ABSTRACT Background and Aims Gain‐of‐function variants in SCN9A, encoding the Nav1.7 sodium channel, cause inherited painful neuropathic disorders. We report a young man with severe childhood‐onset heat‐triggered paroxysmal pain, autonomic dysfunction, skeletal abnormalities, and a de novo SCN9A p.Ile234Thr variant, emphasizing the diagnostic and therapeutic relevance of comprehensive phenotyping. Case Report The patient developed excruciating lower‐limb pain in early childhood, partially relieved by prolonged immersion in cold running water. Evaluation demonstrated marked small‐fibre dysfunction, absent sympathetic skin responses, impaired sweating, absent lower‐limb pain‐related evoked potentials, loss of dermal and epidermal nerve fibres, pronounced small myelinated fibre loss on sural nerve biopsy, and mild large‐fibre involvement. Whole‐exome sequencing identified the de novo pathogenic SCN9A variant c.701 T>C; p.Ile234Thr. Carbamazepine led to more than 90% pain improvement and substantial functional recovery. Interpretation This case expands the clinical spectrum associated with SCN9A p.Ile234Thr and illustrates how genetic diagnosis may directly guide treatment. The associated large‐fibre abnormalities and acetabular dysplasia are interpreted cautiously, as their relationship to SCN9A dysfunction remains uncertain.
Tomaselli et al. (Sun,) studied this question.