Pseudohypoaldosteronism Type Ii

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2021-01-18

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Genes

KLHL3, WNK4, WNK1, NR3C2, GNAS, STX16, GNAS-AS1, SCNN1A, SCNN1B, SCNN1G, CUL3, SLC12A3, REN, PIEZO2, OSR1, PHA2A, STK24, KCNJ1, CLDN8, RAPGEF5, KLHL2, SLC12A2, STK39, SLC26A4, MUL1, PRKN, CBLL2

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Summary

Clinical characteristics.

Pseudohypoaldosteronism type II (PHAII) is characterized by hyperkalemia despite normal glomerular filtration rate (GFR) and frequently by hypertension. 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 well described.

Diagnosis/testing.

The diagnosis of PHAII is established in a proband:

With hyperkalemia (in the setting of normal glomerular filtration), hypertension, metabolic acidosis, hyperchloremia, and suppressed plasma renin levels;
AND/OR
By the identification of a heterozygous pathogenic variant in CUL3, WNK1, or WNK4 or a heterozygous pathogenic variant or biallelic pathogenic variants in KLHL3.

Management.

Treatment of manifestations: Electrolyte and blood pressure abnormalities of PHAII in children and adults are often corrected with thiazide diuretics.

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.

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: Measurement of serum potassium concentration and blood pressure or identification of the known familial CUL3, KLHL3, WNK1, and WNK4 pathogenic variant(s) in first-degree relatives of individuals with PHAII allows for early diagnosis and treatment .

Pregnancy management: Affected pregnant women should undergo routine monitoring of electrolytes and blood pressure, with adjustments to antihypertensive medication dosage as needed. Some antihypertensive medications, including thiazide diuretics, have been associated with adverse fetal outcome, especially when taken during the first trimester of pregnancy; referral to an obstetrics group with expertise in high-risk pregnancies should be considered.

Genetic counseling.

PHAII is frequently inherited in an autosomal dominant manner; PHAIID (caused by pathogenic variants in KLHL3) may also be inherited in an autosomal recessive manner. Many pathogenic variants in CUL3 arise de novo and are not inherited from a parent. Each child of an individual with autosomal dominant PHAII has a 50% chance of inheriting the pathogenic variant. Prenatal testing for a pregnancy at increased risk is possible if the pathogenic variant(s) in the family are known.

Diagnosis

No formal diagnostic criteria for PHAII have been published.

Suggestive Findings

Pseudohypoaldosteronism type II (PHAII) should be suspected in individuals with the following clinical features, supportive laboratory findings, and family history.

Clinical features. Hypertension (blood pressure >140/90 mm Hg) generally manifesting in adolescence or adulthood but also reported in children. Note: The absence of frank hypertension does not preclude the diagnosis.

Supportive laboratory findings

Hyperkalemia in the absence of impaired glomerular filtration
- Serum concentration of potassium ranges from mildly (serum K ~5.0-6.0 mmol/L) to severely elevated (>8.0 mmol/L) (normal range: ~3.5-5.1 mmol/L).
- This finding is nearly universal in affected individuals at all ages.
Metabolic acidosis: serum concentration of bicarbonate ranging from 14 to 24 mmol/L (normal range: ~22-29 mmol/L)
Hyperchloremia: serum concentration of chloride ranging from 105 to 117 mmol/L (normal range: ~99-108 mmol/L)
Suppressed plasma renin levels
Variable serum aldosterone levels that tend to be relatively suppressed in the context of hyperkalemia
Serum calcium and parathyroid hormone levels that are normal. However, hypercalciuria is noted in at least a subset of individuals.

Family history. A first-degree relative with similar findings. Note: Absence of a family history of a first-degree relative with similar findings does not preclude the diagnosis.

Establishing the Diagnosis

The diagnosis of PHAII is established in a proband with hyperkalemia (in the setting of normal glomerular filtration) often accompanied by hypertension, metabolic acidosis, hyperchloremia, and suppressed plasma renin levels and/or by the identification of a heterozygous pathogenic variant in CUL3, KLHL3, WNK1, or WNK4 or biallelic pathogenic variants in KLHL3 (see Table 1). Note: PHAII is sometimes referred to by a subtype designation based on the associated gene; see Nomenclature.

Molecular genetic testing approaches can include serial single-gene testing and use of a multigene panel.

Serial single-gene testing

It is reasonable to perform sequence analysis for pathogenic variants in CUL3 and/or KLHL3 first.
If only one pathogenic variant in KLHL3 is identified in an individual in whom autosomal recessive inheritance is suspected, gene-targeted deletion/duplication analysis of KLHL3 should be considered.
Sequence analysis of WNK4 may be performed next.
If no pathogenic variant is identified through sequencing of WNK4, gene-targeted deletion/duplication analysis of WNK1 may be considered next.
If no disease-causing deletion or duplication is found in WNK1, consider sequencing of WNK1.

A multigene panel that includes CUL3, KLHL3, WNK1, and WNK4 and other genes of interest (see Differential Diagnosis) may also be considered. Note: (1) The genes included and the sensitivity of multigene panels vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview; thus, clinicians need to determine which multigene panel is most likely to identify the genetic cause of the condition at the most reasonable cost while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests

For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.

Table 1.

Molecular Genetic Testing Used in Pseudohypoaldosteronism Type II

Gene ¹	Proportion of PHAII Attributed to Pathogenic Variants in Gene	Proportion of Pathogenic Variants ² Detectable by Method
Gene ¹		Sequence analysis ³	Gene-targeted deletion / duplication analysis ⁴
CUL3	25/86 families reported	All reported cases to date	None reported
KLHL3	41/86 families reported ⁵	AD: 29/86 AR: 12/86	Unknown ⁶
WNK1	8/86 families reported	See footnote 7.	2/2 ⁸
WNK4	8/86 families reported	All reported cases to date	None reported
Unknown ⁹	4/52 ¹⁰	NA

: AD = autosomal dominant; AR = autosomal recessive
1.: See Table A. Genes and Databases for chromosome locus and protein.
2.: See Molecular Genetics for information on allelic variants detected in this gene.
3.: Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.
4.: Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
5.: Both heterozygous (autosomal dominant) and biallelic (autosomal recessive) pathogenic variants in KLHL3 cause PHAII [Mayan et al 2004, Boyden et al 2012, Picard et al 2015a, Mitani et al 2016].
6.: No data on detection rate of gene-targeted deletion/duplication analysis are available.
7.: Recently, six kindreds (9 individuals) were reported in preliminary results to have pathogenic missense variants in WNK1 (detailed in Molecular Genetics).
8.: Two large deletions have been reported (see Molecular Genetics) [Wilson et al 2001].
9.: An additional locus on 1q31-q42 has been identified as harboring a gene associated with PHAII [Mansfield et al 1997]. The identity of this gene is unknown. PHAII has been reported in at least ten families that lack identifiable pathogenic variants in CUL3, KLHL3, WNK1, and WNK4 [Boyden et al 2012, Glover et al 2014].
10.: Denominator is from the only report to document the number of PHAII individuals who did not have variants in CUL3, KLHL3, WNK1, or WNK4 [Boyden et al 2012].

Clinical Characteristics

Clinical Description

Pseudohypoaldosteronism type II (PHAII) is characterized by hyperkalemia despite normal glomerular filtration rate (GFR) and frequently by hypertension. More than 180 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].

Phenotype Correlations by Gene

Individuals with a heterozygous CUL3 pathogenic variant tend to have more severe hyperkalemia and metabolic acidosis, earlier development of hypertension, and greater likelihood of growth impairment compared to those harboring KLHL3, WNK1, or WNK4 alterations [Boyden et al 2012].

In general, clinical manifestations of PHAII appear to be milder in individuals with a heterozygous WNK1 or WNK4 pathogenic variant compared to those with a heterozygous CUL3 or a heterozygous or biallelic KLHL3 pathogenic variant(s) [Boyden et al 2012].

Individuals with biallelic KLHL3 pathogenic variants may have a more severe phenotype than individuals with a heterozygous pathogenic variant in KLHL3 [Boyden et al 2012, Louis-Dit-Picard et al 2012].

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).

Therefore, the term "pseudohypoaldosteronism" is a misnomer in the context of PHAII, as affected individuals have hyperkalemia with hypertension (instead of volume depletion). Some authorities prefer the descriptive name familial hyperkalemic hypertension (FHHt) for this reason.

PHAII is sometimes referred to by a subtype designation based on the associated gene, as follows:

PHA type IIA (PHA2A): Unknown genetic cause (see Table 1, footnotes 9 and 10)
PHA type IIB (PHA2B): WNK4
PHA type IIC (PHA2C): WNK1
PHA type IIE (PHA2E): CUL3
PHA type IID (PHA2D): KLHL3

Prevalence

The prevalence of the disorder is unknown. To date more than 180 individuals and families with PHAII have been reported.

Differential Diagnosis

Other causes of hyperkalemia. Hyperkalemia resulting from the following can generally be distinguished from hyperkalemia caused by PHAII on the basis of plasma renin levels, which are increased in the following conditions and suppressed in PHAII:

Chronic kidney disease, especially when secondary to diabetes, is the most commonly identified cause of hyperkalemia.
When renal function is normal, consider the following:
- Hypoaldosteronism or acquired renal tubular acidosis (type 4), particularly in the setting of marked volume depletion
- Medication effects. Examples include potassium-sparing diuretics (e.g., spironolactone), nonsteroidal anti-inflammatory drugs (NSAIDs), angiotensin inhibitors, trimethoprim, and cyclosporine.
- Primary adrenal insufficiency or deficiency of an adrenal synthetic enzyme

Management

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs of an individual diagnosed with pseudohypoaldosteronism type II (PHAII), the following evaluations (if not performed as part of the diagnostic evaluation) are recommended:

Serum electrolyte analysis
Noninvasive blood pressure measurement
Consultation with a clinical geneticist and/or genetic counselor

Treatment of Manifestations

Electrolyte and blood pressure abnormalities of PHAII are often 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 will need to be increased over time or that additional anti-hypertensives will 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 for cardiovascular and renal disease and stroke.

Surveillance

Appropriate surveillance includes routine electrolyte and blood pressure measurements, monitored in the same manner as for any person 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

It is appropriate to evaluate apparently asymptomatic older and younger at-risk relatives of an affected individual in order to identify as early as possible those who would benefit from prompt initiation of treatment. Evaluations can include:

Measurement of serum potassium concentration and blood pressure;
Molecular genetic testing if the pathogenic variant(s) in the family are known.

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.

Some antihypertensive medications (including thiazide diuretics) have been associated with adverse fetal outcome, especially when taken during the first trimester of pregnancy. The best time to discuss the risk to the fetus associated with a maternal medication is prior to conception. Women with PHAII who become pregnant should be referred to an obstetrics group with expertise in high-risk pregnancies.

See MotherToBaby for further information on medication use during pregnancy.

Therapies Under Investigation

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe 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.