Causes of Erythromelalgia
Erythromelalgia has three main etiological categories: primary (inherited) disease caused by SCN9A gene mutations (5% of cases), secondary disease associated with myeloproliferative disorders (5% of cases), and idiopathic disease with no identifiable cause (the majority of cases). 1
Primary (Inherited) Erythromelalgia
Approximately 5% of patients have a family history with autosomal dominant inheritance 1. The molecular basis involves:
- SCN9A gene mutations encoding the Nav1.7 sodium channel, which is preferentially located in sympathetic ganglia and nociceptive sensory neurons 1
- These are gain-of-function mutations causing channels to open more easily and stay open longer, resulting in prolonged neuronal activation and explaining the disproportionate pain 1
- The mutation leads to hypoexcitability of sympathetic neurons 1
- Not all familial cases link to SCN9A - other genes may be involved, as demonstrated in a 3-generation family without SCN9A variants 1
- Recent evidence shows mutations can occur in alternatively spliced exons (exon 6A) that should be included in genomic testing 2
Secondary Erythromelalgia
Myeloproliferative diseases underlie approximately 5% of cases 1:
- Essential thrombocythemia and polycythemia vera are the primary hematologic associations 1
- These cases are more likely to respond to aspirin due to microvascular involvement 1
- Polycythemia can cause erythromelalgia through secondary erythropoiesis mechanisms 3
Other secondary associations (though less constant) 1:
- Autoimmune conditions - including lupus erythematosus, psoriatic arthritis, and vitiligo 4
- Medications - particularly cyclosporine (a reversible cause) 5
- Peripheral nerve injury - including carpal tunnel syndrome and its surgical interventions 6
Association with Neuropathy
Small and large fiber neuropathy is strongly associated with erythromelalgia, though the causal relationship remains unclear 1:
- Large fiber neuropathy found on EMG/nerve conduction studies in almost 50% of patients 1
- Small fiber neuropathy detected in approximately 90% via thermoregulatory sweat testing 1
- Skin biopsy shows decreased epidermal nerve fiber density in only a minority of cases 1
- Recent pathology studies reveal autonomic denervation of eccrine coils and arteries, mirroring small fiber neuropathy patterns 4
The directionality is uncertain: small fiber neuropathies could precipitate erythromelalgia, or conversely, hyperexcitable Nav1.7 channels and cold water treatment (used for symptom relief) may lead to small fiber neuropathy 1.
Idiopathic Erythromelalgia
The majority of cases have no identifiable underlying cause 1. These are classified as primary (idiopathic) erythromelalgia, though this terminology can be confusing as "primary" is also used for inherited forms.
Clinical Pitfall
The distinction between primary and secondary erythromelalgia does not substantially affect management 1, with the notable exception that myeloproliferative-associated cases respond better to aspirin. Therefore, always screen for myeloproliferative disorders (CBC with differential, JAK2 mutation testing) and obtain a detailed medication history (specifically cyclosporine use) as these represent treatable causes 3, 5.