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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 characterized 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.
Splenomegaly
MedGen UID:
52469
Concept ID:
C0038002
Finding
Abnormal increased size of the spleen.
Lymphadenopathy
MedGen UID:
96929
Concept ID:
C0497156
Disease or Syndrome
Enlargement (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.
Skin rash
MedGen UID:
1830322
Concept ID:
C5779628
Sign or Symptom
A red eruption of the skin.
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

Xu Y, Li W, Gan J, He X, Huang X
Ann Hematol 2023 Dec;102(12):3325-3333. Epub 2023 Oct 3 doi: 10.1007/s00277-023-05476-z. PMID: 37787838
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
Chellapandian D, Chitty-Lopez M, Leiding JW
Immunol Allergy Clin North Am 2020 Aug;40(3):511-526. doi: 10.1016/j.iac.2020.04.001. PMID: 32654696
Marsh RA, Jordan MB, Talano JA, Nichols KE, Kumar A, Naqvi A, Vaiselbuh SR; Histiocyte Society Salvage Therapy Working Group
Pediatr Blood Cancer 2017 Apr;64(4) Epub 2016 Oct 27 doi: 10.1002/pbc.26308. PMID: 27786410
Mehta RS, Smith RE
Med Oncol 2013 Dec;30(4):740. Epub 2013 Oct 9 doi: 10.1007/s12032-013-0740-3. PMID: 24105023

Diagnosis

Le Calvez B, Thomas C, Huault A, Cassagnau E, Béné MC, Eveillard M
Am J Hematol 2022 Apr;97(4):508-509. Epub 2021 Oct 5 doi: 10.1002/ajh.26364. PMID: 34591997
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
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
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
Marsh RA, Jordan MB, Talano JA, Nichols KE, Kumar A, Naqvi A, Vaiselbuh SR; Histiocyte Society Salvage Therapy Working Group
Pediatr Blood Cancer 2017 Apr;64(4) Epub 2016 Oct 27 doi: 10.1002/pbc.26308. PMID: 27786410

Therapy

Merli P, Quintarelli C, Strocchio L, Locatelli F
Pediatr Blood Cancer 2021 Apr;68(4):e28900. Epub 2021 Jan 23 doi: 10.1002/pbc.28900. PMID: 33484058
Knaak C, Schuster FS, Spies C, Vorderwülbecke G, Nyvlt P, Schenk T, Balzer F, La Rosée P, Janka G, Brunkhorst FM, Keh D, Lachmann G
Shock 2020 Jun;53(6):701-709. doi: 10.1097/SHK.0000000000001454. PMID: 31626037
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
Kumar S, Ward BR, Irani AM
Immunol Allergy Clin North Am 2017 May;37(2):431-448. doi: 10.1016/j.iac.2017.01.013. PMID: 28366486
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

Prognosis

Xu L, Guo X, Guan H
Int J Lab Hematol 2022 Feb;44(1):74-81. Epub 2021 Oct 28 doi: 10.1111/ijlh.13736. PMID: 34709704
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
Knaak C, Schuster FS, Spies C, Vorderwülbecke G, Nyvlt P, Schenk T, Balzer F, La Rosée P, Janka G, Brunkhorst FM, Keh D, Lachmann G
Shock 2020 Jun;53(6):701-709. doi: 10.1097/SHK.0000000000001454. PMID: 31626037
Marsh RA, Jordan MB, Talano JA, Nichols KE, Kumar A, Naqvi A, Vaiselbuh SR; Histiocyte Society Salvage Therapy Working Group
Pediatr Blood Cancer 2017 Apr;64(4) Epub 2016 Oct 27 doi: 10.1002/pbc.26308. PMID: 27786410
Malhotra AK, Bhaskar G, Nanda M, Kabra M, Singh MK, Ramam M
J Am Acad Dermatol 2006 Aug;55(2):337-40. doi: 10.1016/j.jaad.2005.11.1056. PMID: 16844525

Clinical prediction guides

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
Ascierto PA, Fu B, Wei H
J Immunother Cancer 2021 Apr;9(4) doi: 10.1136/jitc-2020-002285. PMID: 33837054Free 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
Ab-Rahman HA, Rahim H, AbuBakar S, Wong PF
Int J Med Sci 2016;13(3):179-86. Epub 2016 Feb 17 doi: 10.7150/ijms.13680. PMID: 26941578Free PMC Article

Recent systematic reviews

Meena DS, Kumar A, Kumar D, Bohra GK, Purohit A
Am J Trop Med Hyg 2024 Jun 5;110(6):1217-1222. Epub 2024 Apr 2 doi: 10.4269/ajtmh.23-0787. PMID: 38579699Free PMC Article
Tan CJ, Ng ZQ, Bhattacharyya R, Sultana R, Lee JH
Pediatr Blood Cancer 2023 Mar;70(3):e30122. Epub 2022 Dec 29 doi: 10.1002/pbc.30122. PMID: 36579732
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
Rajagopala S, Singh N
Acta Med Acad 2012;41(2):161-74. doi: 10.5644/ama2006-124.49. PMID: 23331391

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