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Periodic fever-infantile enterocolitis-autoinflammatory syndrome(AIFEC)

MedGen UID:
863504
Concept ID:
C4015067
Disease or Syndrome
Synonym: Autoinflammation with infantile enterocolitis
SNOMED CT: Periodic fever, infantile enterocolitis, autoinflammatory syndrome (1197594000); NLRC4-related infantile enterocolitis, autoinflammatory syndrome (1197594000); NLRC4-related macrophage activation syndrome (1197594000); NLRC4-related autoinflammatory syndrome with macrophage activation syndrome (1197594000)
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): NLRC4 (2p22.3)
 
Monarch Initiative: MONDO:0014472
OMIM®: 616050
Orphanet: ORPHA436166

Definition

Autoinflammation with infantile enterocolitis is an autosomal dominant disorder characterized by onset of recurrent flares of autoinflammation in early infancy. Affected individuals tend to have poor overall growth and gastrointestinal symptoms in infancy associated with laboratory evidence of activated inflammation. This initial presentation is followed by recurrent febrile episodes with splenomegaly and sometimes hematologic disturbances, arthralgias, or myalgias. The disorder results from overactivation of an arm of the immune response system (Romberg et al., 2014; Canna et al., 2014). [from OMIM]

Clinical features

From HPO
Arthralgia
MedGen UID:
13917
Concept ID:
C0003862
Sign or Symptom
Joint pain.
Fatigue
MedGen UID:
41971
Concept ID:
C0015672
Sign or Symptom
A subjective feeling of tiredness characterized by a lack of energy and motivation.
Myalgia
MedGen UID:
68541
Concept ID:
C0231528
Sign or Symptom
Pain in muscle.
Diffuse alveolar hemorrhage
MedGen UID:
1381751
Concept ID:
C4476767
Disease or Syndrome
A type of of pulmonary hemorrhage that originates from the pulmonary microcirculation, including the alveolar capillaries, arterioles, and venules. It presents with hemoptysis, anemia, diffuse lung infiltration, and acute respiratory failure. The diagnosis is confirmed by the observation of the accumulation of red blood cells, fibrin, or hemosiderin-laden macrophage in the alveolar space on pathologic biopsy. Hemosiderin, a product of hemoglobin degradation, appears at least 48-72 hours after bleeding and is helpful in distinguishing diffuse alveolar hemorrhage from surgical trauma. Mild interstitial thickening, organizing pneumonia, or diffuse alveolar damage can also be seen.
Short stature
MedGen UID:
87607
Concept ID:
C0349588
Finding
A height below that which is expected according to age and gender norms. Although there is no universally accepted definition of short stature, many refer to "short stature" as height more than 2 standard deviations below the mean for age and gender (or below the 3rd percentile for age and gender dependent norms).
Failure to thrive
MedGen UID:
746019
Concept ID:
C2315100
Disease or Syndrome
Failure to thrive (FTT) refers to a child whose physical growth is substantially below the norm.
Enterocolitis
MedGen UID:
4966
Concept ID:
C0014356
Disease or Syndrome
An inflammation of the colon and small intestine. However, most conditions are either categorized as Enteritis (inflammation of the small intestine) or Colitis (inflammation of the large intestine).
Secretory diarrhea
MedGen UID:
75635
Concept ID:
C0267557
Disease or Syndrome
Watery voluminous diarrhea resulting from an imbalance between ion and water secretion and absorption.
Villous atrophy
MedGen UID:
154306
Concept ID:
C0554101
Finding
The enteric villi are atrophic or absent.
Episodic vomiting
MedGen UID:
333228
Concept ID:
C1838993
Finding
Paroxysmal, recurrent episodes of vomiting.
Feeding difficulties in infancy
MedGen UID:
436211
Concept ID:
C2674608
Finding
Impaired feeding performance of an infant as manifested by difficulties such as weak and ineffective sucking, brief bursts of sucking, and falling asleep during sucking. There may be difficulties with chewing or maintaining attention.
Anemia
MedGen UID:
1526
Concept ID:
C0002871
Disease or Syndrome
A reduction in erythrocytes volume or hemoglobin concentration.
Disseminated intravascular coagulation
MedGen UID:
41620
Concept ID:
C0012739
Disease or Syndrome
Disseminated intravascular coagulation is characterized by the widespread activation of coagulation, which results in the intravascular formation of fibrin and ultimately thrombotic occlusion of small and midsize vessels.
Pancytopenia
MedGen UID:
18281
Concept ID:
C0030312
Disease or Syndrome
An abnormal reduction in numbers of all blood cell types (red blood cells, white blood cells, and platelets).
Thrombocytopenia
MedGen UID:
52737
Concept ID:
C0040034
Disease or Syndrome
A reduction in the number of circulating thrombocytes.
Hypofibrinogenemia
MedGen UID:
107511
Concept ID:
C0553681
Disease or Syndrome
Decreased concentration of fibrinogen in the blood.
Meningitis
MedGen UID:
6298
Concept ID:
C0025289
Disease or Syndrome
Inflammation of the meninges.
Splenomegaly
MedGen UID:
52469
Concept ID:
C0038002
Finding
Abnormal increased size of the spleen.
Reduced natural killer cell activity
MedGen UID:
333452
Concept ID:
C1839969
Finding
Reduced ability of the natural killer cell to function in the adaptive immune response.
Reduced natural killer cell count
MedGen UID:
383765
Concept ID:
C1855767
Finding
Less than normal number of natural killer cells, a type of lymphocyte in the innate immune system with an ability to mediate cytotoxicity and produce cytokines after the ligation of a germline-encoded activation receptor.
Skin rash
MedGen UID:
1830322
Concept ID:
C5779628
Sign or Symptom
A red eruption of the skin.
Fever
MedGen UID:
5169
Concept ID:
C0015967
Sign or Symptom
Body temperature elevated above the normal range.
Hypoalbuminemia
MedGen UID:
68694
Concept ID:
C0239981
Finding
Reduction in the concentration of albumin in the blood.
Increased circulating ferritin concentration
MedGen UID:
69130
Concept ID:
C0241013
Finding
Increased concentration of ferritin in the blood circulation.
Recurrent fever
MedGen UID:
811468
Concept ID:
C3714772
Sign or Symptom
Periodic (episodic or recurrent) bouts of fever.
Elevated circulating C-reactive protein concentration
MedGen UID:
892906
Concept ID:
C4023452
Finding
An abnormal elevation of the C-reactive protein level in the blood circulation.
Urticaria
MedGen UID:
22587
Concept ID:
C0042109
Disease or Syndrome
Raised, well-circumscribed areas of erythema and edema involving the dermis and epidermis. Urticaria is intensely pruritic, and blanches completely with pressure.

Term Hierarchy

CClinical test,  RResearch test,  OOMIM,  GGeneReviews,  VClinVar  
  • CROGVPeriodic fever-infantile enterocolitis-autoinflammatory syndrome

Professional guidelines

PubMed

Gossard TR, Trotti LM, Videnovic A, St Louis EK
Neurotherapeutics 2021 Jan;18(1):140-155. Epub 2021 Apr 20 doi: 10.1007/s13311-021-01019-4. PMID: 33880737Free PMC Article
Oliveira CB, Maher CG, Pinto RZ, Traeger AC, Lin CC, Chenot JF, van Tulder M, Koes BW
Eur Spine J 2018 Nov;27(11):2791-2803. Epub 2018 Jul 3 doi: 10.1007/s00586-018-5673-2. PMID: 29971708
Brioude F, Kalish JM, Mussa A, Foster AC, Bliek J, Ferrero GB, Boonen SE, Cole T, Baker R, Bertoletti M, Cocchi G, Coze C, De Pellegrin M, Hussain K, Ibrahim A, Kilby MD, Krajewska-Walasek M, Kratz CP, Ladusans EJ, Lapunzina P, Le Bouc Y, Maas SM, Macdonald F, Õunap K, Peruzzi L, Rossignol S, Russo S, Shipster C, Skórka A, Tatton-Brown K, Tenorio J, Tortora C, Grønskov K, Netchine I, Hennekam RC, Prawitt D, Tümer Z, Eggermann T, Mackay DJG, Riccio A, Maher ER
Nat Rev Endocrinol 2018 Apr;14(4):229-249. Epub 2018 Jan 29 doi: 10.1038/nrendo.2017.166. PMID: 29377879Free PMC Article

Recent clinical studies

Etiology

Schutt C, Siegel DM
Pediatr Rev 2023 Sep 1;44(9):481-490. doi: 10.1542/pir.2022-005635. PMID: 37653132
Könemann H, Ellermann C, Zeppenfeld K, Eckardt L
JACC Clin Electrophysiol 2023 May;9(5):715-728. Epub 2023 Feb 22 doi: 10.1016/j.jacep.2022.12.008. PMID: 37225314
Weakley J, Halson SL, Mujika I
Int J Sports Physiol Perform 2022 May 1;17(5):675-681. Epub 2022 Mar 23 doi: 10.1123/ijspp.2021-0448. PMID: 35320774
Sales C, Calma AD
Clin Neurol Neurosurg 2022 Feb;213:107120. Epub 2022 Jan 10 doi: 10.1016/j.clineuro.2022.107120. PMID: 35074686
Scholl PR
Curr Opin Pediatr 2000 Dec;12(6):563-6. doi: 10.1097/00008480-200012000-00009. PMID: 11106276

Diagnosis

Schutt C, Siegel DM
Pediatr Rev 2023 Sep 1;44(9):481-490. doi: 10.1542/pir.2022-005635. PMID: 37653132
Weakley J, Halson SL, Mujika I
Int J Sports Physiol Perform 2022 May 1;17(5):675-681. Epub 2022 Mar 23 doi: 10.1123/ijspp.2021-0448. PMID: 35320774
Wennig R, Eyer F, Schaper A, Zilker T, Andresen-Streichert H
Dtsch Arztebl Int 2020 Oct 16;117(42):701-708. doi: 10.3238/arztebl.2020.0701. PMID: 33559585Free PMC Article
Lachmann HJ
Best Pract Res Clin Rheumatol 2017 Aug;31(4):596-609. Epub 2018 Jan 11 doi: 10.1016/j.berh.2017.12.001. PMID: 29773275
Li BU, Lefevre F, Chelimsky GG, Boles RG, Nelson SP, Lewis DW, Linder SL, Issenman RM, Rudolph CD; North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition
J Pediatr Gastroenterol Nutr 2008 Sep;47(3):379-93. doi: 10.1097/MPG.0b013e318173ed39. PMID: 18728540

Therapy

Soriano A, Soriano M, Espinosa G, Manna R, Emmi G, Cantarini L, Hernández-Rodríguez J
Front Immunol 2020;11:865. Epub 2020 Jun 3 doi: 10.3389/fimmu.2020.00865. PMID: 32655539Free PMC Article
Lachmann HJ
Best Pract Res Clin Rheumatol 2017 Aug;31(4):596-609. Epub 2018 Jan 11 doi: 10.1016/j.berh.2017.12.001. PMID: 29773275
Vanoni F, Theodoropoulou K, Hofer M
Pediatr Rheumatol Online J 2016 Jun 27;14(1):38. doi: 10.1186/s12969-016-0101-9. PMID: 27349388Free PMC Article
Yaffe K, Falvey CM, Hoang T
Lancet Neurol 2014 Oct;13(10):1017-28. doi: 10.1016/S1474-4422(14)70172-3. PMID: 25231524
Li BU, Lefevre F, Chelimsky GG, Boles RG, Nelson SP, Lewis DW, Linder SL, Issenman RM, Rudolph CD; North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition
J Pediatr Gastroenterol Nutr 2008 Sep;47(3):379-93. doi: 10.1097/MPG.0b013e318173ed39. PMID: 18728540

Prognosis

Schutt C, Siegel DM
Pediatr Rev 2023 Sep 1;44(9):481-490. doi: 10.1542/pir.2022-005635. PMID: 37653132
Logroscino G, Piccininni M, Graff C, Hardiman O, Ludolph AC, Moreno F, Otto M, Remes AM, Rowe JB, Seelaar H, Solje E, Stefanova E, Traykov L, Jelic V, Rydell MT, Pender N, Anderl-Straub S, Barandiaran M, Gabilondo A, Krüger J, Murley AG, Rittman T, van der Ende EL, van Swieten JC, Hartikainen P, Stojmenovic GM, Mehrabian S, Benussi L, Alberici A, Dell'Abate MT, Zecca C, Borroni B; FRONTIERS group
JAMA Neurol 2023 Mar 1;80(3):279-286. doi: 10.1001/jamaneurol.2022.5128. PMID: 36716024Free PMC Article
Guy R, Henderson KL, Coelho J, Hughes H, Mason EL, Gerver SM, Demirjian A, Watson C, Sharp A, Brown CS, Lamagni T
Euro Surveill 2023 Jan;28(1) doi: 10.2807/1560-7917.ES.2023.28.1.2200942. PMID: 36695450Free PMC Article
Martin-Loeches I, Soares M, Torres A
Intensive Care Med 2016 May;42(5):928-930. Epub 2016 Feb 3 doi: 10.1007/s00134-016-4243-5. PMID: 26846514Free PMC Article
Li BU, Lefevre F, Chelimsky GG, Boles RG, Nelson SP, Lewis DW, Linder SL, Issenman RM, Rudolph CD; North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition
J Pediatr Gastroenterol Nutr 2008 Sep;47(3):379-93. doi: 10.1097/MPG.0b013e318173ed39. PMID: 18728540

Clinical prediction guides

Lantto U, Tapiainen T, Pokka T, Koivunen P, Helminen M, Piitulainen J, Rekola J, Uhari M, Renko M
Laryngoscope 2024 Feb;134(2):968-972. Epub 2023 Jul 21 doi: 10.1002/lary.30863. PMID: 37477273
Outeiro TF, Alcalay RN, Antonini A, Attems J, Bonifati V, Cardoso F, Chesselet MF, Hardy J, Madeo G, McKeith I, Mollenhauer B, Moore DJ, Rascol O, Schlossmacher MG, Soreq H, Stefanis L, Ferreira JJ
Mov Disord 2023 Jul;38(7):1127-1142. Epub 2023 May 8 doi: 10.1002/mds.29419. PMID: 37156737
Weakley J, Halson SL, Mujika I
Int J Sports Physiol Perform 2022 May 1;17(5):675-681. Epub 2022 Mar 23 doi: 10.1123/ijspp.2021-0448. PMID: 35320774
Donnet A, Redon S
Curr Pain Headache Rep 2018 Mar 19;22(4):30. doi: 10.1007/s11916-018-0684-6. PMID: 29556858
Gallentine WB, Mikati MA
J Clin Neurophysiol 2012 Oct;29(5):408-19. doi: 10.1097/WNP.0b013e31826bd92a. PMID: 23027098

Recent systematic reviews

Asmis L, Hellstern P
Clin Lab 2023 Apr 1;69(4) doi: 10.7754/Clin.Lab.2022.220817. PMID: 37057948
Alkodaymi MS, Omrani OA, Fawzy NA, Shaar BA, Almamlouk R, Riaz M, Obeidat M, Obeidat Y, Gerberi D, Taha RM, Kashour Z, Kashour T, Berbari EF, Alkattan K, Tleyjeh IM
Clin Microbiol Infect 2022 May;28(5):657-666. Epub 2022 Feb 3 doi: 10.1016/j.cmi.2022.01.014. PMID: 35124265Free PMC Article
Tiseo C, Vacca A, Felbush A, Filimonova T, Gai A, Glazyrina T, Hubalek IA, Marchenko Y, Overeem LH, Piroso S, Tkachev A, Martelletti P, Sacco S; European Headache Federation School of Advanced Studies (EHF-SAS)
J Headache Pain 2020 Oct 27;21(1):126. doi: 10.1186/s10194-020-01192-5. PMID: 33109076Free PMC Article
Munshi L, Del Sorbo L, Adhikari NKJ, Hodgson CL, Wunsch H, Meade MO, Uleryk E, Mancebo J, Pesenti A, Ranieri VM, Fan E
Ann Am Thorac Soc 2017 Oct;14(Supplement_4):S280-S288. doi: 10.1513/AnnalsATS.201704-343OT. PMID: 29068269
Vakil N, van Zanten SV, Kahrilas P, Dent J, Jones R; Global Consensus Group
Am J Gastroenterol 2006 Aug;101(8):1900-20; quiz 1943. doi: 10.1111/j.1572-0241.2006.00630.x. PMID: 16928254

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