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Familial hemophagocytic lymphohistiocytosis type 1(FHL1)

MedGen UID:
1642840
Concept ID:
C4551514
Disease or Syndrome
Synonyms: ERYTHROPHAGOCYTIC LYMPHOHISTIOCYTOSIS, FAMILIAL; HEMOPHAGOCYTIC RETICULOSIS, FAMILIAL; RETICULOSIS, FAMILIAL HISTIOCYTIC
 
Monarch Initiative: MONDO:0009974
OMIM®: 267700

Definition

Familial Hemophagocytic lymphohistiocytosis (FHL) is a rare primary immunodeficiency characterized by a macrophage activation syndrome with an onset usually occurring within a few months or less common several years after birth. [from MONDO]

Clinical features

From HPO
Failure to thrive
MedGen UID:
746019
Concept ID:
C2315100
Disease or Syndrome
Failure to thrive (FTT) refers to a child whose physical growth is substantially below the norm.
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.
Cerebellar ataxia
MedGen UID:
849
Concept ID:
C0007758
Disease or Syndrome
Cerebellar ataxia refers to ataxia due to dysfunction of the cerebellum. This causes a variety of elementary neurological deficits including asynergy (lack of coordination between muscles, limbs and joints), dysmetria (lack of ability to judge distances that can lead to under- or overshoot in grasping movements), and dysdiadochokinesia (inability to perform rapid movements requiring antagonizing muscle groups to be switched on and off repeatedly).
Coma
MedGen UID:
1054
Concept ID:
C0009421
Disease or Syndrome
The complete absence of wakefulness and consciousness, which is evident through a lack of response to any form of external stimuli.
Hemiplegia
MedGen UID:
9196
Concept ID:
C0018991
Sign or Symptom
Paralysis (complete loss of muscle function) in the arm, leg, and in some cases the face on one side of the body.
Tetraplegia
MedGen UID:
19617
Concept ID:
C0034372
Disease or Syndrome
Paralysis of all four limbs, and trunk of the body below the level of an associated injury to the spinal cord. The etiology of quadriplegia is similar to that of paraplegia except that the lesion is in the cervical spinal cord rather than in the thoracic or lumbar segments of the spinal cord.
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.
Increased intracranial pressure
MedGen UID:
56241
Concept ID:
C0151740
Finding
An increase of the pressure inside the cranium (skull) and thereby in the brain tissue and cerebrospinal fluid.
CSF pleocytosis
MedGen UID:
56247
Concept ID:
C0151857
Disease or Syndrome
An increased white blood cell count in the cerebrospinal fluid.
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.
Increased CSF protein concentration
MedGen UID:
329971
Concept ID:
C1806780
Finding
Increased concentration of protein in the cerebrospinal fluid.
Irritability
MedGen UID:
397841
Concept ID:
C2700617
Mental Process
A proneness to anger, i.e., a tendency to become easily bothered or annoyed.
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.
Prolonged partial thromboplastin time
MedGen UID:
66815
Concept ID:
C0240671
Finding
Increased time to coagulation in the partial thromboplastin time (PTT) test, a measure of the intrinsic and common coagulation pathways. Phospholipid, and activator, and calcium are mixed into an anticoagulated plasma sample, and the time is measured until a thrombus forms.
Hypofibrinogenemia
MedGen UID:
107511
Concept ID:
C0553681
Disease or Syndrome
Decreased concentration of fibrinogen in the blood.
Prolonged prothrombin time
MedGen UID:
208879
Concept ID:
C0853225
Finding
Increased time to coagulation in the prothrombin time test, which is a measure of the extrinsic pathway of coagulation. The results of the prothrombin time test are often expressed in terms of the International normalized ratio (INR), which is calculated as a ratio of the patient's prothrombin time (PT) to a control PT standardized for the potency of the thromboplastin reagent developed by the World Health Organization (WHO) using the formula
Hypertonia
MedGen UID:
10132
Concept ID:
C0026826
Finding
A condition in which there is increased muscle tone so that arms or legs, for example, are stiff and difficult to move.
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.
Generalized hypotonia
MedGen UID:
346841
Concept ID:
C1858120
Finding
Generalized muscular hypotonia (abnormally low muscle tone).
Leukopenia
MedGen UID:
6073
Concept ID:
C0023530
Disease or Syndrome
An abnormal decreased number of leukocytes in the blood.
Meningitis
MedGen UID:
6298
Concept ID:
C0025289
Disease or Syndrome
Inflammation of the meninges.
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.
Infectious encephalitis
MedGen UID:
108917
Concept ID:
C0596773
Disease or Syndrome
A disorder of the brain caused by an infectious agent that presents with fever, headache, and an altered level of consciousness. There may also be focal or multifocal neurologic deficits, and focal or generalized seizure activity.
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.
Hyponatremia
MedGen UID:
6984
Concept ID:
C0020625
Finding
An abnormally decreased sodium concentration in the blood.
Decreased HDL cholesterol concentration
MedGen UID:
57731
Concept ID:
C0151691
Finding
An decreased concentration of high-density lipoprotein cholesterol in the blood.
Hypoalbuminemia
MedGen UID:
68694
Concept ID:
C0239981
Finding
Reduction in the concentration of albumin in the blood.
Increased circulating ferritin concentration
MedGen UID:
69130
Concept ID:
C0241013
Finding
Increased concentration of ferritin in the blood circulation.
Hypoproteinemia
MedGen UID:
581229
Concept ID:
C0392692
Finding
A decreased concentration of protein in the blood.
Increased LDL cholesterol concentration
MedGen UID:
154289
Concept ID:
C0549399
Finding
An elevated concentration of low-density lipoprotein cholesterol in the blood.
Increased total bilirubin
MedGen UID:
152856
Concept ID:
C0741494
Finding
Increased concentration of total (conjugated and unconjugated) bilirubin in the blood.
Hypertriglyceridemia
MedGen UID:
167238
Concept ID:
C0813230
Finding
An abnormal increase in the level of triglycerides in the blood.
Generalized edema
MedGen UID:
376817
Concept ID:
C1850534
Pathologic Function
Generalized abnormal accumulation of fluid beneath the skin, or in one or more cavities of the body.
Increased VLDL cholesterol concentration
MedGen UID:
867364
Concept ID:
C4021729
Finding
An increase in the amount of very-low-density lipoprotein cholesterol in the blood.

Professional guidelines

PubMed

Kim JS, Lee JY, Yang JW, Lee KH, Effenberger M, Szpirt W, Kronbichler A, Shin JI
Theranostics 2021;11(1):316-329. Epub 2021 Jan 1 doi: 10.7150/thno.49713. PMID: 33391477Free PMC Article
Zhang J, Sun Y, Shi X, Zhang R, Wang Y, Xiao J, Cao J, Gao Z, Wang J, Wu L, Wei W, Wang Z
Orphanet J Rare Dis 2020 May 6;15(1):112. doi: 10.1186/s13023-020-01390-z. PMID: 32375849Free PMC Article
Gholam C, Grigoriadou S, Gilmour KC, Gaspar HB
Clin Exp Immunol 2011 Mar;163(3):271-83. doi: 10.1111/j.1365-2249.2010.04302.x. PMID: 21303357Free PMC Article

Recent clinical studies

Etiology

Xu X, Liang F, Chen J, Chen F, Kong L, Ding Y
Aging Male 2023 Dec;26(1):2235005. doi: 10.1080/13685538.2023.2235005. PMID: 37452735
Groß M, Speckmann C, May A, Gajardo-Carrasco T, Wustrau K, Maier SL, Panning M, Huzly D, Agaimy A, Bryceson YT, Choo S, Chow CW, Dückers G, Fasth A, Fraitag S, Gräwe K, Haxelmans S, Holzinger D, Hudowenz O, Hübschen JM, Khurana C, Kienle K, Klifa R, Korn K, Kutzner H, Lämmermann T, Ledig S, Lipsker D, Meeths M, Naumann-Bartsch N, Rascon J, Schänzer A, Seidl M, Tesi B, Vauloup-Fellous C, Vollmer-Kary B, Warnatz K, Wehr C, Neven B, Vargas P, Sepulveda FE, Lehmberg K, Schmitt-Graeff A, Ehl S
J Allergy Clin Immunol 2022 Jan;149(1):388-399.e4. Epub 2021 May 24 doi: 10.1016/j.jaci.2021.05.007. PMID: 34033843
Wustrau K, Greil J, Sykora KW, Albert MH, Burkhardt B, Lang P, Meisel R, Wössmann W, Beier R, Schulz A, Bader P, Chada M, Kühl JS, Schlegel PG, Speckmann C, Gruhn B, Seidel M, Wawer A, Ozga AK, Janka G, Ehl S, Müller I, Lehmberg K
Pediatr Blood Cancer 2020 Sep;67(9):e28523. Epub 2020 Jul 3 doi: 10.1002/pbc.28523. PMID: 32618429
Capuano C, Paolini R, Molfetta R, Frati L, Santoni A, Galandrini R
Blood 2012 Mar 8;119(10):2252-62. Epub 2012 Jan 23 doi: 10.1182/blood-2010-12-324160. PMID: 22271450
Imashuku S
J Pediatr Hematol Oncol 2011 Jan;33(1):35-9. doi: 10.1097/MPH.0b013e3181f84a52. PMID: 21088619

Diagnosis

Xu X, Liang F, Chen J, Chen F, Kong L, Ding Y
Aging Male 2023 Dec;26(1):2235005. doi: 10.1080/13685538.2023.2235005. PMID: 37452735
Fukuda K, Takeuchi A, Tamai K, Nakamura M, Kageyama M
Pediatr Int 2023 Jan;65(1):e15382. doi: 10.1111/ped.15382. PMID: 36214076
Chaturvedi V, Marsh RA, Zoref-Lorenz A, Owsley E, Chaturvedi V, Nguyen TC, Goldman JR, Henry MM, Greenberg JN, Ladisch S, Hermiston ML, Jeng M, Naqvi A, Allen CE, Wong HR, Jordan MB
Blood 2021 Apr 29;137(17):2337-2346. doi: 10.1182/blood.2020009499. PMID: 33512385Free PMC Article
Durmaz A, Ozkinay F, Onay H, Tombuloglu M, Atay A, Gursel O, Peker E, Atmaca M, Genel F, Bozabali S, Akin H, Ozkinay C
J Pediatr Hematol Oncol 2012 Oct;34(7):541-4. doi: 10.1097/MPH.0b013e31826781ad. PMID: 22983416
Imashuku S
J Pediatr Hematol Oncol 2011 Jan;33(1):35-9. doi: 10.1097/MPH.0b013e3181f84a52. PMID: 21088619

Therapy

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
Stark K, Rowe C, Mathur A, Matossian J, Lawrie A
J R Coll Physicians Edinb 2024 Mar;54(1):29-33. Epub 2023 Dec 30 doi: 10.1177/14782715231220108. PMID: 38160201
Groß M, Speckmann C, May A, Gajardo-Carrasco T, Wustrau K, Maier SL, Panning M, Huzly D, Agaimy A, Bryceson YT, Choo S, Chow CW, Dückers G, Fasth A, Fraitag S, Gräwe K, Haxelmans S, Holzinger D, Hudowenz O, Hübschen JM, Khurana C, Kienle K, Klifa R, Korn K, Kutzner H, Lämmermann T, Ledig S, Lipsker D, Meeths M, Naumann-Bartsch N, Rascon J, Schänzer A, Seidl M, Tesi B, Vauloup-Fellous C, Vollmer-Kary B, Warnatz K, Wehr C, Neven B, Vargas P, Sepulveda FE, Lehmberg K, Schmitt-Graeff A, Ehl S
J Allergy Clin Immunol 2022 Jan;149(1):388-399.e4. Epub 2021 May 24 doi: 10.1016/j.jaci.2021.05.007. PMID: 34033843
Gothe F, Hatton CF, Truong L, Klimova Z, Kanderova V, Fejtkova M, Grainger A, Bigley V, Perthen J, Mitra D, Janda A, Fronkova E, Moravcikova D, Hambleton S, Duncan CJA
Clin Infect Dis 2022 Jan 7;74(1):136-139. doi: 10.1093/cid/ciaa1790. PMID: 33252644Free PMC Article
Vavassori S, Chou J, Faletti LE, Haunerdinger V, Opitz L, Joset P, Fraser CJ, Prader S, Gao X, Schuch LA, Wagner M, Hoefele J, Maccari ME, Zhu Y, Elakis G, Gabbett MT, Forstner M, Omran H, Kaiser T, Kessler C, Olbrich H, Frosk P, Almutairi A, Platt CD, Elkins M, Weeks S, Rubin T, Planas R, Marchetti T, Koovely D, Klämbt V, Soliman NA, von Hardenberg S, Klemann C, Baumann U, Lenz D, Klein-Franke A, Schwemmle M, Huber M, Sturm E, Hartleif S, Häffner K, Gimpel C, Brotschi B, Laube G, Güngör T, Buckley MF, Kottke R, Staufner C, Hildebrandt F, Reu-Hofer S, Moll S, Weber A, Kaur H, Ehl S, Hiller S, Geha R, Roscioli T, Griese M, Pachlopnik Schmid J
J Allergy Clin Immunol 2021 Aug;148(2):381-393. Epub 2021 Apr 17 doi: 10.1016/j.jaci.2021.03.045. PMID: 33872655Free PMC Article

Prognosis

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
Xu X, Liang F, Chen J, Chen F, Kong L, Ding Y
Aging Male 2023 Dec;26(1):2235005. doi: 10.1080/13685538.2023.2235005. PMID: 37452735
Chaturvedi V, Marsh RA, Zoref-Lorenz A, Owsley E, Chaturvedi V, Nguyen TC, Goldman JR, Henry MM, Greenberg JN, Ladisch S, Hermiston ML, Jeng M, Naqvi A, Allen CE, Wong HR, Jordan MB
Blood 2021 Apr 29;137(17):2337-2346. doi: 10.1182/blood.2020009499. PMID: 33512385Free PMC Article
Wustrau K, Greil J, Sykora KW, Albert MH, Burkhardt B, Lang P, Meisel R, Wössmann W, Beier R, Schulz A, Bader P, Chada M, Kühl JS, Schlegel PG, Speckmann C, Gruhn B, Seidel M, Wawer A, Ozga AK, Janka G, Ehl S, Müller I, Lehmberg K
Pediatr Blood Cancer 2020 Sep;67(9):e28523. Epub 2020 Jul 3 doi: 10.1002/pbc.28523. PMID: 32618429
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

Chaturvedi V, Marsh RA, Zoref-Lorenz A, Owsley E, Chaturvedi V, Nguyen TC, Goldman JR, Henry MM, Greenberg JN, Ladisch S, Hermiston ML, Jeng M, Naqvi A, Allen CE, Wong HR, Jordan MB
Blood 2021 Apr 29;137(17):2337-2346. doi: 10.1182/blood.2020009499. PMID: 33512385Free PMC Article
Hattori N, Sato M, Uesugi Y, Nakata A, Sasaki Y, Shimada S, Watanuki M, Fujiwara S, Kawaguchi Y, Arai N, Uto Y, Matsui T, Yanagisawa K, Tahara S, Koeffler HP, Iezumi K, Nakamaki T
Int J Hematol 2021 May;113(5):693-702. Epub 2021 Jan 1 doi: 10.1007/s12185-020-03067-6. PMID: 33385294
Bigenwald C, Fardet L, Coppo P, Meignin V, Lazure T, Fabiani B, Kohn M, Oksenhendler E, Boutboul D, Uzzan M, Lambotte O, Galicier L
Br J Haematol 2018 Oct;183(1):68-75. Epub 2018 Jul 24 doi: 10.1111/bjh.15506. PMID: 30043391
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
Capuano C, Paolini R, Molfetta R, Frati L, Santoni A, Galandrini R
Blood 2012 Mar 8;119(10):2252-62. Epub 2012 Jan 23 doi: 10.1182/blood-2010-12-324160. PMID: 22271450

Recent systematic reviews

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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