MCID: HMP014
MIFTS: 36

Hemophagocytic Lymphohistiocytosis, Familial, 4

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

Aliases & Classifications for Hemophagocytic Lymphohistiocytosis, Familial, 4

MalaCards integrated aliases for Hemophagocytic Lymphohistiocytosis, Familial, 4:

Name: Hemophagocytic Lymphohistiocytosis, Familial, 4 57 53 29 13 6 73
Hplh4 57 12 53 75
Hlh4 57 12 53 75
Familial Hemophagocytic Lymphohistiocytosis 4 12 75 15
Fhl4 57 12 75
Lymphohistiocytosis, Hemophagocytic, Familial, Type 4 40

Characteristics:

OMIM:

57
Inheritance:
autosomal recessive

Miscellaneous:
onset in infancy or early childhood
fatal without hematopoietic stem cell transplantation


HPO:

32
hemophagocytic lymphohistiocytosis, familial, 4:
Inheritance autosomal recessive inheritance


Classifications:



Summaries for Hemophagocytic Lymphohistiocytosis, Familial, 4

OMIM : 57 Hemophagocytic lymphohistiocytosis is a hyperinflammatory disorder clinically diagnosed based on the fulfillment of 5 of 8 criteria, including fever, splenomegaly, bicytopenia, hypertriglyceridemia and/or hypofibrinogenemia, hemophagocytosis, low or absent natural killer (NK) cell activity, hyperferritinemia, and high soluble IL2 receptor levels (IL2R; 147730). The disorder typically presents in infancy or early childhood. Persistent remission is rarely achieved with chemo- or immunotherapy; hematopoietic stem cell transplantation is the only cure (summary by Muller et al., 2014). For a phenotypic description and a discussion of genetic heterogeneity of familial hemophagocytic lymphohistiocytosis (FHL), see 267700. (603552)

MalaCards based summary : Hemophagocytic Lymphohistiocytosis, Familial, 4, also known as hplh4, is related to hemophagocytic lymphohistiocytosis and good syndrome, and has symptoms including fever An important gene associated with Hemophagocytic Lymphohistiocytosis, Familial, 4 is STX11 (Syntaxin 11), and among its related pathways/superpathways are Nicotine Pathway (Dopaminergic Neuron), Pharmacodynamics and Deregulation of Rab and Rab Effector Genes in Bladder Cancer. Affiliated tissues include nk cells, bone and lymph node, and related phenotypes are seizures and global developmental delay

UniProtKB/Swiss-Prot : 75 Familial hemophagocytic lymphohistiocytosis 4: 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.

Disease Ontology : 12 A hemophagocytic lymphohistiocytosis that has material basis in an autosomal recessive mutation of STX11 on chromosome 6q24.2.

Related Diseases for Hemophagocytic Lymphohistiocytosis, Familial, 4

Graphical network of the top 20 diseases related to Hemophagocytic Lymphohistiocytosis, Familial, 4:



Diseases related to Hemophagocytic Lymphohistiocytosis, Familial, 4

Symptoms & Phenotypes for Hemophagocytic Lymphohistiocytosis, Familial, 4

Symptoms via clinical synopsis from OMIM:

57
AbdomenSpleen:
splenomegaly

Metabolic Features:
fever

Neurologic Central Nervous System:
seizures (in some patients)
hypotonia (in some patients)
delayed psychomotor development (in some patients)

Immunology:
hyperinflammatory disorder
hemophagocytosis in bone marrow and lymph nodes

Abdomen Liver:
hepatomegaly

Hematology:
anemia
thrombocytopenia
neutropenia
defective nk cell activity
defective nk cell degranulation

Laboratory Abnormalities:
decreased fibrinogen
increased ferritin
increased triglycerides
increased soluble il2 receptor

Neoplasia:
increased risk of myelodysplastic syndrome or leukemia (in some patients)


Clinical features from OMIM:

603552

Human phenotypes related to Hemophagocytic Lymphohistiocytosis, Familial, 4:

32 (show all 13)
# Description HPO Frequency HPO Source Accession
1 seizures 32 occasional (7.5%) HP:0001250
2 global developmental delay 32 occasional (7.5%) HP:0001263
3 splenomegaly 32 very rare (1%) HP:0001744
4 hepatomegaly 32 very rare (1%) HP:0002240
5 fever 32 HP:0001945
6 hypertriglyceridemia 32 very rare (1%) HP:0002155
7 anemia 32 very rare (1%) HP:0001903
8 thrombocytopenia 32 very rare (1%) HP:0001873
9 neutropenia 32 very rare (1%) HP:0001875
10 increased serum ferritin 32 very rare (1%) HP:0003281
11 generalized hypotonia 32 occasional (7.5%) HP:0001290
12 hemophagocytosis 32 very rare (1%) HP:0012156
13 hypofibrinogenemia 32 very rare (1%) HP:0011900

UMLS symptoms related to Hemophagocytic Lymphohistiocytosis, Familial, 4:


fever

Drugs & Therapeutics for Hemophagocytic Lymphohistiocytosis, Familial, 4

Search Clinical Trials , NIH Clinical Center for Hemophagocytic Lymphohistiocytosis, Familial, 4

Genetic Tests for Hemophagocytic Lymphohistiocytosis, Familial, 4

Genetic tests related to Hemophagocytic Lymphohistiocytosis, Familial, 4:

# Genetic test Affiliating Genes
1 Hemophagocytic Lymphohistiocytosis, Familial, 4 29 STX11

Anatomical Context for Hemophagocytic Lymphohistiocytosis, Familial, 4

MalaCards organs/tissues related to Hemophagocytic Lymphohistiocytosis, Familial, 4:

41
Nk Cells, Bone, Lymph Node, Bone Marrow

Publications for Hemophagocytic Lymphohistiocytosis, Familial, 4

Articles related to Hemophagocytic Lymphohistiocytosis, Familial, 4:

# Title Authors Year
1
Defective cytotoxic lymphocyte degranulation in syntaxin-11 deficient familial hemophagocytic lymphohistiocytosis 4 (FHL4) patients. ( 17525286 )
2007

Variations for Hemophagocytic Lymphohistiocytosis, Familial, 4

ClinVar genetic disease variations for Hemophagocytic Lymphohistiocytosis, Familial, 4:

6
(show all 29)
# Gene Variation Type Significance SNP ID Assembly Location
1 STX11 NM_003764.3(STX11): c.369_376delAGTGGCGCinsTGG (p.Val124Glyfs) indel Pathogenic rs483352901 GRCh37 Chromosome 6, 144508133: 144508140
2 STX11 NM_003764.3(STX11): c.369_376delAGTGGCGCinsTGG (p.Val124Glyfs) indel Pathogenic rs483352901 GRCh38 Chromosome 6, 144186996: 144187003
3 STX11 NC_000006.12: g.144176889_144196077del19189 deletion Pathogenic GRCh38 Chromosome 6, 144176889: 144196077
4 STX11 NM_003764.3(STX11): c.802C> T (p.Gln268Ter) single nucleotide variant Pathogenic rs104893996 GRCh37 Chromosome 6, 144508566: 144508566
5 STX11 NM_003764.3(STX11): c.802C> T (p.Gln268Ter) single nucleotide variant Pathogenic rs104893996 GRCh38 Chromosome 6, 144187429: 144187429
6 STX11 NM_003764.3(STX11): c.173T> C (p.Leu58Pro) single nucleotide variant Pathogenic rs431905512 GRCh37 Chromosome 6, 144507937: 144507937
7 STX11 NM_003764.3(STX11): c.173T> C (p.Leu58Pro) single nucleotide variant Pathogenic rs431905512 GRCh38 Chromosome 6, 144186800: 144186800
8 STX11 NM_003764.3(STX11): c.391C> T (p.Gln131Ter) single nucleotide variant Likely pathogenic rs794729649 GRCh37 Chromosome 6, 144508155: 144508155
9 STX11 NM_003764.3(STX11): c.391C> T (p.Gln131Ter) single nucleotide variant Likely pathogenic rs794729649 GRCh38 Chromosome 6, 144187018: 144187018
10 STX11 NM_003764.3(STX11): c.146G> A (p.Arg49Gln) single nucleotide variant Benign/Likely benign rs17073498 GRCh37 Chromosome 6, 144507910: 144507910
11 STX11 NM_003764.3(STX11): c.146G> A (p.Arg49Gln) single nucleotide variant Benign/Likely benign rs17073498 GRCh38 Chromosome 6, 144186773: 144186773
12 STX11 NM_003764.3(STX11): c.546G> A (p.Glu182=) single nucleotide variant Conflicting interpretations of pathogenicity rs146949718 GRCh37 Chromosome 6, 144508310: 144508310
13 STX11 NM_003764.3(STX11): c.546G> A (p.Glu182=) single nucleotide variant Conflicting interpretations of pathogenicity rs146949718 GRCh38 Chromosome 6, 144187173: 144187173
14 STX11 NM_003764.3(STX11): c.799G> A (p.Val267Met) single nucleotide variant Benign rs45574234 GRCh38 Chromosome 6, 144187426: 144187426
15 STX11 NM_003764.3(STX11): c.799G> A (p.Val267Met) single nucleotide variant Benign rs45574234 GRCh37 Chromosome 6, 144508563: 144508563
16 STX11 NM_003764.3(STX11): c.829A> G (p.Thr277Ala) single nucleotide variant Benign/Likely benign rs9496891 GRCh38 Chromosome 6, 144187456: 144187456
17 STX11 NM_003764.3(STX11): c.829A> G (p.Thr277Ala) single nucleotide variant Benign/Likely benign rs9496891 GRCh37 Chromosome 6, 144508593: 144508593
18 STX11 NM_003764.3(STX11): c.589G> A (p.Val197Met) single nucleotide variant Uncertain significance rs141499372 GRCh37 Chromosome 6, 144508353: 144508353
19 STX11 NM_003764.3(STX11): c.589G> A (p.Val197Met) single nucleotide variant Uncertain significance rs141499372 GRCh38 Chromosome 6, 144187216: 144187216
20 STX11 NM_003764.3(STX11): c.585C> A (p.Ala195=) single nucleotide variant Uncertain significance rs147525157 GRCh37 Chromosome 6, 144508349: 144508349
21 STX11 NM_003764.3(STX11): c.585C> A (p.Ala195=) single nucleotide variant Uncertain significance rs147525157 GRCh38 Chromosome 6, 144187212: 144187212
22 STX11 NM_003764.3(STX11): c.26T> G (p.Leu9Arg) single nucleotide variant Uncertain significance rs34470310 GRCh37 Chromosome 6, 144507790: 144507790
23 STX11 NM_003764.3(STX11): c.26T> G (p.Leu9Arg) single nucleotide variant Uncertain significance rs34470310 GRCh38 Chromosome 6, 144186653: 144186653
24 STX11 NM_003764.3(STX11): c.369A> G (p.Ala123=) single nucleotide variant Likely benign rs763493074 GRCh37 Chromosome 6, 144508133: 144508133
25 STX11 NM_003764.3(STX11): c.369A> G (p.Ala123=) single nucleotide variant Likely benign rs763493074 GRCh38 Chromosome 6, 144186996: 144186996
26 STX11 NM_003764.3(STX11): c.839G> A (p.Cys280Tyr) single nucleotide variant Likely benign rs34282765 GRCh37 Chromosome 6, 144508603: 144508603
27 STX11 NM_003764.3(STX11): c.839G> A (p.Cys280Tyr) single nucleotide variant Likely benign rs34282765 GRCh38 Chromosome 6, 144187466: 144187466
28 STX11 NM_003764.3(STX11): c.668A> C (p.Asp223Ala) single nucleotide variant Uncertain significance GRCh38 Chromosome 6, 144187295: 144187295
29 STX11 NM_003764.3(STX11): c.668A> C (p.Asp223Ala) single nucleotide variant Uncertain significance GRCh37 Chromosome 6, 144508432: 144508432

Expression for Hemophagocytic Lymphohistiocytosis, Familial, 4

Search GEO for disease gene expression data for Hemophagocytic Lymphohistiocytosis, Familial, 4.

Pathways for Hemophagocytic Lymphohistiocytosis, Familial, 4

Pathways related to Hemophagocytic Lymphohistiocytosis, Familial, 4 according to GeneCards Suite gene sharing:

# Super pathways Score Top Affiliating Genes
1
Show member pathways
11.16 STX11 STX7
2 10.16 RAB27A UNC13D
3 9.7 RAB27A UNC13D

GO Terms for Hemophagocytic Lymphohistiocytosis, Familial, 4

Cellular components related to Hemophagocytic Lymphohistiocytosis, Familial, 4 according to GeneCards Suite gene sharing:

# Name GO ID Score Top Affiliating Genes
1 endosome GO:0005768 9.63 RAB27A STX7 UNC13D
2 lysosome GO:0005764 9.61 RAB27A STX7 UNC13D
3 endomembrane system GO:0012505 9.58 RAB27A STX11 STX7
4 recycling endosome GO:0055037 9.48 STX7 UNC13D
5 late endosome GO:0005770 9.43 RAB27A STX7 UNC13D
6 exocytic vesicle GO:0070382 9.37 RAB27A UNC13D
7 azurophil granule GO:0042582 9.32 STX7 STXBP2
8 Weibel-Palade body GO:0033093 9.16 RAB27A UNC13D
9 tertiary granule GO:0070820 8.96 STX7 STXBP2
10 SNARE complex GO:0031201 8.8 STX11 STX7 STXBP2

Biological processes related to Hemophagocytic Lymphohistiocytosis, Familial, 4 according to GeneCards Suite gene sharing:

# Name GO ID Score Top Affiliating Genes
1 neutrophil degranulation GO:0043312 9.65 RAB27A STXBP2 UNC13D
2 intracellular protein transport GO:0006886 9.61 RAB27A STX11 STX7
3 vesicle fusion GO:0006906 9.46 STX11 STX7
4 vesicle docking GO:0048278 9.4 STX11 STX7
5 positive regulation of exocytosis GO:0045921 9.37 RAB27A UNC13D
6 regulation of mast cell degranulation GO:0043304 9.32 STXBP2 UNC13D
7 natural killer cell degranulation GO:0043320 9.26 RAB27A UNC13D
8 vesicle-mediated transport GO:0016192 9.26 RAB27A STX11 STX7 STXBP2
9 positive regulation of regulated secretory pathway GO:1903307 9.16 RAB27A UNC13D
10 exocytosis GO:0006887 8.92 RAB27A STX11 STXBP2 UNC13D

Molecular functions related to Hemophagocytic Lymphohistiocytosis, Familial, 4 according to GeneCards Suite gene sharing:

# Name GO ID Score Top Affiliating Genes
1 SNARE binding GO:0000149 8.96 STX11 STX7
2 SNAP receptor activity GO:0005484 8.62 STX11 STX7

Sources for Hemophagocytic Lymphohistiocytosis, Familial, 4

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17 ExPASy
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62 PubMed
64 QIAGEN
69 SNOMED-CT via HPO
70 SNOMED-CT via Orphanet
71 TGDB
72 Tocris
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74 UMLS via Orphanet
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