Key result
ENaC mutations in PHA-1 link to higher potassium levels vs MR mutations, especially with truncating variants.
Why the study?
Pseudohypoaldosteronism type 1 includes cases with and without genetic mutations, but clinical characteristics and genotype–phenotype correlations remain unclear.
Distinct clinical and biochemical features, such as aldosterone and potassium levels, can help differentiate genetic subtypes of Pseudohypoaldosteronism type 1 and guide genetic testing.
May aid subtype differentiation in PHA-1; leaves open whether findings guide testing or alter outcomes.
Background/Objectives: Pseudohypoaldosteronism type 1 (PHA-1) is a rare disorder characterized by aldosterone resistance, leading to hyponatremia, hyperkalemia, and elevated renin and aldosterone levels in neonates and infants. While genetic mutations in NR3C2 (mineralocorticoid receptor, MR) and SCNN1A/B/G (epithelial sodium channel, ENaC) are established causes of primary PHA-1, cases without detectable mutations have also been reported. This study aimed to compare the clinical characteristics of genetically confirmed PHA-1 cases—with or without mutations—and to assess genotype–phenotype correlations. Methods: A literature review was conducted using the Medline database, covering studies published from 1966 to October 2023. Included cases were diagnosed with PHA-1 and had undergone genetic testing for NR3C2 and SCNN1A/B/G. Clinical and biochemical data were compared across three groups: MR, ENaC, and non-mutation. Additional subgroup analysis based on mutation type (truncating vs. non-truncating) was also performed. Results: A total of 164 patients from 64 studies met the inclusion criteria. The ENaC group showed significantly higher serum potassium levels than the MR and non-mutation groups. Serum aldosterone levels were significantly higher in the MR group compared to the non-mutation group. A genotype–phenotype correlation was evident in the ENaC group, with truncating variants associated with more severe hyperkalemia. No such correlation was observed in the MR group. Conclusions: This review highlights distinct clinical features of PHA-1 according to genetic status. Aldosterone levels may aid in guiding decisions regarding genetic testing. Furthermore, variant type in ENaC-related PHA-1 may predict biochemical severity and should be considered in clinical management strategies.
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Nakata et al. (2025) conducted a review in Pseudohypoaldosteronism type 1 (n=164). Genetic mutations (MR or ENaC) vs. Non-mutation was evaluated on Serum potassium and aldosterone levels. ENaC mutations in PHA-1 were associated with significantly higher serum potassium levels compared to MR and non-mutation groups, with truncating variants predicting more severe hyperkalemia.
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