Pseudohypoaldosteronism type 2 (PHA2) is a rare autosomal dominant electrolyte disorder characterized by hypertension, hyperkalemia, metabolic acidosis, and suppressed renin activity, usually with preserved renal function. Pathogenic variants in WNK1, WNK4, KLHL3, and CUL3 have been identified, with CUL3 mutations particularly associated with early-onset and severe phenotypes. Thiazide diuretics are effective in correcting both electrolyte imbalance and hypertension. We report a pediatric patient with early-onset PHA2 caused by a de novo splice-site variant (c.1207-2A>C) in the CUL3 gene. The patient, first evaluated at 2 years and 7 months of age for recurrent vomiting, was found to have hyponatremia, hyperkalemia, and metabolic acidosis, initially treated with fludrocortisone. On referral, significant hypertension, hyperkalemia, and suppressed renin and aldosterone were observed. Initiation of low-dose thiazide therapy led to normalization of blood pressure and electrolytes. Long-term follow-up confirmed clinical stability, normal growth, and appropriate developmental milestones. Aldosterone pathway defects may be misdiagnosed during the initial clinical assessment. This underscores the importance of a comprehensive diagnostic approach incorporating biochemical profiling and genetic testing to ensure accurate identification. Next-generation sequencing has emerged as a valuable tool for establishing a definitive diagnosis, particularly in cases with aldosterone defects. Timely and accurate diagnosis of PHA2 is critical, as persistent metabolic acidosis and hypertension may lead to significant growth and developmental impairments in pediatric patients. Despite the potential severity of clinical manifestations associated with CUL3-related PHA2, it is noteworthy that treatment with thiazide diuretics alone can effectively restore electrolyte balance and support normal growth and development.

We report a case of pseudo-hypoaldosteronism type 2 (PHA II) in a hypertensive 55-year-old woman who carried new variants of the KLHL3 gene. Hypersensitivity to hydrochlorothiazide was noted. Low dosages of hydrochlorothiazide were needed to restore potassium levels. PHA II must be excluded in adult hypertensive subjects with unexplained hyperkalemia.

We present the case of a 14-year-old male with a novel diagnosis of Gordon's syndrome (GS, pseudohypoaldosteronism type 2), notable for its atypical presentation in the absence of hypertension. The patient exhibited persistent hyperkalemia, metabolic acidosis, and normotension, prompting genetic testing that identified a heterozygous mutation in the WNK1 gene. Subsequent evaluation of the patient's father, who had no history of hypertension but demonstrated similar biochemical abnormalities, revealed the same genetic variant, confirming the diagnosis in both individuals. The lack of hypertension in both cases deviates from the classic phenotype of GS. Treatment with low-dose thiazide diuretics led to gradual correction of the electrolyte disturbances, supporting the diagnosis and highlighting phenotypic variability within this rare condition.

Pseudohypoaldosteronism type 2 (PHA2) is a rare inherited condition of altered tubular salt handling. It is characterized by the specific constellation of hyperkalaemic hyporeninemic hypertension, hyperchloremic metabolic acidosis and hypercalciuria. Molecular genetic testing confirms the diagnosis in the majority of cases. Thiazides constitute effective treatment. Due to its rarity, the diagnosis is often delayed. We here present two children with PHA2, who were initially treated with fludrocortisone and bicarbonate complicated mainly by exacerbation of their hypertension. Discontinuation of their previous therapy and commencement of thiazide diuretics led to normalisation of their blood pressure and electrolyte and acid-base status.

Mutations in with-no-lysine [K] kinase 4 (WNK4) and kelch-like 3 (KLHL3) are linked to pseudohypoaldosteronism type 2 (PHAII, also known as familial hyperkalemic hypertension or Gordon's syndrome). WNK4 is degraded by a ubiquitin E3 ligase with KLHL3 as the substrate adaptor for WNK4. Several PHAII-causing mutations, e.g. those in the acidic motif (AM) of WNK4 and in the Kelch domain of KLHL3, impair the binding between WNK4 and KLHL3. This results in a reduction in WNK4 degradation and an increase in WNK4 activity, leading to PHAII. Although the AM is important in interacting with KLHL3, it is unclear whether this is the only motif in WNK4 responsible for KLHL3-interacting. In this study, a novel motif of WNK4 that is capable of mediating the degradation of the protein by KLHL3 was identified. This C-terminal motif (termed as CM) is located in amino acids 1051-1075 of WNK4 and is rich in negatively charged residues. Both AM and CM responded to the PHAII mutations in the Kelch domain of KLHL3 in a similar manner, but AM is dominant among the two motifs. The presence of this motif likely allows WNK4 protein to respond to the KLHL3-mediated degradation when the AM is dysfunctional due to a PHAII mutation. This may be one of the reasons why PHAII is less severe when WNK4 is mutated compared to KLHL3 is mutated.