Presentation: Patient with suspected pseudohypoaldosteronism type 2

A previously fit and healthy 23-year-old man is next in your clinic. He was found to be hypertensive and hyperkalaemic post-operatively. On clinical review, hypertension and hyperkalaemia persisted with normal anion gap acidosis. No culprit medications were identified. His father had uncontrolled hypertension. Results confirmed hyporeninaemia and hypoaldosteronism, suggestive of type 4 renal tubular acidosis due to pseudohypoaldosteronism type 2 (Gordon syndrome).

• Genomic testing should be considered after excluding an acquired cause of hyperkalaemic acidosis and hypoaldosteronism, if you suspect a primary renal tubulopathy.
• Patients are eligible for genomic testing if they have 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 (Gordon syndrome)).
  • Hypokalaemic acidosis (pRTA and renal Fanconi syndromes).
  • Hypomagnesaemia.
  • Nephrogenic diabetes insipidus.
  • Other rare types 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 our Knowledge Hub resource ‘Genomic testing in the devolved nations’.
  • To find out which genes 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 renal tubulopathies there are a number of options, including:
  • R198 Renal tubulopathies: This indication is for a medium-sized gene panel test, comprising a panel of genes known to be associated with this phenotype, and also includes multiplex ligation-dependent probe amplification (MLPA).
  • R240 Diagnostic testing for known mutation(s): This indication can be used for a patient who is clinically affected with pseudohypoaldosteronism type 2, if a member of the family already has a known pathogenic or likely pathogenic genomic variant. In this situation, the laboratory will only test for the known familial variant.
  • R242 Predictive testing for known familial mutation(s) is a predictive (also known as presymptomatic) test for unaffected individuals who have a family member with a known pathogenic or likely pathogenic variant. This test requires authorisation from clinical genetics.
• The tests listed above do not include whole genome sequencing (WGS). For these tests:
  •  You can use your local Genomic Laboratory Hub (GLH) test order and consent (record of discussion) forms.
  • Parental samples may be needed for interpretation of the proband’s result, for example to determine whether a variant is de novo or inherited. These samples may be requested by the testing laboratory or you may wish to contact clinical genetics.
• Note that different forms are required for any test involving WGS.
• These tests are DNA based, so an EDTA sample (purple-topped tube) is required.

For clinicians

• GeneReviews: Pseudohypoaldosteronism Type II
• Genomics England: NHS Genomic Medicine Service (GMS) signed off panels resource
• NHS England: National Genomic Test Directory

References:

• Downie ML, Lopez Garcia SC, Kleta R and others. ‘Inherited Tubulopathies of the Kidney’. Clinical Journal of the American Society of Nephrology 2021: volume 16, issue 4, pages 620–630. DOI: 10.2215/CJN.14481119
• Mabillard H, Sayer JA. ‘The Molecular Genetics of Gordon Syndrome‘. Genes (Basel) 2019: volume 10, issue 12, page 986. DOI: 10.3390/genes10120986

For patients

• Genetic and Rare Diseases Information Center (GARD): Pseudohypoaldosteronism type 2