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Hemophagocytic lymphohistiocytosis, familial, 6(FHL6, FORMERLY; IMDYSHI)

MedGen UID:
1736944
•Concept ID:
C5436563
•
Disease or Syndrome
Synonym: IMMUNE DYSREGULATION AND SYSTEMIC HYPERINFLAMMATION SYNDROME
 
Gene (location): RC3H1 (1q25.1)
 
Monarch Initiative: MONDO:0033557
OMIM®: 618998

Definition

Immune dysregulation and systemic hyperinflammation syndrome (IMDYSHI) is an autosomal recessive immunologic disorder characterized by systemic hyperinflammation in the absence of an infectious agent or autoimmune trigger. Features include lymphadenopathy, hepatosplenomegaly, recurrent fever, and laboratory evidence of immune dysregulation with abnormal immune cell populations and increased serum levels of inflammatory cytokines. The phenotype is reminiscent of relapsing hemophagocytic lymphohistiocytosis (HLH; see FHL1, 267700) (summary by Tavernier et al., 2019). [from OMIM]

Professional guidelines

PubMed

The 2022 EULAR/ACR points to consider at the early stages of diagnosis and management of suspected haemophagocytic lymphohistiocytosis/macrophage activation syndrome (HLH/MAS).
Shakoory B, Geerlinks A, Wilejto M, Kernan K, Hines M, Romano M, Piskin D, Ravelli A, Sinha R, Aletaha D, Allen C, Bassiri H, Behrens EM, Carcillo J, Carl L, Chatham W, Cohen JI, Cron RQ, Drewniak E, Grom AA, Henderson LA, Horne A, Jordan MB, Nichols KE, Schulert G, Vastert S, Demirkaya E, Goldbach-Mansky R, de Benedetti F, Marsh RA, Canna SW; HLH/MAS task force
Ann Rheum Dis 2023 Oct;82(10):1271-1285. Epub 2023 Jul 24 doi: 10.1136/ard-2023-224123. PMID: 37487610Free PMC Article
Recent advances in the treatment of hemophagocytic lymphohistiocytosis and macrophage activation syndrome.
Jesudas R, Nichols KE
Curr Opin Allergy Clin Immunol 2022 Dec 1;22(6):364-370. Epub 2022 Sep 28 doi: 10.1097/ACI.0000000000000865. PMID: 36206094
Use of the JAK Inhibitor Ruxolitinib in the Treatment of Hemophagocytic Lymphohistiocytosis.
Keenan C, Nichols KE, Albeituni S
Front Immunol 2021;12:614704. Epub 2021 Feb 16 doi: 10.3389/fimmu.2021.614704. PMID: 33664745Free PMC Article

Recent clinical studies

Etiology

Malignancy-associated haemophagocytic lymphohistiocytosis.
Setiadi A, Zoref-Lorenz A, Lee CY, Jordan MB, Chen LYC
Lancet Haematol 2022 Mar;9(3):e217-e227. Epub 2022 Jan 31 doi: 10.1016/S2352-3026(21)00366-5. PMID: 35101205
Macrophage Activation Syndrome and Secondary Hemophagocytic Lymphohistiocytosis in Childhood Inflammatory Disorders: Diagnosis and Management.
Henderson LA, Cron RQ
Paediatr Drugs 2020 Feb;22(1):29-44. doi: 10.1007/s40272-019-00367-1. PMID: 31732958Free PMC Article
Revised classification of histiocytoses and neoplasms of the macrophage-dendritic cell lineages.
Emile JF, Abla O, Fraitag S, Horne A, Haroche J, Donadieu J, Requena-Caballero L, Jordan MB, Abdel-Wahab O, Allen CE, Charlotte F, Diamond EL, Egeler RM, Fischer A, Herrera JG, Henter JI, Janku F, Merad M, Picarsic J, Rodriguez-Galindo C, Rollins BJ, Tazi A, Vassallo R, Weiss LM; Histiocyte Society
Blood 2016 Jun 2;127(22):2672-81. Epub 2016 Mar 10 doi: 10.1182/blood-2016-01-690636. PMID: 26966089Free PMC Article
Development and validation of the HScore, a score for the diagnosis of reactive hemophagocytic syndrome.
Fardet L, Galicier L, Lambotte O, Marzac C, Aumont C, Chahwan D, Coppo P, Hejblum G
Arthritis Rheumatol 2014 Sep;66(9):2613-20. doi: 10.1002/art.38690. PMID: 24782338
The haemophagocytic syndrome.
Dierickx D, Cortoos A, Vanderschueren S
Acta Clin Belg 2011 Nov-Dec;66(6):448-52. doi: 10.2143/ACB.66.6.2062613. PMID: 22338310

Diagnosis

The 2022 EULAR/ACR points to consider at the early stages of diagnosis and management of suspected haemophagocytic lymphohistiocytosis/macrophage activation syndrome (HLH/MAS).
Shakoory B, Geerlinks A, Wilejto M, Kernan K, Hines M, Romano M, Piskin D, Ravelli A, Sinha R, Aletaha D, Allen C, Bassiri H, Behrens EM, Carcillo J, Carl L, Chatham W, Cohen JI, Cron RQ, Drewniak E, Grom AA, Henderson LA, Horne A, Jordan MB, Nichols KE, Schulert G, Vastert S, Demirkaya E, Goldbach-Mansky R, de Benedetti F, Marsh RA, Canna SW; HLH/MAS task force
Ann Rheum Dis 2023 Oct;82(10):1271-1285. Epub 2023 Jul 24 doi: 10.1136/ard-2023-224123. PMID: 37487610Free PMC Article
Cytokine Storm Syndrome.
Cron RQ, Goyal G, Chatham WW
Annu Rev Med 2023 Jan 27;74:321-337. Epub 2022 Oct 13 doi: 10.1146/annurev-med-042921-112837. PMID: 36228171
Malignancy-associated haemophagocytic lymphohistiocytosis.
Setiadi A, Zoref-Lorenz A, Lee CY, Jordan MB, Chen LYC
Lancet Haematol 2022 Mar;9(3):e217-e227. Epub 2022 Jan 31 doi: 10.1016/S2352-3026(21)00366-5. PMID: 35101205
Hemophagocytic syndromes (HPSs) including hemophagocytic lymphohistiocytosis (HLH) in adults: A systematic scoping review.
Hayden A, Park S, Giustini D, Lee AY, Chen LY
Blood Rev 2016 Nov;30(6):411-420. Epub 2016 May 20 doi: 10.1016/j.blre.2016.05.001. PMID: 27238576
Development and validation of the HScore, a score for the diagnosis of reactive hemophagocytic syndrome.
Fardet L, Galicier L, Lambotte O, Marzac C, Aumont C, Chahwan D, Coppo P, Hejblum G
Arthritis Rheumatol 2014 Sep;66(9):2613-20. doi: 10.1002/art.38690. PMID: 24782338

Therapy

Recent advances and evolving concepts in Still's disease.
Ruscitti P, Cantarini L, Nigrovic PA, McGonagle D, Giacomelli R
Nat Rev Rheumatol 2024 Feb;20(2):116-132. Epub 2024 Jan 11 doi: 10.1038/s41584-023-01065-6. PMID: 38212542
Recent advances in the treatment of hemophagocytic lymphohistiocytosis and macrophage activation syndrome.
Jesudas R, Nichols KE
Curr Opin Allergy Clin Immunol 2022 Dec 1;22(6):364-370. Epub 2022 Sep 28 doi: 10.1097/ACI.0000000000000865. PMID: 36206094
Use of the JAK Inhibitor Ruxolitinib in the Treatment of Hemophagocytic Lymphohistiocytosis.
Keenan C, Nichols KE, Albeituni S
Front Immunol 2021;12:614704. Epub 2021 Feb 16 doi: 10.3389/fimmu.2021.614704. PMID: 33664745Free PMC Article
Macrophage activation syndrome in the era of biologic therapy.
Grom AA, Horne A, De Benedetti F
Nat Rev Rheumatol 2016 May;12(5):259-68. Epub 2016 Mar 24 doi: 10.1038/nrrheum.2015.179. PMID: 27009539Free PMC Article
The haemophagocytic syndrome.
Dierickx D, Cortoos A, Vanderschueren S
Acta Clin Belg 2011 Nov-Dec;66(6):448-52. doi: 10.2143/ACB.66.6.2062613. PMID: 22338310

Prognosis

Recent advances and evolving concepts in Still's disease.
Ruscitti P, Cantarini L, Nigrovic PA, McGonagle D, Giacomelli R
Nat Rev Rheumatol 2024 Feb;20(2):116-132. Epub 2024 Jan 11 doi: 10.1038/s41584-023-01065-6. PMID: 38212542
Use of the JAK Inhibitor Ruxolitinib in the Treatment of Hemophagocytic Lymphohistiocytosis.
Keenan C, Nichols KE, Albeituni S
Front Immunol 2021;12:614704. Epub 2021 Feb 16 doi: 10.3389/fimmu.2021.614704. PMID: 33664745Free PMC Article
Hemophagocytic syndromes (HPSs) including hemophagocytic lymphohistiocytosis (HLH) in adults: A systematic scoping review.
Hayden A, Park S, Giustini D, Lee AY, Chen LY
Blood Rev 2016 Nov;30(6):411-420. Epub 2016 May 20 doi: 10.1016/j.blre.2016.05.001. PMID: 27238576
Adult-onset Still's disease.
Gerfaud-Valentin M, Jamilloux Y, Iwaz J, Sève P
Autoimmun Rev 2014 Jul;13(7):708-22. Epub 2014 Mar 19 doi: 10.1016/j.autrev.2014.01.058. PMID: 24657513
The haemophagocytic syndrome.
Dierickx D, Cortoos A, Vanderschueren S
Acta Clin Belg 2011 Nov-Dec;66(6):448-52. doi: 10.2143/ACB.66.6.2062613. PMID: 22338310

Clinical prediction guides

Chronic active Epstein-Barr virus disease originates from infected hematopoietic stem cells.
Wang J, Su M, Wei N, Yan H, Zhang J, Gong Y, Wu L, Suolitiken D, Pi Y, Song D, Chen L, Liu H, Yang S, Wang X, Wang Z
Blood 2024 Jan 4;143(1):32-41. doi: 10.1182/blood.2023021074. PMID: 37824804
Hemophagocytic lymphohistiocytosis in critically ill patients: diagnostic reliability of HLH-2004 criteria and HScore.
Knaak C, Nyvlt P, Schuster FS, Spies C, Heeren P, Schenk T, Balzer F, La Rosée P, Janka G, Brunkhorst FM, Keh D, Lachmann G
Crit Care 2020 May 24;24(1):244. doi: 10.1186/s13054-020-02941-3. PMID: 32448380Free PMC Article
Macrophage Activation-Like Syndrome: A Distinct Entity Leading to Early Death in Sepsis.
Karakike E, Giamarellos-Bourboulis EJ
Front Immunol 2019;10:55. Epub 2019 Jan 31 doi: 10.3389/fimmu.2019.00055. PMID: 30766533Free PMC Article
Macrophage activation syndrome in the era of biologic therapy.
Grom AA, Horne A, De Benedetti F
Nat Rev Rheumatol 2016 May;12(5):259-68. Epub 2016 Mar 24 doi: 10.1038/nrrheum.2015.179. PMID: 27009539Free PMC Article
Development and validation of the HScore, a score for the diagnosis of reactive hemophagocytic syndrome.
Fardet L, Galicier L, Lambotte O, Marzac C, Aumont C, Chahwan D, Coppo P, Hejblum G
Arthritis Rheumatol 2014 Sep;66(9):2613-20. doi: 10.1002/art.38690. PMID: 24782338

Recent systematic reviews

A systematic review and meta-analysis of nonrelapse mortality after CAR T cell therapy.
Cordas Dos Santos DM, Tix T, Shouval R, Gafter-Gvili A, Alberge JB, Cliff ERS, Theurich S, von Bergwelt-Baildon M, Ghobrial IM, Subklewe M, Perales MA, Rejeski K
Nat Med 2024 Sep;30(9):2667-2678. Epub 2024 Jul 8 doi: 10.1038/s41591-024-03084-6. PMID: 38977912
The 2022 EULAR/ACR points to consider at the early stages of diagnosis and management of suspected haemophagocytic lymphohistiocytosis/macrophage activation syndrome (HLH/MAS).
Shakoory B, Geerlinks A, Wilejto M, Kernan K, Hines M, Romano M, Piskin D, Ravelli A, Sinha R, Aletaha D, Allen C, Bassiri H, Behrens EM, Carcillo J, Carl L, Chatham W, Cohen JI, Cron RQ, Drewniak E, Grom AA, Henderson LA, Horne A, Jordan MB, Nichols KE, Schulert G, Vastert S, Demirkaya E, Goldbach-Mansky R, de Benedetti F, Marsh RA, Canna SW; HLH/MAS task force
Ann Rheum Dis 2023 Oct;82(10):1271-1285. Epub 2023 Jul 24 doi: 10.1136/ard-2023-224123. PMID: 37487610Free PMC Article
The 2022 EULAR/ACR Points to Consider at the Early Stages of Diagnosis and Management of Suspected Haemophagocytic Lymphohistiocytosis/Macrophage Activation Syndrome (HLH/MAS).
Shakoory B, Geerlinks A, Wilejto M, Kernan K, Hines M, Romano M, Piskin D, Ravelli A, Sinha R, Aletaha D, Allen C, Bassiri H, Behrens EM, Carcillo J, Carl L, Chatham W, Cohen JI, Cron RQ, Drewniak E, Grom AA, Henderson LA, Horne A, Jordan MB, Nichols KE, Schulert G, Vastert S, Demirkaya E, Goldbach-Mansky R, de Benedetti F, Marsh RA, Canna SW
Arthritis Rheumatol 2023 Oct;75(10):1714-1732. Epub 2023 Jul 24 doi: 10.1002/art.42636. PMID: 37486733Free PMC Article
Systemic inflammatory syndromes as life-threatening side effects of immune checkpoint inhibitors: case report and systematic review of the literature.
Liu LL, Skribek M, Harmenberg U, Gerling M
J Immunother Cancer 2023 Mar;11(3) doi: 10.1136/jitc-2022-005841. PMID: 36878533Free PMC Article
Hemophagocytic syndromes (HPSs) including hemophagocytic lymphohistiocytosis (HLH) in adults: A systematic scoping review.
Hayden A, Park S, Giustini D, Lee AY, Chen LY
Blood Rev 2016 Nov;30(6):411-420. Epub 2016 May 20 doi: 10.1016/j.blre.2016.05.001. PMID: 27238576

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