MCID: HMP014
MIFTS: 41

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 54 50 29 13 69
Familial Hemophagocytic Lymphohistiocytosis 4 12 24 71 14
Hplh4 12 50 71
Fhl4 12 24 71
Hlh4 12 50 71

Characteristics:

OMIM:

54
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 : 54
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 familial hemophagocytic lymphohistiocytosis 4, is related to spondyloenchondrodysplasia with immune dysregulation and hemophagocytic lymphohistiocytosis, and has symptoms including neutropenia, hypertriglyceridemia and hepatomegaly. An important gene associated with Hemophagocytic Lymphohistiocytosis, Familial, 4 is STX11 (Syntaxin 11), and among its related pathways/superpathways is Nicotine Pathway (Dopaminergic Neuron), Pharmacodynamics. The drugs alemtuzumab and Cyclophosphamide have been mentioned in the context of this disorder. Affiliated tissues include nk cells, t cells and liver.

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

UniProtKB/Swiss-Prot : 71 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.

Related Diseases for Hemophagocytic Lymphohistiocytosis, Familial, 4

Diseases in the Hemophagocytic Lymphohistiocytosis family:

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

Diseases related to Hemophagocytic Lymphohistiocytosis, Familial, 4 via text searches within MalaCards or GeneCards Suite gene sharing:

id Related Disease Score Top Affiliating Genes
1 spondyloenchondrodysplasia with immune dysregulation 9.9 STX3 STXBP2
2 hemophagocytic lymphohistiocytosis 9.8
3 pediatric supratentorial ependymoma 9.2 STX11 STXBP2 UNC13D
4 hepatitis b 8.7 FHL2 STX11 STXBP2 UNC13D
5 thyroid dyshormonogenesis 4 7.5 FHL2 STX11 STX3 STX7 STXBP2 UNC13D

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:

54

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

Abdomen- Liver:
hepatomegaly

Metabolic Features:
fever

Immunology:
hyperinflammatory disorder
hemophagocytosis in bone marrow and lymph nodes

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

Abdomen- Spleen:
splenomegaly

Laboratory- Abnormalities:
increased triglycerides
decreased fibrinogen
increased ferritin
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)
id Description HPO Frequency HPO Source Accession
1 neutropenia 32 very rare (1%) HP:0001875
2 hypertriglyceridemia 32 very rare (1%) HP:0002155
3 hepatomegaly 32 very rare (1%) HP:0002240
4 splenomegaly 32 very rare (1%) HP:0001744
5 seizures 32 occasional (7.5%) HP:0001250
6 thrombocytopenia 32 very rare (1%) HP:0001873
7 anemia 32 very rare (1%) HP:0001903
8 global developmental delay 32 occasional (7.5%) HP:0001263
9 increased serum ferritin 32 very rare (1%) HP:0003281
10 fever 32 HP:0001945
11 muscular hypotonia 32 occasional (7.5%) HP:0001252
12 hypofibrinogenemia 32 very rare (1%) HP:0011900
13 hemophagocytosis 32 very rare (1%) HP:0012156

UMLS symptoms related to Hemophagocytic Lymphohistiocytosis, Familial, 4:


fever

Drugs & Therapeutics for Hemophagocytic Lymphohistiocytosis, Familial, 4

Drugs for Hemophagocytic Lymphohistiocytosis, Familial, 4 (from DrugBank, HMDB, Dgidb, PharmGKB, IUPHAR, NovoSeek, BitterDB):

(show all 39)
id Name Status Phase Clinical Trials Cas Number PubChem Id
1
alemtuzumab Approved, Investigational Phase 2,Phase 1 216503-57-0
2
Cyclophosphamide Approved, Investigational Phase 2,Phase 1 50-18-0, 6055-19-2 2907
3
Cytarabine Approved, Investigational Phase 2 147-94-4 6253
4
Busulfan Approved, Investigational Phase 1, Phase 2 55-98-1 2478
5
Everolimus Approved Phase 1, Phase 2 159351-69-6 6442177
6
Fludarabine Approved Phase 1, Phase 2 21679-14-1, 75607-67-9 30751
7
Melphalan Approved Phase 1, Phase 2 148-82-3 4053 460612
8
Methylprednisolone Approved, Vet_approved Phase 1, Phase 2 83-43-2 6741
9
Prednisolone Approved, Vet_approved Phase 1, Phase 2 50-24-8 5755
10
Sirolimus Approved, Investigational Phase 1, Phase 2 53123-88-9 5284616 6436030 46835353
11
Tacrolimus Approved, Investigational Phase 1, Phase 2 104987-11-3 445643 439492
12 Thiotepa Approved Phase 1, Phase 2 52-24-4 5453
13 Alkylating Agents Phase 2,Phase 1
14 Anti-Infective Agents Phase 2
15 Antimetabolites Phase 2,Phase 1
16 Antimetabolites, Antineoplastic Phase 2,Phase 1
17 Antirheumatic Agents Phase 2,Phase 1
18 Antiviral Agents Phase 2
19 Immunosuppressive Agents Phase 2,Phase 1
20 Antiemetics Phase 1, Phase 2
21 Anti-Inflammatory Agents Phase 1, Phase 2
22 Antineoplastic Agents, Hormonal Phase 1, Phase 2
23 Autonomic Agents Phase 1, Phase 2
24 Calcineurin Inhibitors Phase 1, Phase 2
25 Gastrointestinal Agents Phase 1, Phase 2
26 glucocorticoids Phase 1, Phase 2
27 Hormone Antagonists Phase 1, Phase 2
28 Hormones Phase 1, Phase 2
29 Hormones, Hormone Substitutes, and Hormone Antagonists Phase 1, Phase 2
30 Liver Extracts Phase 1, Phase 2
31 Methylprednisolone acetate Phase 1, Phase 2
32 Methylprednisolone Hemisuccinate Phase 1, Phase 2
33 Neuroprotective Agents Phase 1, Phase 2
34 Peripheral Nervous System Agents Phase 1, Phase 2
35 Pharmaceutical Solutions Phase 1, Phase 2
36 Prednisolone acetate Phase 1, Phase 2
37 Prednisolone hemisuccinate Phase 1, Phase 2
38 Prednisolone phosphate Phase 1, Phase 2
39 Protective Agents Phase 1, Phase 2

Interventional clinical trials:


id Name Status NCT ID Phase Drugs
1 T Cell Depletion for Recipients of HLA Haploidentical Related Donor Stem Cell Grafts Recruiting NCT00368355 Phase 2 Ara-C;Cyclophosphamide
2 CD34+ (Malignant) Stem Cell Selection for Patients Receiving Allogenic Stem Cell Transplant Recruiting NCT02061800 Phase 1, Phase 2 Thiotepa;Cyclophosphamide;Alemtuzumab;Tacrolimus;Melphalan;Busulfan;Fludarabine;Methylprednisolone
3 Administration of Donor T Cells With the Caspase-9 Suicide Gene Active, not recruiting NCT01494103 Phase 1 AP1903
4 Rare Disease Patient Registry & Natural History Study - Coordination of Rare Diseases at Sanford Recruiting NCT01793168

Search NIH Clinical Center for Hemophagocytic Lymphohistiocytosis, Familial, 4

Genetic Tests for Hemophagocytic Lymphohistiocytosis, Familial, 4

Genetic tests related to Hemophagocytic Lymphohistiocytosis, Familial, 4:

id Genetic test Affiliating Genes
1 Hemophagocytic Lymphohistiocytosis, Familial, 4 29
2 Familial Hemophagocytic Lymphohistiocytosis 4 24 STX11

Anatomical Context for Hemophagocytic Lymphohistiocytosis, Familial, 4

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

39
Nk Cells, T Cells, Liver, Bone, Bone Marrow, Lymph Node

Publications for Hemophagocytic Lymphohistiocytosis, Familial, 4

Variations for Hemophagocytic Lymphohistiocytosis, Familial, 4

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

6
id 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 NC_000006.12: g.144176889_144196077del19189 deletion Pathogenic GRCh38 Chromosome 6, 144176889: 144196077
3 STX11 NM_003764.3(STX11): c.802C> T (p.Gln268Ter) single nucleotide variant Pathogenic rs104893996 GRCh37 Chromosome 6, 144508566: 144508566
4 STX11 NM_003764.3(STX11): c.173T> C (p.Leu58Pro) single nucleotide variant Pathogenic rs431905512 GRCh37 Chromosome 6, 144507937: 144507937
5 STX11 NM_003764.3(STX11): c.391C> T (p.Gln131Ter) single nucleotide variant Likely pathogenic rs794729649 GRCh38 Chromosome 6, 144187018: 144187018

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:

id Super pathways Score Top Affiliating Genes
1
Show member pathways
10.81 STX11 STX3 STX7

GO Terms for Hemophagocytic Lymphohistiocytosis, Familial, 4

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

id Name GO ID Score Top Affiliating Genes
1 late endosome GO:0005770 9.43 STX7 UNC13D
2 recycling endosome GO:0055037 9.4 STX7 UNC13D
3 synaptic vesicle GO:0008021 9.37 STX11 STX3
4 specific granule GO:0042581 9.32 STX3 STXBP2
5 zymogen granule membrane GO:0042589 9.26 STX3 STXBP2
6 tertiary granule GO:0070820 9.16 STX7 STXBP2
7 azurophil granule GO:0042582 9.13 STX3 STX7 STXBP2
8 SNARE complex GO:0031201 8.92 STX11 STX3 STX7 STXBP2

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

id Name GO ID Score Top Affiliating Genes
1 intracellular protein transport GO:0006886 9.54 STX11 STX3 STX7
2 vesicle fusion GO:0006906 9.43 STX3 STX7
3 membrane fusion GO:0061025 9.4 STX11 STX3
4 exocytosis GO:0006887 9.33 STX3 STXBP2 UNC13D
5 synaptic vesicle fusion to presynaptic active zone membrane GO:0031629 9.32 STX11 STX3
6 regulation of mast cell degranulation GO:0043304 9.26 STXBP2 UNC13D
7 vesicle-mediated transport GO:0016192 9.26 STX11 STX3 STX7 STXBP2
8 vesicle docking GO:0048278 8.8 STX11 STX3 STX7

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

id Name GO ID Score Top Affiliating Genes
1 SNARE binding GO:0000149 9.13 STX11 STX3 STX7
2 SNAP receptor activity GO:0005484 8.8 STX11 STX3 STX7

Sources for Hemophagocytic Lymphohistiocytosis, Familial, 4

3 CDC
7 CNVD
9 Cosmic
10 dbSNP
11 DGIdb
16 ExPASy
18 FMA
28 GO
29 GTR
30 HGMD
31 HMDB
32 HPO
33 ICD10
34 ICD10 via Orphanet
35 ICD9CM
36 IUPHAR
37 KEGG
38 LifeMap
40 MedGen
42 MeSH
43 MESH via Orphanet
44 MGI
46 NCI
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48 NDF-RT
51 NINDS
52 Novoseek
54 OMIM
55 OMIM via Orphanet
59 PubMed
60 QIAGEN
65 SNOMED-CT via HPO
66 SNOMED-CT via Orphanet
67 TGDB
68 Tocris
69 UMLS
70 UMLS via Orphanet
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