Pseudohypoaldosteronism

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Pseudohypoaldosteronism (PHA) is a condition that mimics hypoaldosteronism. [1]

Contents

Pseudohypoaldosteronism Type 1
Aldosterone-2D-skeletal.svg
In pseudohypoaldosteronism type 1, aldosterone is elevated (hyperaldosteronism), but because the body fails to respond to it, it appears similar to hypoaldosteronism.
Specialty Nephrology   OOjs UI icon edit-ltr-progressive.svg
Symptoms Failure to thrive, dehydration, hyponatremia, metabolic acidosis, hyperkalemia, and other non-specific symptoms including nausea, vomiting, extreme fatigue, and muscle weakness.
CausesMutations in the MLR, NR3C2, SCNN1A, SCNN1B, or SCNN1G genes

Pseudohypoaldosteronism Type 1 (PHA1)

Pseudohypoaldosteronism type 1 (PHA1) is characterized by the body's inability to respond adequately to aldosterone, a hormone crucial for regulating electrolyte levels. This condition often manifests with dehydration as the kidneys struggle to retain sufficient salt, leading to symptoms like increased thirst and dry mouth. Additionally, PHA1 disrupts electrolyte balance, resulting in high levels of sodium and low levels of potassium in the blood.

Mechanism

Onset

Symptoms

Types

Type OMIM GeneInheritanceAge of OnsetDescription
PHA1A 177735 MLR, NR3C2 Autosomal dominantNeonatal but improves with age. Adults are usually asymptomatic without treatment.Salt wasting caused by renal unresponsiveness to mineralocorticoids. Patients often present with hyperkalaemic acidosis despite high aldosterone levels. Not all individuals with the mutation develop PHA1A suggesting that illness and volume depletion may play a role in the development of the clinically recognized PHA1A.
PHA1B 264350 SCNN1A, SCNN1B, SCNN1G of the epithelial sodium channel Autosomal recessiveNeonatal, appears to become less aggressive with ageRenal salt wasting and high concentrations of sodium in sweat, stool, and saliva. The disorder often involves multiple organ systems and can be life threatening in the neonatal period. Patients usually present with hyponatremia, hyperkalemia, and increased plasma renin activity with high serum aldosterone concentrations. PHA1B is often mistaken for cystic fibrosis.

Treatment

Treatment of severe forms of PHA1 requires relatively large amounts of sodium chloride. [2] These conditions also involve hyperkalemia. [3]

Risks

Individuals with PHA1B can have additional symptoms such as cardiac arrhythmia, shock, recurrent lung infections, or lesions on the skin due to imbalanced salts in the body especially in infancy.

A stop mutation in the SCNN1A gene has been shown to be associated with female infertility. [4]

Pseudohypoaldosteronism Type 2 (PHA2)

PHA2 also known as Familial hyperkalemic hypertension or Gordon syndrome is a rare disorder characterized by abnormalities in how the body regulates sodium and potassium levels. This condition stems from mutations in specific genes involved in sodium transport within the kidneys.

Unlike in PHA1 in which aldosterone resistance is present, in PHA2 blood volume increases occur regardless of normal or low aldosterone levels due to the enhanced activity of sodium transporters in the kidney. [5]

Mechanism

PHA2 is associated with mutations in the WNK4, WNK1, KLHL3 and CUL3 genes. These genes regulate the Sodium-chloride symporter (NCC) transporter, which is involved in controlling the levels of sodium and chloride in the body. Normally, the NCC transporter helps reabsorb sodium and chloride in a part of the kidney called the distal convoluted tubule (DCT), however in PHA2 this process is disrupted. Mutations in these genes lead to overactivity of NCC, causing excessive sodium and chloride reabsorption.

Mutations in KLHL3 and WNK4 are also known to create an overactivity in ENaC. EnaC is responsible for sodium and water reabsorption in the kidney. An overactiveity in ENaC can result in sodium wasting similar to PHA1. [6]

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. [7]

Onset

The age of onset is difficult to pinpoint and can range from infancy to adulthood.

Symptoms

People with PHA2 have hypertension and hyperkalemia despite having normal kidney function. Many individuals with PHA2 will develop hyperkalemia first, and will not present with hypertension until later in life. They also commonly experience both hyperchloremia and metabolic acidosis together, a condition called hyperchloremic metabolic acidosis.

People with PHA2 may experience other nonspecific symptoms including nausea, vomiting, extreme fatigue, muscle weakness, and hypercalcuria.

Some PHA2E patients present with dental abnormalities. [8] Patients with recessive KLHL3 mutations and dominant CUL3 mutations tend to have more severe phenotypes. [9]

A study in 2024 linked PHA2 to epilepsy. Epileptic seizures were seen in 3 of the 44 affected subjects. Two of the subjects had Generalized tonic–clonic seizure and one subject had migraine seizures. All three subjects had WNK4 mutations. It's speculated that the epilepsy may be caused by potassium spikes resulting in abnormal CNS neuron activity. The study also linked PHA2 to Proximal Renal Tubular Acidosis. [10] Metabolic acidosis is also known to cause epileptic seizures.

Types

Type OMIM GeneInheritanceAge Of OnsetDescription
PHA2A 145260 mapped to chromosome 1q31-q42 [11] Autosomal dominantVariesDoes not involve salt wasting.
PHA2B 614491 WNK4 Autosomal dominant10+ with a mean age of 28 [12] May involve salt wasting. [6] Patients typically do not experience hypertension until adulthood. [12] Bicarbonate is higher than other PHA2 types. Aldosterone concentrations are often normal. [13] TRPV6 may be involved. [14]
PHA2C 614492 WNK1 Autosomal dominant15+ with a mean age of 36 [12] Does not involve salt wasting. [6] Significantly less severely affected than other PHA2 types. [12] Affected patients have hypertension together with long-term hyperkalemia, hyperchloremia, normal plasma creatinine, reduced bicarbonate, and low renin levels. Aldestrone levels may be normal or elevated.
PHA2D 614495 KLHL3 Autosomal dominant or Autosomal recessiveMean age at diagnosis was found to be around 24 to 26, but it varies widely. [12] May involve salt wasting. [6] Individuals with the autosomal dominant mutations typically show higher potassium levels than those with autosomal recessive mutations. Hypertension usually develops in adulthood. Patients often present with low bicarbonate (17-18). [12]
PHA2E 614496 CUL3 Autosomal dominant3-15 years old [12] Most severe manifestations of PHA2 compared to patients with other mutations. Almost all individuals present with hypertension before age 18. [12]


Treatment

PHA2 requires salt restriction and use of thiazide diuretics to block sodium chloride reabsorption and normalise blood pressure and serum potassium.[ citation needed ]

Risks

Pregnancy Risks

As of 2018, at least 7 reported cases of severe metabolic acidosis occurring during pregnancy have been reported in PHA2 patients. [15]

A study in 2023 also described a patient with severe preeclampsia later being diagnosed with PHA2D. The twin babies born healthy and discharged from the hospital. [16]

Other Risks

One study noted that severe hypercalciuria from untreated PHA2 resulted in kidney stones, and osteoporosis in some patients. [17]

History

This syndrome was first described by Cheek and Perry in 1958. [18] 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. [19] [20]

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. [21] 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. [22]

See also

Related Research Articles

<span class="mw-page-title-main">Primary aldosteronism</span> Medical condition

Primary aldosteronism (PA), also known as primary hyperaldosteronism, refers to the excess production of the hormone aldosterone from the adrenal glands, resulting in low renin levels and high blood pressure. This abnormality is caused by hyperplasia or tumors. About 35% of the cases are caused by a single aldosterone-secreting adenoma, a condition known as Conn's syndrome.

<span class="mw-page-title-main">Hyperkalemia</span> Medical condition with excess potassium

Hyperkalemia is an elevated level of potassium (K+) in the blood. Normal potassium levels are between 3.5 and 5.0 mmol/L (3.5 and 5.0 mEq/L) with levels above 5.5 mmol/L defined as hyperkalemia. Typically hyperkalemia does not cause symptoms. Occasionally when severe it can cause palpitations, muscle pain, muscle weakness, or numbness. Hyperkalemia can cause an abnormal heart rhythm which can result in cardiac arrest and death.

<span class="mw-page-title-main">Amiloride</span> Medication

Amiloride, sold under the trade name Midamor among others, is a medication typically used with other medications to treat high blood pressure or swelling due to heart failure or cirrhosis of the liver. Amiloride is classified as a potassium-sparing diuretic. Amiloride is often used together with another diuretic, such as a thiazide or loop diuretic. It is taken by mouth. Onset of action is about two hours and it lasts for about a day.

<span class="mw-page-title-main">Thiazide</span> Class of chemical compounds

Thiazide refers to both a class of sulfur-containing organic molecules and a class of diuretics based on the chemical structure of benzothiadiazine. The thiazide drug class was discovered and developed at Merck and Co. in the 1950s. The first approved drug of this class, chlorothiazide, was marketed under the trade name Diuril beginning in 1958. In most countries, thiazides are the least expensive antihypertensive drugs available.

<span class="mw-page-title-main">Gitelman syndrome</span> Medical condition

Gitelman syndrome (GS) is an autosomal recessive kidney tubule disorder characterized by low blood levels of potassium and magnesium, decreased excretion of calcium in the urine, and elevated blood pH. It is the most frequent hereditary salt-losing tubulopathy. Gitelman syndrome is caused by disease-causing variants on both alleles of the SLC12A3 gene. The SLC12A3 gene encodes the thiazide-sensitive sodium-chloride cotransporter, which can be found in the distal convoluted tubule of the kidney.

<span class="mw-page-title-main">Potassium-sparing diuretic</span> Drugs that cause diuresis without causing potassium loss in the urine and leading to hyperkalemia

Potassium-sparing diuretics or antikaliuretics refer to drugs that cause diuresis without causing potassium loss in the urine. They are typically used as an adjunct in management of hypertension, cirrhosis, and congestive heart failure. The steroidal aldosterone antagonists can also be used for treatment of primary hyperaldosteronism. Spironolactone, a steroidal aldosterone antagonist, is also used in management of female hirsutism and acne from PCOS or other causes.

<span class="mw-page-title-main">Hypoaldosteronism</span> Medical condition

Hypoaldosteronism is an endocrinological disorder characterized by decreased levels of the hormone aldosterone. Similarly, isolated hypoaldosteronism is the condition of having lowered aldosterone without corresponding changes in cortisol.

<span class="mw-page-title-main">Metabolic alkalosis</span> Medical condition

Metabolic alkalosis is a metabolic condition in which the pH of tissue is elevated beyond the normal range (7.35–7.45). This is the result of decreased hydrogen ion concentration, leading to increased bicarbonate, or alternatively a direct result of increased bicarbonate concentrations. The condition typically cannot last long if the kidneys are functioning properly.

<span class="mw-page-title-main">Renal tubular acidosis</span> Medical condition

Renal tubular acidosis (RTA) is a medical condition that involves an accumulation of acid in the body due to a failure of the kidneys to appropriately acidify the urine. In renal physiology, when blood is filtered by the kidney, the filtrate passes through the tubules of the nephron, allowing for exchange of salts, acid equivalents, and other solutes before it drains into the bladder as urine. The metabolic acidosis that results from RTA may be caused either by insufficient secretion of hydrogen ions into the latter portions of the nephron or by failure to reabsorb sufficient bicarbonate ions from the filtrate in the early portion of the nephron. Although a metabolic acidosis also occurs in those with chronic kidney disease, the term RTA is reserved for individuals with poor urinary acidification in otherwise well-functioning kidneys. Several different types of RTA exist, which all have different syndromes and different causes. RTA is usually an incidental finding based on routine blood draws that show abnormal results. Clinically, patients may present with vague symptoms such as dehydration, mental status changes, or delayed growth in adolescents.

<span class="mw-page-title-main">Mineralocorticoid receptor antagonist</span> Drug class

A mineralocorticoid receptor antagonist or aldosterone antagonist, is a diuretic drug which antagonizes the action of aldosterone at mineralocorticoid receptors. This group of drugs is often used as adjunctive therapy, in combination with other drugs, for the management of chronic heart failure. Spironolactone, the first member of the class, is also used in the management of hyperaldosteronism and female hirsutism. Most antimineralocorticoids, including spironolactone, are steroidal spirolactones. Finerenone is a nonsteroidal antimineralocorticoid.

<span class="mw-page-title-main">Liddle's syndrome</span> Medical condition

Liddle's syndrome, also called Liddle syndrome, is a genetic disorder inherited in an autosomal dominant manner that is characterized by early, and frequently severe, high blood pressure associated with low plasma renin activity, metabolic alkalosis, low blood potassium, and normal to low levels of aldosterone. Liddle syndrome involves abnormal kidney function, with excess reabsorption of sodium and loss of potassium from the renal tubule, and is treated with a combination of low sodium diet and potassium-sparing diuretics. It is extremely rare, with fewer than 30 pedigrees or isolated cases having been reported worldwide as of 2008.

<span class="mw-page-title-main">Bartter syndrome</span> Medical condition

Bartter syndrome (BS) is a rare inherited disease characterised by a defect in the thick ascending limb of the loop of Henle, which results in low potassium levels (hypokalemia), increased blood pH (alkalosis), and normal to low blood pressure. There are two types of Bartter syndrome: neonatal and classic. A closely associated disorder, Gitelman syndrome, is milder than both subtypes of Bartter syndrome.

<span class="mw-page-title-main">Epithelial sodium channel</span> Group of membrane proteins

The epithelial sodium channel(ENaC), (also known as amiloride-sensitive sodium channel) is a membrane-bound ion channel that is selectively permeable to sodium ions (Na+). It is assembled as a heterotrimer composed of three homologous subunits α or δ, β, and γ, These subunits are encoded by four genes: SCNN1A, SCNN1B, SCNN1G, and SCNN1D. The ENaC is involved primarily in the reabsorption of sodium ions at the collecting ducts of the kidney's nephrons. In addition to being implicated in diseases where fluid balance across epithelial membranes is perturbed, including pulmonary edema, cystic fibrosis, COPD and COVID-19, proteolyzed forms of ENaC function as the human salt taste receptor.

<span class="mw-page-title-main">Sodium-chloride symporter</span> Protein-coding gene in the species Homo sapiens

The sodium-chloride symporter (also known as Na+-Cl− cotransporter, NCC or NCCT, or as the thiazide-sensitive Na+-Cl− cotransporter or TSC) is a cotransporter in the kidney which has the function of reabsorbing sodium and chloride ions from the tubular fluid into the cells of the distal convoluted tubule of the nephron. It is a member of the SLC12 cotransporter family of electroneutral cation-coupled chloride cotransporters. In humans, it is encoded by the SLC12A3 gene (solute carrier family 12 member 3) located in 16q13.

<span class="mw-page-title-main">Dent's disease</span> Medical condition

Dent's disease is a rare X-linked recessive inherited condition that affects the proximal renal tubules of the kidney. It is one cause of Fanconi syndrome, and is characterized by tubular proteinuria, excess calcium in the urine, formation of calcium kidney stones, nephrocalcinosis, and chronic kidney failure.

<span class="mw-page-title-main">SCNN1B</span> Protein-coding gene in the species Homo sapiens

The SCNN1B gene encodes for the β subunit of the epithelial sodium channel ENaC in vertebrates. ENaC is assembled as a heterotrimer composed of three homologous subunits α, β, and γ or δ, β, and γ. The other ENAC subunits are encoded by SCNN1A, SCNN1G, and SCNN1D.

<span class="mw-page-title-main">SCNN1A</span> Protein-coding gene in the species Homo sapiens

The SCNN1A gene encodes for the α subunit of the epithelial sodium channel ENaC in vertebrates. ENaC is assembled as a heterotrimer composed of three homologous subunits α, β, and γ or δ, β, and γ. The other ENAC subunits are encoded by SCNN1B, SCNN1G, and SCNN1D.

<span class="mw-page-title-main">SCNN1G</span> Protein-coding gene in the species Homo sapiens

The SCNN1G gene encodes for the γ subunit of the epithelial sodium channel ENaC in vertebrates. ENaC is assembled as a heterotrimer composed of three homologous subunits α, β, and γ or δ, β, and γ. The other ENAC subunits are encoded by SCNN1A, SCNN1B, and SCNN1D.

<span class="mw-page-title-main">WNK1</span> Protein-coding gene in the species Homo sapiens

WNK , also known as WNK1, is an enzyme that is encoded by the WNK1 gene. WNK1 is serine-threonine protein kinase and part of the "with no lysine/K" kinase WNK family. The predominant role of WNK1 is the regulation of cation-Cl− cotransporters (CCCs) such as the sodium chloride cotransporter (NCC), basolateral Na-K-Cl symporter (NKCC1), and potassium chloride cotransporter (KCC1) located within the kidney. CCCs mediate ion homeostasis and modulate blood pressure by transporting ions in and out of the cell. WNK1 mutations as a result have been implicated in blood pressure disorders/diseases; a prime example being familial hyperkalemic hypertension (FHHt).

<span class="mw-page-title-main">WNK4</span> Protein-coding gene in the species Homo sapiens

Serine/threonine protein kinase WNK4 also known as WNK lysine deficient protein kinase 4 or WNK4, is an enzyme that in humans is encoded by the WNK4 gene. Missense mutations cause a genetic form of pseudohypoaldosteronism type 2, also called Gordon syndrome.

References

  1. ↑ "Pseudohypoaldosteronism: Overview - eMedicine Pediatrics: General Medicine" . Retrieved 2009-03-06.
  2. ↑ 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.
  3. ↑ Pseudohypoaldosteronism at the U.S. National Library of Medicine Medical Subject Headings (MeSH)
  4. ↑ 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.
  5. ↑ 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.
  6. 1 2 3 4 Susa, Koichiro (2014). "Impaired degradation of WNK1 and WNK4 kinases causes PHAII in mutant KLHL3 knock-in mice". Human Molecular Genetics. 23 (19): 5052–506. doi:10.1093/hmg/ddu217. PMID   24821705.
  7. ↑ Garovic, Vesna D. (2006). "Monogenic Forms of Low-Renin Hypertension". Nature Clinical Practice. Nephrology. 2 (11). Nature Clinical Practice Nephrology: 624–30. doi:10.1038/ncpneph0309. PMID   17066054. S2CID   27864633 . Retrieved 18 October 2019.
  8. ↑ Nagahara, Keiko (December 2015). "Evaluation of Phosphorylated Urinary Na-Cl Cotransporter Is Potentially Useful in a Patient With Pseudohypoaldosteronism Type II due to Mutation in CUL3". Journal of the American Society of Nephrology. 27 (8): 2309–2318. doi:10.1681/ASN.2015020154. PMC   4978035 . PMID   26701978.
  9. ↑ Fernandez, Cornelius J. (2023). Monogenic hypertension with hyperkalemic acidosis, low renin, and variable aldosterone. pp. 1–117. doi:10.1016/C2021-0-01825-3. ISBN   978-0-323-96120-2.
  10. ↑ Shirin, Neta (2024). "Association of Familial Hyperkalemia and Hypertension with Proximal Renal Tubular Acidosis and Epileptic Seizures". Nephron. 3 (148): 179–184. doi:10.1159/000531868. PMID   37666233.
  11. ↑ Mansfield, Traci A. (1997). "Multilocus linkage of familial hyperkalaemia and hypertension, pseudohypoaldosteronism type II, to chromosomes 1q31-42 and 17p11-q21". Nat Genet. 16 (2): 202–205. doi:10.1038/ng0697-202. PMID   9171836.
  12. 1 2 3 4 5 6 7 8 Boyden, Lynn M (2012). "Mutations in kelch-like 3 and cullin 3 cause hypertension and electrolyte abnormalities". Nature. 482 (7383): 98–102. Bibcode:2012Natur.482...98B. doi:10.1038/nature10814. PMC   3278668 . PMID   22266938.
  13. ↑ Farfel, Zvi (1978). "Proximal Renal Tubular Acidosis Association With Familial Normaldosteronemic Hyperpotassemia and Hypertension". Arch Intern Med. 138 (12): 1837–1840. doi:10.1001/archinte.1978.03630370047021. PMID   718349.
  14. ↑ 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.
  15. ↑ Awad, Sara (2018). "Resolution of Metabolic Abnormalities During Pregnancy in a Patient with Gordon Syndrome and KLHL3 Mutation". AACE Clinical Case Reports. 4 (3): 235–239. doi:10.4158/AACR-2017-0006.
  16. ↑ Taylor, Cater (2023). "Pseudohypoaldosteronism Type 2: A New Variant Of A Rare Disease". Journal of the Endocrine Society. doi: 10.1210/jendso/bvad114 (inactive 2024-04-07).{{cite journal}}: CS1 maint: DOI inactive as of April 2024 (link)
  17. ↑ D’ambrosio, Viola (June 2023). "#6875 Complications and Treatment of Hypercalciuria in Familial Hyperkalaemic Hypertension (FHHT)". Nephrology Dialysis Transplantation. 38 (1). doi:10.1093/ndt/gfad063c_6875.
  18. ↑ 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.
  19. ↑ 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.
  20. ↑ 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.
  21. ↑ 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.
  22. ↑ 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.
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