinicians

• NHS England: National Genomic Test Directory

For patients

• Association for Multiple Endocrine Neoplasia (AMEND)
• Parathyroid UK