Presentation: Pregnant patient with severe hypercalcaemia refractory to treatment

A female patient, with unrelated parents and an absent family history, first presented aged 17 with nephrocalcinosis but normocalcaemia. Now, at the age of 25, she presents in pregnancy with severe hypercalcaemia. PTH levels are low. Clinical examination and blood pressure measurement are normal. Laboratory tests show elevated adjusted calcium, elevated 25(OH)D and 1,25(OH) vitamin D, and immeasurably low 24,25 (OH) vitamin D.

• You should consider genomic testing when:
  • there are elevated calcium and vitamin D metabolites, particularly in conjunction with nephrocalcinosis and/or nephrolithiasis; and/or
  • there is a history of nephrolithiasis or nephrocalcinosis in siblings.
• Other causes of hypercalcuric hypercalcaemia, such as vitamin D toxicity and granulomatous disease, should be considered before organising genomic testing.

• 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 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 tests best suits the needs of your patient/family. For patients with nephrocalcinosis or nephrolithiasis, there are a number of options, including:
  • R256 Nephrocalcinosis or nephrolithiasis: This indication involves a medium-sized panel test, which is sometimes performed using whole exome sequencing (WES), and multiplex ligation-dependent probe amplification (MLPA). Analysis includes those genes associated with renal tract calcification. R256 is the most appropriate choice if there is evidence of nephrocalcinosis and/or a calcium disorder and history of renal stones.
  • R198 Renal tubulopathies: This indication involves the use of WES and MLPA to examine those genes associated with renal calcium malabsorption. See ‘Adult with hypokalaemic metabolic alkalosis’, ‘Patient with suspected pseudohypoaldosteronism type 2’ and ‘Patient with incidental finding of asymptomatic hypercalcaemia’.
  • R240 Diagnostic testing for known variant(s): This indication should be used when your patient is clinically affected with severe hypercalcaemia refractory to treatment in pregnancy and has a family member with a known pathogenic or likely pathogenic gene variant(s).
  • R242 Predictive testing for known familial variant(s): This is for a predictive (also known as presymptomatic) test and should be used for anyone who is clinically unaffected but has a relative with a pathogenic or likely pathogenic variant(s). It must be requested by clinical genetics.
• None of the tests outlined above use whole genome sequencing (WGS), so you should use your local Genomic Laboratory Hub test order form and consent (record of discussion) forms.
• Note that different forms are required for any test involving WGS.
• 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 were 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
• Medline Plus: Idiopathic infantile hypercalcemia
• NHS England: National Genomic Test Directory

For patients

• Medline Plus: Idiopathic infantile hypercalcemia