MCID: HMP012
MIFTS: 47

Hemophagocytic Lymphohistiocytosis, Familial, 2

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

Aliases & Classifications for Hemophagocytic Lymphohistiocytosis, Familial, 2

MalaCards integrated aliases for Hemophagocytic Lymphohistiocytosis, Familial, 2:

Name: Hemophagocytic Lymphohistiocytosis, Familial, 2 53 49 28 13 69
Hplh2 53 12 49 71
Fhl2 53 12 49 71
Hlh2 53 12 49 71
Familial Hemophagocytic Lymphohistiocytosis 2 12 71 14

Characteristics:

OMIM:

53
Inheritance:
autosomal recessive


HPO:

31
hemophagocytic lymphohistiocytosis, familial, 2:
Inheritance autosomal recessive inheritance


Classifications:



Summaries for Hemophagocytic Lymphohistiocytosis, Familial, 2

OMIM : 53 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, seizures and hemiplegia. 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.

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

UniProtKB/Swiss-Prot : 71 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:

53
Neurologic Central Nervous System:
ataxia
seizures
hemiplegia
encephalitis
tetraplegia
more
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

Abdomen Spleen:
splenomegaly

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

Muscle Soft Tissue:
generalized edema


Clinical features from OMIM:

603553

Human phenotypes related to Hemophagocytic Lymphohistiocytosis, Familial, 2:

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

UMLS symptoms related to Hemophagocytic Lymphohistiocytosis, Familial, 2:


bulging fontanelle, seizures, icterus, hemiplegia, ataxia

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 28 PRF1

Anatomical Context for Hemophagocytic Lymphohistiocytosis, Familial, 2

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

38
T Cells, Liver, Bone, Lymph Node, Bone Marrow, Spleen, Nk Cells

Publications for Hemophagocytic Lymphohistiocytosis, Familial, 2

Articles related to Hemophagocytic Lymphohistiocytosis, Familial, 2:

(show top 50) (show all 79)
# Title Authors Year
1
FHL2 mediates tooth development and human dental pulp cell differentiation into odontoblasts, partially by interacting with Runx2. ( 26759258 )
2016
2
Protein-protein interactions of the LIM-only protein FHL2 and functional implication of the interactions relevant in cardiovascular disease. ( 26548523 )
2016
3
Scaffold protein FHL2 facilitates MDM2-mediated degradation of IER3 to regulate proliferation of cervical cancer cells. ( 26973248 )
2016
4
The four and a half LIM domains 2 (FHL2) regulates ovarian granulosa cell tumor progression via controlling AKT1 transcription. ( 27415427 )
2016
5
Mammalian Actin-binding Protein-1/Hip-55 Interacts with FHL2 and Negatively Regulates Cell Invasion. ( 27129278 )
2016
6
Tumoral expression of nuclear cofactor FHL2 is associated with lymphatic metastasis in sporadic but not in HNPCC-associated colorectal cancer. ( 25554651 )
2015
7
Deficiency of FHL2 attenuates airway inflammation in mice and genetic variation associates with human bronchial hyper-responsiveness. ( 26222912 )
2015
8
LIM-only protein FHL2 critically determines survival and radioresistance of pancreatic cancer cells. ( 25917075 )
2015
9
High risk HPV E6 oncoproteins impair the subcellular distribution of the four and a half LIM-only protein 2 (FHL2). ( 25540819 )
2015
10
The FHL2 regulation in the transcriptional circuitry of human cancers. ( 26211626 )
2015
11
FHL2 regulates hematopoietic stem cell functions under stress conditions. ( 25179730 )
2015
12
KLF8 promotes tumorigenesis, invasion and metastasis of colorectal cancer cells by transcriptional activation of FHL2. ( 26320172 )
2015
13
Enhanced FHL2 and TGF-I^1 Expression Is Associated With Invasive Growth and Poor Survival in Malignant Melanomas. ( 25596251 )
2015
14
LIM-only protein FHL2 is a positive regulator of liver X receptors in smooth muscle cells involved in lipid homeostasis. ( 25332231 )
2015
15
TGF-I^1-dependent induction and nuclear translocation of FHL2 promotes keratin expression in pilomatricoma. ( 25477051 )
2015
16
FHL2 expression and variants in hypertrophic cardiomyopathy. ( 25358972 )
2014
17
Transcriptional regulation of the tumor suppressor FHL2 by p53 in human kidney and liver cells. ( 25121502 )
2014
18
Structural and functional analysis of perforin mutations in association with clinical data of familial hemophagocytic lymphohistiocytosis type 2 (FHL2) patients. ( 23592409 )
2013
19
Regulation of the transcriptional coactivator FHL2 licenses activation of the androgen receptor in castrate-resistant prostate cancer. ( 23801747 )
2013
20
The four and a half LIM-only protein 2 (FHL2) activates transforming growth factor I^ (TGF-I^) signaling by regulating ubiquitination of the E3 ligase Arkadia. ( 23212909 )
2013
21
Deletion of FHL2 gene impaired ischemia-induced blood flow recovery by modulating circulating proangiogenic cells. ( 23413425 )
2013
22
FHL2 silencing reduces Wnt signaling and osteosarcoma tumorigenesis in vitro and in vivo. ( 23383046 )
2013
23
Epithelial expression of FHL2 is negatively associated with metastasis-free and overall survival in colorectal cancer. ( 23756870 )
2013
24
FHL2 binds calcineurin and represses pathological cardiac growth. ( 22851699 )
2012
25
FHL2 inhibits the Id3-promoted proliferation and invasive growth of human MCF-7 breast cancer cells. ( 22882857 )
2012
26
The adaptor protein FHL2 enhances the cellular innate immune response to influenza A virus infection. ( 22417706 )
2012
27
FHL2 exhibits anti-proliferative and anti-apoptotic activities in liver cancer cells. ( 21377781 )
2011
28
FHL2 protein is a novel co-repressor of nuclear receptor Nur77. ( 22049082 )
2011
29
FHL2 expression in peritumoural fibroblasts correlates with lymphatic metastasis in sporadic but not in HNPCC-associated colon cancer. ( 21826055 )
2011
30
FHL2 interacts with CALM and is highly expressed in acute erythroid leukemia. ( 22829078 )
2011
31
Synergistic repression of estrogen receptor transcriptional activity by FHL2 and Smad4 in breast cancer cells. ( 20734429 )
2010
32
FHL2 suppresses growth and differentiation of the colon cancer cell line HT-29. ( 20428824 )
2010
33
Sp1 upregulates the four and half lim 2 (FHL2) expression in gastrointestinal cancers through transcription regulation. ( 20607723 )
2010
34
Deficiency of the LIM-only protein FHL2 reduces intestinal tumorigenesis in Apc mutant mice. ( 20442768 )
2010
35
The cell migration protein Grb7 associates with transcriptional regulator FHL2 in a Grb7 phosphorylation-dependent manner. ( 18853468 )
2009
36
Enhanced expression of FHL2 leads to abnormal myelopoiesis in vivo. ( 19369964 )
2009
37
FHL2 interacts with and acts as a functional repressor of Id2 in human neuroblastoma cells. ( 19417068 )
2009
38
FHL2 mediates dexamethasone-induced mesenchymal cell differentiation into osteoblasts by activating Wnt/beta-catenin signaling-dependent Runx2 expression. ( 18653765 )
2008
39
The four-and-a-half-LIM protein 2 (FHL2) is overexpressed in gliomas and associated with oncogenic activities. ( 18615633 )
2008
40
Deficiency in the LIM-only protein FHL2 impairs assembly of extracellular matrix proteins. ( 18356303 )
2008
41
IL-1beta regulates FHL2 and other cytoskeleton-related genes in human chondrocytes. ( 18224250 )
2008
42
Suppression of FHL2 expression induces cell differentiation and inhibits gastric and colon carcinogenesis. ( 17383428 )
2007
43
The biological relevance of FHL2 in tumour cells and its role as a putative cancer target. ( 17352216 )
2007
44
FHL2 regulates cell cycle-dependent and doxorubicin-induced p21Cip1/Waf1 expression in breast cancer cells. ( 17682292 )
2007
45
Identification of the FHL2 transcriptional coactivator as a new functional target of the E7 oncoprotein of human papillomavirus type 16. ( 17093190 )
2007
46
The LIM-only protein FHL2 is a negative regulator of E4F1. ( 16652157 )
2006
47
FHL2 interacts with both ADAM-17 and the cytoskeleton and regulates ADAM-17 localization and activity. ( 16619241 )
2006
48
The multifunctional roles of the four-and-a-half-LIM only protein FHL2. ( 16389449 )
2006
49
Expression of the transcriptional coregulator FHL2 in human breast cancer: a clinicopathologic study. ( 16378916 )
2006
50
FHL2 mediates p53-induced transcriptional activation through a direct association with HIPK2. ( 16343438 )
2006

Variations for Hemophagocytic Lymphohistiocytosis, Familial, 2

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

71
# 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 all 17)
# 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.190C> T (p.Gln64Ter) single nucleotide variant Pathogenic rs104894180 GRCh37 Chromosome 10, 72360469: 72360469
4 PRF1 NM_001083116.2(PRF1): c.673C> T (p.Arg225Trp) single nucleotide variant Pathogenic rs28933973 GRCh37 Chromosome 10, 72358804: 72358804
5 PRF1 NM_001083116.2(PRF1): c.1286G> A (p.Gly429Glu) single nucleotide variant Pathogenic rs104894181 GRCh37 Chromosome 10, 72358191: 72358191
6 PRF1 NM_001083116.2(PRF1): c.1034C> T (p.Pro345Leu) single nucleotide variant Pathogenic rs28933374 GRCh37 Chromosome 10, 72358443: 72358443
7 PRF1 NM_001083116.2(PRF1): c.836G> A (p.Cys279Tyr) single nucleotide variant Pathogenic rs104894182 GRCh37 Chromosome 10, 72358641: 72358641
8 PRF1 NM_001083116.2(PRF1): c.548T> G (p.Val183Gly) single nucleotide variant Pathogenic rs104894183 GRCh37 Chromosome 10, 72358929: 72358929
9 PRF1 NM_001083116.2(PRF1): c.1304C> T (p.Thr435Met) single nucleotide variant Pathogenic rs28933376 GRCh37 Chromosome 10, 72358173: 72358173
10 PRF1 NM_001083116.2(PRF1): c.1090_1091delCT (p.Leu364Glufs) deletion Pathogenic rs771552960 GRCh38 Chromosome 10, 70598630: 70598631
11 PRF1 NM_001083116.2(PRF1): c.207delC (p.Asp70Thrfs) deletion Pathogenic rs786205093 GRCh37 Chromosome 10, 72360452: 72360452
12 PRF1 NM_001083116.2(PRF1): c.1246C> T (p.Gln416Ter) single nucleotide variant Pathogenic rs193302876 GRCh37 Chromosome 10, 72358231: 72358231
13 PRF1 NM_005041.5(PRF1): c.1337A> C (p.Gln446Pro) single nucleotide variant Likely pathogenic rs751161742 GRCh38 Chromosome 10, 70598384: 70598384
14 PRF1 NM_001083116.2(PRF1): c.666C> A (p.His222Gln) single nucleotide variant Pathogenic rs751247865 GRCh37 Chromosome 10, 72358811: 72358811
15 PRF1 NM_001083116.2(PRF1): c.1120T> G (p.Trp374Gly) single nucleotide variant Likely pathogenic rs1060499556 GRCh37 Chromosome 10, 72358357: 72358357
16 PRF1 NM_001083116.2(PRF1): c.50delT (p.Leu17Argfs) deletion Pathogenic rs147035858 GRCh37 Chromosome 10, 72360609: 72360609
17 PRF1 NM_001083116.2(PRF1): c.1349C> T (p.Thr450Met) single nucleotide variant Likely pathogenic rs189650890 GRCh38 Chromosome 10, 70598372: 70598372

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

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