Pseudohypoaldosteronism

Author: Robert J Ferry Jr, MD; Chief Editor: Stephen Kemp, MD, PhD more...

Updated: Aug 12, 2010

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Background
Pathophysiology
Epidemiology
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Background

Pseudohypoaldosteronism (PHA) refers to a heterogeneous group of disorders of electrolyte metabolism characterized by an apparent state of renal tubular unresponsiveness or resistance to the action of aldosterone. The condition is characterized by hyperkalemia, metabolic acidosis, and normal glomerular filtration rate (GFR). Volume depletion or hypervolemia; renal salt wasting or retention; hypotension or hypertension; and elevated, normal, or low levels of renin and aldosterone may be observed in the various conditions that result in this syndrome.

Since primary PHA was first described, it has been further classified into a classic form of PHA (PHA type I [PH-I]) and PHA type II (PHA-II), which is also referred to as chloride shunt syndrome. Recently, PHA-I has been recognized as a heterogeneous syndrome that includes at least 2 clinically distinguishable entities with either renal or multiple target organ defects (MTOD). Early childhood hyperkalemia, or renal tubular acidosis (RTA) IV subtype 5, is a variant of the renal form of PHA-I.

PHA-II (also known as Gordon syndrome or chloride shunt syndrome) is a rare familial renal tubular defect characterized by hypertension and hyperkalemic metabolic acidosis in the presence of low renin and aldosterone levels. Paver and Pauline first reported PHA-II in 1964,^[1]although Gordon described it as a new clinical entity in 1970.^[2]

The molecular basis for most individuals who have PHA-II was linked to loss-of-function mutations in WNK1 or WNK4.^{[3, 4, 5, 6, 7]}WNKs comprise a family of serine-threonine protein kinases with unusual placement of the catalytic lysine compared with all other protein kinases. WNK1 or WNK4 regulate chloride cotransporters of the distal nephron and other epithelia.

An acquired or secondary form of PHA has also been described.

A summary of the forms of PHA is as follows:

Primary pseudohypoaldosteronism
- Type I (PHA-I)
  - Renal type I (renal PHA-I)
  - Multiple target organ defect type I (MTOD PHA-I)
  - Early childhood hyperkalemia
- Type II (PHA-II)
  - Gordon syndrome
  - Adolescent hyperkalemic syndrome
Secondary pseudohypoaldosteronism

Renal pseudohypoaldosteronism type I

Renal PHA-I, or early childhood hyperkalemia, is probably due to a maturation disorder in the number or function of aldosterone receptors. This autosomal dominant disorder has been associated with mutations in the human mineralocorticoid receptor gene (MLR) in numerous kindreds and also in sporadic cases.

Multiple target organ defect pseudohypoaldosteronism type I

In this variant, other organs are involved, such as the sweat glands, salivary glands, and colon. The fundamental abnormality in MTOD PHA-I is a loss-of-function mutation in the alpha or beta subunits of the epithelial sodium channel (ENaC), resulting in defective sodium transport in many organs containing the ENaC (eg, kidney, lung, colon, sweat and salivary glands). This amiloride-sensitive member of the degenerin/epithelial sodium channel (Deg/ENaC) superfamily of ion channels is comprised of 3 homologous units (alpha, beta, gamma) and is expressed in the apical membrane of epithelial cells lining the airway, colon, and distal nephron. ENaC plays an essential role in transepithelial Na⁺ and fluid balance.

The state of hyper-reninism and hyperaldosteronism in these children is the result of sustained extracellular fluid (ECF) volume depletion and is not due to peripheral resistance to mineralocorticoids.

Pseudohypoaldosteronism type II

As first reported in 2003 and confirmed with molecular studies, the defect for PHA-II involves absent WNK1 or WNK4 kinase function in the distal nephron.^{[3, 5, 6, 7]}WNK4 is exclusively expressed in the distal nephron, whereas WNK1 functions in most polarized epithelia (cells that line the lumen of hepatic biliary ducts, gallbladder, pancreatic ducts, epididymis, sweat ducts, and colonic crypts). These kinases regulate the thiazide-sensitive Na-Cl cotransporter (NCCT) in the distal nephron. Specifically, loss-of-function mutations in WNK1 or WNK4 abolish WNK regulation of NCCT, resulting in the uninhibited NCCT activity that causes PHA-II.

Prior studies had implicated both proximal and tubular defects. Enhanced chloride absorption in the distal nephron had been suggested as the primary abnormality; thus, the name chloride shunt syndrome was proposed. This increased reabsorptive avidity of the distal nephron for chloride, in turn, limits the sodium-dependent and mineralocorticoid-dependent voltage that is the driving force for potassium and hydrogen ion secretion, resulting in hyperkalemia and acidosis. The increased reabsorption of sodium chloride results in hyperchloremia with ensuing volume expansion and hypertension. Volume expansion results in secondary hypoaldosteronism and, consequently, in hyporeninemia.

Evidence suggests that enhanced sodium chloride reabsorption takes place in several nephron segments proximal to the potassium-secreting sites (proximal to the proximal tubule and thick ascending limb of the loop of Henle). An alternative mechanism to explain the renal tubular defect in this syndrome is abnormally low levels of urinary prostaglandin metabolites, a product of renal prostaglandin synthesis. Mutations in the thiazide-sensitive Na⁺/Cl^- cotransporter gene have been excluded as a cause.

Other authors still speculate that Gordon syndrome could result from a generalized increase in the activity of the bumetanide-sensitive Na⁺ -K⁺ -2Cl^- cotransporter; however, this has not been studied. Based on lack of response to the infusion of atrial natriuretic peptide (ANP), an increased proximal tubular reabsorption caused by inherited insensitivity to the action of the natriuretic factor has been proposed. However, other authors have not demonstrated this.

Table. Summary of Pseudohypoaldosteronism (Open Table in a new window)

Details	Pseudohypoaldosteronism Type I			Pseudohypoaldosteronism Type II
Details	Renal PHA-I	MTOD PHA-I	Early Childhood Hyperkalemia	PHA-II
Synonyms	Classic PHA of infancy, Cheek and Perry syndrome, autosomal dominant PHA-I, subtype 4 RTA IV	Autosomal recessive PHA-I	Subtype 5 RTA IV	Adolescent hyperkalemic syndrome, Spitzer-Weinstein syndrome, subtype 3 RTA IV	Gordon syndrome, mineralocorticoid-resistant hyperkalemia, chloride shunt syndrome
Age	Newborn period, infancy	Newborn period, infancy	Infancy, childhood	Childhood	Adulthood
Organs	Kidney	Kidney, sweat glands, salivary glands, colon	Kidney	Kidney	Kidney
Genetics	Autosomal dominant, sporadic	Autosomal recessive, sporadic	Unknown	Unknown	Autosomal dominant, sporadic
Mechanism	Heterozygous MLR mutations (possible)	Defective Na transport in organs that contain ENaC	Maturation disorder in the number or function of aldosterone receptors	Chloride shunt	Chloride shunt
Serum potassium	High	High	High	High	High
Acidosis	Present	Present	Present	Present	Present
Serum sodium	Normal or low	Normal or low	Normal	Normal	Normal
PRA*	High	High	Normal or high	Normal or low	Low
Aldosterone	High	High	Normal or high	Normal or low	Low
Blood volume	Normovolemia, hypovolemia	Normovolemia, hypovolemia	Normovolemia	Hypervolemia	Hypervolemia
Blood pressure	Normal or low	Normal or low	Normal or low	Normal or low	Normal or low
GFR	Normal	Normal	Normal	Normal	Normal
Salt wasting	Renal	Renal, sweat or salivary glands, colon	Absent	Absent	Absent
Hypercalciuria	Present or absent	Absent	Absent	Present	Present
Therapy	Na supplementation, K-binding resins	High-Na, low-K diet, K-binding resins, hydrochlorothiazide	Na bicarbonate, K-binding resins	Dietary Na restriction, hydrochlorothiazide	Dietary Na restriction, hydrochlorothiazide
Prognosis	Outgrow by age 2 y	Lifelong therapy	Outgrow by age 5 y	Lifelong therapy	Lifelong therapy
*Plasma renin activity

Frequency

International

Renal PHA-I: More than 70 cases of this salt-wasting syndrome have been reported in the literature since the first description in 1958.^[8]Renal PHA-I, also called Cheek and Perry syndrome or classic PHA of infancy, represents the most common form of PHA-I. The early childhood hyperkalemia variant of renal PHA-I is the most common subtype of type IV RTA in children and is found with equal frequency in males and females. Occasionally, several siblings are affected.
MTOD PHA-I: Multiple target organ resistance has been reported in several kindreds.
PHA-II: This is a rare form of PHA.
Secondary PHA: An acquired form of PHA has been rarely reported but may occur more frequently in clinical practice.

Mortality/Morbidity

Renal PHA-I: Individuals may present with severe symptoms early after birth and throughout the first two weeks of life or may be asymptomatic.
MTOD PHA-I: Individuals are prone to developing respiratory symptoms; death may ensue during the neonatal period.
PHA-II: Most individuals are asymptomatic until adolescence when hypertension develops.

Sex

The early childhood hyperkalemia variant of renal PHA-I is found with equal frequency in males and females.

Age

Renal PHA-I only occurs in newborns and infants and usually improves with age.
Early childhood hyperkalemia occurs in infants and young children.
MTOD PHA-I occurs in newborns and infants but persists into adulthood.
PHA-II occurs in older children and adults. Although the defect is present at birth, the disease is not usually diagnosed until adolescence.
Secondary PHA may occur at any age.

Proceed to Clinical Presentation

Contributor Information and Disclosures

Author

Robert J Ferry Jr, MD Professor and Chief, Division of Pediatric Endocrinology and Metabolism, Department of Pediatrics, University of Tennessee Health Science Center; Brigade Surgeon, 36th Sustainment Brigade, US Army; Adjunct Professor, Pediatric Surgery Department, King Saud University, Saudi Arabia

Robert J Ferry Jr, MD is a member of the following medical societies: American Academy of Pediatrics, American Diabetes Association, American Medical Association, Endocrine Society, Pediatric Endocrine Society, Society for Pediatric Research, and Texas Pediatric Society

Disclosure: Nutropin Speakers Bureau Honoraria Speaking and teaching; Genotropin Speakers Bureau Honoraria Speaking and teaching; Eli Lilly & Co. Grant/research funds Investigator; MacroGenics, Inc. Grant/research funds Investigator; Ipsen, S.A. (formerly Tercica, Inc.) Grant/research funds Investigator; NovoNordisk SA Grant/research funds Investigator; Diamyd Investigator

Coauthor(s)

Jose F Pascual-y-Baralt, MD Chief, Division of Pediatric Nephrology, San Antonio Military Pediatric Center; Clinical Professor, Department of Pediatrics, University of Texas Health Science Campus

Jose F Pascual-y-Baralt, MD is a member of the following medical societies: American Academy of Pediatrics, American Society of Nephrology, American Society of Pediatric Nephrology, Association of Military Surgeons of the US, and International Society of Nephrology

Disclosure: Nothing to disclose.

Specialty Editor Board

Arlan L Rosenbloom, MD Adjunct Distinguished Service Professor Emeritus of Pediatrics, University of Florida College of Medicine; Fellow of the American Academy of Pediatrics; Fellow of the American College of Epidemiology

Arlan L Rosenbloom, MD is a member of the following medical societies: American Academy of Pediatrics, American College of Epidemiology, American Pediatric Society, Endocrine Society, Florida Pediatric Society, Pediatric Endocrine Society, and Society for Pediatric Research

Disclosure: Nothing to disclose.

Mary L Windle, PharmD Adjunct Associate Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Nothing to disclose.

Lynne Lipton Levitsky, MD Chief, Pediatric Endocrine Unit, Massachusetts General Hospital; Associate Professor of Pediatrics, Harvard Medical School

Lynne Lipton Levitsky, MD is a member of the following medical societies: Alpha Omega Alpha, American Academy of Pediatrics, American Diabetes Association, American Pediatric Society, Endocrine Society, Pediatric Endocrine Society, and Society for Pediatric Research

Disclosure: Pfizer Grant/research funds P.I.; Tercica Grant/research funds Other; Eli Lily Grant/research funds PI; NovoNordisk Grant/research funds PI

Merrily P M Poth, MD Professor, Department of Pediatrics and Neuroscience, Uniformed Services University of the Health Sciences

Merrily P M Poth, MD is a member of the following medical societies: American Academy of Pediatrics, Endocrine Society, and Pediatric Endocrine Society

Disclosure: Nothing to disclose.

Chief Editor

Stephen Kemp, MD, PhD Professor, Department of Pediatrics, Section of Pediatric Endocrinology, University of Arkansas for Medical Sciences College of Medicine, Arkansas Children's Hospital

Stephen Kemp, MD, PhD is a member of the following medical societies: American Academy of Pediatrics, American Association of Clinical Endocrinologists, American Pediatric Society, Endocrine Society, Phi Beta Kappa, Southern Medical Association, and Southern Society for Pediatric Research

Disclosure: Nothing to disclose.

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Table. Summary of Pseudohypoaldosteronism

Table. Summary of Pseudohypoaldosteronism

Details	Pseudohypoaldosteronism Type I			Pseudohypoaldosteronism Type II
Details	Renal PHA-I	MTOD PHA-I	Early Childhood Hyperkalemia	PHA-II
Synonyms	Classic PHA of infancy, Cheek and Perry syndrome, autosomal dominant PHA-I, subtype 4 RTA IV	Autosomal recessive PHA-I	Subtype 5 RTA IV	Adolescent hyperkalemic syndrome, Spitzer-Weinstein syndrome, subtype 3 RTA IV	Gordon syndrome, mineralocorticoid-resistant hyperkalemia, chloride shunt syndrome
Age	Newborn period, infancy	Newborn period, infancy	Infancy, childhood	Childhood	Adulthood
Organs	Kidney	Kidney, sweat glands, salivary glands, colon	Kidney	Kidney	Kidney
Genetics	Autosomal dominant, sporadic	Autosomal recessive, sporadic	Unknown	Unknown	Autosomal dominant, sporadic
Mechanism	Heterozygous MLR mutations (possible)	Defective Na transport in organs that contain ENaC	Maturation disorder in the number or function of aldosterone receptors	Chloride shunt	Chloride shunt
Serum potassium	High	High	High	High	High
Acidosis	Present	Present	Present	Present	Present
Serum sodium	Normal or low	Normal or low	Normal	Normal	Normal
PRA*	High	High	Normal or high	Normal or low	Low
Aldosterone	High	High	Normal or high	Normal or low	Low
Blood volume	Normovolemia, hypovolemia	Normovolemia, hypovolemia	Normovolemia	Hypervolemia	Hypervolemia
Blood pressure	Normal or low	Normal or low	Normal or low	Normal or low	Normal or low
GFR	Normal	Normal	Normal	Normal	Normal
Salt wasting	Renal	Renal, sweat or salivary glands, colon	Absent	Absent	Absent
Hypercalciuria	Present or absent	Absent	Absent	Present	Present
Therapy	Na supplementation, K-binding resins	High-Na, low-K diet, K-binding resins, hydrochlorothiazide	Na bicarbonate, K-binding resins	Dietary Na restriction, hydrochlorothiazide	Dietary Na restriction, hydrochlorothiazide
Prognosis	Outgrow by age 2 y	Lifelong therapy	Outgrow by age 5 y	Lifelong therapy	Lifelong therapy
*Plasma renin activity

View Table List

Read more about Pseudohypoaldosteronism on Medscape

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