HIDS
MCID: HYP088
MIFTS: 59

Hyper-Igd Syndrome (HIDS) malady

Genetic diseases, Rare diseases, Bone diseases, Skin diseases, Blood diseases categories

Summaries for Hyper-Igd Syndrome

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44NIH Rare Diseases, 48OMIM, 34MalaCards
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NIH Rare Diseases:44 Hyper igd syndrome is an inflammatory genetic disorder characterized by periodic episodes of fever associated with additional symptoms including joint pain, skin rash and abdominal pain. most episodes last several days and occur periodically throughout life. the frequency of episodes and their severity vary greatly from case to case.  hyper igd syndrome is caused by mutations in the gene encoding mevalonate kinase (mvk). it is inherited in an autosomal recessive manner.  last updated: 3/5/2013

MalaCards: Hyper-Igd Syndrome, also known as hyper igd syndrome, is related to mevalonic aciduria and amyloidosis, and has symptoms including gastrointestinal bleeding/hemorrhage/hematemesis/melena/rectorrhagia, facial pain/cephalalgia/migraine and purpura/petichiae. An important gene associated with Hyper-Igd Syndrome is MVK (mevalonate kinase), and among its related pathways are 14-3-3 and Regulation of BAD Activity and Jak/Stat Pathway. The compounds toxin-1 and amphotericin b have been mentioned in the context of this disorder. Affiliated tissues include skin, bone and liver, and related mouse phenotypes are reproductive system and immune system.

Description from OMIM:48 260920

Aliases & Classifications for Hyper-Igd Syndrome

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44NIH Rare Diseases, 48OMIM, 46Novoseek, 50Orphanet, 21GeneTests, 63UMLS, 27ICD10 via Orphanet, 60SNOMED-CT via Orphanet
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Classifications:



Characteristics (Orphanet epidemiological data):

50
hyper-igd syndrome:
Inheritance: Autosomal recessive; Age of onset: Neonatal/infancy


Aliases & Descriptions:

hyper-igd syndrome 44 48 46 50
hyper igd syndrome 44 21
hyperimmunoglobulinemia d and periodic fever syndrome 44
hyperimmunoglobulinemia d with periodic fever 50
hyperimmunoglobinemia d with recurrent fever 50
partial mevalonate kinase deficiency 50
hyperimmunoglobulinemia d syndrome 50
periodic fever dutch type 44
hyperimmunoglobulinemia d 63
hids 50


External Ids:

OMIM48 260920
ICD10 via Orphanet27 E85.0
SNOMED-CT via Orphanet60 234538002

Related Diseases for Hyper-Igd Syndrome

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Sources:
18GeneCards, 19GeneDecks
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Diseases related to Hyper-Igd Syndrome via text searches within MalaCards or GeneCards/GeneDecks gene sharing:

(show top 50)    (show all 68)
idRelated DiseaseScoreTop Affiliating Genes
1mevalonic aciduria30.7MVK, IL1RN
2amyloidosis30.6TNFRSF1A, SAA1, CRP
3familial mediterranean fever30.4TNF, TNFRSF1A
4kid syndrome10.3
5crescentic glomerulonephritis10.2
6glomerulonephritis10.2
7keratopathy10.2
8pericarditis10.2
9schnitzler syndrome10.1IL1RN
10dengue shock syndrome10.1IL1RN
11malaria10.1TNF
12muckle-wells syndrome10.1TNFRSF1A
13leishmaniasis10.1TNFRSF1A
14epidural abscess10.1CRP
15systemic lupus erythematosus10.1CRP
16adult-onset still's disease10.1CRP
17rheumatic disease10.1CRP
18blau syndrome10.1MVK, TNF
19acute graft versus host disease10.1TNF, IL1RN
20cerebral malaria10.0IL1RN, TNF
21relapsing fever10.0TNFRSF1A, MVK
22toxic shock syndrome10.0TNF, IL1RN
23adult respiratory distress syndrome10.0IL1RN, TNF
24periodontitis10.0IL1RN, TNF
25cryopyrin-associated periodic syndrome10.0
26ichthyosis, hystrix-like, with deafness10.0
27arthritis10.0TNFRSF1A, TNF
28polymyalgia rheumatica10.0IL1RN, CRP
29exanthem10.0IL1RN, CRP
30spondylarthropathy10.0CRP, TNF
31amyloidosis, secondary10.0CRP, SAA1
32sarcoidosis10.0IL1RN, TNF
33chronic infantile neurological cutaneous articular syndrome10.0IL1RN, MVK, TNFRSF1A
34graft versus host disease10.0TNF, TNFRSF1A
35ankylosing spondylitis10.0TNF, CRP
36uveitis10.0TNFRSF1A, TNF
37psoriatic arthritis10.0CRP, TNF
38inflammatory bowel disease10.0IL1RN, TNFRSF1A
39monocytic leukemia10.0TNFRSF1A, TNF
40periodic fever, familial, autosomal dominant10.0MVK, TNFRSF1A, TNF
41respiratory failure10.0CRP, TNF
42behcet's disease10.0CRP, TNF
43periodontal disease10.0CRP, TNF
44ulcerative colitis10.0CRP, TNF
45vascular disease10.0TNF, TNFRSF1A, IL1RN
46hypersensitivity reaction type ii disease10.0IL1RN, TNFRSF1A, TNF
47crohn's disease10.0CRP, TNF
48neutropenia10.0TNFRSF1A, IL1RN
49peritonitis10.0CRP, TNF
50acute pancreatitis10.0IL1RN, CRP

Graphical network of the top 20 diseases related to Hyper-Igd Syndrome:



Diseases related to hyper-igd syndrome

Symptoms for Hyper-Igd Syndrome

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48OMIM, 50Orphanet
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Symptoms by clinical synopsis from OMIM:

260920

Clinical features from OMIM:

260920

Symptoms:

50 (show all 28)
  • gastrointestinal bleeding/hemorrhage/hematemesis/melena/rectorrhagia
  • facial pain/cephalalgia/migraine
  • purpura/petichiae
  • intestinal obstruction/ileus
  • biological inflammatory syndrome/increased erythrocyte sedimentation rate/crp
  • acute diarrhea
  • vascularitis/vasculitides/arteritis
  • lymphadenopathy/polyadenopathies
  • enanthema/aphtosa/aphta/leukoplakia
  • monoclonal immunoglobulins/gammapathy/dysglobulinemia
  • peritonitis/peritoneal abscess
  • acute abdominal pain/colic
  • urticaria
  • seizures/epilepsy/absences/spasms/status epilepticus
  • intellectual deficit/mental/psychomotor retardation/learning disability
  • failure to thrive/difficulties for feeding in infancy/growth delay
  • ataxia/incoordination/trouble of the equilibrium
  • dermal/subcutaneous infiltration/induration
  • hepatomegaly/liver enlargement (excluding storage disease)
  • arthritis/synovitis/synovial proliferation
  • restricted joint mobility/joint stiffness/ankylosis
  • fever/chilling
  • articular/joint pain/arthralgia
  • acrocyanosis/raynaud's phenomenon/vasomotor disorders
  • erythema/erythematous lesions/erythroderma/polymorphous erythema
  • follicular/erythematous/edematous papules/milium
  • myalgia/muscular pain
  • autosomal recessive inheritance

Drugs & Therapeutics for Hyper-Igd Syndrome

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Sources:
6CenterWatch, 43NIH Clinical Center, 7ClinicalTrials, 63UMLS, 42NDF-RT
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Approved drugs:

Search CenterWatch for Hyper-Igd Syndrome

Drug clinical trials:

Search ClinicalTrials for Hyper-Igd Syndrome

Search NIH Clinical Center for Hyper-Igd Syndrome

Search CenterWatch for Hyper-Igd Syndrome

Genetic Tests for Hyper-Igd Syndrome

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21GeneTests
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Genetic tests related to Hyper-Igd Syndrome:

id Genetic test Affiliating Genes
1 Hyper Igd Syndrome21 MVK

Anatomical Context for Hyper-Igd Syndrome

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34MalaCards
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MalaCards organs/tissues related to Hyper-Igd Syndrome:

34
Skin, Bone, Liver, Monocytes

Animal Models for Hyper-Igd Syndrome or affiliated genes

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38MGI
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MGI Mouse Phenotypes related to Hyper-Igd Syndrome:

38
idDescriptionMGI Source AccessionScoreTop Affiliating Genes
1MP:00053898.2IL1RN, PTX3, TNFRSF1A, TNF
2MP:00053877.5CRP, IL1RN, PTX3, TNFRSF1A, TNF
3MP:00053767.3TNF, TNFRSF1A, SAA1, IL1RN, CRP

Publications for Hyper-Igd Syndrome

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Sources:
53PubMed
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Articles related to Hyper-Igd Syndrome:

(show all 31)
idTitleAuthorsYear
1
Long chain fatty acid (Lcfa) abnormalities in hyper Igd syndrome (Hids) and Familial Mediterranean Fever (Fmf): new insight into heritable periodic fevers. (23375471)
2013
2
Aberrant expression of costimulatory molecules in splenocytes of the mevalonate kinase-deficient mouse model of human hyper-IgD syndrome (HIDS). (21607759)
2012
3
Renal amyloidosis due to hyper-IgD syndrome. (23169386)
2012
4
Mevalonate kinase deficiency (hyper IgD syndrome with periodic fever)--different faces with separate treatments: two cases and review of the literature. (23692791)
2012
5
Hyper-IgD syndrome or mevalonate kinase deficiency. (21760510)
2011
6
A novel mutation in TNFRSF1A associated with overlapping features of tumor necrosis factor receptor-associated periodic syndrome and hyper-IgD syndrome. (20346247)
2010
7
Nummular keratopathy in a patient with Hyper-IgD Syndrome. (19656398)
2009
8
Recurrent pericarditis in hyper-IgD syndrome. (19772809)
2009
9
Hyper-IgD syndrome with novel mutation in a Japanese girl. (18941711)
2009
10
A patient with hyper-IgD syndrome responding to simvastatin treatment. (19046710)
2008
11
MVK gene abnormality and new approach to treatment of hyper IgD syndrome and periodic fever syndrome]. (17473510)
2007
12
Deletion of a single mevalonate kinase (Mvk) allele yields a murine model of hyper-IgD syndrome. (18008182)
2007
13
Diagnostic value of serum immunoglobulinaemia D level in patients with a clinical suspicion of hyper IgD syndrome. (17804452)
2007
14
A patient with hyper-IgD syndrome responding to anti-TNF treatment. (17171314)
2007
15
Diagnostic challenge of hyper-IgD syndrome in four children with inflammatory gastrointestinal complaints. (16635911)
2006
16
Hereditary periodic fever with systemic amyloidosis: is hyper-IgD syndrome really a benign disease? (16931207)
2006
17
Serum amyloid A serum concentrations and genotype do not explain low incidence of amyloidosis in Hyper-IgD syndrome. (16011988)
2005
18
Effect of etanercept and anakinra on inflammatory attacks in the hyper-IgD syndrome: introducing a vaccination provocation model. (16093577)
2005
19
A patient with hyper-IgD syndrome in Antalya, Turkey. (15045637)
2004
20
Inefficacy of etanercept in a child with hyper-IgD syndrome and periodic fever. (15638064)
2004
21
Effect of inflammatory attacks in the classical type hyper-IgD syndrome on immunoglobulin D, cholesterol and parameters of the acute phase response. (15324368)
2004
22
Hyper IgD syndrome (HIDS) associated with in vitro evidence of defective monocyte TNFRSF1A shedding and partial response to TNF receptor blockade with etanercept. (12452839)
2002
23
Mevalonic aciduria and hyper-IgD syndrome: two sides of the same coin? (11486910)
2001
24
Non-steroidal anti-inflammatory drugs in the treatment of hyper-IgD syndrome. (11534513)
2001
25
Identification of the gene for hyper-IgD syndrome: a model of modern genetics]. (10800545)
2000
26
Hyper-IgD syndrome and familial Hibernian fever are true periodic fever syndromes. (10969277)
2000
27
Crescentic glomerulonephritis in hyper IgD syndrome. (10229000)
1999
28
Hyper-IgD syndrome and pregnancy. (8886712)
1996
29
Unstimulated peripheral blood mononuclear cells from patients with the hyper-IgD syndrome produce cytokines capable of potent induction of C-reactive protein and serum amyloid A in Hep3B cells. (8683144)
1996
30
Clinical and immunological follow-up in children with hyper-IgD syndrome. (8167736)
1993
31
Hyper-IGD syndrome: a new case treated with colchicine. (3229086)
1988

Variations for Hyper-Igd Syndrome

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Sources:
65UniProtKB/Swiss-Prot, 1 National Center for Biotechnology Information (Clinvar), 8dbSNP
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UniProtKB/Swiss-Prot genetic disease variations for Hyper-Igd Syndrome:

65 (show all 21)
id Symbol AA change Variation ID SNP ID
1MVKp.His20ProVAR_004022
2MVKp.Pro167LeuVAR_004023
3MVKp.Ile268ThrVAR_004024
4MVKp.Val377IleVAR_004027rs28934897
5MVKp.Val310MetVAR_009068
6MVKp.His20AsnVAR_010956rs11544299
7MVKp.Leu39ProVAR_010957
8MVKp.Ser135LeuVAR_010959
9MVKp.Ala148ThrVAR_010960
10MVKp.Ser150LeuVAR_010961
11MVKp.Gly202ArgVAR_010962
12MVKp.Arg215GlnVAR_010963
13MVKp.Gly309SerVAR_010967
14MVKp.Gly326ArgVAR_010968
15MVKp.His20GlnVAR_029519
16MVKp.Val132IleVAR_029520
17MVKp.Gly171ArgVAR_029521
18MVKp.Gly211GluVAR_029522
19MVKp.Val250IleVAR_029523
20MVKp.Leu265ArgVAR_029524
21MVKp.Gly376ValVAR_029527

Clinvar genetic disease variations for Hyper-Igd Syndrome:

1 (show all 11)
id Gene Name Type Significance SNP ID Assembly Location
1MVKNM_000431.3(MVK): c.1129G> A (p.Val377Ile)single nucleotide variantPathogenicrs28934897GRCh37Chr 12, 110034320: 110034320
2MVKNM_000431.3(MVK): c.1000G> A (p.Ala334Thr)single nucleotide variantPathogenicrs104895317GRCh37Chr 12, 110032947: 110032947
3MVKNM_000431.3(MVK): c.59A> C (p.His20Pro)single nucleotide variantPathogenicrs104895295GRCh37Chr 12, 110012686: 110012686
4MVKNM_000431.3(MVK): c.803T> C (p.Ile268Thr)single nucleotide variantPathogenicrs104895304GRCh37Chr 12, 110029080: 110029080
5MVKNM_000431.3(MVK): c.494C> T (p.Pro165Leu)single nucleotide variantPathogenicrs121917790GRCh37Chr 12, 110019322: 110019322
6MVKNM_000431.3(MVK): c.928G> A (p.Val310Met)single nucleotide variantPathogenicrs104895319GRCh37Chr 12, 110032875: 110032875
7MVKNM_000431.3(MVK): c.500C> T (p.Pro167Leu)single nucleotide variantPathogenicrs104895300GRCh37Chr 12, 110019328: 110019328
8MVKNM_000431.3(MVK): c.604G> A (p.Gly202Arg)single nucleotide variantPathogenicrs104895301GRCh37Chr 12, 110023903: 110023903
9MVKNM_000431.3(MVK): c.417dupC (p.Gly140Argfs)duplicationPathogenicrs104895373GRCh37Chr 12, 110019245: 110019246
10MVKNM_000431.3(MVK): c.72dupT (p.Gly25Trpfs)duplicationPathogenicrs104895322GRCh37Chr 12, 110012699: 110012700
11MVKNM_000431.3(MVK): c.421dupG (p.Ala141Glyfs)duplicationPathogenicrs104895323GRCh37Chr 12, 110019249: 110019250

Expression for genes affiliated with Hyper-Igd Syndrome

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2BioGPS, 16Gene Expression Omnibus DataSets
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Expression patterns in normal tissues for genes affiliated with Hyper-Igd Syndrome

Search GEO for disease gene expression data for Hyper-Igd Syndrome.

Pathways for genes affiliated with Hyper-Igd Syndrome

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Sources:
51PathCards, 54QIAGEN, 5Cell Signaling Technology, 61Thomson Reuters, 56Reactome, 31KEGG, 55R&D Systems, 39NCBI BioSystems Database
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Pathways related to Hyper-Igd Syndrome according to GeneCards/GeneDecks:

(show all 21)
idSuper pathways (with members indented)ScoreTop Affiliating Genes
110.0TNFRSF1A
2
Show member pathways
Development Thrombopoetin signaling via JAK STAT pathway61
9.4CRP, IL1RN
3
Show member pathways
9.2SAA1, TNF
4
Show member pathways
9.1TNF, TNFRSF1A
5
Show member pathways
Apoptosis and survival Apoptotic TNF family pathways61
9.1TNFRSF1A, TNF
69.1TNF, TNFRSF1A
7
Show member pathways
FAS pathway and Stress induction of HSP regulation39
Apoptosis and survival FAS signaling cascades61
Caspase cascade in apoptosis39
9.1TNFRSF1A, TNF
8
Show member pathways
Transcription NF kB signaling pathway61
Immune response Toll like receptor TLR ligands and common TLR signaling pathway leading to cell proinflammatory response61
9.1TNFRSF1A, TNF
99.1TNFRSF1A, TNF
109.1TNF, TNFRSF1A
119.1TNFRSF1A, TNF
12
Show member pathways
Apoptosis and survival Anti apoptotic TNFs NF kB IAP pathway61
9.1TNF, TNFRSF1A
13
Show member pathways
9.1TNFRSF1A, TNF
149.1TNF, TNFRSF1A
15
Show member pathways
9.1TNFRSF1A, TNF
16
Show member pathways
9.1TNF, TNFRSF1A
179.1TNF, TNFRSF1A
189.1TNFRSF1A, TNF
199.1TNF, TNFRSF1A
20
Show member pathways
Amyotrophic lateral sclerosis (ALS)39
9.1TNFRSF1A, TNF
21
Show member pathways
thioredoxin pathway39
8.6CRP, SAA1, TNF

Compounds for genes affiliated with Hyper-Igd Syndrome

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Sources:
46Novoseek, 12DrugBank, 52PharmGKB, 62Tocris Bioscience, 3BitterDB, 30IUPHAR, 25HMDB
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Compounds related to Hyper-Igd Syndrome according to GeneCards/GeneDecks:

(show top 50)    (show all 85)
idCompoundScoreTop Affiliating Genes
1toxin-1469.5TNF, IL1RN
2amphotericin b469.4CRP, IL1RN
3bcma469.4TNF, TNFRSF1A
4blys469.4TNFRSF1A, TNF
5tocilizumab46 1210.4CRP, TNF
6gold sodium thiomalate469.4IL1RN, TNF
7cdp571469.4CRP, TNF
8actinomycin469.3TNFRSF1A, TNF
9hydroxychloroquine46 1210.3TNF, CRP
10gabexate mesilate469.3TNF, CRP
11polyethylene glycol469.3TNFRSF1A, CRP, IL1RN
12p003469.3IL1RN, TNFRSF1A, CRP
13p002469.3CRP, IL1RN, TNFRSF1A
14tab-1469.2TNF, TNFRSF1A
15leflunomide46 52 1211.1TNF, TNFRSF1A, IL1RN
16ns 39846 6210.1TNFRSF1A, TNF, IL1RN
17manganese superoxide469.1IL1RN, TNFRSF1A, TNF
18chloroquine46 3 52 30 1213.1IL1RN, TNFRSF1A, TNF
19tgf beta1469.0IL1RN, TNF, TNFRSF1A
20nash469.0TNFRSF1A, TNF
21sulfasalazine30 46 52 1212.0CRP, IL1RN, TNF
22fmlp469.0IL1RN, TNF, TNFRSF1A
23tenidap46 3010.0SAA1, TNF, CRP
24atorvastatin46 52 30 25 1213.0TNF, CRP, IL1RN
25rituximab46 52 1211.0SAA1, TNF, CRP
26prednisolone46 30 1211.0CRP, IL1RN, TNF
27rosiglitazone30 46 52 25 1212.9CRP, IL1RN, TNF
28okt3468.9TNF, TNFRSF1A, CRP
29prostacyclin468.8CRP, TNFRSF1A, TNF
30anakinra46 129.7CRP, TNF, MVK, IL1RN
31fibrinogen468.6IL1RN, CRP, TNF, SAA1
32adalimumab46 52 1210.5TNFRSF1A, TNF, CRP, IL1RN
33etanercept46 52 1210.5TNF, IL1RN, CRP, TNFRSF1A
34infliximab46 52 1210.5CRP, TNFRSF1A, TNF, IL1RN
35ivig468.5TNF, TNFRSF1A, IL1RN, CRP
36neopterin468.5IL1RN, CRP, TNF, TNFRSF1A
37methotrexate52 46 1210.5TNF, TNFRSF1A, IL1RN, CRP
38n acetylcysteine468.5TNF, TNFRSF1A, CRP
39sb 20358046 629.5CRP, IL1RN, TNF, TNFRSF1A
40alanine468.5TNFRSF1A, CRP, SAA1, MVK, IL1RN
41creatinine468.5TNFRSF1A, MVK, IL1RN, CRP, PTX3
42rantes468.4TNF, TNFRSF1A, IL1RN
43vegf468.3CRP, TNF, TNFRSF1A, IL1RN
44nitric oxide46 25 1210.3TNF, PTX3, IL1RN, TNFRSF1A
45dexamethasone46 52 30 1211.2IL1RN, PTX3, SAA1, TNFRSF1A, TNF
46endotoxin468.1SAA1, TNF, TNFRSF1A, CRP, IL1RN
47cholesterol46 30 25 1211.0TNFRSF1A, IL1RN, MVK, SAA1, PTX3, CRP
48cycloheximide468.0TNFRSF1A, PTX3, TNF, IL1RN, CRP
49simvastatin46 52 62 30 25 1212.7SAA1, TNF, TNFRSF1A, MVK, CRP, IL1RN
50lipid467.7CRP, IL1RN, MVK, SAA1, TNFRSF1A, TNF

GO Terms for genes affiliated with Hyper-Igd Syndrome

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17Gene Ontology
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Cellular components related to Hyper-Igd Syndrome according to GeneCards/GeneDecks:

idNameGO IDScoreTop Affiliating Genes
1extracellular spaceGO:0056158.1CRP, IL1RN, TNFRSF1A, TNF
2extracellular regionGO:0055767.2CRP, SAA1, PTX3, TNFRSF1A, TNF

Biological processes related to Hyper-Igd Syndrome according to GeneCards/GeneDecks:

(show all 17)
idNameGO IDScoreTop Affiliating Genes
1opsonizationGO:0082289.6CRP, PTX3
2chronic inflammatory response to antigenic stimulusGO:0024399.5IL1RN, TNF
3positive regulation of JUN kinase activityGO:0435079.4IL1RN, TNF
4negative regulation of inflammatory responseGO:0507289.4SAA1, TNFRSF1A, MVK
5positive regulation of cytokine secretionGO:0507159.4SAA1, TNF
6negative regulation of interleukin-6 productionGO:0327159.4TNFRSF1A, TNF
7response to ethanolGO:0454719.3TNFRSF1A, CRP
8acute-phase responseGO:0069539.3CRP, IL1RN, SAA1
9negative regulation of lipid storageGO:0108889.3TNF, CRP
10positive regulation of nitric oxide biosynthetic processGO:0454299.3PTX3, TNF
11extrinsic apoptotic signaling pathway via death domain receptorsGO:0086259.2TNFRSF1A, TNF
12defense response to Gram-positive bacteriumGO:0508309.1CRP, TNF
13response to glucocorticoidGO:0513849.1IL1RN, TNF
14intrinsic apoptotic signaling pathway in response to DNA damageGO:0086309.1TNFRSF1A, TNF
15negative regulation of gene expressionGO:0106298.8TNF, TNFRSF1A
16response to hypoxiaGO:0016668.8CRP, TNFRSF1A, TNF
17inflammatory responseGO:0069548.3CRP, TNF, TNFRSF1A, PTX3

Molecular functions related to Hyper-Igd Syndrome according to GeneCards/GeneDecks:

idNameGO IDScoreTop Affiliating Genes
1protease bindingGO:0020209.1TNFRSF1A, TNF

Products for genes affiliated with Hyper-Igd Syndrome

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  • Antibodies
  • Proteins
  • Lysates
  • Antibodies

Sources for Hyper-Igd Syndrome

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4CDC
14ExPASy
15FMA
23GTR
24HGMD
25HMDB
26ICD10
27ICD10 via Orphanet
28ICD9CM
30IUPHAR
31KEGG
36MeSH
37MESH via Orphanet
38MGI
41NCIt
42NDF-RT
45NINDS
46Novoseek
48OMIM
49OMIM via Orphanet
53PubMed
54QIAGEN
60SNOMED-CT via Orphanet
63UMLS
64UMLS via Orphanet