Erythermalgia, Primary

A number sign (#) is used with this entry because primary erythermalgia is caused by heterozygous mutation in the SCN9A gene (603415), encoding a voltage-gated sodium channel, on chromosome 2q24.

Small fiber neuropathy can also be caused by heterozygous mutation in the SCN9A gene.

Description

'Primary erythermalgia' is an autosomal dominant disorder characterized by childhood or adolescent 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).

Clinical Features

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.

Devigili et al. (2014) reported a woman, her sister, and their mother with small fiber neuropathy manifest as paroxysmal intense neuropathic itching and flushing, mainly triggered by warmth and spicy food. The proband developed itching symptoms at age 15 years, and the itch episodes were followed by prolonged burning pain in her thirties. There were no cardiovascular autonomic symptoms. The mother and sister had onset of itching as adults; they too described burning pain and flushing after the itch attacks. All 3 patients showed preferential involvement of the proximal arms, trunk, and neck, and all had impaired superficial sensation in the affected body areas. Skin biopsy in 2 patients showed reduced intraepithelial nerve fiber density. Treatment with pregabalin resulted in excellent relief.

Clinical Management

A great variety of therapeutic options have been tested for primary erythermalgia, with mixed results (Davis et al., 2000). D'Angelo et al. (1992) claimed success with continuous epidural infusion of various combinations of Bupivacaine and morphine.

In 4 unrelated patients with genetically confirmed primary erythermalgia, Goldberg et al. (2012) found that treatment with an oral compound (XEN402) that blocks the SCN9A channel significantly attenuated constant or induced pain compared to placebo. The findings underscored the use of rare genetic disorders to develop targeted therapeutics.

Mapping

Drenth et al. (2001) identified 5 kindreds with multiple cases of primary erythermalgia. By a genomewide search in the largest of these kindreds, they detected strong evidence for linkage of the disorder to markers from chromosome 2q. The highest lod score was obtained with D2S2330; maximum lod = 6.51. Analysis of recombination events identified markers D2S2370 and D2S1776 as flanking the locus on 2q31-q32. This defined a critical interval of 7.94 cM that harbors the primary erythermalgia gene. Affected members within the additional families also shared a common haplotype on 2q31-q32.

In a Chinese family segregating primary erythermalgia, Yang et al. (2004) found linkage of the disorder to a 5.98-cM region between D2S2370 and D2S2345.

Molecular Genetics

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., 603415.0023-603415.0025). 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.

In a woman, her sister, and their mother with small fiber neuropathy manifest as paroxysmal itching, Devigili et al. (2014) identified a heterozygous missense mutation in the SCN9A gene (I739V; 603415.0027).

Pathogenesis

Cummins et al. (2004) demonstrated by functional expression studies that L858H and I848T mutant SCN9A channels were activated at more negative potentials and approximately 10-fold and 3-fold slower inactivation kinetics, respectively, than wildtype channels. The findings indicated that the mutant channel confers hyperexcitability to peripheral sensory and sympathetic neurons, contributing to symptom production in erythermalgia.

Genotype/Phenotype Correlations

Han et al. (2012) found that 2 patients with small fiber neuropathy without prominent autonomic symptoms reported by Faber et al. (2012) carried the same heterozygous R185H mutation in the SCN9A gene (603415.0026). Three additional patients with small fiber neuropathy and severe autonomic dysfunction carried a heterozygous I739V mutation (603415.0027). In vitro functional expression assays showed that the R185H mutation rendered dorsal root ganglion neurons hyperexcitable and enhanced resurgent currents, but did not produce detectable changes in sympathetic neurons of the superior cervical ganglion. The I739V mutation impaired channel slow inactivation in both dorsal root ganglion cells and sympathetic neurons of the superior cervical ganglion, and rendered dorsal root ganglion neurons hyperexcitable. In contrast to R185H, I739V rendered superior ganglion neurons hypoexcitable. Han et al. (2012) suggested that the effects of the mutation on 2 different types of neurons correlated with the symptoms of pain and the variable autonomic dysfunction.

History

Erythromelalgia was first described and named by S. Weir Mitchell (1878).

Cross (1962) described a family in which members of 4 generations had renal disease, and the males had erythromelalgia as well. Two females had erythromelalgia without renal disease, and 1 female who was thought not to have renal disease had a son with both erythromelalgia and renal disease. It appeared that the renal disease was more severe in the males than in the females. It turned out that the family of Cross (1962) in fact had Fabry disease (301500), a diagnosis first made by David Wise, who visited Cross and studied the family in 1962 (Cross, 1989). The family and a second one from Toronto were included in the study of Opitz et al. (1965).