Pseudohypoaldosteronism

Pseudohypoaldosteronism
In pseudohypoaldosteronism, aldosterone is elevated (hyperaldosteronism), but because the body fails to respond to it, it appears similar to hypoaldosteronism.

Pseudohypoaldosteronism (PHA) is a condition that mimics hypoaldosteronism.[1] However, the condition is due to a failure of response to aldosterone, and levels of aldosterone are actually elevated, due to a lack of feedback inhibition.

Types

Type OMIM Gene Inheritance Description
PHA1A 177735 MLR NRC Autosomal dominant with sodium wasting
PHA1B 264350 SCNN1A, SCNN1B, SCNN1G of the epithelial sodium channel Autosomal recessive with sodium wasting
PHA2 145260 WNK4, WNK1 without sodium wasting. TRPV6 may be involved.[2]

Signs and symptoms

White opaque discharge with appearance of a row of teeth at bottom of the eyelashes

PHA2 is clinically characterised by hypertension, hyperkalaemia, metabolic acidosis and normal renal function.[3]

Mechanism

PHA2 is also known as familial hyperkalaemic hypertension, or Gordon syndrome. The underlying genetic defect leads to increased sodium chloride reabsorption in the distal tubule in the kidney, leading to volume expansion, hypertension and lowered renin levels. The hyperkalemia found in PHA2 is proposed to be a function of diminished sodium delivery to the cortical collecting tubule (potassium excretion is mediated by the renal outer medullary potassium channel ROMK in which sodium reabsorption plays a role). Alternatively, WNK4 mutations that result in a gain of function of the Na-Cl co-transporter may inhibit ROMK activity resulting in hyperkalemia.[4] Unlike in PHA1 in which aldosterone resistance is present, in PHA2 the volume expansion leads to relatively low aldosterone levels.[3]

Diagnosis

While there are no formal diagnostic criteria for PHAII ( published), it should be suspected if:[5]

Treatment

Treatment of severe forms of PHA1 requires relatively large amounts of sodium chloride.[6] These conditions also involve hyperkalemia.[7]

In contrast, PHA2 (Gordon's syndrome) requires salt restriction and use of thiazide diuretics to block sodium chloride reabsorption and normalise blood pressure and serum potassium.

History

This syndrome was first described by Cheek and Perry in 1958.[8] Later pediatric endocrinologist Aaron Hanukoglu reported that there are two independent forms of PHA with different inheritance patterns: A renal form with autosomal dominant inheritance exhibiting salt loss mainly from the kidneys, and a multi-system form with autosomal recessive form exhibiting salt loss from kidney, lung, and sweat and salivary glands.[9][10]

The hereditary lack of responsiveness to aldosterone could be due to at least two possibilities: 1. A mutation in the mineralocorticoid receptor that binds aldosterone, or 2. A mutation in a gene that is regulated by aldosterone. Linkage analysis on patients with the severe form of PHA excluded the possibility of linkage of the disease with the mineralocorticoid receptor gene region.[11] Later, the severe form of PHA was discovered to be due to mutations in the genes SCNN1A, SCNN1B, and SCNN1G that code for the epithelial sodium channel subunits, α, β, and γ, respectively.[12]

A stop mutation in the SCNN1A gene has been shown to be associated with female infertility.[13]

See also

References

  1. ↑ "Pseudohypoaldosteronism: Overview - eMedicine Pediatrics: General Medicine". Archived from the original on 2020-10-28. Retrieved 2009-03-06.
  2. ↑ Yang SS, Hsu YJ, Chiga M, Rai T, Sasaki S, Uchida S, Lin SH (Apr 2010). "Mechanisms for hypercalciuria in pseudohypoaldosteronism type II-causing WNK4 knock-in mice". Endocrinology. 151 (4): 1829–36. doi:10.1210/en.2009-0951. PMID 20181799.
  3. 1 2 O'Shaughnessy, Kevin M. (November 2015). "Gordon Syndrome: a continuing story". Pediatric Nephrology (Berlin, Germany). 30 (11): 1903–1908. doi:10.1007/s00467-014-2956-7. ISSN 1432-198X. PMID 25503323. S2CID 195676310.
  4. ↑ Garovic, Vesna D. (2006). "Monogenic Forms of Low-Renin Hypertension". Nature Clinical Practice. Nephrology. Nature Clinical Practice Nephrology. 2 (11): 624–30. doi:10.1038/ncpneph0309. PMID 17066054. S2CID 27864633. Archived from the original on 18 October 2019. Retrieved 18 October 2019.
  5. ↑ Ellison, David H. (1993). "Pseudohypoaldosteronism Type II". GeneReviews®. University of Washington, Seattle. Archived from the original on 19 January 2022. Retrieved 22 June 2022.
  6. ↑ Hanukoglu A, Hanukoglu I (2010). "Clinical improvement in patients with autosomal recessive pseudohypoaldosteronism and the necessity for salt supplementation". Clinical and Experimental Nephrology. 14 (5): 518–519. doi:10.1007/s10157-010-0326-8. PMID 20661616. S2CID 9764720.
  7. ↑ Pseudohypoaldosteronism at the US National Library of Medicine Medical Subject Headings (MeSH)
  8. ↑ CHEEK DB, PERRY JW (1958). "A salt wasting syndrome in infancy". Arch Dis Child. 33 (169): 252–6. doi:10.1136/adc.33.169.252. PMC 2012226. PMID 13545877.
  9. ↑ Hanukoglu A (Nov 1991). "Type I pseudohypoaldosteronism includes two clinically and genetically distinct entities with either renal or multiple target organ defects". The Journal of Clinical Endocrinology and Metabolism. 73 (5): 936–44. doi:10.1210/jcem-73-5-936. PMID 1939532. Archived from the original on 2019-10-03. Retrieved 2022-05-24.
  10. ↑ Hanukoglu I, Hanukoglu A (Jan 2016). "Epithelial sodium channel (ENaC) family: Phylogeny, structure-function, tissue distribution, and associated inherited diseases". Gene. 579 (2): 95–132. doi:10.1016/j.gene.2015.12.061. PMC 4756657. PMID 26772908.
  11. ↑ Chung E, Hanukoglu A, Rees M, Thompson R, Dillon M, Hanukoglu I, et al. (1995). "Exclusion of the locus for autosomal recessive pseudohypoaldosteronism type 1 from the mineralocorticoid receptor gene region on human chromosome 4q by linkage analysis". J Clin Endocrinol Metab. 80 (11): 3341–5. doi:10.1210/jcem.80.11.7593448. PMID 7593448. Archived from the original on 2022-06-30. Retrieved 2022-05-24.
  12. ↑ Chang SS, Grunder S, Hanukoglu A, Rösler A, Mathew PM, Hanukoglu I, et al. (1996). "Mutations in subunits of the epithelial sodium channel cause salt wasting with hyperkalaemic acidosis, pseudohypoaldosteronism type 1". Nat Genet. 12 (3): 248–53. doi:10.1038/ng0396-248. PMID 8589714. S2CID 8185511.
  13. ↑ Boggula VR, Hanukoglu I, Sagiv R, Enuka Y, Hanukoglu A (October 2018). "Expression of the epithelial sodium channel (ENaC) in the endometrium - Implications for fertility in a patient with pseudohypoaldosteronism". The Journal of Steroid Biochemistry and Molecular Biology. 183: 137–141. doi:10.1016/j.jsbmb.2018.06.007. PMID 29885352. S2CID 47010706.
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