FHL2
MCID: HMP012
MIFTS: 42

Hemophagocytic Lymphohistiocytosis, Familial, 2 (FHL2)

Categories: Blood diseases, Genetic diseases, Immune diseases, Liver diseases, Neuronal diseases, Rare 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 acute erythroid leukemia, and has symptoms including seizures, ataxia 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, bone and liver, and related phenotypes are seizures and ataxia

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

Diseases in the Hemophagocytic Lymphohistiocytosis family:

Hemophagocytic Lymphohistiocytosis, Familial, 1 Hemophagocytic Lymphohistiocytosis, Familial, 4
Hemophagocytic Lymphohistiocytosis, Familial, 2 Hemophagocytic Lymphohistiocytosis, Familial, 3
Hemophagocytic Lymphohistiocytosis, Familial, 5

Diseases related to Hemophagocytic Lymphohistiocytosis, Familial, 2 via text searches within MalaCards or GeneCards Suite gene sharing:

(show all 31)
# Related Disease Score Top Affiliating Genes
1 hemophagocytic lymphohistiocytosis 11.6
2 acute erythroid leukemia 11.4
3 rhabdomyosarcoma 11.4
4 dilated cardiomyopathy 11.2
5 hypogonadotropic hypogonadism 24 without anosmia 11.1
6 lymphoproliferative syndrome, x-linked, 1 11.1
7 hemophagocytic lymphohistiocytosis, familial, 4 11.1
8 cervical polyp 11.1
9 adrenal rest tumor 11.1
10 testis seminoma 11.1
11 cardiac rupture 11.1
12 left ventricular noncompaction 11.0
13 familial isolated dilated cardiomyopathy 11.0
14 breast cancer 10.2
15 colorectal cancer 10.2
16 leukemia 10.2
17 prostate cancer 10.1
18 cervical cancer 10.1
19 ovarian cancer 9.9
20 neuroblastoma 9.9
21 pancreatic cancer 9.9
22 leukemia, acute myeloid 9.9
23 pachyonychia congenita 3 9.9
24 ischemia 9.9
25 influenza 9.9
26 myeloid leukemia 9.9
27 viral infectious disease 9.9
28 hypertrophic cardiomyopathy 9.9
29 cranioectodermal dysplasia 1 9.9 IFT122 WDR35
30 short-rib thoracic dysplasia 3 with or without polydactyly 9.8 IFT122 WDR35
31 hemophagocytic lymphohistiocytosis, familial, 1 9.8 ELMO2 IFT122 WDR35

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
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

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

UMLS symptoms related to Hemophagocytic Lymphohistiocytosis, Familial, 2:


seizures, ataxia, hemiplegia, bulging fontanelle, icterus

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

Publications for Hemophagocytic Lymphohistiocytosis, Familial, 2

Articles related to Hemophagocytic Lymphohistiocytosis, Familial, 2:

# Title Authors Year
1
Bone marrow derived mesenchymal stem cells ameliorate inflammatory response in an in vitro model of familial hemophagocytic lymphohistiocytosis 2. ( 30021624 )
2018

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 141)
# 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.755A> G (p.Asn252Ser) single nucleotide variant Conflicting interpretations of pathogenicity rs28933375 GRCh37 Chromosome 10, 72358722: 72358722
17 PRF1 NM_001083116.2(PRF1): c.755A> G (p.Asn252Ser) single nucleotide variant Conflicting interpretations of pathogenicity rs28933375 GRCh38 Chromosome 10, 70598966: 70598966
18 PRF1 NM_001083116.2(PRF1): c.1304C> T (p.Thr435Met) single nucleotide variant Pathogenic rs28933376 GRCh37 Chromosome 10, 72358173: 72358173
19 PRF1 NM_001083116.2(PRF1): c.1304C> T (p.Thr435Met) single nucleotide variant Pathogenic rs28933376 GRCh38 Chromosome 10, 70598417: 70598417
20 PRF1 NM_001083116.2(PRF1): c.272C> T (p.Ala91Val) single nucleotide variant Conflicting interpretations of pathogenicity rs35947132 GRCh37 Chromosome 10, 72360387: 72360387
21 PRF1 NM_001083116.2(PRF1): c.272C> T (p.Ala91Val) single nucleotide variant Conflicting interpretations of pathogenicity rs35947132 GRCh38 Chromosome 10, 70600631: 70600631
22 PRF1 NM_001083116.2(PRF1): c.11G> A (p.Arg4His) single nucleotide variant Conflicting interpretations of pathogenicity rs35418374 GRCh37 Chromosome 10, 72360648: 72360648
23 PRF1 NM_001083116.2(PRF1): c.11G> A (p.Arg4His) single nucleotide variant Conflicting interpretations of pathogenicity rs35418374 GRCh38 Chromosome 10, 70600892: 70600892
24 PRF1 NM_001083116.2(PRF1): c.1090_1091delCT (p.Leu364Glufs) deletion Pathogenic rs771552960 GRCh38 Chromosome 10, 70598630: 70598631
25 PRF1 NM_001083116.2(PRF1): c.1090_1091delCT (p.Leu364Glufs) deletion Pathogenic rs771552960 GRCh37 Chromosome 10, 72358386: 72358387
26 PRF1 NM_001083116.2(PRF1): c.207delC (p.Asp70Thrfs) deletion Pathogenic rs786205093 GRCh37 Chromosome 10, 72360452: 72360452
27 PRF1 NM_001083116.2(PRF1): c.207delC (p.Asp70Thrfs) deletion Pathogenic rs786205093 GRCh38 Chromosome 10, 70600696: 70600696
28 PRF1 NM_001083116.2(PRF1): c.1246C> T (p.Gln416Ter) single nucleotide variant Pathogenic rs193302876 GRCh37 Chromosome 10, 72358231: 72358231
29 PRF1 NM_001083116.2(PRF1): c.1246C> T (p.Gln416Ter) single nucleotide variant Pathogenic rs193302876 GRCh38 Chromosome 10, 70598475: 70598475
30 PRF1 NM_005041.5(PRF1): c.1337A> C (p.Gln446Pro) single nucleotide variant Likely pathogenic rs751161742 GRCh38 Chromosome 10, 70598384: 70598384
31 PRF1 NM_005041.5(PRF1): c.1337A> C (p.Gln446Pro) single nucleotide variant Likely pathogenic rs751161742 GRCh37 Chromosome 10, 72358140: 72358140
32 PRF1 NM_001083116.2(PRF1): c.900C> T (p.His300=) single nucleotide variant Benign rs885822 GRCh37 Chromosome 10, 72358577: 72358577
33 PRF1 NM_001083116.2(PRF1): c.900C> T (p.His300=) single nucleotide variant Benign rs885822 GRCh38 Chromosome 10, 70598821: 70598821
34 PRF1 NM_001083116.2(PRF1): c.807C> T (p.His269=) single nucleotide variant Benign/Likely benign rs147453010 GRCh37 Chromosome 10, 72358670: 72358670
35 PRF1 NM_001083116.2(PRF1): c.807C> T (p.His269=) single nucleotide variant Benign/Likely benign rs147453010 GRCh38 Chromosome 10, 70598914: 70598914
36 PRF1 NM_001083116.2(PRF1): c.726C> T (p.Cys242=) single nucleotide variant Benign/Likely benign rs35329429 GRCh38 Chromosome 10, 70598995: 70598995
37 PRF1 NM_001083116.2(PRF1): c.726C> T (p.Cys242=) single nucleotide variant Benign/Likely benign rs35329429 GRCh37 Chromosome 10, 72358751: 72358751
38 PRF1 NM_001083116.2(PRF1): c.630C> T (p.Pro210=) single nucleotide variant Conflicting interpretations of pathogenicity rs144004164 GRCh38 Chromosome 10, 70599091: 70599091
39 PRF1 NM_001083116.2(PRF1): c.630C> T (p.Pro210=) single nucleotide variant Conflicting interpretations of pathogenicity rs144004164 GRCh37 Chromosome 10, 72358847: 72358847
40 PRF1 NM_001083116.2(PRF1): c.528C> T (p.Cys176=) single nucleotide variant Benign/Likely benign rs138588977 GRCh38 Chromosome 10, 70600375: 70600375
41 PRF1 NM_001083116.2(PRF1): c.528C> T (p.Cys176=) single nucleotide variant Benign/Likely benign rs138588977 GRCh37 Chromosome 10, 72360131: 72360131
42 PRF1 NM_001083116.2(PRF1): c.462A> G (p.Ala154=) single nucleotide variant Conflicting interpretations of pathogenicity rs116554195 GRCh38 Chromosome 10, 70600441: 70600441
43 PRF1 NM_001083116.2(PRF1): c.462A> G (p.Ala154=) single nucleotide variant Conflicting interpretations of pathogenicity rs116554195 GRCh37 Chromosome 10, 72360197: 72360197
44 PRF1 NM_001083116.2(PRF1): c.435G> A (p.Val145=) single nucleotide variant Benign rs115281140 GRCh37 Chromosome 10, 72360224: 72360224
45 PRF1 NM_001083116.2(PRF1): c.435G> A (p.Val145=) single nucleotide variant Benign rs115281140 GRCh38 Chromosome 10, 70600468: 70600468
46 PRF1 NM_001083116.2(PRF1): c.666C> A (p.His222Gln) single nucleotide variant Pathogenic rs751247865 GRCh37 Chromosome 10, 72358811: 72358811
47 PRF1 NM_001083116.2(PRF1): c.666C> A (p.His222Gln) single nucleotide variant Pathogenic rs751247865 GRCh38 Chromosome 10, 70599055: 70599055
48 PRF1 NM_001083116.2(PRF1): c.1310C> T (p.Ala437Val) single nucleotide variant Uncertain significance rs138126912 GRCh37 Chromosome 10, 72358167: 72358167
49 PRF1 NM_001083116.2(PRF1): c.1310C> T (p.Ala437Val) single nucleotide variant Uncertain significance rs138126912 GRCh38 Chromosome 10, 70598411: 70598411
50 PRF1 NM_001083116.2(PRF1): c.1120T> G (p.Trp374Gly) single nucleotide variant Likely pathogenic rs1060499556 GRCh37 Chromosome 10, 72358357: 72358357

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 apoptotic process GO:0006915 9.58 DOCK1 ELMO2 PRF1
2 Fc-gamma receptor signaling pathway involved in phagocytosis GO:0038096 9.37 DOCK1 ELMO2
3 phagocytosis GO:0006909 9.32 DOCK1 ELMO2
4 vascular endothelial growth factor receptor signaling pathway GO:0048010 9.26 DOCK1 ELMO2
5 intraciliary transport involved in cilium assembly GO:0035735 9.16 IFT122 WDR35
6 protein localization to cilium GO:0061512 8.96 IFT122 WDR35
7 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
9 Cosmic
10 dbSNP
11 DGIdb
17 ExPASy
19 FMA
28 GO
29 GTR
30 HGMD
31 HMDB
32 HPO
33 ICD10
34 ICD10 via Orphanet
35 ICD9CM
36 IUPHAR
37 KEGG
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44 MeSH
45 MESH via Orphanet
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62 PubMed
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71 TGDB
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74 UMLS via Orphanet
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