Isolated Hyperchlorhidrosis Caused by Novel Biallelic CA12 Variants Mimicking Pseudohypoaldosteronism

Isolated hyperchlorhidrosis (HYCHL; OMIM 143860) is caused by biallelic CA12 variants encoding carbonic anhydrase XII (CA XII), a transmembrane enzyme that mediates sodium and chloride reabsorption in sweat glands, leading to excessive salt loss. Clinically, HYCHL presents in infancy with recurrent hyponatremic dehydration secondary to excessive salt loss, often mimicking pseudohypoaldosteronism (PHA) or cystic fibrosis (CF).

A 5-month-old girl presented with irritability, lethargy, poor feeding, severe hyponatremia (110 mEq/L), and hyperkalemia (7.1 mEq/L). Congenital adrenal hyperplasia was excluded by endocrine evaluation. Markedly elevated plasma renin activity and aldosterone initially suggested PHA; however, low urinary sodium excretion during hyponatremia indicated an extrarenal source of salt loss. Three further episodes occurred, predominantly during summer. Although the parents consistently reported a salty taste of the infant's skin. Clinical exome sequencing identified two unreported compound heterozygous CA12 missense variants, c.823C>T p.(Arg275Trp) and c.694C>A p.(Pro232Thr), with parental testing confirming trans inheritance. No pathogenic variants were detected in CFTR or PHA-associated genes. By 19 months of age, the patient had remained free of hyponatremic episodes for nine months without disease-specific treatment, with normal growth and neurodevelopment.

This case expands the mutational spectrum of isolated hyperchlorhidrosis by identifying two unreported variants in CA12 and highlights the importance of considering isolated hyperchlorhidrosis in infants with recurrent salt-wasting when routine evaluation does not support PHA or CF.