Clinical and molecular characteristics of a series of Chinese children with pseudohypoaldosteronism: a case series.

Abstract

Background: Pseudohypoaldosteronism (PHA) is a rare disorder characterized by renal resistance to mineralocorticoids, leading to hyperkalemia, hyponatremia, and metabolic acidosis. It is primarily classified into type I (PHAI), with subtypes including renal (caused by NR3C2 mutation), systemic (caused by SCNN1A/B/G mutations), and secondary forms, and type II (PHAII), which is commonly associated with mutations in genes involved in the WNK signaling pathway (WNK1, WNK4, KLHL3, CUL3). However, comprehensive cohorts delineating the clinical and genetic spectrum of PHA in Chinese children are lacking.

Case description: We present six unrelated Chinese children with PHA. Genetic testing enabled precise etiological classification: two with autosomal recessive systemic PHAI (harboring SCNN1B mutations) presented with severe neonatal salt-wasting; one with autosomal dominant renal PHAI (a heterozygous NR3C2 mutation); three with PHAII (heterozygous KLHL3 or CUL3 mutations) exhibiting hyperkalemia and acidosis that were responsive to thiazides. Management was tailored to the subtype, including aggressive salt supplementation for systemic PHAI and thiazide diuretics for PHAII. Notably, one patient with systemic PHAI subsequently developed severe atopic dermatitis and extreme hyperimmunoglobulin E (4,080 IU/mL), a rarely documented comorbidity. Outcomes were generally favorable; however, one infant with systemic PHAI succumbed to refractory electrolyte imbalance, and another experienced persistent failure to thrive.

Conclusions: In this study, we present six patients with different types of PHA (PHAI and PHAII), and describe their unique phenotypic, genetic characteristics. Our findings compellingly demonstrate that genetic testing is indispensable for precise subtyping, which in turn directs etiology-specific management and enables accurate prognostication, thereby optimizing long-term outcomes for affected children.