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

Pseudohypoaldosteronism Type 1
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

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Onset

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Symptoms

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Types

Type	OMIM	Gene	Inheritance	Age of Onset	Description
PHA1A	177735	NR3C2	Autosomal dominant	Neonatal 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 recessive	Neonatal, appears to become less aggressive with age	Renal 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

, 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

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

.

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

is also known to cause epileptic seizures.

Types

Type	OMIM	Gene	Inheritance	Age Of Onset	Description
PHA2A	145260	mapped to chromosome 1q31-q42[11]	Autosomal dominant	Varies	Does not involve salt wasting.
PHA2B	614491	WNK4	Autosomal dominant	10+ 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 dominant	15+ 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 recessive	Mean 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 dominant	3-15 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

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

• Hyperchloremic acidosis
• Pseudohyperaldosteronism

References

External links

• GeneReviews/NCBI/NIH/UW entry on Pseudohypoaldosteronism Type II