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Pseudohypoaldosteronism Clinical Presentation

  • Author: Alicia Diaz-Thomas, MD, MPH; Chief Editor: Stephen Kemp, MD, PhD  more...
 
Updated: Apr 30, 2014
 

History

The clinical expression of renal pseudohypoaldosteronism (PHA) type I (PHA-I) varies widely, even among members of the same family who have the same gene defect. Affected children may have severe symptoms in early infancy (the first 2 weeks of life) or may be essentially asymptomatic.

Salt wasting and polyuria may be present in utero and result in polyhydramnios. Anorexia and vomiting generally develop immediately after birth. Symptoms are similar to those observed in mineralocorticoid deficiency. Salt craving is observed in older children. Vomiting is usually the only symptom in those with early childhood hyperkalemia.

In multiple target organ defects (MTOD) PHA-I, salt-wasting episodes develop soon after birth and usually are more severe than in renal PHA-I. Individuals with MTOD PHA-I have a high incidence of lower respiratory tract involvement secondary to impaired bacterial killing, resulting from increased sodium chloride concentration in airway surface fluid, which can mimic cystic fibrosis.

With respect to PHA type II (PHA-II), a condition has been described in children (Spitzer-Weinstein syndrome) that is characterized by short stature, hyperkalemic metabolic acidosis, blood pressure within the reference range, and reference range aldosterone levels. Urolithiasis may be present.

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Physical Examination

In symptomatic individuals with renal PHA-I, failure to thrive, weight loss, vomiting, and dehydration may appear as early as the first 2 weeks of life. Affected individuals experience repeated episodes of dehydration and may appear to be in shock and comatose. Weight loss may occur. If therapy is delayed, patients may become severely undernourished, and failure to thrive becomes evident during infancy. Affected individuals have a marked tendency to develop low blood volume and hypotension, just like individuals with true hypoaldosteronism.

In children with the early childhood hyperkalemia variant of renal PHA-I, failure to thrive or growth retardation is the only physical finding. Hypertension is absent.

In MTOD PHA-I, the clinical picture is similar to that seen in renal PHA-I, but symptoms may be more severe. These individuals may have recurrent episodes of dyspnea, cyanosis, fever, tachypnea, and intercostal retractions. Crackles may be auscultated over pulmonary fields.

Individuals with PHA-II, in contrast to those with PHA-I, are usually volume-expanded and hypertensive. Hypertension is limited to adolescent or adult individuals and is the cardinal feature of adults with this syndrome. Short stature is the cardinal feature in children, who are usually asymptomatic. Because hypertension during adolescence or young adulthood is usually the initial sign, this syndrome is often called adolescent hyperkalemic syndrome.

Children with the chloride shunt syndrome have blood pressure within the reference range (Spitzer-Weinstein syndrome). A finding of 2 affected normotensive children (aged 4 and 11 years) and an older affected sibling (aged 21 years) in the same family suggests that Gordon syndrome and Spitzer-Weinstein syndrome are the same genetic entity. In fact, hypertension may be absent in adults and present in children. Muscular weakness and periodic paralysis have been described in children with Gordon syndrome.

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Complications

Potential complications of PHA include the following:

  • Severe hyperkalemia and even death as a result of cardiac arrhythmia
  • Nephrocalcinosis (in PHA-I)
  • Nephrolithiasis (in PHA-II)
  • Frequent episodes of dehydration
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Contributor Information and Disclosures
Author

Alicia Diaz-Thomas, MD, MPH Assistant Professor of Pediatrics, University of Tennessee Health Science Center

Alicia Diaz-Thomas, MD, MPH is a member of the following medical societies: American Association of Clinical Endocrinologists, Endocrine Society, Pediatric Endocrine Society, Tennessee Medical Association

Disclosure: Nothing to disclose.

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 School of Medicine at San Antonio

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, International Society of Nephrology

Disclosure: Nothing to disclose.

Chief Editor

Stephen Kemp, MD, PhD Former 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, Southern Society for Pediatric Research

Disclosure: Nothing to disclose.

Acknowledgements

Robert J Ferry Jr, MD Le Bonheur Chair of Excellence in Endocrinology, Professor and Chief, Division of Pediatric Endocrinology and Metabolism, Department of Pediatrics, University of Tennessee Health Science Center

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: Eli Lilly & Co Grant/research funds Investigator; MacroGenics, Inc Grant/research funds Investigator; Ipsen, SA (formerly Tercica, Inc) Grant/research funds Investigator; NovoNordisk SA Grant/research funds Investigator; Diamyd Grant/research funds Investigator; Bristol-Myers-Squibb Grant/research funds Other; Amylin Other; Pfizer Grant/research funds Other; Takeda Grant/research funds Other

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

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.

References
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  2. Geller DS, Zhang J, Zennaro MC, et al. Autosomal dominant pseudohypoaldosteronism type 1: mechanisms, evidence for neonatal lethality, and phenotypic expression in adults. J Am Soc Nephrol. 2006. 17:1429-1436. [Medline].

  3. Chitayat D, Spirer Z, Ayalon D, Golander A. Pseudohypoaldosteronism in a female infant and her family: diversity of clinical expression and mode of inheritance. Acta Paediatr Scand. 1985 Jul. 74(4):619-22. [Medline].

  4. Hogg R, Marks J, Marver D, Frolich J. Long-term observation in a patient with pseudohypoaldosteronism. Pediatr Nephrol. 1991. 5:205-210. [Medline].

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  7. Valimaki M, Pelkonen R, Tikkanem I, Fyhriquist F. Normal renin sensitivity to atrial natriuretic peptide in Gordon's syndrome. Pediatr Nephrol. 1992. 6:44-45. [Medline].

  8. Sheridan MB, Fong P, Groman JD, et al. Mutations in the beta-subunit of the epithelial Na+ channel in patients with a cystic fibrosis-like syndrome. Hum Mol Genet. 2005. 14:3493-3498. [Medline].

  9. Adachi M, Asakura Y, Muroya K, Tajima T, Fujieda K, Kuribayashi E, et al. Increased Na reabsorption via the Na-Cl cotransporter in autosomal recessive pseudohypoaldosteronism. Clin Exp Nephrol. 2010 Apr 8. [Medline].

  10. Sartorato P, Lapeyraque AL, Armanini D, et al. Different inactivating mutations of the mineralocorticoid receptor in fourteen families affected by type I pseudohypoaldosteronism. J Clin Endocrinol Metab. 2003 Jun. 88(6):2508-17. [Medline].

  11. Boyden LM, Choi M, Choate KA, et al. Mutations in kelch-like 3 and cullin 3 cause hypertension and electrolyte abnormalities. Nature. 2012 Jan 22. 482(7383):98-102. [Medline]. [Full Text].

  12. Chang SS, Grunder S, Hanukoglu A, et al. Mutations in subunits of the epithelial sodium channel cause salt wasting with hyperkalaemic acidosis, pseudohypoaldosteronism type 1. Nat Genet. 1996 Mar. 12(3):248-53. [Medline].

  13. Mastrandrea LD, Martin DJ, Springate JE. Clinical and biochemical similarities between reflux/obstructive uropathy and salt-wasting congenital adrenal hyperplasia. Clin Pediatr (Phila). 2005. 44:809-812. [Medline].

  14. Perimenis P, Wemeau JL, Vantyghem MC. Hypercalciuria [French]. Ann Endocrinol (Paris). 2005. 66:532-539. [Medline].

 
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Renin angiotensin aldosterone system
Table. Characteristics of Primary Pseudohypoaldosteronism (Types I and II)
Details PHA Type I PHA Type II
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.



ENaC = epithelial sodium channel; GFR = glomerular filtration rate; MLR = mineralocorticoid receptor gene; PHA = pseudohypoaldosteronism; RTA = renal tubular acidosis.



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