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.

The article presents a clinical case of secondary erythromelalgia in a comorbid patient with antiphospholipid syndrome, accompanied by burning pain, hyperemia and swelling of the lower extremities. A comprehensive examination involving a neurologist, dermatologist, and rheumatologist was conducted to establish the diagnosis and select the optimal therapy. Significant clinical improvement in the patient's condition is demonstrated against the background of pregabalin therapy. The importance of a multidisciplinary approach and the difficulty of diagnosis due to the lack of specific examination methods and insufficient awareness of doctors about this disease are emphasized. The described case demonstrates the need for a personalized approach to managing patients with erythromelalgia to improve their quality of life.

Thrombocytosis, defined as platelet counts >450 × 10⁹/L, is frequent in the pediatric population and usually secondary to inflammatory conditions or iron deficiency. Essential thrombocythemia (ET), a Philadelphia chromosome-negative myeloproliferative neoplasm, is exceptionally rare in childhood. Pediatric ET often follows an indolent course but carries risks of thrombotic and hemorrhagic events, as well as late progression to myelofibrosis or leukemia. We report the case of a 14-year-old girl presenting with recurrent acral edema, erythema alternating with cyanosis, burning pain, paresthesia, and headaches. Physical examination was unremarkable. Initial suspicion of Raynaud's phenomenon was excluded by nailfold capillaroscopy. Laboratory studies revealed persistent thrombocytosis with platelets over 1,092 × 10⁹/L. Secondary causes were excluded. Bone marrow biopsy revealed megakaryocytic hyperplasia with hyperlobulated megakaryocytes, abdominal ultrasound revealed hepatosplenomegaly, and molecular testing identified a JAK2 V617F mutation, confirming ET. She was initially treated with low-dose acetylsalicylic acid, with partial improvement, but microvascular symptoms persisted, and platelet counts remained >1,000 × 10⁹/L. Hydroxyurea was initiated, leading to progressive platelet reduction and marked clinical benefit. Over three years of follow-up, the patient remained clinically stable, without adverse effects or leukemic transformation. This case illustrates the rarity and diagnostic complexity of pediatric ET, which requires exclusion of reactive causes, bone marrow evaluation, and molecular testing. Management remains particularly challenging due to the absence of pediatric-specific guidelines, with current approaches being largely derived from adult protocols. Cytoreductive therapy may be indicated in cases with extreme thrombocytosis or refractory symptoms, and long-term follow-up is crucial to monitor disease evolution and treatment outcomes. This case highlights the need for multicenter studies and international registries to have pediatric-specific evidence that can better inform diagnostic and therapeutic strategies.

Gain-of-function mutations in SCN9A, which encodes the Nav1.7 voltage-gated sodium channel, are known to cause primary erythromelalgia (PEM). This condition is characterized by recurrent episodes of erythema, burning pain, and warmth in the extremities. These genetic insights have spurred the development of Nav1.7 blockers as a promising therapeutic strategy for PEM. However, translating these findings into effective clinical treatments has remained challenging. In this study, we demonstrate that mepyramine, a compound previously shown to alleviate pain in animal models, effectively targets hNav1.7 channels carrying PEM-associated gain-of-function mutations, providing substantial pain relief in PEM patients. Using voltage-clamp recordings in human embryonic kidney (HEK) 293 cells, we demonstrated that mepyramine inhibits hNav1.7 channels carrying three distinct PEM mutations, I848T, L858F, and L1267V, which differentially affect the gating properties of hNav1.7. Importantly, mepyramine's efficacy was consistent regardless of how these mutations altered channel activation or inactivation properties. To evaluate its clinical potential, we administered a high-dose topical formulation of mepyramine to a group of PEM patients suffering from severe pain that was unresponsive to conventional analgesics, including cases with identified SCN9A mutations. This treatment rapidly and durably reduced burning pain and erythema, providing meaningful relief for patients who had not responded to, or could not tolerate, previous therapies. These results suggest that mepyramine can inhibit PEM-associated Nav1.7 channel mutants and may offer a new therapeutic approach for PEM patients.

Spontaneous activity of peripheral sensory nerve fibers is one of the main drivers of neuropathic pain. It can be assessed in microneurography recordings of patients' C fibers and in patch-clamp recordings of dissociated dorsal root ganglia from humans and rodents. In microneurography of human C fibers, a distinct subgroup of neurons, the so-called mechano-insensitive (CMi) or sleeping nociceptors, shows spontaneous activity during neuropathic pain. It was shown before that sensory neurons from patient-derived induced pluripotent stem cells (iSNs) can be used to model this increased spontaneous activity in vitro, suggesting that a disease relevant cell type is generated with this approach. The origin of the spontaneous activity in human C fibers is not fully understood. Derived sensory neurons offer the unique possibility to study patient-derived, single-cell function, allowing for identification of potential mechanisms underlying spontaneous C-fiber activity. Here, we identify 4 distinct functional subtypes of iSNs from healthy donors and a patient suffering from the neuropathic pain syndrome inherited erythromelalgia using patch-clamp recordings. Similar to microneurography recordings from the same patient, spontaneous activity is restricted to 1 functional subgroup that shows tonic firing behavior and seems to be especially prone to develop neuronal hyperexcitability. We demonstrate that spontaneous activity correlates with a reduced voltage threshold of action potential generation and increased spontaneous depolarizing fluctuations of the membrane potential. Our findings reveal that only the tonically firing functional subclass of iSNs shows spontaneous activity and suggest that these neurons may be related to the pathologically active CMi fibers identified during microneurography recordings in patients with pain.

Red ear syndrome (RES) is a rare, poorly understood disorder characterized by episodic ear erythema and pain. Its pathophysiology remains unclear, with proposed associations to migraine, erythromelalgia, and rosacea. Existing treatments are often ineffective, emphasizing the need for novel approaches. We describe a 33-year-old male with bilateral, non-headache RES refractory to standard therapies. A novel botulinum toxin type A (BoNT-A) injection paradigm, targeting both sensory and autonomic innervation, was implemented. Although episode frequency remained unchanged, the patient experienced significant reductions in pain intensity, episode duration, and improvement in quality of life.

Background/Objectives: 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. Methods: 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. Results: 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. Conclusions: 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.