Erythromelalgia

Written by: Dr Jeremy Steinberg – created: 12 March 2023; last modified: 23 March 2023

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Erythromelalgia
Inheritance	Primary disease: Autosomal dominant
Genetics	Primary disease: SCN9A gain of function heterozygous pathogenic variant

Primary erythromelalgia is a genetic pain condition that is caused by an autosomal dominant mutation in the SCN9A gene. It is a type of sodium channelopathy. Secondary erythromelalgia occurs in older people and is associated with certain conditions like myeloproliferative disorders.

Classification

Key differences between primary and secondary erythromelalgia

Parameter	Primary	Secondary
Gene involved	SCN9A gene	None identified
Disease association	Not applicable	Multiple disease associations
Distribution	Symmetrical distribution more likely	Asymmetrical distribution more likely
Age of onset	Younger age of onset	Older age of onset
Treatment	Standard treatment plus targeted treatment (e.g. mexilitine, novel selective Nav1.7 modulators in trials)	Standard treatment plus diagnosis and treatment of associated disease

The primary form of the disease is related to the other two SCN9A neuropathic pain syndromes: small fibre neuropathy and paroxysmal extreme pain disorder.

Aetiology

Primary erythromelalgia is caused by a gain of function mutation in the SCN9A gene

Secondary erythromelalgia has the following associated conditions

• Haematological disease: Polycythaemia vera, Essential thrombocythaemia, Idiopathic thrombocytopenia, Leukaemia, Systemic macrocytosis
• Medications: Iodine contrast, Calcium channel blockers (e.g. verapamil, nifedipine), Bromocriptine
• Rheumatological: Systemic lupus erythematosus, Rheumatoid arthritis, Sjogren syndrome, Vasculitis, Gout.
• Neoplasia: Primary colon or breast carcinoma, Paraneoplastic, Subcutaneous panniculitis-like T-cell lymphoma, Astrocytoma, Thymoma
• Toxins: mercury poisoning

Clinical Features

Patients complain of red or purple, swollen, burning hands and feet that is aggravated by warmth and exercise. The feet are more commonly affected then hands. These episodes usually occur in the evening or at night. Affected individuals may fail to notice or mention the redness especially if it only affects the feet. The symptoms are typically bilateral. Manifestations of this disorder may vary significantly within a family.

SCN9A-EM usually begins in childhood or adolescence, but in some families, it has been identified in infants. While rare, later onset (age >20 years) has been reported in some individuals and families. Initially, the symptoms involve the soles of the feet and hands, but with time, the lower legs and arms may become affected. In advanced cases, symptoms may occur many times a day and persist for hours, particularly at night or become constant and unremitting.

Episodes are typically triggered by exposure to warmth and are relieved by cold. Other less consistent triggering factors include exercise, tight shoes, wearing socks, alcohol, spicy foods, and other vasodilating agents. Some patients have allodynia and hyperalgesia. This can affect sleep and normal activities, and even wearing shoes and socks.

Neurologic examination is typically normal, although reduced ankle reflexes and decreased distal sensation can be seen. Skin biopsy of individuals with erythromelalgia shows nonspecific thickening of blood vessel basement membrane, perivascular edema and mononuclear infiltrate, and reduced density of the autonomic nerve plexuses.

Differential Diagnosis

• Neuropathies: Diabetes mellitus, alcoholism, HIV, neurofibromatosis, Multiple sclerosis, Small fibre neuropathies. Patients may have burning pain but are less likely to have redness, warmth, heat intolerance or relief with cooling.
• Complex Regional Pain Syndrome. The condition may be indistinguishable in the early stages however CRPS is more likely to be unilateral and occur following trauma.
• Peripheral Vascular Disease
• Raynaud's phenomenon
• Fabry disease
• Other genetic neuropathic pain conditions: TRPA1, SCN10A, and SCN11A familial episodic pain syndromes

Treatment

Non pharmacological: Wear open toed shoes or have uncovered feet and stay in cool environments. Swimming for cooling of the limbs. Avoid triggers. Cool the extremities.

Medication: Mexiletine in primary disease. Topical capsaicin may help but can increase pain. SSRIs, anticonvulsants, calcium channel blockers, TCAs, gabapentin, carbamazepine.

For secondary erythromelalgia associated with essential thrombocythaemia, aspirin can relieve pain for up to several days. Other secondary causes and primary disease do not have the same response.

See Also

GeneReviews - SCN9A Pain Syndromes

Resources

Erythromelalgia - Mann 2018.pdf - 171 KB (f)

Literature Review

Literature Review

Reviews from the last 7 years: review articles, free review articles, systematic reviews, meta-analyses, NCBI Bookshelf

Articles from all years: PubMed search, Google Scholar search.

TRIP Database: clinical publications about evidence-based medicine.

Other Wikis: Radiopaedia, Wikipedia Search, Wikipedia I Feel Lucky, Orthobullets,