MCID: HMP012
MIFTS: 40

Hemophagocytic Lymphohistiocytosis, Familial, 2

Categories: Genetic diseases, Rare diseases, Immune diseases, Blood diseases, Neuronal diseases

Aliases & Classifications for Hemophagocytic Lymphohistiocytosis, Familial, 2

MalaCards integrated aliases for Hemophagocytic Lymphohistiocytosis, Familial, 2:

Name: Hemophagocytic Lymphohistiocytosis, Familial, 2 57 53 29 13 6 73
Hplh2 57 12 53 75
Fhl2 57 12 53 75
Hlh2 57 12 53 75
Familial Hemophagocytic Lymphohistiocytosis 2 12 75 15
Hemophagocytic Lymphohistiocytosis, Familial, 2, Susceptibility to 6
Lymphohistiocytosis, Hemophagocytic, Familial, Type 2 40

Characteristics:

OMIM:

57
Inheritance:
autosomal recessive


HPO:

32
hemophagocytic lymphohistiocytosis, familial, 2:
Inheritance autosomal recessive inheritance


Classifications:



Summaries for Hemophagocytic Lymphohistiocytosis, Familial, 2

OMIM : 57 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. (603553)

MalaCards based summary : Hemophagocytic Lymphohistiocytosis, Familial, 2, also known as hplh2, is related to hemophagocytic lymphohistiocytosis and rhabdomyosarcoma, and has symptoms including ataxia, hemiplegia and icterus. An important gene associated with Hemophagocytic Lymphohistiocytosis, Familial, 2 is PRF1 (Perforin 1), and among its related pathways/superpathways are Signaling by PTK6 and Bacterial invasion of epithelial cells. Affiliated tissues include t cells, liver and bone marrow, and related phenotypes are irritability and jaundice

Disease Ontology : 12 A hemophagocytic lymphohistiocytosis that has material basis in an autosomal recessive mutation of PRF1 on chromosome 10q22.1.

UniProtKB/Swiss-Prot : 75 Familial hemophagocytic lymphohistiocytosis 2: A rare disorder characterized by immune dysregulation with hypercytokinemia, defective function of natural killer cell, and massive infiltration of several organs by activated lymphocytes and macrophages. The clinical features of the disease include fever, hepatosplenomegaly, cytopenia, and less frequently neurological abnormalities ranging from irritability and hypotonia to seizures, cranial nerve deficits and ataxia.

Related Diseases for Hemophagocytic Lymphohistiocytosis, Familial, 2

Graphical network of the top 20 diseases related to Hemophagocytic Lymphohistiocytosis, Familial, 2:



Diseases related to Hemophagocytic Lymphohistiocytosis, Familial, 2

Symptoms & Phenotypes for Hemophagocytic Lymphohistiocytosis, Familial, 2

Symptoms via clinical synopsis from OMIM:

57
Neurologic Central Nervous System:
seizures
ataxia
encephalitis
tetraplegia
increased intracranial pressure
more
AbdomenSpleen:
splenomegaly

Laboratory Abnormalities:
hypertriglyceridemia
hyponatremia
prolonged prothrombin time
hypoalbuminemia
hypoproteinemia
more
Skin Nails Hair Skin:
jaundice
purpuric rashes

Muscle Soft Tissue:
generalized edema

Growth Other:
failure to thrive

Abdomen Liver:
hepatomegaly

Hematology:
anemia
thrombocytopenia
leukopenia

Immunology:
lymphadenopathy
overproduction by t lymphocytes and macrophages of cytokines, particularly interferon gamma and tumor necrosis factor alpha
activated hla dr+ t cells in peripheral blood
reduced natural killer cell cytotoxicity
reduced t cell cytotoxicity
more
Head And Neck Head:
bulging fontanelle


Clinical features from OMIM:

603553

Human phenotypes related to Hemophagocytic Lymphohistiocytosis, Familial, 2:

32 (show all 32)
# Description HPO Frequency HPO Source Accession
1 irritability 32 HP:0000737
2 jaundice 32 HP:0000952
3 seizures 32 HP:0001250
4 ataxia 32 HP:0001251
5 coma 32 HP:0001259
6 global developmental delay 32 HP:0001263
7 hypertonia 32 HP:0001276
8 meningitis 32 HP:0001287
9 generalized hypotonia 32 HP:0001290
10 failure to thrive 32 HP:0001508
11 splenomegaly 32 HP:0001744
12 thrombocytopenia 32 HP:0001873
13 leukopenia 32 HP:0001882
14 anemia 32 HP:0001903
15 hypertriglyceridemia 32 HP:0002155
16 hepatomegaly 32 HP:0002240
17 hemiplegia 32 HP:0002301
18 encephalitis 32 HP:0002383
19 tetraplegia 32 HP:0002445
20 increased intracranial pressure 32 HP:0002516
21 lymphadenopathy 32 HP:0002716
22 hyponatremia 32 HP:0002902
23 increased csf protein 32 HP:0002922
24 hypoalbuminemia 32 HP:0003073
25 hypoproteinemia 32 HP:0003075
26 increased serum ferritin 32 HP:0003281
27 increased total bilirubin 32 HP:0003573
28 generalized edema 32 HP:0007430
29 prolonged prothrombin time 32 HP:0008151
30 hypofibrinogenemia 32 HP:0011900
31 hemophagocytosis 32 HP:0012156
32 csf pleocytosis 32 HP:0012229

UMLS symptoms related to Hemophagocytic Lymphohistiocytosis, Familial, 2:


ataxia, hemiplegia, icterus, seizures, bulging fontanelle

Drugs & Therapeutics for Hemophagocytic Lymphohistiocytosis, Familial, 2

Search Clinical Trials , NIH Clinical Center for Hemophagocytic Lymphohistiocytosis, Familial, 2

Genetic Tests for Hemophagocytic Lymphohistiocytosis, Familial, 2

Genetic tests related to Hemophagocytic Lymphohistiocytosis, Familial, 2:

# Genetic test Affiliating Genes
1 Hemophagocytic Lymphohistiocytosis, Familial, 2 29 PRF1

Anatomical Context for Hemophagocytic Lymphohistiocytosis, Familial, 2

MalaCards organs/tissues related to Hemophagocytic Lymphohistiocytosis, Familial, 2:

41
T Cells, Liver, Bone Marrow, Spleen, Lymph Node, Bone, Nk Cells

Publications for Hemophagocytic Lymphohistiocytosis, Familial, 2

Variations for Hemophagocytic Lymphohistiocytosis, Familial, 2

UniProtKB/Swiss-Prot genetic disease variations for Hemophagocytic Lymphohistiocytosis, Familial, 2:

75
# Symbol AA change Variation ID SNP ID
1 PRF1 p.Val183Gly VAR_010744 rs104894183
2 PRF1 p.Arg225Trp VAR_010745 rs28933973
3 PRF1 p.Asn252Ser VAR_010746 rs28933375
4 PRF1 p.Cys279Tyr VAR_010747 rs104894182
5 PRF1 p.Pro345Leu VAR_010748 rs28933374
6 PRF1 p.Gly429Glu VAR_010749 rs104894181
7 PRF1 p.Val50Met VAR_010772
8 PRF1 p.Ile224Asn VAR_010774

ClinVar genetic disease variations for Hemophagocytic Lymphohistiocytosis, Familial, 2:

6
(show top 50) (show all 107)
# Gene Variation Type Significance SNP ID Assembly Location
1 PRF1 PRF1, 1-BP DEL, 50T deletion Pathogenic
2 PRF1 NM_001083116.2(PRF1): c.1122G> A (p.Trp374Ter) single nucleotide variant Pathogenic rs104894176 GRCh37 Chromosome 10, 72358355: 72358355
3 PRF1 NM_001083116.2(PRF1): c.1122G> A (p.Trp374Ter) single nucleotide variant Pathogenic rs104894176 GRCh38 Chromosome 10, 70598599: 70598599
4 PRF1 NM_001083116.2(PRF1): c.190C> T (p.Gln64Ter) single nucleotide variant Pathogenic rs104894180 GRCh37 Chromosome 10, 72360469: 72360469
5 PRF1 NM_001083116.2(PRF1): c.190C> T (p.Gln64Ter) single nucleotide variant Pathogenic rs104894180 GRCh38 Chromosome 10, 70600713: 70600713
6 PRF1 NM_001083116.2(PRF1): c.673C> T (p.Arg225Trp) single nucleotide variant Pathogenic rs28933973 GRCh37 Chromosome 10, 72358804: 72358804
7 PRF1 NM_001083116.2(PRF1): c.673C> T (p.Arg225Trp) single nucleotide variant Pathogenic rs28933973 GRCh38 Chromosome 10, 70599048: 70599048
8 PRF1 NM_001083116.2(PRF1): c.1286G> A (p.Gly429Glu) single nucleotide variant Pathogenic rs104894181 GRCh37 Chromosome 10, 72358191: 72358191
9 PRF1 NM_001083116.2(PRF1): c.1286G> A (p.Gly429Glu) single nucleotide variant Pathogenic rs104894181 GRCh38 Chromosome 10, 70598435: 70598435
10 PRF1 NM_001083116.2(PRF1): c.1034C> T (p.Pro345Leu) single nucleotide variant Pathogenic rs28933374 GRCh37 Chromosome 10, 72358443: 72358443
11 PRF1 NM_001083116.2(PRF1): c.1034C> T (p.Pro345Leu) single nucleotide variant Pathogenic rs28933374 GRCh38 Chromosome 10, 70598687: 70598687
12 PRF1 NM_001083116.2(PRF1): c.836G> A (p.Cys279Tyr) single nucleotide variant Pathogenic rs104894182 GRCh37 Chromosome 10, 72358641: 72358641
13 PRF1 NM_001083116.2(PRF1): c.836G> A (p.Cys279Tyr) single nucleotide variant Pathogenic rs104894182 GRCh38 Chromosome 10, 70598885: 70598885
14 PRF1 NM_001083116.2(PRF1): c.548T> G (p.Val183Gly) single nucleotide variant Pathogenic rs104894183 GRCh37 Chromosome 10, 72358929: 72358929
15 PRF1 NM_001083116.2(PRF1): c.548T> G (p.Val183Gly) single nucleotide variant Pathogenic rs104894183 GRCh38 Chromosome 10, 70599173: 70599173
16 PRF1 NM_001083116.2(PRF1): c.1304C> T (p.Thr435Met) single nucleotide variant Pathogenic rs28933376 GRCh37 Chromosome 10, 72358173: 72358173
17 PRF1 NM_001083116.2(PRF1): c.1304C> T (p.Thr435Met) single nucleotide variant Pathogenic rs28933376 GRCh38 Chromosome 10, 70598417: 70598417
18 PRF1 NM_001083116.2(PRF1): c.1090_1091delCT (p.Leu364Glufs) deletion Pathogenic rs771552960 GRCh38 Chromosome 10, 70598630: 70598631
19 PRF1 NM_001083116.2(PRF1): c.1090_1091delCT (p.Leu364Glufs) deletion Pathogenic rs771552960 GRCh37 Chromosome 10, 72358386: 72358387
20 PRF1 NM_001083116.2(PRF1): c.207delC (p.Asp70Thrfs) deletion Pathogenic rs786205093 GRCh37 Chromosome 10, 72360452: 72360452
21 PRF1 NM_001083116.2(PRF1): c.207delC (p.Asp70Thrfs) deletion Pathogenic rs786205093 GRCh38 Chromosome 10, 70600696: 70600696
22 PRF1 NM_001083116.2(PRF1): c.1246C> T (p.Gln416Ter) single nucleotide variant Pathogenic rs193302876 GRCh37 Chromosome 10, 72358231: 72358231
23 PRF1 NM_001083116.2(PRF1): c.1246C> T (p.Gln416Ter) single nucleotide variant Pathogenic rs193302876 GRCh38 Chromosome 10, 70598475: 70598475
24 PRF1 NM_005041.5(PRF1): c.1337A> C (p.Gln446Pro) single nucleotide variant Likely pathogenic rs751161742 GRCh38 Chromosome 10, 70598384: 70598384
25 PRF1 NM_005041.5(PRF1): c.1337A> C (p.Gln446Pro) single nucleotide variant Likely pathogenic rs751161742 GRCh37 Chromosome 10, 72358140: 72358140
26 PRF1 NM_001083116.2(PRF1): c.900C> T (p.His300=) single nucleotide variant Benign rs885822 GRCh37 Chromosome 10, 72358577: 72358577
27 PRF1 NM_001083116.2(PRF1): c.900C> T (p.His300=) single nucleotide variant Benign rs885822 GRCh38 Chromosome 10, 70598821: 70598821
28 PRF1 NM_001083116.2(PRF1): c.807C> T (p.His269=) single nucleotide variant Benign rs147453010 GRCh37 Chromosome 10, 72358670: 72358670
29 PRF1 NM_001083116.2(PRF1): c.807C> T (p.His269=) single nucleotide variant Benign rs147453010 GRCh38 Chromosome 10, 70598914: 70598914
30 PRF1 NM_001083116.2(PRF1): c.726C> T (p.Cys242=) single nucleotide variant Benign rs35329429 GRCh38 Chromosome 10, 70598995: 70598995
31 PRF1 NM_001083116.2(PRF1): c.726C> T (p.Cys242=) single nucleotide variant Benign rs35329429 GRCh37 Chromosome 10, 72358751: 72358751
32 PRF1 NM_001083116.2(PRF1): c.630C> T (p.Pro210=) single nucleotide variant Conflicting interpretations of pathogenicity rs144004164 GRCh38 Chromosome 10, 70599091: 70599091
33 PRF1 NM_001083116.2(PRF1): c.630C> T (p.Pro210=) single nucleotide variant Conflicting interpretations of pathogenicity rs144004164 GRCh37 Chromosome 10, 72358847: 72358847
34 PRF1 NM_001083116.2(PRF1): c.528C> T (p.Cys176=) single nucleotide variant Benign rs138588977 GRCh38 Chromosome 10, 70600375: 70600375
35 PRF1 NM_001083116.2(PRF1): c.528C> T (p.Cys176=) single nucleotide variant Benign rs138588977 GRCh37 Chromosome 10, 72360131: 72360131
36 PRF1 NM_001083116.2(PRF1): c.462A> G (p.Ala154=) single nucleotide variant Conflicting interpretations of pathogenicity rs116554195 GRCh38 Chromosome 10, 70600441: 70600441
37 PRF1 NM_001083116.2(PRF1): c.462A> G (p.Ala154=) single nucleotide variant Conflicting interpretations of pathogenicity rs116554195 GRCh37 Chromosome 10, 72360197: 72360197
38 PRF1 NM_001083116.2(PRF1): c.435G> A (p.Val145=) single nucleotide variant Benign rs115281140 GRCh37 Chromosome 10, 72360224: 72360224
39 PRF1 NM_001083116.2(PRF1): c.435G> A (p.Val145=) single nucleotide variant Benign rs115281140 GRCh38 Chromosome 10, 70600468: 70600468
40 PRF1 NM_001083116.2(PRF1): c.666C> A (p.His222Gln) single nucleotide variant Pathogenic rs751247865 GRCh37 Chromosome 10, 72358811: 72358811
41 PRF1 NM_001083116.2(PRF1): c.666C> A (p.His222Gln) single nucleotide variant Pathogenic rs751247865 GRCh38 Chromosome 10, 70599055: 70599055
42 PRF1 NM_001083116.2(PRF1): c.1120T> G (p.Trp374Gly) single nucleotide variant Likely pathogenic rs1060499556 GRCh37 Chromosome 10, 72358357: 72358357
43 PRF1 NM_001083116.2(PRF1): c.1120T> G (p.Trp374Gly) single nucleotide variant Likely pathogenic rs1060499556 GRCh38 Chromosome 10, 70598601: 70598601
44 PRF1 NM_001083116.2(PRF1): c.311G> A (p.Arg104His) single nucleotide variant Uncertain significance rs139225004 GRCh37 Chromosome 10, 72360348: 72360348
45 PRF1 NM_001083116.2(PRF1): c.311G> A (p.Arg104His) single nucleotide variant Uncertain significance rs139225004 GRCh38 Chromosome 10, 70600592: 70600592
46 PRF1 NM_001083116.2(PRF1): c.1219T> G (p.Cys407Gly) single nucleotide variant Uncertain significance rs753751595 GRCh38 Chromosome 10, 70598502: 70598502
47 PRF1 NM_001083116.2(PRF1): c.1219T> G (p.Cys407Gly) single nucleotide variant Uncertain significance rs753751595 GRCh37 Chromosome 10, 72358258: 72358258
48 PRF1 NM_001083116.2(PRF1): c.879C> T (p.His293=) single nucleotide variant Likely benign GRCh38 Chromosome 10, 70598842: 70598842
49 PRF1 NM_001083116.2(PRF1): c.879C> T (p.His293=) single nucleotide variant Likely benign GRCh37 Chromosome 10, 72358598: 72358598
50 PRF1 NM_001083116.2(PRF1): c.702G> A (p.Ser234=) single nucleotide variant Benign rs138508223 GRCh38 Chromosome 10, 70599019: 70599019

Expression for Hemophagocytic Lymphohistiocytosis, Familial, 2

Search GEO for disease gene expression data for Hemophagocytic Lymphohistiocytosis, Familial, 2.

Pathways for Hemophagocytic Lymphohistiocytosis, Familial, 2

GO Terms for Hemophagocytic Lymphohistiocytosis, Familial, 2

Cellular components related to Hemophagocytic Lymphohistiocytosis, Familial, 2 according to GeneCards Suite gene sharing:

# Name GO ID Score Top Affiliating Genes
1 ciliary basal body GO:0036064 9.16 IFT122 WDR35
2 ciliary tip GO:0097542 8.96 IFT122 WDR35
3 intraciliary transport particle A GO:0030991 8.62 IFT122 WDR35

Biological processes related to Hemophagocytic Lymphohistiocytosis, Familial, 2 according to GeneCards Suite gene sharing:

# Name GO ID Score Top Affiliating Genes
1 Fc-gamma receptor signaling pathway involved in phagocytosis GO:0038096 9.37 DOCK1 ELMO2
2 vascular endothelial growth factor receptor signaling pathway GO:0048010 9.32 DOCK1 ELMO2
3 phagocytosis GO:0006909 9.26 DOCK1 ELMO2
4 intraciliary transport involved in cilium assembly GO:0035735 9.16 IFT122 WDR35
5 protein localization to cilium GO:0061512 8.96 IFT122 WDR35
6 intraciliary retrograde transport GO:0035721 8.62 IFT122 WDR35

Molecular functions related to Hemophagocytic Lymphohistiocytosis, Familial, 2 according to GeneCards Suite gene sharing:

# Name GO ID Score Top Affiliating Genes
1 SH3 domain binding GO:0017124 8.62 DOCK1 ELMO2

Sources for Hemophagocytic Lymphohistiocytosis, Familial, 2

3 CDC
7 CNVD
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10 dbSNP
11 DGIdb
17 ExPASy
19 FMA
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44 MeSH
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74 UMLS via Orphanet
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