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

Luke Arthur; Kirsty Keen; Madeleine Verriotis; Judy Peters; Alison Kelly; Richard F Howard; Sulayman D Dib-Hajj; Stephen G Waxman; Suellen M Walker

doi:10.1016/j.jpeds.2018.10.024

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

J Pediatr. 2019 Mar:206:217-224.e9. doi: 10.1016/j.jpeds.2018.10.024. Epub 2018 Nov 9.

Authors

Luke Arthur¹, Kirsty Keen², Madeleine Verriotis¹, Judy Peters¹, Alison Kelly³, Richard F Howard¹, Sulayman D Dib-Hajj⁴, Stephen G Waxman⁴, Suellen M Walker⁵

Affiliations

¹ Clinical Neurosciences (Pediatric Pain Research Group), UCL GOS Institute of Child Health, London, UK; Department of Pediatric Anesthesia and Pain Medicine, Great Ormond Street Hospital NHS Foundation Trust, London, UK.
² Department of Pediatric Anesthesia and Pain Medicine, Great Ormond Street Hospital NHS Foundation Trust, London, UK.
³ Department of Pediatric Rheumatology, Bristol Royal Hospital for Children, Bristol, UK.
⁴ Department of Neurology and Center for Neuroscience and Regeneration Research, Yale University School of Medicine, New Haven, CT; Center for Restoration of Nervous System Function, Veterans Affairs Connecticut Healthcare System, West Haven, CT.
⁵ Clinical Neurosciences (Pediatric Pain Research Group), UCL GOS Institute of Child Health, London, UK; Department of Pediatric Anesthesia and Pain Medicine, Great Ormond Street Hospital NHS Foundation Trust, London, UK. Electronic address: suellen.walker@ucl.ac.uk.

PMID: 30416015
DOI: 10.1016/j.jpeds.2018.10.024

Abstract

Objectives: To evaluate the clinical features of erythromelalgia in childhood associated with gain-of-function SCN9A mutations that increase activity of the Na_v1.7 voltage-gated sodium channel, we conducted a systematic review of pediatric presentations of erythromelalgia related to SCN9A mutations, and compared pediatric clinical presentations of symptomatic erythromelalgia, with or without SCN9A mutations.

Study design: PubMed, Embase, and PsycINFO Databases were searched for reports of inherited erythromelalgia in childhood. Clinical features, management, and genotype were extracted. Case notes of pediatric patients with erythromelalgia from the Great Ormond Street Hospital Pain Service were reviewed for clinical features, patient-reported outcomes, and treatments. Children aged over 10 years were recruited for quantitative sensory testing.

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 nonspecific 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_v1.7 sodium channels correlated with symptom onset at younger ages (P = .016). Variability in reporting, and potential publication bias toward severe cases, limit any estimations of overall prevalence. In our case series, symptoms were similar but comorbidities were more common in children with SCN9A mutations. Quantitative sensory testing revealed marked dynamic warm allodynia.

Conclusions: Inherited erythromelalgia in children is associated with difficult-to-manage pain and significant morbidity. Standardized reporting of outcome and management in larger series will strengthen identification of genotype-phenotype relationships. More effective long-term therapies are a significant unmet clinical need.

Keywords: erythromelalgia; neuropathic pain; sodium channelopathy.

Publication types

Research Support, Non-U.S. Gov't
Systematic Review

MeSH terms

Adolescent
Child
Erythromelalgia / complications*
Erythromelalgia / genetics*
Female
Humans
Male
Mutation / genetics*
NAV1.7 Voltage-Gated Sodium Channel / genetics*
Pain / etiology*
Retrospective Studies
Symptom Assessment

Substances

NAV1.7 Voltage-Gated Sodium Channel
SCN9A protein, human