Harvard University

Gene variants associated with pediatric-onset erythromelalgia: Mendelian and rare-variant association analyses.

Erythromelalgia is a descriptive term for burning pain and erythema in distal extremities, often worsened by heat and improved by cold. Inherited erythromelalgia has been primarily linked to gain-of-function variants in , encoding voltage-gated sodium channel NaV1.7. However, approximately 65% to 85% of patients with erythromelalgia do not have pathogenic variants. The objective of this study was to uncover and assess gene variants potentially associated with pediatric-onset erythromelalgia. With IRB approval and informed consent, probands and families with erythromelalgia underwent next-generation sequencing. A list of genes of interest was produced based on Mendelian inheritance models. Selected gene candidates were assessed using the Sequence Kernel Association Test-Optimal (SKAT-O). Sixty-two probands with erythromelalgia and their relatives were included in Mendelian analysis, which identified variants in PR domain zinc finger protein 12 () and dihydropyrimidinase-like protein 2 (). In a targeted 12-gene rare-variant set analysis using SKAT-O, zinc finger homeobox protein 2 () showed evidence of association ( = 6.9 × 10), surpassing Bonferroni correction for 12 tests (α = 4.17 × 10), whereas showed only a nominal association signal ( = 0.03) that did not survive multiple-testing correction. Genes associated with both increased and decreased pain sensitivity are of considerable interest for elucidating pain mechanisms and analgesic development. As rare variants in and were identified in a pediatric erythromelalgia cohort and a gene-based rare-variant association signal for was identified, replication and functional validation are needed.

Pediatric erythromelalgia from multidisciplinary perspectives: a scoping review.

Erythromelalgia is a rare, chronic pain disorder characterized by the triad of intense burning sensation, warmth, and redness, primarily involving the hands and feet, and usually alleviated by cold and worsened by heat. The objective of this scoping review was to: 1) map the existing literature on erythromelalgia in youth, 2) identify knowledge gaps, and 3) inform directions for future research in pediatric erythromelalgia. One hundred and sixty-seven studies reporting 411 cases of childhood-onset erythromelalgia were identified. Variability was found in reporting of clinical symptoms, the clinical presentations and diagnostic criteria used for classification of erythromelagia, the clinical assessments and investigations performed, and the types of interventions and management plans utilised. While factors to aid early recognition and optimize management have been identified, there are also significant gaps for future research to address. Ongoing efforts to develop a multicenter registry of pediatric erythromelalgia cases, with standardized data collection and reporting, will be beneficial to establish consensus recommendations for the diagnosis and management of pediatric erythromelalgia. IMPACT: This scoping review maps the existing literature on pediatric erythromelalgia. Variability was found in reporting of clinical symptoms, the clinical presentations and diagnostic criteria used for classification of erythromelagia, the clinical assessments and investigations performed, and the types of interventions and management plans utilised. The development of an international registry would immensely benefit multidisciplinary experts involved in the care of pediatric erythromelalgia and those with lived experience.

Correction of sodium channel mutations in sensory neurons reverses aberrant properties.

Inherited erythromelalgia, small fibre neuropathy and paroxysmal extreme pain disorder are caused by gain-of-function mutations in the voltage-gated sodium channel Nav1.7. It remains unknown how different mutations in the same channel enhancing electrogenesis in sensory neurons results in such distinct disease presentations. Most of the work analysing the impact of these mutations on electrophysiological properties has used overexpression systems in cell lines and rodent sensory neurons, which might differ from the natural context. We have differentiated sensory neurons from induced pluripotent stem cells derived from patient samples that have the Nav1.7 A1632G mutation. This strategy reveals changes in electrophysiological properties, not previously observed in cell lines, that might be important for disease presentation. Furthermore, using CRISPR/Cas9, we corrected this mutation, which reduced the underlying hyperexcitability, providing a path for personalized medicine to treat these disorders, and we introduced the mutation into control induced pluripotent stem cells, which generated hyperexcitability, providing causality. Induced pluripotent stem cell sensory neurons are a robust, scalable and relevant model to study the effects of gain-of-function mutations in ion channels in pain-related disorders.

Patient-Oriented Priorities for Pediatric Erythromelalgia: A Priority-Setting Process.

: Erythromelalgia is a rare condition characterized by burning pain, redness, and warmth primarily in the extremities, usually worsened by heat and alleviated by cold. The objective of this study was to identify the top 10 priorities in pediatric erythromelalgia from multiple perspectives, including clinicians, people with lived experience of childhood-onset erythromelalgia, and their family members. : A modified James Lind Alliance Priority-Setting Process was conducted. The top priorities were identified through four phases: (1) an international online survey to gather priorities, (2) data processing, (3) an interim prioritization online survey, and (4) a virtual workshop to set the final priorities. : In phase 1, 185 potential priorities were submitted by 74 respondents (53% patients, 24% family members, and 23% clinicians) that were developed into 68 unique research questions (phase 2). In phase 3, of the 68 questions, 50 were rated for importance by 58 participants (38% patients, 36% family members, and 26% clinicians), reducing the list to 25 questions. In phase 4, the top 10 was reached through consensus by 12 participants (33% patients, 25% family members, and 42% clinicians) across Canada, South Africa, the United States of America, and the United Kingdom. : The final priorities focused on the treatment of erythromelalgia, understanding underlying mechanisms, the association of erythromelalgia with various body systems, and generating awareness. This list is the first international patient-centered research agenda for childhood-onset erythromelalgia and a call to action from key partners to improve future research and care.

Na1.7 gain-of-function mutation I228M triggers age-dependent nociceptive insensitivity and C-LTMR dysregulation.

Gain-of-function mutations in Scn9a, which encodes the peripheral sensory neuron-enriched voltage-gated sodium channel Na1.7, cause paroxysmal extreme pain disorder (PEPD), inherited erythromelalgia (IEM), and small fiber neuropathy (SFN). Conversely, loss-of-function mutations in the gene are linked to congenital insensitivity to pain (CIP). These mutations are evidence for a link between altered sodium conductance and neuronal excitability leading to somatosensory aberrations, pain, or its loss. Our previous work in young adult mice with the Na1.7 gain-of-function mutation, I228M, showed the expected DRG neuron hyperexcitability, but unexpectedly the mice had normal mechanical and thermal behavioral sensitivity. We now show that with aging both male and female mice with this mutation unexpectedly develop a profound insensitivity to noxious heat and cold, as well skin lesions that span the body. Electrophysiology demonstrates that, in contrast to young mice, aged I228M mouse DRGs have a profound loss of sodium conductance and changes in activation and slow inactivation dynamics, representing a loss-of-function. Through RNA sequencing we explored how these age-related changes may produce the phenotypic changes and found a striking and specific decrease in C-low threshold mechanoreceptor- (cLTMR) associated gene expression, suggesting a potential contribution of this DRG neuron subtype to Na1.7 dysfunction phenotypes. A GOF mutation in a voltage-gated channel can therefore produce over a prolonged time, highly complex and unexpected alterations in the nervous system beyond excitability changes.

Clinical Characterization of Pediatric Erythromelalgia: A Single-Center Case Series.

Erythromelalgia is a descriptive term for severe burning pain and erythema in the distal extremities relieved by cold and exacerbated by heat. Pediatric case series to date are relatively small. We extracted and analyzed medical record data for 42 pediatric patients to describe clinical characteristics, associated conditions, and responses to treatments. Informed consent was obtained according to an IRB-approved protocol that included gene discovery. Three patients had confirmed Nav1.7 sodium channelopathies, with six additional patients under investigation with novel gene candidates. There was a female predominance (2.5:1), and the median onset age was 12 years (IQR = 3-14). Patients saw a median of three specialists (IQR = 2-3) for a diagnosis. The majority (90%) reported bilateral symptoms. Cooling methods usually provided partial relief, while heat and exercise exacerbated pain. No medication appeared to be consistently effective; commonly prescribed medications included sodium channel blockers ( = 37), topical analgesics ( = 26), gabapentin ( = 22), and aspirin ( = 15). Based on the currently published literature, we believe this cohort is the largest pediatric study of erythromelalgia to date. Many findings are consistent with those of previously published case series. Work is in progress to establish a prospective cohort and multi-center registry.

Topical treatments for erythromelalgia.

Erythromelalgia is a rare neurovascular disease that causes episodes of pain, redness, and warmth in the extremities, and can be debilitating. Currently, there is no universally effective treatment for erythromelalgia. As the precise etiology of erythromelalgia remains obscure, presently available treatments are aimed at alleviating erythromelalgia's wide-ranging symptoms. In general, topical therapies for erythromelalgia are preferred for their more limited side effects and for those with contraindications to systemic therapies. This review will summarize the current topical therapies available to treat erythromelalgia and discuss emerging therapies based on our growing understanding of erythromelalgia pathophysiology.

Evaluating efficacy of treatments for erythromelalgia in the setting of biopsy proven small fibre reduction.

Cutaneous manifestations of small fibre polyneuropathy.

Because typical and atypical features of small fibre polyneuropathy (SFN) in the skin have not been fully elucidated, the diagnosis is often made by the exclusion of alternative conditions rather than by its identification as a primary syndrome. The objective of this study was to characterize dermatologic manifestations in patients with SFN. Large retrospective series of biopsy-proven SFN cases seen at the Massachusetts General Hospital and Brigham and Women's Hospital (January 2000 to December 2019). The majority of the 301 participants included presented with at least one cutaneous manifestation [292/301 (97%)]. Pain was most common with 254/301 (84.4%) perceiving this as occurring in the skin. It was frequently described as 'burning' [95/254 (37.4%)] and affected distal [174/254 (68.5%)] slightly more than proximal [111/254 (43.7%)] limbs. Numbness [182/301 (60.5%)], edema [61/301 (20.3%)] and skin colour changes [53/301 (17.6%)], which include redness [23/53 (43%)], also had predominant distal distribution. Characteristic loss of distal hair occurred among 17/29 (59%) those reporting hair loss. Other findings with classic limb involvement, Raynaud's phenomenon [33/301 (11%)] and erythromelalgia [26/301 (8.6%)] were seen. Itch [45/301 (15%)], mostly localized [22/45 (49%)] and localized eczematous dermatitis were also found. SFN has a wide range of clinical features in which the skin is affected, with characteristic findings affecting the extremities.

Cutaneous reactions reported after Moderna and Pfizer COVID-19 vaccination: A registry-based study of 414 cases.

Cutaneous reactions after messenger RNA (mRNA)-based COVID-19 vaccines have been reported but are not well characterized. To evaluate the morphology and timing of cutaneous reactions after mRNA COVID-19 vaccines. A provider-facing registry-based study collected cases of cutaneous manifestations after COVID-19 vaccination. From December 2020 to February 2021, we recorded 414 cutaneous reactions to mRNA COVID-19 vaccines from Moderna (83%) and Pfizer (17%). Delayed large local reactions were most common, followed by local injection site reactions, urticarial eruptions, and morbilliform eruptions. Forty-three percent of patients with first-dose reactions experienced second-dose recurrence. Additional less common reactions included pernio/chilblains, cosmetic filler reactions, zoster, herpes simplex flares, and pityriasis rosea-like reactions. Registry analysis does not measure incidence. Morphologic misclassification is possible. We report a spectrum of cutaneous reactions after mRNA COVID-19 vaccines. We observed some dermatologic reactions to Moderna and Pfizer vaccines that mimicked SARS-CoV-2 infection itself, such as pernio/chilblains. Most patients with first-dose reactions did not have a second-dose reaction and serious adverse events did not develop in any of the patients in the registry after the first or second dose. Our data support that cutaneous reactions to COVID-19 vaccination are generally minor and self-limited, and should not discourage vaccination.

Evidence of small-fiber polyneuropathy in unexplained, juvenile-onset, widespread pain syndromes.

We tested the hypothesis that acquired small-fiber polyneuropathy (SFPN), previously uncharacterized in children, contributes to unexplained pediatric widespread pain syndromes. Forty-one consecutive patients evaluated for unexplained widespread pain beginning before age 21 had medical records comprehensively analyzed regarding objective diagnostic testing for SFPN (neurodiagnostic skin biopsy, nerve biopsy, and autonomic function testing), plus histories, symptoms, signs, other tests, and treatments. Healthy, demographically matched volunteers provided normal controls for SFPN tests. Age at illness onset averaged 12.3 ± 5.7 years; 73% among this poly-ethnic sample were female (P = .001). Sixty-eight percent were chronically disabled, and 68% had hospitalizations. Objective testing diagnosed definite SFPN in 59%, probable SFPN in 17%, and possible SFPN in 22%. Only 1 of 41 had entirely normal SFPN test results. Ninety-eight percent of patients had other somatic complaints consistent with SFPN dysautonomia (90% cardiovascular, 82% gastrointestinal, and 34% urologic), 83% reported chronic fatigue, and 63% had chronic headache. Neurologic examinations identified reduced sensation in 68% and vasomotor abnormalities in 55%, including 23% with erythromelalgia. Exhaustive investigations for SFPN causality identified only history of autoimmune illnesses in 33% and serologic markers of disordered immunity in 89%. Treatment with corticosteroids and/or intravenous immune globulin objectively and subjectively benefited 80% of patients (12/15). More than half among a large series of patients with childhood-onset, unexplained chronic widespread pain met rigorous, multitest, diagnostic criteria for SFPN, which extends the age range of acquired SFPN into early childhood. Some cases appeared immune-mediated and improved with immunomodulatory therapies.

'Hot feet - hot brain': gene and brain dysfunction in erythromelalgia.

Defining a treatable cause of erythromelalgia: acute adolescent autoimmune small-fiber axonopathy.

Conditions described as "erythromelalgia" and "erythermalgia" are being formally specified by etiological diagnoses that enable the use of disease-modifying as well as symptomatic treatments. We describe an otherwise healthy 20-year-old man with acute-onset erythromelalgia. Severe bilateral distal limb pain and vasodilation persisted despite the use of many antihyperalgesics. Pathological examination of cutaneous nerve endings revealed severe small-fiber predominant axonopathy. Treatment of his apparent autoimmune polyneuropathy with high dose corticosteroids, 4 days of lidocaine infusion, and a prednisone taper cured him. Similarities to other cases allowed us to tentatively characterize a new treatable cause of erythromelalgia; acute adolescent autoimmune small-fiber axonopathy. In this report we evaluate various options for diagnosis and treatment.