Mayo Clinic

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.

Anhidrosis: An underappreciated factor in dermatologic diseases.

Dissipation of body heat, essential to human life, is largely achieved through sweating. If sweating does not occur normally-as in patients with hypohidrosis (reduced sweating) or anhidrosis (lack of sweating)-the ability to dissipate heat via evaporative mechanisms is overwhelmed. Body temperature may rise, leading to heat-related illness, including heat intolerance, hyperthermia, heat exhaustion, heat stroke, and even death. In patients seen by a dermatologist, anhidrosis may underly and contribute to their symptoms and signs but may be difficult to detect given a limited availability of tools to measure anhidrosis. An association between anhidrosis and skin symptoms including flushing syndromes (eg, facial flushing and erythromelalgia) and widespread skin symptoms (eg, itching, burning, numbness, or tingling, and paresthesias) has recently been described. This review explores the existing dermatologic literature on anhidrosis including clues to the pathophysiology of these disorders, its relationship to skin diseases and symptoms, the tests currently available, and approaches to management. Recognition of an underlying anhidrosis by dermatologists may be important for providing optimal management for patients with heat-related symptoms.

Management of erythromelalgia: a narrative review and expert opinion.

Erythromelalgia (EM) is a rare disorder predominantly affecting distal extremities characterized by episodes of painful burning erythema, often precipitated by heat and exercise. Treatment is challenging due to limited evidence and lack of guidelines. This article provides an overview of the available literature on EM, with special emphasis on management strategies including lifestyle modification, nonpharmacologic, pharmacologic, procedural, and rehabilitative interventions. PubMed was searched using the advanced search function with the terms 'erythromelalgia AND therapies AND management' from database inception through 16 April 2026. Management of EM is challenging as there is no cure. It requires an individualized step wise approach due to its heterogenous presentation and variable treatment responses. The primary goal of treatment is to control symptoms and maintain quality of life. In this article, we outline our treatment approach for management including an initial evaluation for underlying causes or associations and treating them if present. First-line therapies include lifestyle modifications, trigger avoidance, and trial of various topical therapies. If not fully responding to first line therapy, we consider initiation of systemic therapies and pain rehabilitative programs.

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.

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.

Expanding the Phenotype Spectrum of β-Mannosidosis.

β-mannosidosis is an ultra-rare lysosomal storage disorder caused by a deficiency of β-mannosidase, which catalyzes the last step of glycoprotein degradation. Owing to the limited number of reported cases, information on the natural history of the disease and brain imaging is scarce. We report 6 new cases and review them together with all the previously reported cases in the literature. We describe the clinical features of 6 unrelated patients with β-mannosidosis, their variants in , enzyme activity, urine oligosaccharide profiles, brain MRI findings, and longitudinal MRI changes in 2 of them. We also review previously reported patients to broaden the spectrum of clinical features and identify genotype-phenotype correlations. Developmental regression, dysphagia, obsessive-compulsive-like behavior, and erythromelalgia are newly described features associated with β-mannosidosis among the 6 patients from our cohort. Nystagmus in association with β-mannosidosis was also found in 1 patient. Half the patients have abnormal brain MRIs, showing delayed myelination before 2 years of age and diffuse hypomyelination thereafter. A new oligosaccharide was found in the urine of the 2 most severely affected patients. Including our 6 patients, a total of 46 cases from 37 different families have been reported. The mean age of diagnosis is 12.8 years, and the mean age of symptom onset is 2.4 years. Hearing loss was the initial symptom most frequently reported, and intellectual disability was the most frequent symptom overall. Across the cohort, 29 pathogenic variants were identified, 61.8% were private, and 38.2% have the recurrent c.2158-2A>G variant. Neuroimaging abnormalities were reported in 40% of published cases and included cortical and subcortical atrophy, basal ganglia and white matter calcification, hydrocephalus, periventricular and subcortical white matter hyperintensities, and delayed myelination. Genotype-phenotype correlation in β-mannosidosis remains elusive, likely due to phenotypic variability, disease rarity, and lack of association between the enzyme activity and the clinical severity. Modifier genes in the N-glycan degradation pathway, such as , may influence disease expression. β-mannosidosis should be considered as a differential diagnosis in patients with syndromic or apparently nonsyndromic hearing loss, unexplained brain hypomyelination, behavioral disturbances, and intellectual disability.

Vascular Disease Patient Information Page: Erythromelalgia.

Procedural interventions for erythromelalgia: A narrative review.

Erythromelalgia is a rare disorder characterized by episodic burning pain with redness and warmth of the extremities. Topical and systemic medications are the mainstay of management. We reviewed the published evidence for using procedural interventions to manage erythromelalgia, including their proposed mechanism of action and possible adverse effects, and included information in this review on epidural infusion, sympathetic ganglion block, sympathectomy, pulsed radiofrequency, spinal cord stimulation, dorsal root ganglion stimulation, brain stimulation, transcranial magnetic stimulation, and botulinum toxin injections. Both successful and unsuccessful outcomes have been reported. Although these procedural interventions extend the therapeutic options for erythromelalgia, the evidence for their use is limited. Case reports and small case series comprise most of the evidence. Based on our review, a multidisciplinary approach to management may be needed for patients with erythromelalgia.

Cytomegalovirus infection associated with livedo reticularis, erythromelalgia, and superficial venous thrombosis.

Essential thrombocytosis: diagnosis, differential diagnosis, complications and treatment considerations of relevance for a cardiologist.

Essential thrombocytosis (ET) is a rare haematological malignancy, with an incidence rate of 1.5-2.5/100,000 per year. For many patients with ET the first manifestation of their underlying disease is a thrombotic or haemorrhagic complication. A recent retrospective study revealed an incidence rate of at least 2.1% in people under 40 years presenting with an acute coronary syndrome, although the diagnosis was initially missed in all cases. Thus, cardiologists face a much higher than average incidence rate of ET in their daily practice, but seem insufficiently aware of the disease. The current review summarises symptoms, (differential) diagnosis, complications and treatment considerations of ET of relevance for a cardiologist. Typical symptoms, besides thrombosis and haemorrhage, include erythromelalgia and aquagenic pruritus, while platelets > 450 × 10/l are a diagnostic for ET once other myeloproliferative neoplasms, secondary and spurious thrombocytosis have been excluded. With regard to treatment, timing of revascularisation depends on the presence of ischaemia and concurrent platelet counts. In the presence of ischaemia, revascularisation should not be delayed and adequate platelet counts can be achieved by platelet apheresis. In the absence of ischaemia, revascularisation can be delayed until adequate platelet counts have been achieved by cytoreductive therapies. Cardiologists should be aware of/screen for possible ET.

Erythromelalgia: A Review of Medical Management Options and Our Approach to Management.

Erythromelalgia (EM) is a rare disorder characterized by episodic, burning pain associated with erythema and warmth of the extremities. The feet and hands are most commonly affected. The pain can be so severe that patients may engage in behaviors, sometimes extreme, to cool the affected areas and change their lifestyle to avoid precipitating factors, such as exercise and increased ambient heat. A literature search was performed with PubMed and MEDLINE with the search term erythromelalgia. Inclusion criteria were studies on EM published after 1985 until January 1, 2022, in the English language and studies that provided information on medical treatment of EM. Studies were excluded if they were duplicates or did not include treatment data. No guidelines exist for the treatment of this complex disorder. Lifestyle modifications and pharmacologic treatments (topical and systemic) are discussed in this article, which provides a comprehensive review of published medical management options for erythromelalgia and a proposed approach to management.

The Case of the Red Extremities.

A 37-year-old man with severe obstructive sleep apnea presented to the emergency department with burning pain, redness and swelling in his hands and feet, worsening for several weeks. Pertinent laboratory studies revealed polycythemia. Erythromelalgia is a clinical diagnosis characterized by painful burning, erythema, warmth, and edema usually involving the distal extremities. Therapeutic goals are focused on symptom reduction, while also managing the underlying condition in cases of secondary erythromelalgia. Pharmacological and non-pharmacological therapies have proven to be of limited success.

Dorsal Root Ganglion Stimulation for Erythromelalgia Related Foot Pain: A Case Report and Review of the Literature.

Erythromelalgia is a rare neurovascular disorder characterized by erythema, warmth, and episodic burning pain, often felt in the face, hands, and feet. Symptoms are typically worse with heat, exercise, stress, and during the overnight hours. Management often requires a multidisciplinary approach, including pain trigger avoidance, cool water baths, and topical and oral neuropathic medications. The use of spinal cord stimulation has been described in multiple case reports with success reported out to 24 months. To our knowledge, the use of dorsal root ganglion (DRG) stimulation for erythromelalgia-related pain has not been described. Herein, we present a case of erythromelalgia-related pain at the bilateral plantar surfaces of the feet, which was treated successfully with bilateral sacral S1 nerve root DRG stimulation.

Erythromelalgia: improvement in pain with transcranial magnetic stimulation.

Facial erythromelalgia?

Erythromelalgia: Identification of a corticosteroid-responsive subset.

Corticosteroids (CS) may benefit certain patients with erythromelalgia. Our objective was to determine clinical predictors of corticosteroid-responsive erythromelalgia. Patients with erythromelalgia who received CS were identified and stratified into corticosteroid nonresponders (NRs), partial corticosteroid responders (PSRs), complete corticosteroid responders (CSRs), and steroid responders (SRs = PSRs + CSRs). In the study variable analysis, P < .05 was considered statistically significant. The median (interquartile range) age of the 31-patient cohort was 47 years (26-57 years), and 22 (71%) were female. Fourteen (45%) were NRs, 17 (55%) SRs, 8 (26%) PSRs, and 9 (29%) CSRs. A subacute temporal profile to disease zenith (<21 days) was described in 15 (48%) patients, of whom 13 (87%) were SRs (P = .003; odds ratio [OR] = 0.069 [95% confidence interval {CI}, 0.011-0.431]). Six (67%) CSRs reported a disease precipitant (eg, surgery, trauma, or infection; P = .007; OR = 12.667 [95% CI, 2-80.142]). SR patients received CS sooner than NR at 3 (3-12) versus 24 (17-45) months (P = .003). A high-dose CS trial (≥200 mg prednisone cumulatively) was administered to 17 (55%) patients, of whom 13 (76%) were SRs (P = .012; OR = 8.125 [95% CI, 1.612-40.752]). This was a retrospective case series. An infectious, traumatic, or surgical precipitant and subacute presentation may portend CR erythromelalgia. A transient "golden window" where CS intervention is useful may exist before irreversible nociceptive remodeling and central sensitization occurs.

Erythromelalgia in patients with essential thrombocythemia and polycythemia vera.

Epidermal Nerve Fiber Quantification in Patients With Erythromelalgia.

Erythromelalgia is a clinical diagnosis based on intermittent warmth, erythema, and pain in the distal extremities. One problem facing physicians is how to objectively test for this disease. Given that other painful conditions of the distal extremities (ie, neuropathy related to human immunodeficiency virus, diabetes, or Fabry disease) can be evaluated with a skin biopsy to visualize pathologically decreased densities of the small nerve fibers that innervate the epidermis, one hypothesis is that erythromelalgia could similarly be associated with a loss of epidermal nerve fiber density (ENFD). To examine whether erythromelalgia is associated with a structural loss of small fibers using the ENFD technique and to compare this with functional studies of small nerve fibers. In a retrospective study of 52 consecutive patients with erythromelalgia who were seen between September 1, 2010, and September 22, 2015, patients were interviewed and examined and their conditions clinically diagnosed by a board-certified dermatologist at a large tertiary referral center, where ENFD testing became a routine part of evaluating erythromelalgia in 2010. Thus, all 52 consecutive patients were included solely based on their clinical diagnosis of erythromelalgia. For quantification of ENFD, observers were masked to all patient information except for name and clinic number. The hypothesis that patients with erythromelalgia would have decreased ENFD was formulated before data collection. Epidermal nerve fiber density, the primary outcome, is a measurement of the density of small nerve fibers within the epidermis. Secondary measures included functional small fiber evaluation, such as autonomic (heart rate, blood pressure, and sweat testing) and subjective testing of pain. In this cohort study, 52 consecutively seen patients were identified (female, 42 [80%]; median age, 44 years; age range, 13-82 years). Whereas only 5 of 52 patients (10%) had ENFD at or below the fifth percentile of healthy control individuals, most patients had functional abnormalities of these small fibers; 29 patients (60%) had abnormal sweat test results, 21 (42%) had abnormal pain thresholds, and 20 (38%) had abnormal blood pressure or heart rate control. Unlike other diseases of the small nerve fibers that cause acral pain syndromes, erythromelalgia is not characterized by loss of ENFD. However, most patients have impaired function of these small fibers. Physicians would benefit from performing functional rather than structural small fiber studies when evaluating erythromelalgia.

Sex differences in the incidence of skin and skin-related diseases in Olmsted County, Minnesota, United States, and a comparison with other rates published worldwide.

Many skin and skin-related diseases affect the sexes unequally, with attendant implications for public health and resource allocation. To evaluate better the incidence of skin and skin-related diseases affecting males vs. females, we reviewed published population-based epidemiology studies of skin disorders performed utilizing Rochester Epidemiology Project data. Females had a higher incidence of the following diseases: connective tissue diseases (scleroderma, morphea, dermatomyositis, primary Sjögren syndrome, systemic lupus erythematosus [not in all studies]), pityriasis rosea, herpes progenitalis, condyloma acuminatum, hidradenitis suppurativa, herpes zoster (except in children), erythromelalgia, venous stasis syndrome, and venous ulcers. Males had a higher incidence of psoriasis and psoriatic arthritis, basal cell carcinoma (exception, females aged ≤40 years), squamous cell carcinoma, and lentigo maligna. Incidence rates were equal in males and females for cutaneous malignant melanoma (exception, higher in females aged 18-39 years), lower-extremity cellulitis, cutaneous nontuberculous mycobacterial infection, Behçet disease, delusional infestation, alopecia areata, and bullous pemphigoid. Many of the population-based sex-specific incidence rates of skin and skin-related diseases derived from the Rochester Epidemiology Project are strikingly different from those estimated elsewhere. In general, females are more commonly affected by skin and skin-related diseases. The reasons for this imbalance remain to be determined and are likely multifactorial.

Topically Applied Midodrine, 0.2%, an α1-Agonist, for the Treatment of Erythromelalgia.

Topical amitriptyline combined with ketamine for the treatment of erythromelalgia: a retrospective study of 36 patients at Mayo Clinic.

Erythromelalgia is an uncommon neurovascular disorder characterized by redness, increased skin temperature, and pain that usually occurs in the extremities. Treatment remains challenging because of its varying response to medical therapy. The objective of this study was to assess the response of erythromelalgia to compounded topical amitriptyline-ketamine. We retrospectively evaluated 36 patients with erythromelalgia who were treated with compounded topical amitriptyline-ketamine from January 1, 2004, through January 31, 2011. Thirty-two patients (89%) were female. Mean (standard deviation) age was 44.7 (15.8) years (range, 5-74 years). Patients applied the medication 1 to 6 times per day (median, 5 times). One patient (3%) had complete relief from symptoms, 14 (39%) had substantial relief, 12 (33%) had some relief, 7 (19%) had no relief, and 2 (6%) had local worsening of symptoms. No patients had systemic adverse effects. A majority of patients with erythromelalgia (75%) reported improvement in pain with topical application of a compounded amitriptyline-ketamine formulation. The medication was well tolerated.

Immersion foot associated with the overuse of ice, cold water, and fans: a distinctive clinical presentation complicating the syndrome of erythromelalgia.

Results of computer-assisted sensory evaluation in 41 patients with erythromelalgia.

Erythromelalgia is a rare disorder characterized by the clinical syndrome of burning pain, warmth and redness of the limbs. Neurological abnormalities (both large- and small-fibre neuropathy) are common. There have been few published reports on the sensory status of patients with erythromelalgia. To investigate the results of quantitative sensation testing in erythromelalgia using computer-assisted sensory evaluation, including vibratory detection threshold, cool detection threshold and heat-pain threshold (HPT). Patients who underwent dermatological or neurological evaluation of suspected erythromelalgia at our institution and received a final diagnosis of erythromelalgia were identified from a master diagnosis index covering the period January 1994 to June 2008. A retrospective chart review was performed. Main outcome measures were sensory abnormalities (e.g. pain, burning sensation, tingling) in response to heat, cooling and vibration during computer-assisted sensory testing. In total, 41 patients with erythromelalgia were enrolled in the study and underwent computer-assisted sensory evaluation. Of these, 34 patients (82.9%) had abnormal results. The commonest abnormality was isolated HPT: 11 patients (26.8%) had heat hypoalgesia and 18 (43.9%) had heat hyperalgesia, whereas only 2 (4.9%) of the healthy control patients had hyperalgesia on testing. Multiple sensory modalities were found to be abnormal in patients with erythromelalgia, with the commonest clinical abnormality being isolated heat-pain abnormality. These findings lend support to the notion that neuropathy underlies the clinical diagnosis of erythromelalgia. Future studies will explore the nature of the relationship between these sensory abnormalities and the clinical features of erythromelalgia.

Incidence of erythromelalgia: a population-based study in Olmsted County, Minnesota.

To estimate the population-based incidence of erythromelalgia. Background Only one report describing the incidence of erythromelalgia has been published previously. A population-based analysis of data from the Rochester Epidemiology Project. Tertiary care medical centre in Olmsted County, Minnesota (a rural county in the south-eastern portion of the state). Thirty-three residents of Olmsted County with a diagnosis of erythromelalgia during the study period. Age- and sex-specific incidence rates of erythromelalgia were determined. None. Population-based incidence rate. The overall age- and sex-adjusted incidence rate (95% confidence interval, 95% CI) was 1.3 (0.8-1.7) per 100,000 people per year. The incidence of primary and secondary erythromelalgia was 1.1 (0.7-1.5) and 0.2 (0.02-0.4) per 100,000 people per year, respectively. The age-adjusted incidence rates (95% CI) were 2.0 (1.2-2.7) per 100,000 women and 0.6 (0.1-1.1) per 100,000 men. The study was limited by the small sample size and potential variability in recognition of erythromelalgia. The population-based incidence of erythromelalgia has increased with each decade in Olmsted County over the past three decades; overall incidence was 1.3 per 100,000 people per year, approximately 5 times higher than previously reported.

Intervention for erythromelalgia, a chronic pain syndrome: comprehensive pain rehabilitation center, Mayo Clinic.

To describe the response in patients with erythromelalgia to the pain rehabilitation program at Mayo Clinic, Rochester, Minnesota. Retrospective case series. Comprehensive Pain Rehabilitation Center at a tertiary referral medical center. Patients Eight patients with erythromelalgia admitted to the pain rehabilitation program from January 1, 2002, through June 30, 2007. The Multidimensional Pain Inventory, the 36-Item Short Form Health Survey, the Pain Catastrophizing Scale, and the Center for Epidemiologic Studies Depression Scale were administered at admission and dismissal from the program. Mean differences in scores were compared using 2-sided paired t tests. Scores for the life interference, life control, and general activity subscales of the Multidimensional Pain Inventory showed significant improvement from admission to dismissal (all P < .05). Similarly, the scores of the Pain Catastrophizing Scale, the Center for Epidemiologic Studies Depression Scale, and the physical functioning and emotional role limitation subscales of the 36-Item Short Form Health Survey were significantly improved after intervention (all P < .01). Conclusion The results of our study indicate that pain rehabilitation is a useful method for managing pain-related impairment in physical and emotional functioning in patients with erythromelalgia.