Reflex sympathetic dystrophy-like unilateral erythema caused by a germline SCN9A variant.Eur J Med Genet 2026 May; 81:105078.EJ
Reflex sympathetic dystrophy (RSD), currently categorized within the spectrum of complex regional pain syndrome (CRPS), is typically considered an acquired disorder characterized by disproportionate pain, erythema, and autonomic changes. In contrast, inherited erythromelalgia is a genetic pain disorder most often caused by gain-of-function variants in SCN9A encoding the Nav1.7 sodium channel and usually presents with bilateral, symmetric distal limb pain and redness. Here, we describe a multigenerational family with a strictly unilateral, trauma-triggered neurovascular pain phenotype associated with a previously unreported heterozygous germline SCN9A variant (c.4784T > G, p. Leu1595Arg). Affected individuals experienced episodic attacks in which minor mechanical or physiological stimuli induced progressive unilateral erythema, warmth, and severe pain spreading from the site of injury and sharply demarcated at the midline, without contralateral involvement. Attacks lasted hours to nearly one day and tended to decrease with age. The variant was absent from population databases and co-segregated with the phenotype within the family, fulfilling ACMG/AMP criteria for likely pathogenicity. The consistent unilateral distribution cannot be explained by mosaicism and is instead compatible with activation of ipsilateral segmental nociceptive and neurovascular reflex circuits that function largely independently across the spinal midline. We propose that excessive positive feedback between C-fiber activation and axon reflex-mediated neurogenic inflammation underlies attack propagation and duration. This framework also suggests therapeutic benefit from agents that interrupt activity-dependent transmitter release, such as gabapentinoids. These findings expand the phenotypic spectrum of SCN9A-related pain disorders and provide a genetically anchored model for unilateral RSD/CRPS-like neurovascular pain.
