Advanced Genetic Testing Comes to the Pain Clinic to Make a Diagnosis of Paroxysmal Extreme Pain Disorder

Table 1

Clinical features, triggers, and mutations of sodium channel pain syndromes. Differences between small nerve fiber neuropathy, inherited erythromelalgia, and paroxysmal extreme pain disorder. The mutations listed are meant to demonstrate phenotypic variability in single mutations; this is not an exhaustive list of mutations.

Pain syndromes	Small nerve fiber neuropathy (SFN)	Inherited erythromelalgia (IEM)	Paroxysmal extreme pain disorder (PEPD)
Clinical features	Cold, burning or electric-like pain, tingling or a pins-and-needles sensation, allodynia and hyperesthesia in feet, and distal extremities [10].	Burning pain, swelling, and skin redness in the distal extremities (feet and, less frequently, the hands). Some individuals have allodynia and hyperalgesia [19, 20].	Skin redness and warmth, severe pain in various parts of the body, typically in the lower part of the body, especially around the rectum, but also can be in head and face, especially the eyes and jaw [16].; Tonic nonepileptic seizures, flushing, watering of eyes or nose, hypersalivation, and weakness (hours to day) related to site of pain [17].
Triggers	None known [10].	Precipitated by mild warmth, standing, exercise, alcohol, and other vasodilating agents, relieved by cooling [16].	Trauma, childbirth, defecation, eating, taking medications, and cold [13].
Duration	Persistent [10].	Occurs multiple times per day and can become constant [4].	Seconds to hours [16].
SCN9A/1.7	c.554G>A, p.R185H [14]; c.684C>G, p.I228M [14]; c.1867G>A, p.D623N [14]; c.2159T>A, p.I720K [14]; c.2215A>G, p.I739V [21]; c.2794A>C, p.M932L [14]; c.2971G>T, p.V991L [14]; c.4596G>A, p.M1532I [14]	c.29A>G, p.Q10R [22, 23]; p.L245V [24]; c.406A>G, p.I136V [25]; c.647T>C, p.F216S [19]; c.721T>A, p.S241T [5]; c.1185C>A, p.N395K [19]; c.2468T>G, p.L823R [26]; c.2543T>C, p.I848T [3]; c.2573T>A, p.L858H [3]; c.2572C>T, p.A863P [27]; c.2623C>G, p.Q875E [28]; c.4345T>G, p.F1449V [4]	c.2986C>T, p.R996C [13]; c.3892G>T, p.V1298F [13]; c.3893T>A, p.V1298D [13]; c.3895G>T, p.V1299F [13]; c.4382T>C, p.I1461T [13]; p.F1462V [13]; c.4391C>T, p.T1464I [13]; G1607K [29]; c.4835T>C, p.L1612P [30]; c.4880T>A, p.M1627K [13]
SCN10A/1.8	c.1661T>C, p.L554P [31]; c.3910G>A, p.A1304T [31]; c.4568G>A, p.C1523Y [31]; c.4984G>A, p.G1662S [32]; c.5116A>G, p.I1706V [33]
SCN11A/1.9	c.1142T>C, p.I381T [34]; c.3473T>C, p.L1158P [34]