Burning pain, episodic, typically in the distal extremities, particularly the hands and feet (bilateral, symmetric), triggered by warm stimuli, exercise, standing
'Primary erythermalgia' is an autosomal dominant disorder characterized by childhood onset of episodic symmetrical red congestion, vasodilatation, and burning pain of the feet and lower legs provoked by exercise, long standing, and exposure to warmth. Relief is obtained ... 'Primary erythermalgia' is an autosomal dominant disorder characterized by childhood onset of episodic symmetrical red congestion, vasodilatation, and burning pain of the feet and lower legs provoked by exercise, long standing, and exposure to warmth. Relief is obtained with cold (Michiels et al., 2005). The severity of the disorder may progress with age, and symptoms may extend over a larger body area, such as over the ankles and lower legs, and become constant (Mandell et al., 1977). Waxman and Dib-Hajj (2005) provided a review of primary erythermalgia. Although 'primary' or 'familial erythromelalgia' are sometimes used as alternative terms for primary erythermalgia (Waxman and Dib-Hajj, 2005), secondary erythromelalgia is a distinct acquired disorder associated with thrombocythemia or myeloproliferative disorders. It has relatively late onset and symptoms are caused by platelet aggregation in end-arteriolar circulation, leading to ischemia and symptoms (Michiels and van Joost, 1990). Treatment with aspirin, which irreversibly inhibits platelet cyclooxygenase activity, affords relief from acquired erythromelalgia (Michiels et al., 1984; Drenth et al., 1996). Similarly, acquired erythromelalgia vanishes with lowering the platelet count to normal with chemotherapy (Michiels et al., 1985). van Genderen et al. (1993) emphasized the distinction between hereditary erythermalgia and acquired erythromelalgia. In primary erythermalgia, the burning pain, redness, and warmth of feet and lower legs, with relative sparing of the toes, are easily provoked by warmth and exercise. In contrast, in acquired erythromelalgia the burning pain and red congestion preferentially involves one or more toes or fingers or sole of the forefoot (Michiels and van Joost, 1990). Van Genderen et al. (1993) noted that 3 of the 5 patients reported by Smith and Allen (1938) were not consistent with the diagnosis of primary erythromelalgia because the symptoms were relieved promptly by aspirin, consistent with acquired erythromelalgia. - Small Fiber Neuropathy Small nerve fiber neuropathy (SFNP) is a relatively common disorder of thinly myelinated and unmyelinated nerve fibers characterized clinically by adult onset of neuropathic pain, often of a burning quality, and autonomic symptoms. Affected individuals have reduced intraepidermal nerve fiber density affecting the small diameter nerve fibers; large diameter fibers are spared (summary by Faber et al., 2012).
Mandell et al. (1977) reported a child with primary erythermalgia with onset at age 3 years.
Finley et al. (1988) described a family in which autosomal dominant inheritance of primary erythermalgia was supported by the fact ... Mandell et al. (1977) reported a child with primary erythermalgia with onset at age 3 years. Finley et al. (1988) described a family in which autosomal dominant inheritance of primary erythermalgia was supported by the fact that some males had unaffected daughters and an affected man had an affected son. The proband, a 26-year-old white female, had onset of burning feet while walking at age 9 years. Gradually the frequency of episodes, correlated with heat, increased. Humidity seemed to aggravate the symptoms. Relief of pain was achieved by an electric fan blowing on the feet, by putting the feet into a bucket of ice, or by taking large doses of aspirin. The same family had been reported by Burbank et al. (1966). Finley et al. (1992) provided follow-up of the family reported by Finley et al. (1988). There were 29 affected individuals spanning 5 generations. Onset was in early childhood, as early as the first year of life. Affected individuals reported intermittent pain, redness, and burning sensation of the hands and feet that was triggered by exercise, warm weather, and humidity. The episodes seemed to increase in frequency and severity with age. Medical treatment was unsatisfactory. Herskovitz et al. (1993) described a 31-year-old man with hereditary sensory neuropathy first manifesting at the age of 18 years and with erythermalgia beginning at the age of 21. The burning pain in the feet occurred episodically especially during the spring and summer months, was precipitated by heat, and was associated with redness or purplish discoloration, warmth, and slight swelling of the feet. It was found that amitriptyline, 75 mg daily, provided marked relief of symptoms. The father was thought to be mildly affected on the basis of pes planus and clinical and nerve conduction studies. Although not described as erythromelalgia, the same situation was described by Dyck et al. (1983) in a family with 'burning feet' as the only manifestation of dominantly inherited sensory neuropathy. Their patient required sural nerve biopsy to demonstrate objective neuropathic abnormalities. Michiels et al. (2005) reported a Flemish family in which 10 members spanning 4 generations had autosomal dominant primary erythermalgia. Five patients were available for study. Age at onset ranged from 2.5 to 10 years. Episodes were typically elicited by warmth, exercise, or standing, and relief was provided by cold. Attacks were characterized by moderate to severe painful, red, swollen feet; some patients developed skin lesions resulting from repeated exposure to cold water. - Small Fiber Neuropathy Faber et al. (2012) reported 8 unrelated Dutch Caucasian patients with SFNP, 3 of whom reported similar complaints in family members. All 8 patients complained of pain, with onset ranging from 16 to 68 years of age. Most had onset of pain in the distal extremities, usually the feet, but 2 presented with pain throughout the body before affecting distal limbs. Pain was aggravated by warmth in 3, and relieved by cooling only in 1. One patient initially experienced excruciating pain in the teeth/jaw triggered by cold and heat, and pain behind the eyes, which was not relieved by multiple tooth extractions. Most patients reported persistence of the pain or burning over several years to involve the hands, mouth, or body. Seven of 8 patients had autonomic symptoms, including orthostatic dizziness, palpitations, dry eyes, and dry mouth. Two patients had significant gastrointestinal complaints. All had a decrease in skin small diameter nerve fibers below the fifth percentile for controls. All patients had some sort of distally altered temperature sensation.
In affected members of a Chinese family with primary erythermalgia linked to chromosome 2q and in a sporadic patient, Yang et al. (2004) identified mutations in the SCN9A gene (L858H, 603415.0001; I848T, 603415.0002).
In 5 affected ... In affected members of a Chinese family with primary erythermalgia linked to chromosome 2q and in a sporadic patient, Yang et al. (2004) identified mutations in the SCN9A gene (L858H, 603415.0001; I848T, 603415.0002). In 5 affected members of a Flemish family with primary erythermalgia, Michiels et al. (2005) identified a heterozygous mutation in the SCN9A gene (603415.0003). In 17 affected members of the family reported by Finley et al. (1992), Dib-Hajj et al. (2005) identified a heterozygous mutation in the SCN9A gene (603415.0004). - Small Fiber Neuropathy In 8 (28.6%) of 28 patients with biopsy-confirmed small fiber neuropathy, Faber et al. (2012) identified a heterozygous gain-of-function mutation in the SCN9A gene (see, e.g., 603415.0023-603415.00025). In vitro functional expression studies in HEK293 cells and dorsal root ganglion neurons showed that all the mutations caused hyperexcitability of dorsal root ganglion neurons, either by impairing slow inactivation, depolarizing slow and fast inactivation, or causing enhanced resurgent currents and increasing the number of action potentials evoked by depolarization. Faber et al. (2012) postulated that increased sodium channel activity may also trigger axonal degeneration via calcium-importing reverse sodium-calcium exchange. None of the mutations were the same as those found in primary erythermalgia or paroxysmal extreme pain disorder (PEPD; 167400). The findings expanded the phenotype associated with SCN9A mutations.