Clinical Diagnosis

A diagnosis of pseudohypoaldosteronism type II (PHAII) should be considered with the following clinical presentation:

• Hyperkalemia in the absence of impaired glomerular filtration
• Hypertension (blood pressure >140/90 mm Hg) generally manifesting in adolescence or adulthood but also reported in children with PHAII
• Metabolic acidosis
• Hyperchloremia
• Suppressed plasma renin levels
• A first-degree relative with similar findings
• Other
  • Serum aldosterone levels are variable but tend to be relatively suppressed in the context of hyperkalemia.
  • Serum calcium and parathyroid hormone levels are normal; however, hypercalciuria is noted in at least a subset of individuals.

Testing

Serum concentration of potassium. Hyperkalemia in PHAII ranges from mild (serum K ~5.0-6.0 mmol/L) to severe (>8.0 mmol/L) (normal range: ~3.5-5.1 mmol/L).

Serum concentration of bicarbonate. Reported serum bicarbonate levels in PHAII range from 14 to 24 mmol/L (normal range: ~22-29 mmol/L).

Serum concentration of chloride. Reported serum chloride levels in PHAII range from 105 to 117 mmol/L (normal range: ~99-108 mmol/L).

Molecular Genetic Testing

Genes. The two genes in which mutations are known to cause pseudohypoaldosteronism type II (PHAII) are WNK4 (PHA type IIB) and WNK1 (PHA type IIC).

Evidence for additional locus heterogeneity

• An additional locus on 1q31-q42 has been identified as harboring a gene associated with PHAIIA [Mansfield et al 1997]. The identity of this gene is unknown.
• Genetic evidence suggests the existence of at least a fourth locus [Disse-Nicodeme et al 2001].

Clinical testing

• WNK4. All reported missense mutations in WNK4 that cause PHAII occur in exons 7 and 17 and are detectable by sequence analysis.
• WNK1. Deletion/duplication analysis that includes the large 60-kb intron 1 of WNK1 is required to detect the two reported large intronic deletions in WNK1 that cause PHAII (see Molecular Genetics).
  
  Note: Sequence analysis of WNK1 is clinically available; however, no coding region mutations have been reported to cause PHAII. Sequence analysis of the coding region and flanking intronic regions cannot detect the large deletions that have been reported in the first intron of WNK1.

Table 1. Summary of Molecular Genetic Testing Used in Pseudohypoaldosteronism Type II

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Gene Symbol / Phenotype Designation	Proportion of PHAII Attributed to Mutations in This Gene	Test Method	Mutations Detected	Test Availability
WNK4 / PHAIIB	9 families reported	Sequence analysis	Sequence variants 1	Clinical
		Sequencing of select exons 2	Sequence variants in select exons
WNK1 / PHAIIC	2 families reported	Sequence analysis	Sequence variants 2, 3	Clinical
		Deletion/ duplication analysis 4	Deletions within intron 1 5	Research 6

Test Availability refers to availability in the GeneTests™ Laboratory Directory. GeneReviews designates a molecular genetic test as clinically available only if the test is listed in the GeneTests Laboratory Directory by either a US CLIA-licensed laboratory or a non-US clinical laboratory. GeneTests does not verify laboratory-submitted information or warrant any aspect of a laboratory's licensure or performance. Clinicians must communicate directly with the laboratories to verify information.

1. The ability of the test method used to detect a mutation that is present in the indicated gene

2. All mutations reported to date have been identified in exons 7 and 17.

3. No WNK1 coding region mutations that cause PHAII have been reported to date.

4. Testing that identifies deletions/duplications not readily detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA; a variety of methods including quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), or targeted chromosomal microarray analysis (gene/segment-specific) may be used. A full chromosomal microarray analysis that detects deletions/duplications across the genome may also include this gene/segment. See array GH.

5. Two large (41-kb and 21-kb) deletions occurring within the 60-kb first intron of WNK1 have been reported (see Molecular Genetics).

6. No laboratories offering clinical testing for this gene are listed in the GeneTests™ Laboratory Directory; clinical confirmation of mutations identified in a research laboratory may be available. See .

Interpretation of test results. For issues to consider in interpretation of sequence analysis results, click here.

Testing Strategy

To confirm/establish the diagnosis in a proband

1.

Measurement of blood pressure and routine laboratory evaluation of serum potassium, chloride, bicarbonate, and renal function (including blood urea nitrogen [BUN] and creatinine levels)

2.

Molecular genetic testing of WNK4, then WNK1

Predictive testing for asymptomatic at-risk family members requires prior identification of the disease-causing mutation in the family.

Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing mutation in the family.

Note: It is the policy of GeneReviews to include in GeneReviews™ chapters any clinical uses of testing available from laboratories listed in the GeneTests™ Laboratory Directory; inclusion does not necessarily reflect the endorsement of such uses by the author(s), editor(s), or reviewer(s).

Genetically Related (Allelic) Disorders

WNK1. Hereditary sensory and autonomic neuropathy type IIA (HSAN2A) is also associated with mutations in specific exons of WNK1. See Hereditary Sensory and Autonomic Neuropathy Type II.

WNK4. No other phenotypes are known to be associated with mutations in WNK4.

Natural History

Pseudohypoaldosteronism type II (PHAII) is characterized by hypertension and hyperkalemia despite normal glomerular filtration rate (GFR). The first case report, published in 1964, described a 15 year-old Australian male with hyperkalemia, hypertension, and normal GFR [Paver & Pauline 1964]. This cluster of clinical findings was first described as a familial disorder in a large multi-generation Israeli pedigree with autosomal dominant inheritance [Farfel et al 1978]. Since that time, more than 90 individuals and families with PHAII have been reported.

The clinical presentation of PHAII is heterogeneous. The most consistent clinical feature in both children and young adults is hyperkalemia [Gordon 1986]. As with essential hypertension, blood pressure is usually normal in young persons, with hypertension developing later in life. Untreated individuals with elevated blood pressure are at risk of developing complications of hypertension including cardiac disease, renal impairment, and stroke.

Other associated findings in both children and adults include hyperchloremia, metabolic acidosis, and suppressed plasma renin levels. Aldosterone levels are variable, but are relatively low given the degree of hyperkalemia (elevated serum potassium is a potent stimulus for aldosterone secretion). Hypercalciuria is also well described in PHAII [Mayan et al 2004].

Other features reported in a subset of individuals with PHAII include short stature, myalgias, periodic paralysis, and dental abnormalities [Gordon 1986]. It has been suggested that these findings may be more prevalent in individuals with severe hyperkalemia and metabolic acidosis; however, exceptions have been reported [Gordon 1986, Farfel et al 2011].

Genotype-Phenotype Correlations

There are no known genotype-phenotype correlations in PHAII.

Penetrance

Penetrance of the disorder is high.

Nomenclature

The term “pseudohypoaldosteronism” has historically been used to describe the finding of persistent hyperkalemia despite the presence of normal or elevated serum levels of aldosterone [Schambelan et al 1981]. The term was initially used to describe persons with an inherited disorder characterized by hyperkalemia, elevated serum aldosterone, and volume depletion (now referred to as pseudohypoaldosteronism type I).

As others have pointed out, the term “pseudohypoaldosteronism” is a misnomer in the context of PHAII as affected individuals have hyperkalemia with hypertension (instead of volume depletion).

Prevalence

The prevalence of the disorder is unknown. To date more than 90 individuals and families with PHAII have been reported.

There are no apparent differences with respect to gender or ethnicity.

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs of an individual diagnosed with pseudohypoaldosteronism type II (PHAII), the following evaluations are recommended:

• Serum electrolyte analysis
• Noninvasive blood pressure measurement

Treatment of Manifestations

Electrolyte and blood pressure abnormalities of PHAII are corrected with thiazide diuretics. Metabolic abnormalities and hypertension generally improve within one week.

Different thiazide diuretics exist, with different dosing regimens. In general dosing is titrated to normalization of blood pressure. It is possible that dosing may need to be increased over time or that additional anti-hypertensives may be required to adequately control blood pressure.

There are no established guidelines regarding age at which treatment should begin for individuals with PHAII, but affected children who have hypertension are generally treated.

Prevention of Primary Manifestations

See Treatment of Manifestations.

Prevention of Secondary Complications

Control of blood pressure is important to reduce the risk of cardiovascular and renal disease and stroke.

Surveillance

Routine electrolyte and blood pressure measurements, monitored in the same manner as for any patient treated with a thiazide diuretic.

Agents/Circumstances to Avoid

Untreated individuals with PHAII should avoid excessive intake of foods high in salt and potassium as these may exacerbate hypertension and hyperkalemia.

Evaluation of Relatives at Risk

Testing of first-degree relatives of individuals with PHAII is important to permit early diagnosis and treatment of other family members with the disorder. This can most readily be accomplished by measurement of serum potassium concentration and blood pressure. Genetic testing for the family-specific mutation (if known) can also be performed.

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Pregnancy Management

During the pregnancy of a woman with PHAII, electrolytes and blood pressure should be monitored regularly and blood pressure medication adjusted as needed.

Therapies Under Investigation

Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Other

Genetics clinics, staffed by genetics professionals, provide information for individuals and families regarding the natural history, treatment, mode of inheritance, and genetic risks to other family members as well as information about available consumer-oriented resources. See the GeneTests Clinic Directory.

Mode of Inheritance

Pseudohypoaldosteronism type II (PHAII) is inherited in an autosomal dominant manner.

Risk to Family Members

Parents of a proband

• Many individuals diagnosed with PHAII have an affected parent.
• A proband with PHAII may have the disorder as the result of a de novo mutation. Gong et al [2008] reported a de novo WNK4 mutation; the proportion of cases caused by a de novo mutation is unknown.
• If the disease-causing mutation found in the proband cannot be detected in leukocyte DNA of either parent, a de novo mutation in the proband is a possibility. Although no instances of germline mosaicism have been reported, it also remains a possibility. The incidence of germline mosaicism is unknown
• Recommendations for the evaluation of parents of a proband with an apparent de novo mutation include clinical evaluation (electrolyte analysis and blood pressure measurement) and/or molecular genetic testing for the disease-causing mutation present in the proband.
• Evaluation of parents may determine that one is affected but has escaped previous diagnosis because of failure to recognize the syndrome as a result of a milder phenotypic presentation. Therefore, an apparently negative family history cannot be confirmed until appropriate evaluations have been performed.

Note: Although many individuals diagnosed with pseudohypoaldosteronism type II (PHAII) have an affected parent, the family history may appear to be negative because of failure to recognize the disorder in family members, early death of the parent before the onset of symptoms, or late onset of the disease in the affected parent.

Sibs of a proband

• The risk to the sibs of the proband depends on the genetic status of the proband’s parents.
• If a parent of the proband is affected, the risk to the sibs is 50%.
• When the parents are clinically unaffected, the risk to the sibs of a proband appears to be low.
• The sibs of a proband with clinically unaffected parents are still at increased risk for PHAII because of the possibility of reduced penetrance in a parent.
• If the disease-causing mutation found in the proband cannot be detected in the leukocyte DNA of either parent, the risk to sibs is low, but greater than that of the general population because of the possibility of germline mosaicism.

Offspring of a proband. Each child of an individual with PHAII has a 50% chance of inheriting the mutation.

Other family members. The risk to other family members depends on the status of the proband's parents. If a parent is affected, his or her family members may be at risk.

Related Genetic Counseling Issues

See Management, Evaluation of Relatives at Risk for information on evaluating at-risk relatives for the purpose of early diagnosis and treatment.

Considerations in families with an apparent de novo mutation. When neither parent of a proband with an autosomal dominant condition has the disease-causing mutation or clinical evidence of the disorder, it is likely that the proband has a de novo mutation. However, possible non-medical explanations including alternate paternity or maternity (e.g., with assisted reproduction) or undisclosed adoption could also be explored.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, mutations, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals. See for a list of laboratories offering DNA banking.

Prenatal Testing

Prenatal diagnosis for pregnancies at increased risk is possible by analysis of DNA extracted from fetal cells obtained by amniocentesis usually performed at approximately 15 to 18 weeks’ gestation or chorionic villus sampling (CVS) at approximately ten to 12 weeks’ gestation. The disease-causing mutation of an affected family member must have been identified in the family before prenatal testing can be performed.

Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.

Requests for prenatal testing for conditions which (like PHAII) do not affect intellect and have effective treatment available are not common. Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing, particularly if the testing is being considered for the purpose of pregnancy termination rather than early diagnosis. Although decisions regarding prenatal testing are the choice of the parents, discussion of these issues is appropriate.

Preimplantation genetic diagnosis (PGD) may be available for families in which the disease-causing mutation has been identified. For laboratories offering PGD, see .

Note: It is the policy of GeneReviews to include in GeneReviews™ chapters any clinical uses of testing available from laboratories listed in the GeneTests™ Laboratory Directory; inclusion does not necessarily reflect the endorsement of such uses by the author(s), editor(s), or reviewer(s).

Molecular Genetic Pathogenesis

Mutations in the genes encoding two members of the WNK protein family of serine-threonine kinases, WNK1 and WNK4, have been implicated in the pathogenesis of pseudohypoaldosteronism type II (PHAII) [Wilson et al 2001]. Members of this kinase family are named WNK, or with no lysine (K), kinases because of their unique substitution of cysteine for lysine at a highly conserved residue within the catalytic kinase domain [Xu et al 2000]. Over the past decade, members of the WNK kinase family have been shown to regulate the coordinated transport of Na⁺, K⁺, and Cl^- ions across epithelia in a variety of tissues [Kahle et al 2008].

The electrolyte and blood pressure abnormalities in individuals with PHAII are readily corrected with thiazide diuretics, inhibitors of the Na-Cl cotransporter (NCC; encoded by SLC12A3) expressed in the renal distal convoluted and connecting tubules (see Management, Treatment of Manifestations). This clinical observation led to the initial hypothesis that increased activity of NCC could play a role in the pathogenesis of PHAII [Gordon 1986]. However, to date, no PHAII-causing mutations in the gene encoding NCC have been demonstrated.

Literature Cited

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Suggested Reading

1. Brooks AM, Owens M, Sayer JA, Salzmann M, Ellard S, Vaidya B. Pseudohypoaldosteronism type 2 presenting with hypertension and hyperkalaemia due to a novel mutation in the WNK4 gene. QJM. 2011 [PubMed: 21764813]
2. Golbang AP, Murthy M, Hamad A, Liu CH, Cope G, Van’t Hoff W, Cuthbert A, O’Shaughnessy KM. A new kindred with pseudohypoaldosteronism type II and a novel mutation (564D>H) in the acidic motif of the WNK4 gene. Hypertension. 2005;46:295–300. [PubMed: 15998707]
3. Zhang C, Wang Z, Xie J, Yan F, Wang W, Feng X, Zhang W, Chen N. Identification of a novel WNK4 mutation in Chinese patients with pseudohypoaldosteronism type II. Nephron Physiol. 2011;118:53–61. [PubMed: 21196779]

Revision History

• 10 November 2011 (me) Review posted live
• 25 April 2011 (ktk) Original submission