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Primary erythromelalgia

MedGen UID:
8688
Concept ID:
C0014805
Disease or Syndrome
Synonyms: Erythermalgia, primary; SCN9A-Related Inherited Erythromelalgia
SNOMED CT: Primary erythromelalgia (403390002); Erythromelalgia Type II (403390002)
Modes of inheritance:
Autosomal dominant inheritance
MedGen UID:
141047
Concept ID:
C0443147
Intellectual Product
Source: Orphanet
A mode of inheritance that is observed for traits related to a gene encoded on one of the autosomes (i.e., the human chromosomes 1-22) in which a trait manifests in heterozygotes. In the context of medical genetics, an autosomal dominant disorder is caused when a single copy of the mutant allele is present. Males and females are affected equally, and can both transmit the disorder with a risk of 50% for each child of inheriting the mutant allele.
 
Gene (location): SCN9A (2q24.3)
 
Monarch Initiative: MONDO:0007571
OMIM®: 133020
Orphanet: ORPHA90026

Disease characteristics

Excerpted from the GeneReview: SCN9A Neuropathic Pain Syndromes
SCN9A neuropathic pain syndromes (SCN9A-NPS) comprise SCN9A erythromelalgia (EM), SCN9A paroxysmal extreme pain disorder (PEPD), and SCN9A small fiber neuropathy (SFN). SCN9A-EM is characterized by recurrent episodes of bilateral intense, burning pain, and redness, warmth, and occasionally swelling. While the feet are more commonly affected than the hands, in severely affected individuals the legs, arms, face, and/or ears may be involved. SCN9A-PEPD is characterized by neonatal or infantile onset of autonomic manifestations that can include skin flushing, harlequin (patchy or asymmetric) color change, tonic non-epileptic attacks (stiffening), and syncope with bradycardia. Later manifestations are episodes of excruciating deep burning rectal, ocular, or submandibular pain accompanied by flushing (erythematous skin changes). SCN9A-SFN is characterized by adult-onset neuropathic pain in a stocking and glove distribution, often with a burning quality; autonomic manifestations such as dry eyes, mouth, orthostatic dizziness, palpitations, bowel or bladder disturbances; and preservation of large nerve fiber functions (normal strength, tendon reflexes, and vibration sense). [from GeneReviews]
Authors:
Fuki M Hisama  |  Sulayman D Dib-Hajj  |  Stephen G Waxman   view full author information

Additional descriptions

From OMIM
'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).  http://www.omim.org/entry/133020
From MedlinePlus Genetics
Erythromelalgia is a condition characterized by episodes of pain, redness, and swelling in various parts of the body, particularly the hands and feet. These episodes are usually triggered by increased body temperature, which may be caused by exercise or entering a warm room. Ingesting alcohol or spicy foods may also trigger an episode. Wearing warm socks, tight shoes, or gloves can cause a pain episode so debilitating that it can impede everyday activities such as wearing shoes and walking. Pain episodes can prevent an affected person from going to school or work regularly.

The signs and symptoms of erythromelalgia typically begin in childhood, although mildly affected individuals may have their first pain episode later in life. As individuals with erythromelalgia get older and the disease progresses, the hands and feet may be constantly red, and the affected areas can extend from the hands to the arms, shoulders, and face, and from the feet to the entire legs.

Erythromelalgia is often considered a form of peripheral neuropathy because it affects the peripheral nervous system, which connects the brain and spinal cord to muscles and to cells that detect sensations such as touch, smell, and pain.  https://medlineplus.gov/genetics/condition/erythromelalgia

Clinical features

From HPO
Erythromelalgia
MedGen UID:
8687
Concept ID:
C0014804
Disease or Syndrome
Recurrent episodes of redness, burning pain, and warmth of the extremities following exposure to heat or exercise with symptoms predominantly involving the feet.
Pain
MedGen UID:
45282
Concept ID:
C0030193
Sign or Symptom
An unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damage.
Myalgia
MedGen UID:
68541
Concept ID:
C0231528
Sign or Symptom
Pain in muscle.
Jaw pain
MedGen UID:
451005
Concept ID:
C0236000
Sign or Symptom
An unpleasant sensation characterized by physical discomfort (such as pricking, throbbing, or aching) localized to the jaw.
Palpitations
MedGen UID:
14579
Concept ID:
C0030252
Finding
A sensation that the heart is pounding or racing, which is a non-specific sign but may be a manifestation of arrhythmia.
Constipation
MedGen UID:
1101
Concept ID:
C0009806
Sign or Symptom
Infrequent or difficult evacuation of feces.
Diarrhea
MedGen UID:
8360
Concept ID:
C0011991
Sign or Symptom
Abnormally increased frequency (usually defined as three or more) loose or watery bowel movements a day.
Abnormal autonomic nervous system physiology
MedGen UID:
8511
Concept ID:
C0013363
Disease or Syndrome
A functional abnormality of the autonomic nervous system.
Keratoconjunctivitis sicca
MedGen UID:
9620
Concept ID:
C0022575
Disease or Syndrome
Dryness of the eye related to deficiency of the tear film components (aqueous, mucin, or lipid), lid surface abnormalities, or epithelial abnormalities. Keratoconjunctivitis sicca often results in a scratchy or sandy sensation (foreign body sensation) in the eyes, and may also be associated with itching, inability to produce tears, photosensitivity, redness, pain, and difficulty in moving the eyelids.
Xerostomia
MedGen UID:
22735
Concept ID:
C0043352
Disease or Syndrome
Dryness of the mouth due to salivary gland dysfunction.
Hyperhidrosis
MedGen UID:
5690
Concept ID:
C0020458
Finding
Abnormal excessive perspiration (sweating) despite the lack of appropriate stimuli like hot and humid weather.
Pruritus
MedGen UID:
19534
Concept ID:
C0033774
Sign or Symptom
Pruritus is an itch or a sensation that makes a person want to scratch. This term refers to an abnormally increased disposition to experience pruritus.
Blurred vision
MedGen UID:
91020
Concept ID:
C0344232
Finding
Lack of sharpness of vision resulting in the inability to see fine detail.

Term Hierarchy

CClinical test,  RResearch test,  OOMIM,  GGeneReviews,  VClinVar  
  • CROGVPrimary erythromelalgia
Follow this link to review classifications for Primary erythromelalgia in Orphanet.

Professional guidelines

PubMed

Wang Z, Wang H, Lee M, Lin MY, Lin Z
J Am Acad Dermatol 2022 Sep;87(3):698-700. Epub 2022 Apr 21 doi: 10.1016/j.jaad.2022.04.020. PMID: 35461983
Cregg R, Cox JJ, Bennett DL, Wood JN, Werdehausen R
Br J Pharmacol 2014 Oct;171(19):4455-63. Epub 2014 Aug 29 doi: 10.1111/bph.12788. PMID: 24866741Free PMC Article

Recent clinical studies

Etiology

Wang Z, Wang H, Lee M, Lin MY, Lin Z
J Am Acad Dermatol 2022 Sep;87(3):698-700. Epub 2022 Apr 21 doi: 10.1016/j.jaad.2022.04.020. PMID: 35461983
Klein-Weigel PF, Volz TS, Richter JG
Vasa 2018 Feb;47(2):91-97. Epub 2018 Jan 4 doi: 10.1024/0301-1526/a000675. PMID: 29299961
Vargas-Alarcon G, Alvarez-Leon E, Fragoso JM, Vargas A, Martinez A, Vallejo M, Martinez-Lavin M
BMC Musculoskelet Disord 2012 Feb 20;13:23. doi: 10.1186/1471-2474-13-23. PMID: 22348792Free PMC Article
Ørstavik K, Mørk C, Kvernebo K, Jørum E
Pain 2004 Aug;110(3):531-538. doi: 10.1016/j.pain.2004.03.030. PMID: 15288393
Mork C, Asker CL, Salerud EG, Kvernebo K
J Invest Dermatol 2000 Apr;114(4):643-6. doi: 10.1046/j.1523-1747.2000.00944.x. PMID: 10733667

Diagnosis

Mann N, King T, Murphy R
Clin Exp Dermatol 2019 Jul;44(5):477-482. Epub 2019 Jan 4 doi: 10.1111/ced.13891. PMID: 30609105
Leroux MB
An Bras Dermatol 2018 Jan-Feb;93(1):86-94. doi: 10.1590/abd1806-4841.20187535. PMID: 29641704Free PMC Article
Klein-Weigel PF, Volz TS, Richter JG
Vasa 2018 Feb;47(2):91-97. Epub 2018 Jan 4 doi: 10.1024/0301-1526/a000675. PMID: 29299961
Tang Z, Chen Z, Tang B, Jiang H
Orphanet J Rare Dis 2015 Sep 30;10:127. doi: 10.1186/s13023-015-0347-1. PMID: 26419464Free PMC Article
Layzer RB
J Child Neurol 2001 Mar;16(3):199-202. doi: 10.1177/088307380101600307. PMID: 11305688

Therapy

Mann N, King T, Murphy R
Clin Exp Dermatol 2019 Jul;44(5):477-482. Epub 2019 Jan 4 doi: 10.1111/ced.13891. PMID: 30609105
Kalava K, Roberts C, Adair JD, Raman V
J Clin Rheumatol 2013 Aug;19(5):284-5. doi: 10.1097/RHU.0b013e31829cf8a2. PMID: 23872544
Albuquerque LG, França ER, Kozmhinsky V, Querino MC, Morais AG
An Bras Dermatol 2011 Jan-Feb;86(1):131-4. doi: 10.1590/s0365-05962011000100019. PMID: 21437535
Nathan A, Rose JB, Guite JW, Hehir D, Milovcich K
Pediatrics 2005 Apr;115(4):e504-7. Epub 2005 Mar 1 doi: 10.1542/peds.2004-1395. PMID: 15741349
Sakakibara R, Fukutake T, Kita K, Hattori T
J Auton Nerv Syst 1996 Apr 20;58(1-2):121-2. doi: 10.1016/0165-1838(95)00121-2. PMID: 8740669

Prognosis

Haehner A, Hummel T, Heinritz W, Krueger S, Meinhardt M, Whitcroft KL, Sabatowski R, Gossrau G
Eur J Pain 2018 Nov;22(10):1767-1773. Epub 2018 Jul 11 doi: 10.1002/ejp.1272. PMID: 29934995
Klein-Weigel PF, Volz TS, Richter JG
Vasa 2018 Feb;47(2):91-97. Epub 2018 Jan 4 doi: 10.1024/0301-1526/a000675. PMID: 29299961
Wu B, Zhang Y, Tang H, Yang M, Long H, Shi G, Tang J, Shi X
Curr Mol Med 2017;17(6):450-457. doi: 10.2174/1566524017666171009105029. PMID: 28990532
Ceyhan AM, Gurses I, Yildirim M, Akkaya VB
J Drugs Dermatol 2010 May;9(5):565-7. PMID: 20480803
Delye H, Lagae L, Vermylen J, Nuttin B
Neurosurgery 2005 Oct;57(4 Suppl):E404; discussion E404. doi: 10.1227/01.neu.0000176703.27632.6d. PMID: 16234658

Clinical prediction guides

Öztürk Z, Aydın O, Bodur İ, Yaradılmış RM, Çelik HA, Tuygun N
Turk J Pediatr 2023;65(4):704-706. doi: 10.24953/turkjped.2023.84. PMID: 37661688
Klein-Weigel PF, Volz TS, Richter JG
Vasa 2018 Feb;47(2):91-97. Epub 2018 Jan 4 doi: 10.1024/0301-1526/a000675. PMID: 29299961
Wu B, Zhang Y, Tang H, Yang M, Long H, Shi G, Tang J, Shi X
Curr Mol Med 2017;17(6):450-457. doi: 10.2174/1566524017666171009105029. PMID: 28990532
Wu MT, Huang PY, Yen CT, Chen CC, Lee MJ
PLoS One 2013;8(1):e55212. Epub 2013 Jan 31 doi: 10.1371/journal.pone.0055212. PMID: 23383113Free PMC Article
Sakakibara R, Fukutake T, Kita K, Hattori T
J Auton Nerv Syst 1996 Apr 20;58(1-2):121-2. doi: 10.1016/0165-1838(95)00121-2. PMID: 8740669

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