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PubMed This is a summary of 21 peer-reviewed journal articles Updated
Neurology

Biology and Diagnosis: Finding the Cause

At a Glance

Primary erythromelalgia is often caused by a mutation in the SCN9A gene that makes pain-sensing nerves overactive. Diagnosis involves evaluating your symptoms and using blood tests, like a CBC or ANA screening, to rule out secondary causes such as blood disorders or autoimmune diseases.

Understanding the biology of primary erythromelalgia (PEM) helps clarify why your body reacts so intensely to warmth. At its core, PEM is a disorder of how your nerves and blood vessels communicate, leading to a “perfect storm” of pain and redness [1][2].

The Biology: A “Stuck” Pain Switch

The primary cause of PEM is often a malfunction in the NaV1.7 sodium channel, which is controlled by the SCN9A gene [1][3].

Imagine NaV1.7 as a gate on the surface of your pain-sensing nerves. In a healthy person, this gate only opens when there is an actual injury, allowing sodium to enter the nerve and send a pain signal to the brain. In primary erythromelalgia, a gain-of-function mutation makes this gate much easier to open and much harder to close [1][4].

Because the “pain switch” is essentially stuck in the “on” position, your nerves send intense burning signals even in response to mild triggers like slight warmth or the pressure of standing [5][6]. These overactive nerves also signal your blood vessels to widen (vasodilation), which causes the characteristic deep redness and skin warmth [7][2].

Primary vs. Secondary: Why the Difference Matters

It is vital for doctors to determine if your condition is “Primary” or “Secondary” because the treatments are often entirely different.

Primary Erythromelalgia (PEM)

  • Cause: Typically genetic or “idiopathic” (meaning it occurs on its own without an underlying disease) [8].
  • Onset: Often begins in childhood or adolescence [9].
  • Key Feature: Often linked to the SCN9A mutation, though not every patient with PEM will test positive for it [10][11].

Secondary Erythromelalgia

  • Cause: Triggered by another medical condition or a medication [12][8].
  • Myeloproliferative Disorders: Conditions where the bone marrow makes too many blood cells (like polycythemia vera or essential thrombocythemia) are the most common secondary causes [7][13].
  • Autoimmune Diseases: Lupus, psoriatic arthritis, and other connective tissue diseases can trigger symptoms [7][14].
  • Medications: Certain drugs, such as calcium channel blockers (for blood pressure) or cyclosporine, can cause erythromelalgia as a side effect [15][12].

The Diagnostic Evaluation

Because there is no single blood test for erythromelalgia, diagnosis is a process of matching your clinical “triad” of symptoms while systematically ruling out other conditions [16][15].

You do not necessarily have to wait for a specialist to begin this process. Your primary care doctor can often start the evaluation by ordering initial blood tests.

Essential Testing

A thorough evaluation should include:

  1. Complete Blood Count (CBC): This is the most critical test to rule out blood disorders that cause secondary erythromelalgia. Doctors will look closely at your red blood cells and platelet count [12][17].
  2. Autoimmune Screening: Tests like ANA (Antinuclear Antibody) help determine if an underlying rheumatic disease is the cause [16][18].
  3. Medication Review: A detailed look at your prescriptions to see if any are known triggers [12].
  4. Genetic Testing: Recommended especially for those with early-onset symptoms or family members with similar issues [19][17].

Ruling Out Mimics

Your doctor must distinguish erythromelalgia from conditions that look similar but require different care [16][20]:

  • Raynaud’s Phenomenon: Unlike PEM, Raynaud’s usually starts with the skin turning white or blue in response to cold [16].
  • Cellulitis: This is a skin infection. While it causes redness and heat, it is usually only on one limb, is accompanied by fever, and does not come and go with heat triggers [17][20].
  • Complex Regional Pain Syndrome (CRPS): CRPS typically follows an injury and often involves changes in hair or nail growth, which are not typical for PEM [21].

Common questions in this guide

What causes primary erythromelalgia?
Primary erythromelalgia is often caused by a genetic mutation in the SCN9A gene. This mutation affects the NaV1.7 sodium channel, causing pain-sensing nerves to become overactive and essentially getting "stuck" in the on position.
What is the difference between primary and secondary erythromelalgia?
Primary erythromelalgia usually occurs on its own and is often linked to genetics, typically starting in childhood or adolescence. Secondary erythromelalgia is triggered by another medical condition, such as a blood disorder or autoimmune disease, or as a side effect of certain medications.
How do doctors diagnose erythromelalgia?
There is no single test for erythromelalgia, so doctors diagnose it by evaluating your symptoms and ruling out other conditions. Your doctor will likely order a complete blood count (CBC) and autoimmune screening to check for secondary causes.
Should I get genetic testing for erythromelalgia?
Genetic testing for the SCN9A gene may be recommended if your symptoms started early in life or if you have biological family members with similar issues. Your doctor can help determine if this testing is appropriate for your specific situation.

Questions to Ask Your Doctor

Curated prompts to bring to your next appointment.

  1. 1.Have we performed a Complete Blood Count (CBC) recently to specifically check my red blood cells and platelet count for potential myeloproliferative disorders?
  2. 2.Should we run an Antinuclear Antibody (ANA) test to screen for autoimmune causes?
  3. 3.Are any of my current medications, such as calcium channel blockers, known to cause erythromelalgia-like symptoms?
  4. 4.Given my family history and age of onset, is genetic testing for SCN9A appropriate for me?
  5. 5.How do you distinguish my symptoms from Complex Regional Pain Syndrome (CRPS) or cellulitis?

Questions For You

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References

References (21)
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    Pain triangle phenomenon in possible association with SCN9A: A case report.

    Sopacua M, Hoeijmakers JGJ, van der Kooi AJ, et al.

    Molecular genetics & genomic medicine 2022; (10(10)):e2026 doi:10.1002/mgg3.2026.

    PMID: 36114697
  2. 2

    Eltrombopag-associated erythromelalgia in idiopathic thrombocytopenic purpura.

    Perez J, Khouri C, Park S, et al.

    The British journal of dermatology 2022; (186(3)):585-586 doi:10.1111/bjd.20829.

    PMID: 34698373
  3. 3

    Reduction in pain following treatment with ranolazine in primary erythromelalgia: a case report.

    Greco C, Chaumon S, Viallard ML, Bodemer C

    The British journal of dermatology 2018; (179(3)):783-784 doi:10.1111/bjd.16654.

    PMID: 29624653
  4. 4

    Insensitivity to Pain upon Adult-Onset Deletion of Nav1.7 or Its Blockade with Selective Inhibitors.

    Shields SD, Deng L, Reese RM, et al.

    The Journal of neuroscience : the official journal of the Society for Neuroscience 2018; (38(47)):10180-10201 doi:10.1523/JNEUROSCI.1049-18.2018.

    PMID: 30301756
  5. 5

    Secondary erythromelalgia: a tryptophan dietary supplement-induced case associated with elevated 5-hydroxyindoleacetic acid (5HIAA) urinary levels.

    Michelerio A, Derlino F, Brazzelli V, Vassallo C

    International journal of dermatology 2018; (57(1)):83-85 doi:10.1111/ijd.13760.

    PMID: 29152720
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    Pediatric Erythromelalgia and SCN9A Mutations: Systematic Review and Single-Center Case Series.

    Arthur L, Keen K, Verriotis M, et al.

    The Journal of pediatrics 2019; (206()):217-224.e9 doi:10.1016/j.jpeds.2018.10.024.

    PMID: 30416015
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    The Cutaneous Pathology of Erythromelalgia and Its Role in Establishing Critical Clues Regarding Pathogenesis.

    Magro C, Kalomeris T, Guo L

    The American Journal of dermatopathology 2025; (47(3)):184-190 doi:10.1097/DAD.0000000000002912.

    PMID: 39846717
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    Review of primary and secondary erythromelalgia.

    Mann N, King T, Murphy R

    Clinical and experimental dermatology 2019; (44(5)):477-482 doi:10.1111/ced.13891.

    PMID: 30609105
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    Life-threatening hypothermia in a child with primary erythromelalgia.

    Matarneh B, Witman P

    Pediatric dermatology 2022; (39(1)):135-136 doi:10.1111/pde.14866.

    PMID: 34888934
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    Genetic Variants in the SCN9A Gene are Detected in a Minority of Erythromelalgia Patients.

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    Acta dermato-venereologica 2025; (105()):adv42022 doi:10.2340/actadv.v105.42022.

    PMID: 39850993
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    Sporadic Erythromelalgia Associated with a Homozygous Carrier of Common Missense Polymorphism in SCN9A Gene Coding for NaV1.7 Voltage-gated Sodium Channel.

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    Cureus 2019; (11(5)):e4587 doi:10.7759/cureus.4587.

    PMID: 31309012
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    Cyclosporine-induced Erythromelalgia.

    Bibb LA, Winter RP, Leicht SS

    Cureus 2018; (10(10)):e3506 doi:10.7759/cureus.3506.

    PMID: 30648046
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    Erythromelalgia Caused by Polycythemia Vera Combined with Primary Aldosteronism.

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    European journal of case reports in internal medicine 2020; (7(11)):001852 doi:10.12890/2020_001852.

    PMID: 33194862
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    [A clinical case of erythromelalgia in a patient comorbid with antiphospholipid syndrome].

    Kudrjavtseva AA, Meladze AV, Trapeznikova ES, et al.

    Terapevticheskii arkhiv 2026; (97(12)):1018-1022 doi:10.26442/00403660.2025.12.203468.

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    Annales de dermatologie et de venereologie 2015; (142(8-9)):513-8.

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    Primary erythromelalgia: a review.

    Tang Z, Chen Z, Tang B, Jiang H

    Orphanet journal of rare diseases 2015; (10()):127 doi:10.1186/s13023-015-0347-1.

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    Erythromelalgia: a cutaneous manifestation of neuropathy?

    Leroux MB

    Anais brasileiros de dermatologia 2018; (93(1)):86-94 doi:10.1590/abd1806-4841.20187535.

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This page is for informational purposes only and does not replace professional medical advice. Always consult your healthcare provider for proper diagnosis and testing for erythromelalgia.

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