Primary erythromelalgia (ORPHA:90026)
Primary erythermalgia is characterized by intermittent attacks of red, warm, painful burning extremities. It spontaneously arises during early childhood and adolescence in the absence of any detectable underlying disorder.
Epidemiology
It may occur sporadically or as an inherited disease, but less than 30 kindreds with familial primary erythermalgia have been reported in the literature so far.
Clinical description
Clinically, it is characterized by episodes of symmetrical red congestion, vasodilatation, and burning pain in both the feet and lower legs provoked by exercise, long standing and exposure to warmth that usually compels patients not to wear socks or closed shoes even in winter and to search for relief by immersion of feet in ice-cold water.
Etiology
The gene for autosomal dominant erythermalgia, SCN9a, is located on chromosome 2q. SCN9a is a 26 exon gene encoding the voltage-gated sodium channel alpha subunit Nav1.7. This channel is found mainly in dorsal root ganglia and sympathetic ganglia neurons. All mutations detected so far are missense and lead to a gain of function by lowering the activation threshold of Nav1.7, resulting in hyperexcitability of pain signaling neurons.
Diagnostic methods
The molecular diagnosis relies on sequencing of all coding exons of SCN9a. All mutations so far detected are private mutations (i.e. all families have their own unique mutations). Clinical diagnostic criteria are: attacks of local red congestion and vasodilation with increased local skin temperature and burning pain; a bilateral and symmetric distribution of symptoms; onset and aggravation of symptoms in response to distress, exercise and heat; relief provided by cold, rest and elevation of the affected extremities; the absence of a primary or associated disease; the condition being refractory to treatment.
Differential diagnosis
Differential diagnosis includes erythromelalgia and secondary erythermalgia. In erythromelalgia, the burning pain and red congestion are usually unilateral or asymmetrically distributed with preferential involvement of one or more toes, the forefoot soles or fingertips. The platelet count is always elevated > 400 x 10 9/L, and aspirin relieves symptoms. Secondary erythermalgia is acquired, mostly develops at a later age and is invariably linked with the use of drugs or underlying disease (vasculitis, neuropathy). In contrast to erythromelalgia, the platelet count in both secondary and inherited primary erythermalgia is normal.
Genetic counseling
In familial cases, the disorder is inherited as an autosomal dominant trait. Genetic counselling should be adapted according to the family history of the patient and affected parents should be informed of the 50% risk of reoccurrence.
Management and treatment
Analgesic therapy for the neuropathic pain is problematic. However, voltage-gated sodium channels are potential targets for local anesthetics (lidocaine), systemic antiarrhythmics (mexiletine) and antiepileptic drugs such as phenytoin. In several patients, oral mexiletine (600 mg daily) rapidly improved symptoms suggesting that blocking the voltage-gated sodium channels is a valid therapeutic option.
Prognosis
Prognosis depends on the severity of the disease. In severe cases the burning pain leads to an urgent need to cool the affected extremities. As a consequence, the affected skin from the limb (mostly the feet) can macerate resulting in skin fissures, skin infections and, possibly life-threatening sepsis. Amputation may be required in case of repeated infections. The very severe burning pain can lead to profound psychological consequences and depression.

                            Last update: 
                            January 2007


                            - Expert reviewer(s): 
                            Pr J.P.H. [Joost] DRENTH