Presentation: Adult with hypokalaemic metabolic alkalosis

A 19-year-old female, the first child of unrelated parents and with no relevant family history, presents with paraesthesiae in the fingers after a short self-limiting episode of diarrhoea. She also describes muscle cramps and a feeling of generalised fatigue. She is normotensive. Initial investigations via the GP revealed hypokalaemia. There is no history of vomiting or diuretic use and the patient has normal dietary intake. Further investigations by a nephrologist revealed persistent hypokalaemia, metabolic alkalosis and low magnesium with inappropriate kaliuria and hypocalciuria. A renal ultrasound scan was normal with no evidence of nephrocalcinosis.

• Before opting for genomic testing, consider whether your patient may have an acquired cause of hypokalaemic metabolic alkalosis, which are common. These include:
  • Recurrent vomiting.
  • Diarrhoea.
  • Drug use including diuretic use, hormone treatment or laxative abuse.
  • Mineralocorticoid excess.
  • Cystic fibrosis (this should be excluded in adulthood as it is not always detected in childhood).
• Genomic testing is recommended for patients with a primary renal tubulopathy presenting with:
  • 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 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 test best suits the needs of your patient/family. For renal tubulopathies these include:
  • R198 Renal tubulopathies: This indication is for a panel test that includes the gene variants that cause Gitelman syndrome and Bartter Syndrome, two of the main differential diagnoses, including those genes known to cause this phenotype. This test includes a medium-sized panel test or whole exome sequencing and multiplex ligation-dependent probe amplification (MLPA).
  • R256 Nephrocalcinosis or nephrolithiasis: This indication may be appropriate if there is evidence of nephrocalcinosis and/or in cases of calcium disorders and history of renal stones. This test includes whole exome sequencing or a medium-sized panel and MLPA.
  • R184 Cystic fibrosis diagnostic test: Cystic fibrosis presenting in adulthood is a rare cause of hypokalaemia. This indication should be used if the R198 test result is negative, only if other features of the condition are present.
  • R240 Diagnostic testing for known variant(s): This indication can be used for patients who are clinically affected, if a member of the family already has a known pathogenic or likely pathogenic gene variant(s). In this situation, the laboratory will only test for the known familial 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
• NHS England: National Genomic Test Directory
• Orphanet (information about rare diseases and orphan drugs): Gitelman Syndrome

References:

• Konrad M, Nijenhuis T, Ariceta G and others. ‘Diagnosis and management of Bartter syndrome: executive summary of the consensus and recommendations from the European Rare Kidney Disease Reference Network Working Group for Tubular Disorders‘. Kidney International 2021: volume 99, issue 2, pages 324–35. DOI: 10.1016/j.kint.2020.10.035
• Blanchard A, Bockenhauer D, Bolignano D and others. ‘Gitelman syndrome: consensus and guidance from a Kidney Disease: Improving Global Outcomes (KDIGO) Controversies Conference‘. Kidney International 2017: volume 91, issue 1, pages 24–33. DOI: 10.1016/j.kint.2016.09.046

For patients

• Gitelman Syndrome UK
• UK Kidney Association: Bartter Syndrome
• UK Kidney Association: Gitelman and Type 3 Bartter Syndromes