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Familial hemophagocytic lymphohistiocytosis(FHL)

MedGen UID:
78797
Concept ID:
C0272199
Disease or Syndrome
Synonyms: Familial erythrophagocytic lymphohistiocytosis; Familial histiocytic reticulosis; FHL; Hemophagocytic lymphohistiocytosis; Hereditary hemophagocytic lymphohistiocytosis
SNOMED CT: Familial hemophagocytic lymphohistiocytosis (398250003); Familial hemophagocytic reticulosis (398250003); Familial hemophagocytic histiocytosis (398250003); FHL - Familial hemophagocytic lymphohistiocytosis (398250003); Familial histiocytic reticulosis (398250003); Familial erythrophagocytic lymphohistiocytosis (398250003); FEL - Familial erythrophagocytic lymphohistiocytosis (398250003); Genetic hemophagocytic lymphohistiocytosis (398250003); Primary hemophagocytic lymphohistiocytosis (398250003)
Modes of inheritance:
Autosomal recessive inheritance
MedGen UID:
141025
Concept ID:
C0441748
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 individuals with two pathogenic alleles, either homozygotes (two copies of the same mutant allele) or compound heterozygotes (whereby each copy of a gene has a distinct mutant allele).
 
Related genes: UNC13D, STX11, STXBP2, PRF1
 
Monarch Initiative: MONDO:0015541
OMIM®: 267700
OMIM® Phenotypic series: PS267700
Orphanet: ORPHA540

Disease characteristics

Excerpted from the GeneReview: Familial Hemophagocytic Lymphohistiocytosis
Familial hemophagocytic lymphohistiocytosis (fHLH), defined as the presence of biallelic pathogenic variants in one of four genes (PRF1, STX11, STXBP2, or UNC13D), is an immune deficiency characterized by the overactivation and excessive proliferation of T lymphocytes and macrophages, leading to infiltration and damage of organs including the bone marrow, liver, spleen, and brain. Familial HLH usually presents as an acute illness with prolonged and high fever, cytopenias, and hepatosplenomegaly. Rash and lymphadenopathy are less common. Individuals with fHLH may also exhibit liver dysfunction and neurologic abnormalities. Although manifestations of fHLH are usually evident within the first months or years of life and may develop in utero, symptomatic presentation can occur throughout childhood and into adulthood. Median survival in untreated infants with fHLH who develop active disease is less than two months after onset of manifestations; progressive manifestations of fHLH, organ dysfunction, invasive infection, and bleeding account for the majority of deaths. However, the use of newer chemoimmunotherapy protocols followed by allogeneic hematopoietic stem cell transplantation (HSCT) has improved survival. [from GeneReviews]
Authors:
Kejian Zhang  |  Itziar Astigarraga  |  Yenan Bryceson, et. al.   view full author information

Additional descriptions

From OMIM
Zur Stadt et al. (2005) summarized the clinical features of hemophagocytic lymphohistiocytosis (HLH), a rare autosomal recessive disorder characterized by massive infiltration of several organs by activated lymphocytes and macrophages. The clinical features of the disease include fever, hepatosplenomegaly, cytopenia, and less frequently central nervous system involvement. In FHL, the familial form of the disease, first episodes occur mostly during infancy, with a rapidly fatal outcome if untreated. Diagnostic criteria also include low fibrinogen and high triglyceride and ferritin levels. Chemoimmunotherapy based on corticosteroids, epipodophyllotoxins, and cyclosporin succeeds in controlling the disease in the majority of patients, although remission is rarely obtained (Henter et al., 2002). Most patients suffer an early death unless they are treated by hematopoietic stem cell transplantation (Durken et al., 1999). Genetic Heterogeneity of Familial Hemophagocytic Lymphohistiocytosis Familial hemophagocytic lymphohistiocytosis (FHL1) has been mapped to chromosome 9q. Also see FHL2 (603553), caused by mutation in the PRF1 gene (170280) on chromosome 10q22; FHL3 (608898), caused by mutation in the UNC13D gene (608897) on chromosome 17q25; FHL4 (603552), caused by mutation in the syntaxin-11 gene (STX11; 605014) on chromosome 6q24; and FHL5 (613101), caused by mutation in syntaxin-binding protein-2 (STXBP2; 601717), which is an interaction partner of STX11, on chromosome 19p13. Before the identification of mutations in the RAG1 (179615) and RAG2 (179616) genes, both of which map to 11p, Omenn syndrome (familial reticuloendotheliosis with eosinophilia; 603554) was not thought to be clearly distinct from other reported cases of hemophagocytic lymphohistiocytosis. Mutation in the HAVCR2 gene (606652) on chromosome 5q23 causes an inflammatory disorder that is sometimes associated with HLH (SPTCL; 618398). Mutation in the RC3H1 gene (609424) on chromosome 1q25 causes a hyperinflammatory disorder with HLH-like features (IMDYSHI; 618998).  http://www.omim.org/entry/267700
From MedlinePlus Genetics
Familial hemophagocytic lymphohistiocytosis is a disorder in which the immune system produces too many activated immune cells (lymphocytes) called T cells, natural killer cells, B cells, and macrophages (histiocytes). Excessive amounts of immune system proteins called cytokines are also produced. This overactivation of the immune system causes fever and damages the liver and spleen, resulting in enlargement of these organs.

Familial hemophagocytic lymphohistiocytosis also destroys blood-producing cells in the bone marrow, a process called hemophagocytosis. As a result, affected individuals have low numbers of red blood cells (anemia) and a reduction in the number of platelets, which are involved in clotting. A reduction in platelets may cause easy bruising and abnormal bleeding.

The brain may also be affected in familial hemophagocytic lymphohistiocytosis. As a result, affected individuals may experience irritability, delayed closure of the bones of the skull in infants, neck stiffness, abnormal muscle tone, impaired muscle coordination, paralysis, blindness, seizures, and coma. In addition to neurological problems, familial hemophagocytic lymphohistiocytosis can cause abnormalities of the heart, kidneys, and other organs and tissues. Affected individuals also have an increased risk of developing cancers of blood-forming cells (leukemia and lymphoma).

Signs and symptoms of familial hemophagocytic lymphohistiocytosis usually become apparent during infancy, although occasionally they appear later in life. They usually occur when the immune system launches an exaggerated response to an infection, but may also occur in the absence of infection. Without treatment, most people with familial hemophagocytic lymphohistiocytosis survive only a few months.  https://medlineplus.gov/genetics/condition/familial-hemophagocytic-lymphohistiocytosis

Professional guidelines

PubMed

Kadi Ozan Z, Erduran E, Ceylaner S, Aslan Y, Bahadir A, Reis GP, Mutlu M
J Pediatr Hematol Oncol 2024 Aug 1;46(6):e393-e401. Epub 2024 Jul 2 doi: 10.1097/MPH.0000000000002906. PMID: 38968556
Greenmyer JR, Thompson WS, Mavis S, Hassan S, Weckwerth J, Hobbs C, James K, Nahas S, Galardy P, Collura C
Pediatr Blood Cancer 2023 Jan;70(1):e29871. Epub 2022 Jul 7 doi: 10.1002/pbc.29871. PMID: 35796407
Hines MR, von Bahr Greenwood T, Beutel G, Beutel K, Hays JA, Horne A, Janka G, Jordan MB, van Laar JAM, Lachmann G, Lehmberg K, Machowicz R, Miettunen P, La Rosée P, Shakoory B, Zinter MS, Henter JI
Crit Care Med 2022 May 1;50(5):860-872. Epub 2021 Oct 5 doi: 10.1097/CCM.0000000000005361. PMID: 34605776

Recent clinical studies

Etiology

Steen EA, Nichols KE, Meyer LK
Front Immunol 2023;14:1147603. Epub 2023 Mar 9 doi: 10.3389/fimmu.2023.1147603. PMID: 36969228Free PMC Article
Lindahl H, Bryceson YT
Front Immunol 2021;12:827815. Epub 2022 Jan 19 doi: 10.3389/fimmu.2021.827815. PMID: 35126383Free 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
Azizi G, Pouyani MR, Abolhassani H, Sharifi L, Dizaji MZ, Mohammadi J, Mirshafiey A, Aghamohammadi A
Cell Immunol 2016 Dec;310:14-26. Epub 2016 Aug 27 doi: 10.1016/j.cellimm.2016.08.012. PMID: 27614846
Janka GE
Eur J Pediatr 1983 Jun-Jul;140(3):221-30. doi: 10.1007/BF00443367. PMID: 6354720

Diagnosis

Chinnici A, Beneforti L, Pegoraro F, Trambusti I, Tondo A, Favre C, Coniglio ML, Sieni E
Front Immunol 2023;14:1210041. Epub 2023 Jun 22 doi: 10.3389/fimmu.2023.1210041. PMID: 37426667Free PMC Article
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
Hines MR, von Bahr Greenwood T, Beutel G, Beutel K, Hays JA, Horne A, Janka G, Jordan MB, van Laar JAM, Lachmann G, Lehmberg K, Machowicz R, Miettunen P, La Rosée P, Shakoory B, Zinter MS, Henter JI
Crit Care Med 2022 May 1;50(5):860-872. Epub 2021 Oct 5 doi: 10.1097/CCM.0000000000005361. PMID: 34605776
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
Degar B
Hematol Oncol Clin North Am 2015 Oct;29(5):903-13. Epub 2015 Aug 25 doi: 10.1016/j.hoc.2015.06.008. PMID: 26461150

Therapy

Henter JI, von Bahr Greenwood T
Adv Exp Med Biol 2024;1448:525-551. doi: 10.1007/978-3-031-59815-9_35. PMID: 39117837
Ishimura M, Eguchi K, Sonoda M, Tanaka T, Shiraishi A, Sakai Y, Yasumi T, Miyamoto T, Voskoboinik I, Hashimoto K, Matsumoto S, Ozono S, Moritake H, Takada H, Ohga S
Int J Hematol 2024 May;119(5):592-602. Epub 2024 Mar 20 doi: 10.1007/s12185-024-03721-3. PMID: 38507116
Yasin S, Schulert GS
Curr Opin Rheumatol 2018 Sep;30(5):514-520. doi: 10.1097/BOR.0000000000000526. PMID: 29870499
Chinen J, Badran YR, Geha RS, Chou JS, Fried AJ
J Allergy Clin Immunol 2017 Oct;140(4):959-973. Epub 2017 Aug 19 doi: 10.1016/j.jaci.2017.07.023. PMID: 28826774
Janka GE
Eur J Pediatr 1983 Jun-Jul;140(3):221-30. doi: 10.1007/BF00443367. PMID: 6354720

Prognosis

Shabrish S, Kelkar M, Yadav RM, Bargir UA, Gupta M, Dalvi A, Aluri J, Kulkarni M, Shinde S, Sawant-Desai S, Kambli P, Hule G, Setia P, Jodhawat N, Gaikwad P, Dhawale A, Nambiar N, Gowri V, Pandrowala A, Taur P, Raj R, Uppuluri R, Sharma R, Kini P, Sivasankaran M, Munirathnam D, Vedam R, Vignesh P, Banday A, Rawat A, Aggarwal A, Poddar U, Girish M, Chaudhary A, Sampagar A, Jayaraman D, Chaudhary N, Shah N, Jijina F, Chandrakla S, Kanakia S, Arora B, Sen S, Lokeshwar M, Desai M, Madkaikar M
Front Immunol 2021;12:612583. Epub 2021 Mar 5 doi: 10.3389/fimmu.2021.612583. PMID: 33746956Free PMC Article
Degar B
Hematol Oncol Clin North Am 2015 Oct;29(5):903-13. Epub 2015 Aug 25 doi: 10.1016/j.hoc.2015.06.008. PMID: 26461150
Aronson IK, Worobec SM
Dermatol Ther 2010 Jul-Aug;23(4):389-402. doi: 10.1111/j.1529-8019.2010.01339.x. PMID: 20666826
Aricó M, Caselli D, Burgio GR
Pediatr Hematol Oncol 1989;6(3):247-51. doi: 10.3109/08880018909034294. PMID: 2642083
Janka GE
Eur J Pediatr 1983 Jun-Jul;140(3):221-30. doi: 10.1007/BF00443367. PMID: 6354720

Clinical prediction guides

Kögl T, Chang HF, Staniek J, Chiang SCC, Thoulass G, Lao J, Weißert K, Dettmer-Monaco V, Geiger K, Manna PT, Beziat V, Momenilandi M, Tu SM, Keppler SJ, Pattu V, Wolf P, Kupferschmid L, Tholen S, Covill LE, Ebert K, Straub T, Groß M, Gather R, Engel H, Salzer U, Schell C, Maier S, Lehmberg K, Cornu TI, Pircher H, Shahrooei M, Parvaneh N, Elling R, Rizzi M, Bryceson YT, Ehl S, Aichele P, Ammann S
J Exp Med 2024 Jul 1;221(7) Epub 2024 May 9 doi: 10.1084/jem.20221122. PMID: 38722309Free PMC Article
Hadžić N, Molnar E, Height S, Kovács G, Dhawan A, Andrikovics H, Worth A, Gilmour KC
J Pediatr 2022 Nov;250:67-74.e1. Epub 2022 Jul 11 doi: 10.1016/j.jpeds.2022.07.006. PMID: 35835228
Viñas-Giménez L, Padilla N, Batlle-Masó L, Casals F, Rivière JG, Martínez-Gallo M, de la Cruz X, Colobran R
Front Immunol 2020;11:107. Epub 2020 Jan 31 doi: 10.3389/fimmu.2020.00107. PMID: 32076423Free PMC Article
Yasin S, Schulert GS
Curr Opin Rheumatol 2018 Sep;30(5):514-520. doi: 10.1097/BOR.0000000000000526. PMID: 29870499
Willenbring RC, Johnson AJ
Int J Mol Sci 2017 Jul 25;18(8) doi: 10.3390/ijms18081608. PMID: 28757574Free PMC Article

Recent systematic reviews

Ricci S, Sarli WM, Lodi L, Canessa C, Lippi F, Dini D, Ferrari M, Pisano L, Sieni E, Indolfi G, Resti M, Azzari C
Front Immunol 2024;15:1282804. Epub 2024 Feb 13 doi: 10.3389/fimmu.2024.1282804. PMID: 38415256Free PMC Article
Amirifar P, Ranjouri MR, Abolhassani H, Moeini Shad T, Almasi-Hashiani A, Azizi G, Moamer S, Aghamohammadi A, Yazdani R
Pediatr Allergy Immunol 2021 Jan;32(1):186-197. Epub 2020 Aug 24 doi: 10.1111/pai.13323. PMID: 32679608

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