Pseudohypoaldosteronism type II and sensory neuropathy associated with a heterozygous pathogenic variant in KLHL3...

Pseudohypoaldosteronism type II is a rare Mendelian disorder characterized by hypertension, hyperkalemia, hyperchloremia and metabolic acidosis, despite a normal glomerular filtration rate. Four genes (KLHL3, CUL3, WNK1 and WNK4) are associated with this disease. Mutations in the KLHL3 gene cause pseudohypoaldosteronism type II in either an autosomal dominant or a recessive inheritance pattern. Sensory neuropathy has been associated with autosomal recessive mutations in WNK1, but not with KHLH3. We reported a unique three-generation family with dominant pseudohypoaldosteronism type II and sensory neuropathy. Three affected members of the family underwent neurological examination, nerve conduction studies and exome sequencing. A 13-years-old girl had a history of pseudohypoaldosteronism type II, and suffered from neuropathic pain associated with a sensory neuronopathy. Her mother and grandfather have pseudohypoaldosteronism type II associated with an asymptomatic sensory neuropathy on nerve conduction studies. Exome sequencing revealed in all affected members two missenses at heterozygous state, one pathogenic variant in KLHL3, which may be responsible for the sensory neuropathy. This is the first description of neurological features associated with KLHL3 mutation. Our study expands the genotype-phenotype spectrum of KLHL3 with the addition of sensory neuronopathy.