Structural basis for severe pain caused by mutations in the S4-S5 linkers of voltage-gated sodium channel NaV1.7.

Gain-of-function mutations in voltage-gated sodium channel NaV1.7 cause severe inherited pain syndromes, including inherited erythromelalgia (IEM). The structural basis of these disease mutations, however, remains elusive. Here, we focused on three mutations that all substitute threonine residues in the alpha-helical S4-S5 intracellular linker that connects the voltage sensor to the pore: NaV1.7/I234T, NaV1.7/I848T, and NaV1.7/S241T in order of their positions in the amino acid sequence within the S4-S5 linkers. Introduction of these IEM mutations into the ancestral bacterial sodium channel NaVAb recapitulated the pathogenic gain-of-function of these mutants by inducing a negative shift in the voltage dependence of activation and slowing the kinetics of inactivation. Remarkably, our structural analysis reveals a common mechanism of action among the three mutations, in which the mutant threonine residues create new hydrogen bonds between the S4-S5 linker and the pore-lining S5 or S6 segment in the pore module. Because the S4-S5 linkers couple voltage sensor movements to pore opening, these newly formed hydrogen bonds would stabilize the activated state substantially and thereby promote the 8 to 18 mV negative shift in the voltage dependence of activation that is characteristic of the NaV1.7 IEM mutants. Our results provide key structural insights into how IEM mutations in the S4-S5 linkers may cause hyperexcitability of NaV1.7 and lead to severe pain in this debilitating disease.

Erythromelalgia in a patient with feet erythema and cyanosis.

Erythromelalgia is a rare disease characterised by a triad of a clinical syndrome of redness, warmth and painful extremities. We present the case of a male adolescent with no prior medical history who presents to our family medicine clinic with a 3-month history of bilateral feet erythema followed by episodes of cyanosis in bilateral toes. Given his history, the findings on clinical examination, and the lack of any pathology on the diagnostic testing, the patient is diagnosed with erythromelalgia. He is then counselled on both pharmacological and non-pharmacological treatments for his condition and is discharged on non-pharmacological treatment options such as leg elevation, cooling with a fan and limiting exposure to heat. The patient is also advised to perform an annual complete blood count given the association of erythromelalgia with myeloproliferative disorders.

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.

[Functional vascular acrosyndromes]. / Funktionelle akrale Durchblutungsstörungen.

Vascular acrosyndromes are characterized by sparse, uniform clinical manifestations and a variety of possible pathomechanisms. The present article focuses on the functional entities. Raynaud phenomenon is based on cold- or stress-induced vasospasms of acral arteries. It is defined by the color changes of the skin, in the typical case white-blue-red (tricolore). The long fingers are most commonly affected. The etiology is unknown, and the pathophysiology is poorly understood. A distinction is made between primary and a secondary Raynaud phenomenon. The most important underlying diseases include collagenosis, primarily systemic sclerosis, and malignancies; furthermore, medications and drugs may promote vasospasm. Treatment is aimed at preventing or breaking the vasospasm, but has been only partially effective in doing so. Acrocyanosis is a vasospastic dystonic acral disorder that results in permanent reddish-livid discoloration, especially of the hands and feet. Secondary forms occur in collagenosis, malignancies, and myelodysplastic syndromes. The etiology and pathophysiology are virtually unknown. Targeted pharmacological intervention is not possible. Unlike all other vascular acrosyndromes, erythromelalgia is characterized by hyperemia. The primary form is a genetic sodium channelopathy, while secondary forms include malignancies, connective tissue diseases, and myelodysplastic syndromes. The symptoms are often distressing and disabling. Therapy requires a multimodal approach that includes both nonpharmacological and pharmacological strategies. Close interdisciplinary collaboration is essential for the management of this disease.

Hormone replacement therapy-induced pain and redness of the feet.

We report the first case, to our knowledge, of a patient who developed erythromelalgia after receiving oestrogen-progestin replacement therapy (Femoston). The patient had complete remission after taking glycyrrhizin and pregabalin for 3 months. This case expands the spectrum of erythromelalgia and provides a therapeutic option.

[Paroxysmal vascular acrosyndromes: Practical approach to diagnosis and management]. / Acrosyndromes vasculaires paroxystiques : démarche pratique de diagnostic et de prise en charge.

Paroxysmal vascular acrosyndromes are related to a peripheral vasomotor disorder and presented as paroxysmal color changes of the fingers. They include primary Raynaud's phenomenon (RP), which is the most common, secondary RP and erythermalgia. They are to be distinguished from non-paroxysmal acrosyndromes such as acrocyanosis and chilblains, which are very frequent and often associated with RP, digital ischemia and necrosis, spontaneous digital hematoma and acrocholosis. The challenge of a consultation for a vascular acrosyndrome is to make positive diagnosis through history and clinical examination, and to specify its nature, to prescribe complementary exams. In any patient consulting for RP, assessment includes at least an antinuclear antibody test and capillaroscopy. For erythermalgia, a blood count and even a search for JAK2 mutation are required. A thryoid-stimulating hormon assay, a test for antinuclear antibodies, and a search for small fiber neuropathy are also performed. The treatment of RP is essentially documented for secondary RP where calcium channel blockers are indicated in first line, and iloprost in severe cases. The treatment of primitive erythermalgia is based on sodium channel blockers such as mexiletine or lidocaine infusions, and on drugs effective on neuropathic pain, such as gabapentin or amitryptiline, in case of erythermalgia associated with small fiber neuropathy. The treatment of erythermalgia associated with myeloproliferative syndromes is based on etiological treatment and aspirin.

If your ears are burning we must be talking about red ear syndrome: A brief report.

Red Ear Syndrome is an uncommon disorder that can affect all age groups. It is frequently referred to Dermatology as it can present similarly to erythromelalgia. Although the exact pathophysiology is unknown, a common hypothesis suggests a shared pathophysiological background with migraine due to their well-known association. Currently, there are no established treatment guidelines. Delays in accurate diagnosis and commencing optimal treatment can significantly negatively impact on a patients quality of life. We discuss the clinical presentation and response to treatment of a case of Red Ear Syndrome in an 8-year-old boy.

Intravenous Ketamine Infusion as an Adjunctive Pain Treatment for Erythromelalgia: A Pediatric Case Report.

Erythromelalgia is a rare neurovascular pain condition characterized by erythematous, warm, and painful extremities. Symptoms are exacerbated by heat and relieved by cooling. Treatment is challenging and focuses on symptom control with various medications and therapies targeted toward eliminating destructive cooling behaviors. This pediatric case was notable because the patient's pain dramatically improved after a short-term, low-dose ketamine infusion, allowing her to finally wean off detrimental cooling practices of her extremities. Intravenous ketamine has rarely been described as an adjunctive analgesic strategy for erythromelalgia.

Red scrotum syndrome: An update on clinicopathologic features, pathogenesis, diagnosis, and management.

The genital skin may be affected by a variety of dermatoses, be it inflammatory, infectious, malignant, idiopathic, or others. The red scrotum syndrome is characterized by persistent erythema of the scrotum associated with a burning sensation, hyperalgesia, and itching. Its cause is unknown, but proposed mechanisms include rebound vasodilation after prolonged topical corticosteroid use and localized erythromelalgia. The condition is chronic, and treatment is often difficult. Here we review the etiology, the physical and histopathologic findings, and the management of this condition. We also describe related conditions such as red scalp syndrome, red ear syndrome, and red vulva syndrome. Finally, we summarize the different cases reported in the literature and discuss the features that help in the differentiation of red scrotum syndrome from its mimickers.

Cutaneous manifestations of small fibre polyneuropathy.

BACKGROUND: 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. OBJECTIVE: The objective of this study was to characterize dermatologic manifestations in patients with SFN. METHODS: 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). RESULTS: 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. CONCLUSION: SFN has a wide range of clinical features in which the skin is affected, with characteristic findings affecting the extremities.

Life-threatening hypothermia in a child with primary erythromelalgia.

Primary erythromelalgia is a rare autosomal-dominant condition due to pathogenic variant in the SCN9A gene, characterized by childhood onset of excruciating pain, redness, and warmth of acral sites. Patients often resort to ice water baths and other cooling measures to manage the discomfort. Hypothermia is a rare complication, reported only twice previously. We report a child with primary erythromelalgia due to a confirmed pathogenic variant admitted with life-threatening hypothermia. Although the overuse of cooling mechanisms may have contributed, we postulate that the SCN9A mutation may lead to thermodysregulation and make patients with primary erythromelalgia particularly susceptible to this complication.

Successful treatment of knee erythromelalgia with topical oxymetazoline.

Erythromelalgia is an infrequent syndrome with a profound impact on quality of life. Its management is usually challenging and multiple treatments have been reported with variable response rates. To the best of our knowledge, we present the first case of erythromelalgia successfully treated with topical oxymetazoline.