What causes Erythromelalgia?

What Causes Erythromelalgia?

Erythromelalgia has three main causes: genetic mutations in sodium channels (primary/inherited form), myeloproliferative disorders like polycythemia vera and essential thrombocythemia (secondary form), and idiopathic small fiber neuropathy (sporadic primary form). 1

Primary (Inherited) Erythromelalgia

Genetic mutations account for approximately 5% of cases with a family history, typically following autosomal dominant inheritance patterns. 1

• SCN9A gene mutations are the primary genetic cause, encoding the Nav1.7 sodium channel found in sympathetic ganglia and pain-sensing neurons in dorsal root ganglia. 1
• These are gain-of-function mutations that cause sodium channels to open more easily and remain open longer, leading to excessive and prolonged neuronal firing that explains the severe burning pain during episodes. 1, 2
• The mutations also cause hypoexcitability of sympathetic neurons, contributing to the vascular dysregulation. 1
• Non-SCN9A genetic variants exist - some families with inherited erythromelalgia show no SCN9A mutations, indicating other genes may be involved. 1, 2

Secondary Erythromelalgia

Myeloproliferative disorders are the most common identifiable cause of secondary erythromelalgia, present in approximately 5% of all cases. 1, 2

• Polycythemia vera and essential thrombocythemia are the primary myeloproliferative disorders associated with erythromelalgia, with an estimated 3% incidence in polycythemia vera patients. 1, 2
• The mechanism involves platelet-mediated endothelial injury causing inflammation and transient thrombotic occlusion by platelet aggregates, with thromboxane-mediated platelet activation playing a key pathogenetic role. 2
• Chronic myelogenous leukemia has also been documented as a cause. 3
• Importantly, erythromelalgia symptoms often precede the diagnosis of myeloproliferative disease by a median of 2.5 years, making periodic blood count monitoring essential in all patients. 3, 4

Other secondary causes include:

• Autoimmune conditions such as systemic lupus erythematosus and other rheumatic diseases. 2, 5
• Medications including calcium channel blockers, bromocriptine, ergot derivatives, and pseudoephedrine. 2, 5, 6
• Viral infections. 5

Idiopathic Primary Erythromelalgia with Neuropathy

Small fiber neuropathy is strongly associated with erythromelalgia, found in approximately 90% of patients on thermoregulatory sweat testing. 1, 2

• Large fiber neuropathy is detected on electromyography and nerve conduction studies in almost 50% of patients. 1, 2
• The relationship between neuropathy and erythromelalgia is bidirectional and unclear - small fiber neuropathy may precipitate erythromelalgia, or the underlying disease process may cause both conditions simultaneously. 1, 2
• Skin biopsies typically show decreased epidermal nerve fiber density in only a minority of cases, making them less useful diagnostically. 1

Pathophysiologic Mechanism

Vasodilation of thermoregulatory arteriovenous anastomoses is likely a key factor in the pathophysiology, with endogenous temperature control playing a central role. 1

Critical Clinical Pitfall

Any adult presenting with erythromelalgia requires periodic blood count monitoring because myeloproliferative disorders frequently manifest years after erythromelalgia symptoms begin. 3, 4 An abnormal hemoglobin level, white blood cell count, platelet count, or presence of immature cells should prompt immediate hematologic evaluation, as these findings are not seen in idiopathic erythromelalgia. 3, 4