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Paroxysmal extreme pain disorder(PEXPD)

MedGen UID:
331565
Concept ID:
C1833661
Disease or Syndrome
Synonyms: PAIN, SUBMANDIBULAR, OCULAR, AND RECTAL, WITH FLUSHING; PEXPD; RECTAL PAIN, FAMILIAL
SNOMED CT: Familial rectal pain (699190008); Submandibular, ocular and rectal pain with flushing (699190008); Paroxysmal extreme pain disorder (699190008)
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:0008179
OMIM®: 167400
Orphanet: ORPHA46348

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
Paroxysmal extreme pain disorder (PEXPD), formerly known as familial rectal pain, is characterized by paroxysms of rectal, ocular, or submandibular pain with flushing. Onset is usually in the neonatal period or infancy (Fertleman et al., 2006).  http://www.omim.org/entry/167400
From MedlinePlus Genetics
Paroxysmal extreme pain disorder is a condition characterized by skin redness and warmth (flushing) and attacks of severe pain in various parts of the body. The area of flushing typically corresponds to the site of the pain. The pain attacks experienced by people with paroxysmal extreme pain disorder usually last seconds to minutes, but in some cases can last hours. These attacks can start as early as infancy. Early in life, the pain is typically concentrated in the lower part of the body, especially around the rectum, and is usually triggered by a bowel movement. Some children may develop constipation, which is thought to be due to fear of triggering a pain attack. Pain attacks in these young children may also be accompanied by seizures, slow heartbeat, or short pauses in breathing (apnea).

As a person with paroxysmal extreme pain disorder ages, the location of pain changes. Pain attacks switch from affecting the lower body to affecting the head and face, especially the eyes and jaw. Triggers of these pain attacks include changes in temperature (such as a cold wind) and emotional distress as well as eating spicy foods and drinking cold drinks.

Paroxysmal extreme pain disorder is 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/paroxysmal-extreme-pain-disorder

Clinical features

From HPO
Ocular pain
MedGen UID:
57490
Concept ID:
C0151827
Sign or Symptom
An unpleasant sensation characterized by physical discomfort (such as pricking, throbbing, or aching) localized to the eye.
Anal pain
MedGen UID:
66776
Concept ID:
C0238637
Sign or Symptom
Pain in and around the anus or rectum (perianal region).
Mandibular pain
MedGen UID:
1633770
Concept ID:
C4552061
Sign or Symptom
An unpleasant sensation characterized by physical discomfort (such as pricking, throbbing, or aching) localized to the mandible.
Tachycardia
MedGen UID:
21453
Concept ID:
C0039231
Finding
A rapid heartrate that exceeds the range of the normal resting heartrate for age.
Bradycardia
MedGen UID:
140901
Concept ID:
C0428977
Finding
A slower than normal heart rate (in adults, slower than 60 beats per minute).
Impaired pain sensation
MedGen UID:
373348
Concept ID:
C1837522
Finding
Reduced ability to perceive painful stimuli.
Rhinorrhea
MedGen UID:
226777
Concept ID:
C1260880
Sign or Symptom
Increased discharge of mucus from the nose.
Flushing
MedGen UID:
5234
Concept ID:
C0016382
Sign or Symptom
Recurrent episodes of redness of the skin together with a sensation of warmth or burning of the affected areas of skin.
Lacrimation abnormality
MedGen UID:
867427
Concept ID:
C4021801
Anatomical Abnormality
Abnormality of tear production.

Term Hierarchy

CClinical test,  RResearch test,  OOMIM,  GGeneReviews,  VClinVar  
  • CROGVParoxysmal extreme pain disorder
Follow this link to review classifications for Paroxysmal extreme pain disorder in Orphanet.

Professional guidelines

PubMed

Suter MR
Pain Manag 2015;5(4):229-32. Epub 2015 Jun 10 doi: 10.2217/pmt.15.24. PMID: 26059255
Cross JH
Semin Fetal Neonatal Med 2013 Aug;18(4):192-5. Epub 2013 Apr 30 doi: 10.1016/j.siny.2013.04.003. PMID: 23642846

Recent clinical studies

Etiology

Roulet Perez E
Arch Pediatr 2023 Aug;30(6):415-419. Epub 2023 Jul 4 doi: 10.1016/j.arcped.2023.06.007. PMID: 37414714
Rastogi V, Singh D, Mazza JJ, Parajuli D, Yale SH
Clin Med Res 2018 Jun;16(1-2):29-36. Epub 2018 Apr 12 doi: 10.3121/cmr.2017.1379b. PMID: 29650526Free PMC Article
Kapetis D, Sassone J, Yang Y, Galbardi B, Xenakis MN, Westra RL, Szklarczyk R, Lindsey P, Faber CG, Gerrits M, Merkies IS, Dib-Hajj SD, Mantegazza M, Waxman SG, Lauria G; PROPANE Study Group
BMC Syst Biol 2017 Feb 24;11(1):28. doi: 10.1186/s12918-016-0382-0. PMID: 28235406Free PMC Article
Bennett DL, Woods CG
Lancet Neurol 2014 Jun;13(6):587-99. Epub 2014 May 6 doi: 10.1016/S1474-4422(14)70024-9. PMID: 24813307
Themistocleous AC, Ramirez JD, Serra J, Bennett DL
Pract Neurol 2014 Dec;14(6):368-79. Epub 2014 Apr 28 doi: 10.1136/practneurol-2013-000758. PMID: 24778270Free PMC Article

Diagnosis

Yuan JH, Cheng X, Matsuura E, Higuchi Y, Ando M, Hashiguchi A, Yoshimura A, Nakachi R, Mine J, Taketani T, Maeda K, Kawakami S, Kira R, Tanaka S, Kanai K, Dib-Hajj F, Dib-Hajj SD, Waxman SG, Takashima H
J Peripher Nerv Syst 2023 Dec;28(4):597-607. Epub 2023 Aug 18 doi: 10.1111/jns.12590. PMID: 37555797
Kriegeskorte S, Bott R, Hampl M, Korngreen A, Hausmann R, Lampert A
J Gen Physiol 2023 Sep 4;155(9) Epub 2023 Aug 2 doi: 10.1085/jgp.202213312. PMID: 37531097Free PMC Article
Dib-Hajj SD, Waxman SG
Annu Rev Neurosci 2019 Jul 8;42:87-106. Epub 2019 Jan 31 doi: 10.1146/annurev-neuro-070918-050144. PMID: 30702961
Bennett DL, Woods CG
Lancet Neurol 2014 Jun;13(6):587-99. Epub 2014 May 6 doi: 10.1016/S1474-4422(14)70024-9. PMID: 24813307
Stephenson JB
Handb Clin Neurol 2013;112:861-6. doi: 10.1016/B978-0-444-52910-7.00007-6. PMID: 23622295

Therapy

Dib-Hajj SD, Waxman SG
Annu Rev Neurosci 2019 Jul 8;42:87-106. Epub 2019 Jan 31 doi: 10.1146/annurev-neuro-070918-050144. PMID: 30702961
Rastogi V, Singh D, Mazza JJ, Parajuli D, Yale SH
Clin Med Res 2018 Jun;16(1-2):29-36. Epub 2018 Apr 12 doi: 10.3121/cmr.2017.1379b. PMID: 29650526Free PMC Article
Vetter I, Deuis JR, Mueller A, Israel MR, Starobova H, Zhang A, Rash LD, Mobli M
Pharmacol Ther 2017 Apr;172:73-100. Epub 2016 Dec 2 doi: 10.1016/j.pharmthera.2016.11.015. PMID: 27916648
Goldberg YP, Pimstone SN, Namdari R, Price N, Cohen C, Sherrington RP, Hayden MR
Clin Genet 2012 Oct;82(4):367-73. Epub 2012 Aug 13 doi: 10.1111/j.1399-0004.2012.01942.x. PMID: 22845492
Fertleman CR, Ferrie CD, Aicardi J, Bednarek NA, Eeg-Olofsson O, Elmslie FV, Griesemer DA, Goutières F, Kirkpatrick M, Malmros IN, Pollitzer M, Rossiter M, Roulet-Perez E, Schubert R, Smith VV, Testard H, Wong V, Stephenson JB
Neurology 2007 Aug 7;69(6):586-95. doi: 10.1212/01.wnl.0000268065.16865.5f. PMID: 17679678

Prognosis

Kapetis D, Sassone J, Yang Y, Galbardi B, Xenakis MN, Westra RL, Szklarczyk R, Lindsey P, Faber CG, Gerrits M, Merkies IS, Dib-Hajj SD, Mantegazza M, Waxman SG, Lauria G; PROPANE Study Group
BMC Syst Biol 2017 Feb 24;11(1):28. doi: 10.1186/s12918-016-0382-0. PMID: 28235406Free PMC Article
Suter MR, Bhuiyan ZA, Laedermann CJ, Kuntzer T, Schaller M, Stauffacher MW, Roulet E, Abriel H, Decosterd I, Wider C
Anesthesiology 2015 Feb;122(2):414-23. doi: 10.1097/ALN.0000000000000476. PMID: 25285947
Cross JH
Semin Fetal Neonatal Med 2013 Aug;18(4):192-5. Epub 2013 Apr 30 doi: 10.1016/j.siny.2013.04.003. PMID: 23642846
Dabby R, Sadeh M, Gilad R, Lampl Y, Cohen S, Inbar S, Leshinsky-Silver E
J Neurol Sci 2011 Feb 15;301(1-2):90-2. Epub 2010 Nov 20 doi: 10.1016/j.jns.2010.10.006. PMID: 21094958
Reimann F, Cox JJ, Belfer I, Diatchenko L, Zaykin DV, McHale DP, Drenth JP, Dai F, Wheeler J, Sanders F, Wood L, Wu TX, Karppinen J, Nikolajsen L, Männikkö M, Max MB, Kiselycznyk C, Poddar M, Te Morsche RH, Smith S, Gibson D, Kelempisioti A, Maixner W, Gribble FM, Woods CG
Proc Natl Acad Sci U S A 2010 Mar 16;107(11):5148-53. Epub 2010 Mar 8 doi: 10.1073/pnas.0913181107. PMID: 20212137Free PMC Article

Clinical prediction guides

Yuan JH, Cheng X, Matsuura E, Higuchi Y, Ando M, Hashiguchi A, Yoshimura A, Nakachi R, Mine J, Taketani T, Maeda K, Kawakami S, Kira R, Tanaka S, Kanai K, Dib-Hajj F, Dib-Hajj SD, Waxman SG, Takashima H
J Peripher Nerv Syst 2023 Dec;28(4):597-607. Epub 2023 Aug 18 doi: 10.1111/jns.12590. PMID: 37555797
Stępień A, Sałacińska D, Staszewski J, Durka-Kęsy M, Dobrogowski J
BMC Neurol 2020 May 13;20(1):182. doi: 10.1186/s12883-020-01770-9. PMID: 32404070Free PMC Article
Kapetis D, Sassone J, Yang Y, Galbardi B, Xenakis MN, Westra RL, Szklarczyk R, Lindsey P, Faber CG, Gerrits M, Merkies IS, Dib-Hajj SD, Mantegazza M, Waxman SG, Lauria G; PROPANE Study Group
BMC Syst Biol 2017 Feb 24;11(1):28. doi: 10.1186/s12918-016-0382-0. PMID: 28235406Free PMC Article
Suter MR, Bhuiyan ZA, Laedermann CJ, Kuntzer T, Schaller M, Stauffacher MW, Roulet E, Abriel H, Decosterd I, Wider C
Anesthesiology 2015 Feb;122(2):414-23. doi: 10.1097/ALN.0000000000000476. PMID: 25285947
Reimann F, Cox JJ, Belfer I, Diatchenko L, Zaykin DV, McHale DP, Drenth JP, Dai F, Wheeler J, Sanders F, Wood L, Wu TX, Karppinen J, Nikolajsen L, Männikkö M, Max MB, Kiselycznyk C, Poddar M, Te Morsche RH, Smith S, Gibson D, Kelempisioti A, Maixner W, Gribble FM, Woods CG
Proc Natl Acad Sci U S A 2010 Mar 16;107(11):5148-53. Epub 2010 Mar 8 doi: 10.1073/pnas.0913181107. PMID: 20212137Free PMC Article

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