Presentation: Patient with incidental finding of asymptomatic hypercalcaemia

During investigations for fatigue, a 43-year-old man had a series of screening blood tests that were unremarkable other than adjusted serum calcium of 3.1 mmol/l. Prior to any further investigations he discovered that his sister had undergone similar investigations for hypercalcaemia three years earlier, following an episode of pancreatitis and kidney stones, without any underlying anomaly being identified. Subsequently, 24-hour urine collection was arranged for this man and hypocalciuria was confirmed (1.6 mmol/24 hours (normal >4 mmol/24 hours).

• First exclude common causes of hypercalcaemia, which include:
  • primary (or tertiary) hyperparathyroidism;
  • multiple myeloma;
  • metastatic malignancy;
  • paraneoplastic hypercalcaemia due to PTHrp secretion;
  • iatrogenic hypercalcaemia from calcium and/or vitamin D supplementation; and
  • sarcoidosis.
• Genomic testing should be considered in the following instances:
  • When moderate to severe hypercalcaemia is asymptomatic.
  • For patients with a nephrocalcinosis/nephrolithiasis, if acquired causes have been excluded.
  • Where there is a family history of familial hypocalciuric hypercalcaemia (FHH) or unexplained asymptomatic hypercalcaemia.
  • For patients with a primary renal tubulopathy presenting as one of the following conditions:
    • hypokalaemic alkalosis with normal or low blood pressure (e.g. Bartter/Gitelman syndromes);
    • hypokalaemic alkalosis with elevated blood pressure (e.g. Liddle syndrome);
    • hyperkalaemic acidosis with low/normal BP (PHA type 1);
    • hyperkalaemic acidosis with elevated BP (PHA type 2);
    • hypokalaemic acidosis (pRTA and renal Fanconi syndromes);
    • hypomagnesaemia;
    • nephrogenic diabetes insipidus; or
    • a rare type of renal tubulopathy (seen in an expert centre).

• Consult the National Genomic Test Directory. From this link you can access the rare and inherited disease eligibility criteria document 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 Genomic testing in the devolved nations.
  • For information about the genes that are included on different gene panels, see the NHS Genomic Medicine Service (GMS) Signed Off Panels Resource.
• Decide which of the panels best suits the needs of your patient/family. There are a number of tests available for renal tubulopathies including:
  • R198 Renal tubulopathies: Examines a panel of genes that are known to be associated with anomalies of calcium handling by the kidney. This test includes whole exome sequencing (WES) or a medium-sized panel, and multiplex ligation-dependent probe amplification (MLPA).
  • R151 Familial hyperparathyroidism or hypocalciuric hypercalcaemia: This indication uses a panel test and MLPA and currently looks at only a small number of genes, so it should be selected where you are fairly confident of a diagnosis. This test must be requested by clinical genetics or endocrinology. Read more information about familial hyperparathyroidism here.
  • R256 Nephrocalcinosis or nephrolithiasis: The preferred test for those with calcium disorders and a history of kidney stones or nephrocalcinosis. See ‘Young person with nephrocalcinosis’ and ‘Pregnant patient with severe hypercalcaemia refractory to treatment’.
  • R240 Diagnostic testing for known mutation(s): This indication can be used for a patient who is clinically affected with FHH if a member of the family already has a known pathogenic or likely pathogenic variant. The laboratory will only test for the known familial variant.
  • R242 Predictive testing for known familial mutation(s): This is a predictive (also known as presymptomatic) test to be used for unaffected individuals who have a family member with a known pathogenic or likely pathogenic variant. It must be requested by clinical genetics.
• Also see ‘Patient with possible familial hyperparathyroidism’.
• None of the tests outlined above use whole genome sequencing, so you should use your local Genomic Laboratory Hub test order form and consent (record of discussion, or RoD) forms.
• When testing in children, parental samples may be helpful for interpretation of the proband’s result. Parental samples can be taken alongside that of the proband, and their DNA stored, or can be requested at a later date if needed.
• Most tests are DNA based, and an EDTA sample (typically a purple-topped tube) is required. There are a few tests for which a different type of tube is used; see Samples for genomic testing in rare disease.
• If you are discussing genomics concepts with your patients, you may find it helpful to use the visual communication aids for genomics conversations.
• 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

• Genomics England: NHS Genomic Medicine Service (GMS) signed off panels resource
• NHS England: National Genomic Test Directory
• Orphanet: Familial Hypocalciuric Hypercalacaemia

For patients

• Genetic and Rare Diseases Information Center (GARD): Familial Hypocalciuric Hypercalcaemia