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Familial hemophagocytic lymphohistiocytosis 2(FHL2)

MedGen UID:
400366
Concept ID:
C1863727
Disease or Syndrome
Synonym: FHL2
 
Gene (location): PRF1 (10q22.1)
 
Monarch Initiative: MONDO:0011337
OMIM®: 603553

Definition

Familial hemophagocytic lymphohistiocytosis-2 (FHL2) is an autosomal recessive disorder of immune dysregulation with onset in infancy or early childhood. It is characterized clinically by fever, edema, hepatosplenomegaly, and liver dysfunction. Neurologic impairment, seizures, and ataxia are frequent. Laboratory studies show pancytopenia, coagulation abnormalities, hypofibrinogenemia, and hypertriglyceridemia. There is increased production of cytokines, such as gamma-interferon (IFNG; 147570) and TNF-alpha (191160), by hyperactivation and proliferation of T cells and macrophages. Activity of cytotoxic T cells and NK cells is reduced, consistent with a defect in cellular cytotoxicity. Bone marrow, lymph nodes, spleen, and liver show features of hemophagocytosis. Chemotherapy and/or immunosuppressant therapy may result in symptomatic remission, but the disorder is fatal without bone marrow transplantation (summary by Dufourcq-Lagelouse et al., 1999, Stepp et al., 1999, and Molleran Lee et al., 2004). For a general phenotypic description and a discussion of genetic heterogeneity of FHL, see 267700. [from OMIM]

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.
Hepatosplenomegaly
MedGen UID:
9225
Concept ID:
C0019214
Sign or Symptom
Simultaneous enlargement of the liver and spleen.
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.
CNS demyelination
MedGen UID:
137898
Concept ID:
C0338474
Disease or Syndrome
A loss of myelin from nerve fibers in the central nervous system.
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.
Pancytopenia
MedGen UID:
18281
Concept ID:
C0030312
Disease or Syndrome
An abnormal reduction in numbers of all blood cell types (red blood cells, white blood cells, and platelets).
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.
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.
Reduced natural killer cell activity
MedGen UID:
333452
Concept ID:
C1839969
Finding
Reduced ability of the natural killer cell to function in the adaptive immune response.
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.
Hyponatremia
MedGen UID:
6984
Concept ID:
C0020625
Finding
An abnormally decreased sodium concentration 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 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.
Elevated circulating hepatic transaminase concentration
MedGen UID:
338525
Concept ID:
C1848701
Finding
Elevations of the levels of SGOT and SGPT in the serum. SGOT (serum glutamic oxaloacetic transaminase) and SGPT (serum glutamic pyruvic transaminase) are transaminases primarily found in the liver and heart and are released into the bloodstream as the result of liver or heart damage. SGOT and SGPT are used clinically mainly as markers of liver damage.
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.
Recurrent fever
MedGen UID:
811468
Concept ID:
C3714772
Sign or Symptom
Periodic (episodic or recurrent) bouts of fever.

Professional guidelines

PubMed

Tayal A, Kabra SK, Lodha R
Indian J Pediatr 2023 Feb;90(2):168-177. Epub 2022 Dec 27 doi: 10.1007/s12098-022-04394-8. PMID: 36574088Free PMC Article
Keenan C, Nichols KE, Albeituni S
Front Immunol 2021;12:614704. Epub 2021 Feb 16 doi: 10.3389/fimmu.2021.614704. PMID: 33664745Free PMC Article
Henter JI, Horne A, Aricó M, Egeler RM, Filipovich AH, Imashuku S, Ladisch S, McClain K, Webb D, Winiarski J, Janka G
Pediatr Blood Cancer 2007 Feb;48(2):124-31. doi: 10.1002/pbc.21039. PMID: 16937360

Recent clinical studies

Etiology

Hu LY, Wan L, Wang QH, Shi XY, Meng Y, Yang XF, Yang G, Zou LP
Front Immunol 2023;14:1306338. Epub 2023 Dec 11 doi: 10.3389/fimmu.2023.1306338. PMID: 38149249Free PMC Article
Sienes Bailo P, Goñi Ros N, Menéndez Jándula B, Álvarez Alegret R, González Gómez E, González Tarancón R, Izquierdo Álvarez S
Ann Clin Biochem 2023 Sep;60(5):356-364. Epub 2023 Jun 26 doi: 10.1177/00045632231186076. PMID: 37365821
Popko K, Górska E, Wołowiec M, Malinowska I
J Pediatr Hematol Oncol 2019 Jul;41(5):e277-e283. doi: 10.1097/MPH.0000000000001514. PMID: 31107368

Diagnosis

Hu LY, Wan L, Wang QH, Shi XY, Meng Y, Yang XF, Yang G, Zou LP
Front Immunol 2023;14:1306338. Epub 2023 Dec 11 doi: 10.3389/fimmu.2023.1306338. PMID: 38149249Free PMC Article
Sienes Bailo P, Goñi Ros N, Menéndez Jándula B, Álvarez Alegret R, González Gómez E, González Tarancón R, Izquierdo Álvarez S
Ann Clin Biochem 2023 Sep;60(5):356-364. Epub 2023 Jun 26 doi: 10.1177/00045632231186076. PMID: 37365821
Segal JE, Daley JD, Barnum JL, Salgado CM, Reyes-Mugica M, Schneider C, Gumus S, Thakrar D, Allen SW, Canna SW
J Clin Immunol 2021 Jul;41(5):987-991. Epub 2021 Feb 11 doi: 10.1007/s10875-021-00986-9. PMID: 33570715Free PMC Article

Therapy

Segal JE, Daley JD, Barnum JL, Salgado CM, Reyes-Mugica M, Schneider C, Gumus S, Thakrar D, Allen SW, Canna SW
J Clin Immunol 2021 Jul;41(5):987-991. Epub 2021 Feb 11 doi: 10.1007/s10875-021-00986-9. PMID: 33570715Free PMC Article

Prognosis

Segal JE, Daley JD, Barnum JL, Salgado CM, Reyes-Mugica M, Schneider C, Gumus S, Thakrar D, Allen SW, Canna SW
J Clin Immunol 2021 Jul;41(5):987-991. Epub 2021 Feb 11 doi: 10.1007/s10875-021-00986-9. PMID: 33570715Free PMC Article

Clinical prediction guides

Hu LY, Wan L, Wang QH, Shi XY, Meng Y, Yang XF, Yang G, Zou LP
Front Immunol 2023;14:1306338. Epub 2023 Dec 11 doi: 10.3389/fimmu.2023.1306338. PMID: 38149249Free PMC Article
Popko K, Górska E, Wołowiec M, Malinowska I
J Pediatr Hematol Oncol 2019 Jul;41(5):e277-e283. doi: 10.1097/MPH.0000000000001514. PMID: 31107368

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