Gain-of-function mutations in SCN9A, encoding the voltage-dependent Nav1.7 sodium channel, cause three autosomal-dominant disorders associated with severe pain: primary erythromelalgia, paroxysmal extreme pain disorder (PEPD), and small fiber neuropathy. On the other hand, biallelic loss-of-function mutations have been linked to impaired pain perception. Notably, the coexistence of both hyperalgesia and hypoalgesia within the same patient harboring the I234T variant has been reported in three independent patients to date. We report a 7-year-old girl harboring co-occurring SCN9A (I234T) and PRRT2 variants who presented with paroxysmal extreme pain disorder, contradictory analgesia, sensitivity to heat, and intractable head-drop attacks. Based on the genetic and clinical analyses, she was diagnosed as having PEPD and PRRT2-related paroxysmal dyskinesia. The intractable head-drop attacks were considered as paroxysmal non-kinesigenic dyskinesia. In addition, she exhibited easy fatigability and hypotonia. Taken together with her cold, cyanotic feet, these findings suggest that she may have also had small fiber neuropathy.

Mutations in the SCN9A gene, which encodes the sodium voltage-gated channel alpha subunit 9 on chromosome 2 (Nav1.7), are extremely rare and play a crucial role in pain signaling. Depending on the type of mutation, the clinical presentation of these mutations can vary widely from hyperactive pain phenotypes such as primary erythromelalgia to hypoactive pain phenotypes manifesting as congenital insensitivity to pain. Despite multiple descriptions in the literature of pain-associated behaviors in sodium voltage-gated channelopathies, there are no perioperative guidelines in this patient population that can be used to manage pain-associated procedures. Incorporating reported insights from pain literature into an anesthetic plan may improve perioperative patient satisfaction and outcomes. We present a case of a patient with a novel SCN9A mutation (c.3019C>T) who underwent a common surgical procedure and suffered atypical complications. We propose that her SCN9A mutation may have contributed to these sequelae and recommend a greater familiarity with sodium channelopathies-especially those attributed to the SCN9A gene-to improve perioperative management.

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.

Background and aim COVID-19 mRNA vaccines were granted Emergency Use Authorization by the United States FDA in December 2020. Serious adverse events following immunization (AEFI) with COVID-19 vaccines started to be seen by clinicians soon after the vaccines were available to the public. The objective of this study is to report the clinical course of patients with adverse events following COVID-19 vaccination encountered in medical practice. Methods These cases (age range, 18-82 years) were prospectively identified and collected by the authors during formal or informal consultation from January to December 2021. Cases were excluded from further consideration for AEFI with COVID-19 vaccines if an alternative explanation was deemed more likely at the time of consultation. The authors did not solicit medical providers, patients, or the public, nor screen medical records for adverse events following COVID-19 vaccination. This is a descriptive case series; therefore, no statistical analysis was performed. Results We encountered 18 patients with AEFI, nine (50%) males (range, 22-78 years) and nine (50%) females (range, 18-82 years). Clinical presentations involved various organ systems, including cardiovascular (five), nervous system (five), immune system/hematologic (four), skin (one), gastrointestinal (one), pulmonary (one), and infection (two). This paper details their clinical courses. Conclusions We encountered a variety of AEFI, including myocarditis, demyelinating disease, encephalitis, Bell's palsy, burning mouth syndrome, multisystem inflammatory syndrome, immune thrombocytopenia, pneumonitis, colitis, staphylococcal infection, and erythromelalgia. This detailed case series was presented to help clinicians consider a diagnosis of AEFI for patients when no other explanation has been found after a thorough diagnostic evaluation. These described adverse events following COVID-19 vaccination do not imply causality. We hope this descriptive case series leads to further case-control studies from healthcare organizations to explore the possible risks, incidence, and causal relationships of such adverse events following COVID-19 vaccination.

Erythromelalgia (EM) is an uncommon, multifaceted neurovascular pain disorder. The distal extremities are typically affected, with symptoms of overwhelming warmth, burning pain, and erythema. There is a wide range of presentations with varying severities and courses, including occasional flares, intermittent episodes, and chronic debilitating discomfort. In this narrative review, we aim to raise awareness of EM and synthesize the current state of knowledge through exploring pathophysiology, clinical presentation, differential diagnoses, and treatment options for EM.

Thrombocytosis is defined by guidelines as a platelet count of 450 × 103/μL or greater. It most often results from secondary causes and should resolve with treatment of the underlying condition. Primary thrombocytosis in adults is most commonly due to myeloproliferative neoplasms, including essential thrombocythemia. Thrombocytosis may be identified incidentally in asymptomatic patients or when performing blood tests to investigate symptoms or signs that could indicate microvascular conditions (eg, headaches, paresthesia, erythromelalgia), splenomegaly, thrombosis, and hemorrhage, which are presenting features of essential thrombocythemia. A repeat complete blood cell count with differential and peripheral blood smear should be performed to confirm persistent thrombocytosis and assess other blood cell lines for findings suggestive of myeloproliferative neoplasms. Additional testing, including C-reactive protein levels and iron studies with ferritin levels, should be performed based on history and examination findings. If essential thrombocythemia is suspected in patients with persistent thrombocytosis without an identified cause, testing for Janus kinase 2 gene sequence variations should be performed and, if negative, testing for calreticulin and myeloproliferative leukemia gene sequence variations; a bone marrow biopsy should also be performed. The revised International Prognostic Score of Thrombosis for Essential Thrombocythemia should be calculated to stratify thrombosis risk and guide management, including when to use low-dose aspirin and cytoreductive therapy. Cardiovascular risk factors should also be addressed. Hydroxyurea is the first-line agent in cytoreductive therapy. No treatments have been shown to increase survival or prevent progression to myelofibrosis or leukemia in patients with essential thrombocythemia.

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.