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Familial hemophagocytic lymphohistiocytosis 4(FHL4)

MedGen UID:
350245
Concept ID:
C1863728
Disease or Syndrome
Synonym: FHL4
 
Gene (location): STX11 (6q24.2)
 
Monarch Initiative: MONDO:0011336
OMIM®: 603552

Definition

Hemophagocytic lymphohistiocytosis is a hyperinflammatory disorder clinically diagnosed based on the fulfillment of 5 of 8 criteria, including fever, splenomegaly, bicytopenia, hypertriglyceridemia and/or hypofibrinogenemia, hemophagocytosis, low or absent natural killer (NK) cell activity, hyperferritinemia, and high soluble IL2 receptor levels (IL2R; 147730). The disorder typically presents in infancy or early childhood. Persistent remission is rarely achieved with chemo- or immunotherapy; hematopoietic stem cell transplantation is the only cure (summary by Muller et al., 2014). For a phenotypic description and a discussion of genetic heterogeneity of familial hemophagocytic lymphohistiocytosis (FHL), see 267700. [from OMIM]

Clinical features

From HPO
Hepatomegaly
MedGen UID:
42428
Concept ID:
C0019209
Finding
Abnormally increased size of the liver.
Jaundice
MedGen UID:
43987
Concept ID:
C0022346
Sign or Symptom
Yellow pigmentation of the skin due to bilirubin, which in turn is the result of increased bilirubin concentration in the bloodstream.
Seizure
MedGen UID:
20693
Concept ID:
C0036572
Sign or Symptom
A seizure is an intermittent abnormality of nervous system physiology characterised by a transient occurrence of signs and/or symptoms due to abnormal excessive or synchronous neuronal activity in the brain.
Global developmental delay
MedGen UID:
107838
Concept ID:
C0557874
Finding
A delay in the achievement of motor or mental milestones in the domains of development of a child, including motor skills, speech and language, cognitive skills, and social and emotional skills. This term should only be used to describe children younger than five years of age.
Anemia
MedGen UID:
1526
Concept ID:
C0002871
Disease or Syndrome
A reduction in erythrocytes volume or hemoglobin concentration.
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.
Hypotonia
MedGen UID:
10133
Concept ID:
C0026827
Finding
Hypotonia is an abnormally low muscle tone (the amount of tension or resistance to movement in a muscle). Even when relaxed, muscles have a continuous and passive partial contraction which provides some resistance to passive stretching. Hypotonia thus manifests as diminished resistance to passive stretching. Hypotonia is not the same as muscle weakness, although the two conditions can co-exist.
Conjunctivitis
MedGen UID:
1093
Concept ID:
C0009763
Disease or Syndrome
Inflammation of the conjunctiva.
Skin rash
MedGen UID:
8732
Concept ID:
C0015230
Finding
A red eruption of the skin.
Splenomegaly
MedGen UID:
52469
Concept ID:
C0038002
Finding
Abnormal increased size of the spleen.
Lymphadenopathy
MedGen UID:
96929
Concept ID:
C0497156
Disease or Syndrome
Enlargment (swelling) of a lymph node.
Neutropenia
MedGen UID:
163121
Concept ID:
C0853697
Finding
An abnormally low number of neutrophils in the peripheral blood.
Hemophagocytosis
MedGen UID:
163750
Concept ID:
C0876991
Disease or Syndrome
Phagocytosis by macrophages of erythrocytes, leukocytes, platelets, and their precursors in bone marrow and other tissues.
Edema
MedGen UID:
4451
Concept ID:
C0013604
Pathologic Function
An abnormal accumulation of fluid beneath the skin, or in one or more cavities of the body.
Fever
MedGen UID:
5169
Concept ID:
C0015967
Sign or Symptom
Body temperature elevated above the normal range.
Increased circulating ferritin concentration
MedGen UID:
69130
Concept ID:
C0241013
Finding
Increased concentration of ferritin in the blood circulation.
Hypertriglyceridemia
MedGen UID:
167238
Concept ID:
C0813230
Finding
An abnormal increase in the level of triglycerides in the blood.
Recurrent fever
MedGen UID:
811468
Concept ID:
C3714772
Sign or Symptom
Periodic (episodic or recurrent) bouts of fever.

Professional guidelines

PubMed

Liu B, Cheng L, Gao H, Zhang J, Dong Y, Gao W, Yuan S, Gong T, Huang W
Cancer Lett 2023 Jan 28;553:215996. Epub 2022 Nov 5 doi: 10.1016/j.canlet.2022.215996. PMID: 36343787
Zhang Q, Zhao YZ, Ma HH, Wang D, Cui L, Li WJ, Wei A, Wang CJ, Wang TY, Li ZG, Zhang R
Blood 2022 Jun 16;139(24):3493-3504. doi: 10.1182/blood.2021014860. PMID: 35344583
Liu P, Pan X, Chen C, Niu T, Shuai X, Wang J, Chen X, Liu J, Guo Y, Xie L, Wu Y, Liu Y, Liu T
Blood 2020 Mar 12;135(11):826-833. doi: 10.1182/blood.2019003886. PMID: 31914172

Recent clinical studies

Etiology

Imashuku S, Morimoto A, Ishii E
Acta Paediatr 2021 Oct;110(10):2729-2736. Epub 2021 Jun 22 doi: 10.1111/apa.15973. PMID: 34096649
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
Karakike E, Giamarellos-Bourboulis EJ
Front Immunol 2019;10:55. Epub 2019 Jan 31 doi: 10.3389/fimmu.2019.00055. PMID: 30766533Free PMC Article
Kanegane H, Hoshino A, Okano T, Yasumi T, Wada T, Takada H, Okada S, Yamashita M, Yeh TW, Nishikomori R, Takagi M, Imai K, Ochs HD, Morio T
Allergol Int 2018 Jan;67(1):43-54. Epub 2017 Jul 3 doi: 10.1016/j.alit.2017.06.003. PMID: 28684198
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

Diagnosis

Ponnatt TS, Lilley CM, Mirza KM
Arch Pathol Lab Med 2022 Apr 1;146(4):507-519. doi: 10.5858/arpa.2020-0802-RA. PMID: 34347856
El-Mallawany NK, Curry CV, Allen CE
Br J Haematol 2022 Jan;196(1):31-44. Epub 2021 Jun 24 doi: 10.1111/bjh.17638. PMID: 34169507
Imashuku S, Morimoto A, Ishii E
Acta Paediatr 2021 Oct;110(10):2729-2736. Epub 2021 Jun 22 doi: 10.1111/apa.15973. PMID: 34096649
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
Griffin G, Shenoi S, Hughes GC
Best Pract Res Clin Rheumatol 2020 Aug;34(4):101515. Epub 2020 May 7 doi: 10.1016/j.berh.2020.101515. PMID: 32387063

Therapy

Iba T, Levy JH
Trends Cardiovasc Med 2022 Jul;32(5):249-256. Epub 2022 Feb 22 doi: 10.1016/j.tcm.2022.02.008. PMID: 35202800Free PMC Article
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
Karakike E, Giamarellos-Bourboulis EJ
Front Immunol 2019;10:55. Epub 2019 Jan 31 doi: 10.3389/fimmu.2019.00055. PMID: 30766533Free PMC Article
Bollard CM, Cohen JI
Blood 2018 Jun 28;131(26):2899-2905. Epub 2018 Apr 30 doi: 10.1182/blood-2018-03-785931. PMID: 29712633Free PMC Article
Dumas G, Prendki V, Haroche J, Amoura Z, Cacoub P, Galicier L, Meyer O, Rapp C, Deligny C, Godeau B, Aslangul E, Lambotte O, Papo T, Pouchot J, Hamidou M, Bachmeyer C, Hachulla E, Carmoi T, Dhote R, Gerin M, Mekinian A, Stirnemann J, Charlotte F, Farge D, Molina T, Fain O
Medicine (Baltimore) 2014 Nov;93(24):372-382. doi: 10.1097/MD.0000000000000220. PMID: 25500707Free PMC Article

Prognosis

Zhang H, Zhao S, Cao Z
Front Immunol 2022;13:1001055. Epub 2022 Oct 28 doi: 10.3389/fimmu.2022.1001055. PMID: 36389673Free PMC Article
Ponnatt TS, Lilley CM, Mirza KM
Arch Pathol Lab Med 2022 Apr 1;146(4):507-519. doi: 10.5858/arpa.2020-0802-RA. PMID: 34347856
Blincoe A, Heeg M, Campbell PK, Hines M, Khojah A, Klein-Gitelman M, Talano JA, Speckmann C, Touzot F, Lankester A, Legger GE, Rivière JG, Garcia-Prat M, Alonso L, Putti MC, Lehmberg K, Maier S, El Chazli Y, Elmaksoud MA, Astigarraga I, Kurjane N, Bulina I, Kenina V, Bryceson Y, Rascon J, Lortie A, Goldstein G, Booth C, Worth A, Wassmer E, Schmitt EG, Warren JT, Bednarski JJ, Ali S, Chiang KY, Krueger J, Henry MM, Holland SM, Marsh RA, Ehl S, Haddad E
J Clin Immunol 2020 Aug;40(6):901-916. Epub 2020 Jul 7 doi: 10.1007/s10875-020-00814-6. PMID: 32638196
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
Karakike E, Giamarellos-Bourboulis EJ
Front Immunol 2019;10:55. Epub 2019 Jan 31 doi: 10.3389/fimmu.2019.00055. PMID: 30766533Free PMC Article

Clinical prediction guides

Zoref-Lorenz A, Murakami J, Hofstetter L, Iyer S, Alotaibi AS, Mohamed SF, Miller PG, Guber E, Weinstein S, Yacobovich J, Nikiforow S, Ebert BL, Lane A, Pasvolsky O, Raanani P, Nagler A, Berliner N, Daver N, Ellis M, Jordan MB
Blood 2022 Feb 17;139(7):1098-1110. doi: 10.1182/blood.2021012764. PMID: 34780598Free PMC Article
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
Karakike E, Giamarellos-Bourboulis EJ
Front Immunol 2019;10:55. Epub 2019 Jan 31 doi: 10.3389/fimmu.2019.00055. PMID: 30766533Free PMC Article
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
Dumas G, Prendki V, Haroche J, Amoura Z, Cacoub P, Galicier L, Meyer O, Rapp C, Deligny C, Godeau B, Aslangul E, Lambotte O, Papo T, Pouchot J, Hamidou M, Bachmeyer C, Hachulla E, Carmoi T, Dhote R, Gerin M, Mekinian A, Stirnemann J, Charlotte F, Farge D, Molina T, Fain O
Medicine (Baltimore) 2014 Nov;93(24):372-382. doi: 10.1097/MD.0000000000000220. PMID: 25500707Free PMC Article

Recent systematic reviews

Dolladille C, Ederhy S, Ezine E, Choquet S, Nguyen LS, Alexandre J, Moslehi JJ, Dechartres A, Salem JE
Am J Hematol 2021 Sep 1;96(9):1101-1111. Epub 2021 Jun 23 doi: 10.1002/ajh.26259. PMID: 34057232
Zhang M, Wang H, Tang J, He Y, Xiong T, Li W, Qu Y, Mu D
BMC Pediatr 2021 Mar 15;21(1):127. doi: 10.1186/s12887-021-02599-y. PMID: 33722228Free PMC Article
Knaak C, Schuster FS, Nyvlt P, Spies C, Feinkohl I, Beutel G, Schenk T, La Rosée P, Janka G, Brunkhorst FM, Keh D, Lachmann G
Crit Care Med 2020 Nov;48(11):e1137-e1146. doi: 10.1097/CCM.0000000000004581. PMID: 32947471
Giang HTN, Banno K, Minh LHN, Trinh LT, Loc LT, Eltobgy A, Tai LLT, Khan A, Tuan NH, Reda Y, Samsom M, Nam NT, Huy NT, Hirayama K
Rev Med Virol 2018 Nov;28(6):e2005. Epub 2018 Aug 15 doi: 10.1002/rmv.2005. PMID: 30109914
Rajagopala S, Singh N
Acta Med Acad 2012;41(2):161-74. doi: 10.5644/ama2006-124.49. PMID: 23331391

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