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Hemophagocytic lymphohistiocytosis, familial, 3(FHL3)

MedGen UID:
332383
Concept ID:
C1837174
Disease or Syndrome
Synonyms: FHL3
Modes of inheritance:
Autosomal recessive inheritance
MedGen UID:
141025
Concept ID:
C0441748
Intellectual Product
Sources: HPO, OMIM, 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 homozygotes. In the context of medical genetics, autosomal recessive disorders manifest in homozygotes (with two copies of the mutant allele) or compound heterozygotes (whereby each copy of a gene has a distinct mutant allele).
Autosomal recessive inheritance (HPO, OMIM, Orphanet)
 
Gene (location): UNC13D (17q25.1)
OMIM®: 608898

Disease characteristics

Excerpted from the GeneReview: Hemophagocytic Lymphohistiocytosis, Familial
Familial hemophagocytic lymphohistiocytosis (FHL) is characterized by proliferation and infiltration of hyperactivated macrophages and T-lymphocytes manifesting as acute illness with prolonged fever, cytopenias, and hepatosplenomegaly. Onset is typically within the first months or years of life and, on occasion, in utero, although later childhood or adult onset is more common than previously suspected. Neurologic abnormalities may be present initially or may develop later; they may include increased intracranial pressure, irritability, neck stiffness, hypotonia, hypertonia, convulsions, cranial nerve palsies, ataxia, hemiplegia, quadriplegia, blindness, and coma. Rash and lymphadenopathy are less common. Other findings include liver dysfunction and bone marrow hemophagocytosis. The median survival of children with typical FHL, without treatment, is less than two months; progression of hemophagocytic lymphohistiocytosis and infection account for the majority of deaths in untreated individuals. [from GeneReviews]
Authors:
Kejian Zhang  |  Alexandra H Filipovich  |  Judith Johnson, et. al.   view full author information

Additional descriptions

From OMIM
Secretion of the contents of cytolytic granules at the immunologic synapse is a highly regulated process essential for lymphocyte cytotoxicity. This process requires the rapid transfer of perforin (170280)-containing lytic granules to the target cell interface, followed by their docking and fusion with the plasma membrane. Familial hemophagocytic lymphohistiocytosis is a genetically heterogeneous condition characterized by defective cytotoxicity. For a more detailed description of FHL, see 267700.  http://www.omim.org/entry/608898
From GHR
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://ghr.nlm.nih.gov/condition/familial-hemophagocytic-lymphohistiocytosis

Clinical features

Fever
MedGen UID:
5169
Concept ID:
C0015967
Sign or Symptom
A condition characterized by an abnormally high body temperature. In a hyperthermic state, the hypothalamic set-point is normal but body temperature increases and overrides the ability to lose heat, resulting from exogenous heat exposure or endogenous heat production.
Hepatosplenomegaly
MedGen UID:
9225
Concept ID:
C0019214
Sign or Symptom
An abnormal enlargement of both the liver and spleen.
Hypofibrinogenemia
MedGen UID:
107511
Concept ID:
C0553681
Disease or Syndrome
Decreased concentration of fibrinogen in the 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.
Hypertriglyceridemia
MedGen UID:
279403
Concept ID:
C1522137
Laboratory or Test Result
A laboratory test result indicating elevated triglyceride concentration in the blood.

Recent clinical studies

Etiology

Qian Y, Johnson JA, Connor JA, Valencia CA, Barasa N, Schubert J, Husami A, Kissell D, Zhang G, Weirauch MT, Filipovich AH, Zhang K
Pediatr Blood Cancer 2014 Jun;61(6):1034-40. Epub 2014 Jan 28 doi: 10.1002/pbc.24955. PMID: 24470399
Sieni E, Cetica V, Santoro A, Beutel K, Mastrodicasa E, Meeths M, Ciambotti B, Brugnolo F, zur Stadt U, Pende D, Moretta L, Griffiths GM, Henter JI, Janka G, Aricò M
J Med Genet 2011 May;48(5):343-52. Epub 2011 Jan 19 doi: 10.1136/jmg.2010.085456. PMID: 21248318Free PMC Article

Diagnosis

Kamoun F, Hsairi M, Grandin V, Ben Ameur S, De Saint Basile G, Hachicha M
Arch Pediatr 2017 Jan;24(1):33-35. Epub 2016 Nov 30 doi: 10.1016/j.arcped.2016.10.021. PMID: 27914778
Hori M, Yasumi T, Shimodera S, Shibata H, Hiejima E, Oda H, Izawa K, Kawai T, Ishimura M, Nakano N, Shirakawa R, Nishikomori R, Takada H, Morita S, Horiuchi H, Ohara O, Ishii E, Heike T
J Clin Immunol 2017 Jan;37(1):92-99. Epub 2016 Nov 28 doi: 10.1007/s10875-016-0357-3. PMID: 27896523
Qian Y, Johnson JA, Connor JA, Valencia CA, Barasa N, Schubert J, Husami A, Kissell D, Zhang G, Weirauch MT, Filipovich AH, Zhang K
Pediatr Blood Cancer 2014 Jun;61(6):1034-40. Epub 2014 Jan 28 doi: 10.1002/pbc.24955. PMID: 24470399
Manno EC, Salfa I, Palma P, Bertaina A, Lombardi A, Moretta F, Coniglio ML, Sieni E, Aricò M, Finocchi A
J Pediatr Hematol Oncol 2014 Mar;36(2):e128-30. doi: 10.1097/MPH.0b013e318292bc7c. PMID: 23669735
Seo JY, Song JS, Lee KO, Won HH, Kim JW, Kim SH, Lee SH, Yoo KH, Sung KW, Koo HH, Kang HJ, Shin HY, Ahn HS, Han DK, Kook H, Hwang TJ, Lyu CJ, Lee MJ, Kim JY, Park SS, Lim YT, Kim BE, Koh KN, Im HJ, Seo JJ, Kim HJ; Korea Histiocytosis Working Party.
Ann Hematol 2013 Mar;92(3):357-64. Epub 2012 Nov 24 doi: 10.1007/s00277-012-1628-6. PMID: 23180437

Prognosis

Kamoun F, Hsairi M, Grandin V, Ben Ameur S, De Saint Basile G, Hachicha M
Arch Pediatr 2017 Jan;24(1):33-35. Epub 2016 Nov 30 doi: 10.1016/j.arcped.2016.10.021. PMID: 27914778

Clinical prediction guides

Kamoun F, Hsairi M, Grandin V, Ben Ameur S, De Saint Basile G, Hachicha M
Arch Pediatr 2017 Jan;24(1):33-35. Epub 2016 Nov 30 doi: 10.1016/j.arcped.2016.10.021. PMID: 27914778
Sieni E, Cetica V, Santoro A, Beutel K, Mastrodicasa E, Meeths M, Ciambotti B, Brugnolo F, zur Stadt U, Pende D, Moretta L, Griffiths GM, Henter JI, Janka G, Aricò M
J Med Genet 2011 May;48(5):343-52. Epub 2011 Jan 19 doi: 10.1136/jmg.2010.085456. PMID: 21248318Free PMC Article

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