Severe case and literature review of primary erythromelalgia: Novel SCN9A gene mutation

Abstract

A 15-year-old female presented with a 13-year history of chronic intermittent painful skin redness and swelling of both feet and lower legs.Her problem began when she started to walk. She had difficulty with, and avoided walking on rough textures and warm surfaces. She also cried when rough textured clothing was placed on the lower legs and feet. At the age of 4, the patient started to have frequent episodes of pain in the lower legs and feet with associated erythema, edema and warmth. Symptoms were present more often during the day and were aggravated by warm temperatures. She found symptomatic relief by immersing her feet in cold water. There were no other reported skin abnormalities or complaints, including joint pains, or constitutional symptoms including weight loss, fever, chills or fatigue. Her family history was negative for similar symptoms or vascular disorders.For the subsequent 9 years, the patient had continued to have similar symptoms intermittently that did not affect her daily activities, school performance, or function. She was later diagnosed with hypothyroidism that was easily controlled with thyroid hormone supplement. Her exam was otherwise unremarkable with the exception of her small stature, placed on the fourth and 37th percentiles respectively for height and weight. The patient was diagnosed with growth hormone deficiency. IGF-1 values were low at 218 ng/ml (range: 228-957). She underwent growth hormone stimulation testing with clonidine, which showed her peak growth hormone response was 0.5 ng/ml (normal peak is greater than 10). A sustained trial of growth hormone replacement was not done at the family's preference.At the age of 13 years, the patient started to have intermittent blood pressure elevations that were worse at the times of her symptoms (highest systolic around 180). She used to receive intravenous nitroprusside that seemed to alleviate her skin symptoms. Her secondary hypertension work-up revealed normal electrolyte panels, urinalysis, renal ultrasound, and cardiac echocardiograms. However, during painful crises, plasma free total metanephrine (350 pg/ml; ref. range: < 206) and plasma free normetanephrine (324 pg/ml; ref. range: < 149) were noted to be increased. Abstract Erythromelalgia is a rare clinical syndrome characterized by intermittent heat, redness, swelling and pain more commonly affecting the lower extremities. Symptoms are mostly aggravated by warmth and are eased by a cold temperature. In some cases, symptoms can be very severe and disabling. Erythromelalgia can be classified as either familial or sporadic, with the familial form inherited in an autosomal dominant manner. Recently, there has been a lot of progress in studying Na(v)1.7 sodium channels (expressed mostly in the sympathetic and nociceptive small-diameter sensory neurons of the dorsal root ganglion) and different mutations affecting the encoding SCN9A gene that leads to channelopathies responsible for some disorders, including primary erythromelalgia. We present a severe case of progressive primar...

Drug‐induced Raynaud's phenomenon: beyond β‐adrenoceptor blockers

“…Surprisingly, two cases of erythromelalgia have been described with bromocriptine, in association with calcium channel blockers [36,37] Selective serotonin re-uptake inhibitors (SSRIs). Contradictory effects of SSRIs on peripheral vasoreactivity have been reported.…”

The Perception and Endogenous Modulation of Pain

“…A study of several members that included several generations of 2 Chinese families with hereditary erythromelalgia revealed that the afflicted individuals had one of 2 missense mutations of the SCN9A gene, which encodes the α -subunit of the Na V 1.7 sodium channel [55]. Since then, genetic investigations of families where erythromelalgia was present have revealed that this disorder was caused by more than 20 different mutations of the SCN9A gene [56–59]. These gain of function mutations lower the threshold to open the channel, and the slow deactivation due to the mutations keeps the channel open for a longer period of time and also increases the current amplitude [54, 59].…”

“…Since then, genetic investigations of families where erythromelalgia was present have revealed that this disorder was caused by more than 20 different mutations of the SCN9A gene [56–59]. These gain of function mutations lower the threshold to open the channel, and the slow deactivation due to the mutations keeps the channel open for a longer period of time and also increases the current amplitude [54, 59]. Consequently, these alterations in the kinetics of the Na V 1.7 channel result in hyperactivity of nociceptors [54, 59].…”

“…These gain of function mutations lower the threshold to open the channel, and the slow deactivation due to the mutations keeps the channel open for a longer period of time and also increases the current amplitude [54, 59]. Consequently, these alterations in the kinetics of the Na V 1.7 channel result in hyperactivity of nociceptors [54, 59]. Gain of function mutations of the Na V 1.7 channel are also the cause of paroxysmal extreme pain disorder (PEPD) which is characterized by unprovoked, paroxysmal pain in the rectal, ocular, or submandibular regions [60].…”

Erythromelalgia Mutation Q875E Stabilizes the Activated State of Sodium Channel Nav1.7

“…The Q875E mutation of Nav1.7 was discovered in a 15-yearold girl suffering from typical progressive symptoms of IEM (20): burning pain in the lower extremities as well as redness and swelling of the feet and lower legs triggered by mild warmth or walking on rough surfaces. We determined, using voltageclamp electrophysiology studies, that Q875E induces gating changes in Nav1.7 typical for IEM mutations; activation is shifted to more hyperpolarized potentials, deactivation is slowed, and time to maximum peak of inward current is shortened.…”