Pediatric Erythromelalgia and SCN9A Mutations: Systematic Review and Single-Center Case Series

Abstract

Objectives. To evaluate the clinical features of erythromelalgia in childhood associated with gainof-function SCN9A mutations that increase activity of the Na v 1.7 voltage-gated sodium channel we: i) conducted a systematic review of pediatric presentations of erythromelalgia related to SCN9A mutations; and ii) compared pediatric clinical presentations of symptomatic erythromelalgia, with or without SCN9A mutations. Study Design PubMed, Embase, and PsycINFO Databases were searched for reports of IEM in childhood. Clinical features, management and genotype were extracted. Case notes of pediatric patients with erythromelalgia from the Great Ormond Street Hospital (GOSH) Pain Service were reviewed for clinical features, patient-reported outcomes and treatments. Children aged over 10 years were recruited for quantitative sensory testing (QST). Results Twenty-eight publications described erythromelalgia associated with 15 different SCN9A gene variants in 25 children. Pain was severe and often refractory to multiple treatments, including non-specific sodium channel blockers. Skin damage or other complications of cold immersion for symptomatic relief were common (60%). SCN9A mutations resulting in greater hyperpolarizing shifts in Na v 1.7 sodium channels correlated with symptom onset at younger ages (P=.016). Variability in reporting and potential publication bias towards severe cases limit any estimations of overall incidence. At GOSH, reported symptoms in both groups were similar but co-morbidities were more common in SCN9A-positive cases. QST revealed marked dynamic warm allodynia. Conclusions: IEM in children is associated with difficult-to-manage pain and significant morbidity. Standardized reporting of outcome and management in larger series will strengthen

Primary Erythromelalgia Complicated by Cellulitis: A Case Report and Review of Literature

“…In the year 2000, Davis et al reported that 63% of EM patients had small fiber neuropathy, but it was not until 2004 that a mutant voltage-gated sodium channel (VGSC) 'Nav 1.7' encoded by SCN9 gene was discovered [23,24]. Since then, research has targeted the relationship between pain perception and VGSCs in sensory neurons, especially Nav1.7, Nav1.8 and Nav1.9 encoded by SCN9, SCN10 and SCN 11 genes respectively [24,25,26]. In a systemic review of pediatric population, 15 different SCN9A gene variants were found in 25 children with EM [25].…”

Neuropathic pain in children: Steps towards improved recognition and management

“…QST includes evaluation of small and large fibre function, with a range of stimulus modalities applied at varying intensities to assess detection and pain/discomfort thresholds. Expressing different modalities as Z-score differences from control measures allows group [31] or individual [34] profiles to be plotted independent of the measurement parameter ( Fig. 1b (i)).…”

“…Altered somatosensory function has been identified in a range of paediatric conditions associated with peripheral nerve injury, including chemotherapy-induced neuropathy in cancer survivors [35], erythromelalgia [34], prior surgery [31], and subclinical signs of diabetic neuropathy [36]. In adults with peripheral neuropathic pain, three distinct sensory profiles that may predict mechanism and improved treatment efficacy for subclasses of anti-neuropathic medication have been identified: sensory loss (denervation and spontaneous pain due to ectopic action potentials proximal to injured nociceptors; greater response to anti-depressants); thermal hyperalgesia (peripheral sensitisation with low threshold and spontaneous activity in 'irritable nociceptors'; predicted efficacy with sodium channel blocker and moderate response to anti-depressant or gabapentinoid); and mechanical hyperalgesia (sensitisation and spontaneous activity in peripheral and/or central nervous system; predicted efficacy with gabapentinoid) [37,38].…”

“…Pain is exacerbated by environmental temperature and relieved by cooling, to the extent that prolonged immersion in ice water to gain relief can result in local tissue injury or hypothermia. The genotype and specific amino acid substitution influences the degree of hyperpolarising shift of the Na v 1.7 channel, severity of symptoms, age of onset, and in some cases can predict relative response to non-specific sodium channel agents (mexiletine or carbamazepine) [34,52]. Paroxysmal extreme pain disorder, related to different SCN9A mutations and patterns of altered Na v 1.7 kinetics, is associated with pain and erythema in the buttocks and legs in early infancy and mandibular pain at older ages, can be triggered by mechanical stimuli, and may respond to carbamazepine [52].…”

“…For example, nerve conduction studies with a representative medial plantar sensory recording in an infant[48] (from Jabre et al Clin Neurophysiol 2020, reproduced with permission from Elsevier); (ii) genetic testing. As an example, SCN9A mutations and resultant amino-acid substitutions in the voltage-gated sodium channel Na v 1.7 associated with phenotypes of erythromelalgia (EM; sites associated with onset of erythromelalgia in childhood (EM paed) identified from a systematic review[34]), paroxysmal extreme pain disorder (PEPD), or congenital insensitivity to pain (CIP). Schematic of Na v 1.7 (modified from Dib-Hajj et al Trends Neurosci 2007, reproduced with permission from Elsevier); (iii) neuroimaging, and (iv) skin biopsy.…”