EDS
MCID: EHL001
MIFTS: 61

Ehlers-Danlos Syndrome (EDS) malady

Skin diseases category

Summaries for Ehlers-Danlos Syndrome

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8Disease Ontology, 42NIH Rare Diseases, 33MedlinePlus, 21Genetics Home Reference, 63Wikipedia, 46OMIM, 32MalaCards
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NIH Rare Diseases:42 Ehlers-danlos syndrome (eds) is a group of disorders that affect connective tissue, which supports the skin, bones, tendons, ligaments, blood vessels, and other organs. the signs and symptoms of eds vary by type and range from mildly loose joints to life-threatening complications. an unusually large range of joint movement (hypermobility) occurs with most forms, particularly the hypermobility type. many people with eds also have soft, velvety skin that is highly elastic and fragile. affected individuals tend to bruise easily, and some types of the condition also cause abnormal scarring. some forms of eds, notably the vascular type and kyphoscoliosis type, can involve serious and potentially life-threatening complications. eds may be caused by mutations in any one of several genes; the inheritance pattern varies by type. last updated: 3/2/2012

MalaCards: Ehlers-Danlos Syndrome, also known as ehlers danlos syndrome, is related to ehlers-danlos syndrome, hypermobility type and hypermobility syndrome. An important gene associated with Ehlers-Danlos Syndrome is COL3A1 (collagen, type III, alpha 1), and among its related pathways are GPVI-mediated activation cascade and VEGFR3 signaling in lymphatic endothelium. The compounds Collagenase and nppa have been mentioned in the context of this disorder. Affiliated tissues include skin, bone and colon, and related mouse phenotypes are muscle and integument.

Disease Ontology:8 A collagen disease that is characterized by extremely flexible joints, elastic skin, and excessive bruising caused by a heritable defect in collagen synthesis, which leads to marked healing difficulties. eds has five cardinal signs, which may be present to some degree in all of the subtypes. these five cardinal signs are skin fragility, blood vessel fragility, skin hyperelasticity, joint hypermobility, and characteristic subcutaneous nodules.

MedlinePlus:33 Ehlers-danlos syndrome (eds) is a group of inherited disorders that weaken connective tissues. connective tissues are proteins that support skin, bones, blood vessels, and other organs. eds usually affects your skin, joints and blood vessel walls. symptoms include loose joints fragile, small blood vessels abnormal scar formation and wound healing soft, velvety, stretchy skin that bruises easily there are several types of eds. they can range from mild to life-threatening. about 1 in 5,000 people has eds. there is no cure. treatment involves managing symptoms, often with medicines and physical therapy. it also includes learning how to protect your joints and prevent injuries.

Genetics Home Reference:21 Ehlers-Danlos syndrome is a group of disorders that affect connective tissues, which are tissues that support the skin, bones, blood vessels, and other organs. Defects in connective tissues cause the signs and symptoms of Ehlers-Danlos syndrome, which vary from mildly loose joints to life-threatening complications.

Wikipedia:63 Ehlers–Danlos syndrome (EDS) is an inherited connective tissue disorder with different presentations... more...

Description from OMIM:46 225400,130070

Aliases & Classifications for Ehlers-Danlos Syndrome

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8Disease Ontology, 42NIH Rare Diseases, 22GTR, 21Genetics Home Reference, 10DISEASES, 44Novoseek, 33MedlinePlus, 60UMLS, 39NCIt, 27ICD9CM, 46OMIM, 56SNOMED-CT, 34MeSH
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Classifications:

Malacards categories (disease lists): (See all malacards categories)
Anatomical: Skin diseases


Aliases & Descriptions:

ehlers-danlos syndrome 8 42 21 10 44 33 60
ehlers danlos syndrome 42 22
elastic skin 8 44
eds 42 21
ehlers danlos disease 21
cutis hyperelastica 8
ed syndrome 42


External Ids:

Disease Ontology8 DOID:13359
NCIt39 C34568
ICD9CM27 756.83
MeSH34 D004535

Related Diseases for Ehlers-Danlos Syndrome

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17GeneCards, 18GeneDecks
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Diseases in the Ehlers-Danlos Syndrome Type Iv family:

Type Iii Ehlers-Danlos Syndrome Type Vi Ehlers-Danlos Syndrome
Type I Ehlers-Danlos Syndrome ehlers-danlos syndrome
Ehlers-Danlos Syndrome Type 5 Ehlers-Danlos Syndrome, Type Vii
Ehlers-Danlos Syndrome Type Via Ehlers-Danlos Syndrome Type Viib
Ehlers-Danlos Syndrome, Type Viii

Diseases related to Ehlers-Danlos Syndrome via text searches within MalaCards or GeneCards/GeneDecks gene sharing:

(show top 50)    (show all 287)
idRelated DiseaseScoreTop Affiliating Genes
1ehlers-danlos syndrome, hypermobility type31.6TNXB, COL3A1
2hypermobility syndrome31.5TNXB
3ehlers-danlos syndrome, classic type31.4COL5A1, COL1A1
4ehlers-danlos syndrome kyphoscoliotic type31.0PLOD1, PLOD2
5osteogenesis imperfecta30.8PLOD2, COL1A2, COL1A1, DSPP, CD36, COL3A1
6osteogenesis imperfecta type i30.6COL1A2, COL1A1
7connective tissue disease30.6COL5A1, COL1A1, COL3A1, TNXB, DSPP, CD36
8otosclerosis30.4COL1A2, COL1A1, CD36
9osteoporosis30.2CD36, COL1A1, COL1A2, PLOD1
10idiopathic juvenile osteoporosis30.2COL1A2, CD36
11nail-patella syndrome30.2COL5A1
12ullrich congenital muscular dystrophy30.2PLOD3, FKBP14
13collagen disease30.2COL1A1, CD36
14osteoarthritis30.2COL1A2, COL1A1, DSPP, CD36
15dentinogenesis imperfecta29.7DSPP, COL1A1, CD36, COL1A2
16ehlers-danlos syndrome type iv11.3
17type iii ehlers-danlos syndrome11.1
18type vi ehlers-danlos syndrome11.0
19type i ehlers-danlos syndrome11.0
20ehlers-danlos syndrome type viib10.7
21ehlers-danlos syndrome progeroid type10.7
22ehlers-danlos syndrome dermatosparaxis type10.7
23ehlers-danlos syndrome, musculocontractural type 210.7
24ehlers-danlos syndrome with progressive kyphoscoliosis, myopathy, and hearing loss10.7
25ehlers-danlos syndrome arthrochalasia type10.6
26ehlers-danlos syndrome, kyphoscoliotic form10.6
27ehlers-danlos syndrome, periodontitis type10.6
28ehlers-danlos syndrome, fibronectinemic type10.6
29n syndrome10.6
30aortic aneurysm10.6
31spondylocheirodysplasia, ehlers-danlos syndrome-like10.6
32ehlers-danlos syndrome, musculocontractural type 110.6
33ehlers-danlos syndrome dysfibronectinemic type10.5
34ehlers-danlos syndrome, progeroid type, 110.5
35ehlers-danlos syndrome, autosomal recessive, due to tenascin x deficiency10.5
36x-linked ehlers-danlos syndrome10.5
37cervicitis10.5
38neuropathy10.5
39periodontitis10.5
40joint laxity, familial10.5
41occipital horn syndrome10.5
42cutis laxa10.5
43autosomal recessive type iv ehlers-danlos syndrome10.5
44myocardial infarction10.5
45myopathy10.5
46ehlers-danlos syndrome type 510.5
47ehlers-danlos syndrome, cardiac valvular form10.5
48autosomal dominant type iv ehlers-danlos syndrome10.4
49intracranial aneurysm10.4
50adult syndrome10.4

Graphical network of the top 20 diseases related to Ehlers-Danlos Syndrome:



Diseases related to ehlers-danlos syndrome

Clinical Features for Ehlers-Danlos Syndrome

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46OMIM
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Clinical features from OMIM:

225400,130070

Drugs & Therapeutics for Ehlers-Danlos Syndrome

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5CenterWatch, 41NIH Clinical Center, 6ClinicalTrials, 60UMLS, 40NDF-RT
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Approved drugs:

Search CenterWatch for Ehlers-Danlos Syndrome

Drug clinical trials:

Search ClinicalTrials for Ehlers-Danlos Syndrome

Search NIH Clinical Center for Ehlers-Danlos Syndrome

Search CenterWatch for Ehlers-Danlos Syndrome

Genetic Tests for Ehlers-Danlos Syndrome

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22GTR
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Genetic tests related to Ehlers-Danlos Syndrome:

id Genetic test Affiliating Genes
1 Ehlers-Danlos Syndrome22

Anatomical Context for Ehlers-Danlos Syndrome

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32MalaCards
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MalaCards organs/tissues related to Ehlers-Danlos Syndrome:

32
Skin, Bone, Colon, Liver, Lung, Breast, Small intestine, Spleen, Pancreas, Testes, Eye, Kidney, Brain, Tongue, Trachea

Animal Models for Ehlers-Danlos Syndrome or affiliated genes

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36MGI
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MGI Mouse Phenotypes related to Ehlers-Danlos Syndrome:

36
idDescriptionMGI Source AccessionScoreTop Affiliating Genes
1MP:000536910.1COL5A3, COL1A1, COL3A1, CD36, PLOD1, PLOD3
2MP:00107719.5ADAMTS2, COL1A2, COL5A1, COL5A3, COL5A2, COL1A1

Publications for Ehlers-Danlos Syndrome

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50PubMed
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Articles related to Ehlers-Danlos Syndrome:

(show top 50)    (show all 742)
idTitleAuthorsYear
1
Ehlers-Danlos Syndrome Type VIII: A Rare Cause of Leg Ulcers in Young Patients. (24198978)
2013
2
Tenascin-X haploinsufficiency associated with Ehlers-Danlos syndrome in patients with congenital adrenal hyperplasia. (23284009)
2013
3
Joint hypermobility syndrome (a.k.a. Ehlers-Danlos Syndrome, Hypermobility Type): an updated critique. (23407074)
2013
4
The cornea in classic type ehlers-danlos syndrome: macro- and microstructural changes. (24168998)
2013
5
Successful endovascular treatment of carotid aneurysms in a patient with vascular ehlers-danlos syndrome. (22847070)
2013
6
Hyperlax Ehlers-Danlos Syndrome: Benign Hypermobility? (24055257)
2013
7
Gait strategy in patients with Ehlers-Danlos syndrome hypermobility type and Down syndrome. (22522202)
2012
8
Titin-based stiffening of muscle fibers in Ehlers-Danlos Syndrome. (22223454)
2012
9
The vascular aneurysms of Ehlers-Danlos syndrome type IV. (21831911)
2012
10
Severe conjunctivochalasis in association with classic type Ehlers-Danlos syndrome. (22943506)
2012
11
Ehlers Danlos Syndrome Type IV and pregnancy. (21538010)
2012
12
Gait strategy in patients with Ehlers-Danlos syndrome hypermobility type: a kinematic and kinetic evaluation using 3D gait analysis. (21420276)
2011
13
Rectal redundancy leading to intestinal obstruction in a boy with Ehlers-Danlos syndrome. (21922886)
2011
14
Managing chronic pain in a young adolescent girl with Ehlers-Danlos syndrome. (21916827)
2011
15
Type IV Ehlers-Danlos Syndrome: A Surgical Emergency? A Case of Massive Retroperitoneal Hemorrhage. (21966332)
2011
16
Phenotypic variability of the kyphoscoliotic type of Ehlers-Danlos syndrome (EDS VIA): clinical, molecular and biochemical delineation. (21699693)
2011
17
Clinical and genetic features of 20 Japanese patients with vascular-type Ehlers-Danlos syndrome. (20518783)
2010
18
Clinical utility gene card for: Ehlers-Danlos syndrome types I-VII. (20145674)
2010
19
Ehlers-Danlos Syndrome Type VI in a 17-Year-Old Iranian Boy with Severe Muscular Weakness - A Diagnostic Challenge? (23056730)
2010
20
Sudden and unexpected death in three cases of Ehlers-Danlos syndrome type IV. (20707836)
2010
21
Trachea rupture in tenascin-X-deficient type Ehlers-Danlos syndrome. (20693885)
2010
22
Haemo-pneumothorax and haemoptysis in a patient with suspected Ehlers-Danlos syndrome. (19398484)
2009
23
Successful pregnancy outcome in Ehlers-Danlos syndrome, vascular type. (19591069)
2009
24
Skin extensibility and consistency in patients with Ehlers-Danlos syndrome and benign joint hypermobility syndrome. (19169910)
2009
25
Successful coil embolization for rupture of the subclavian artery associated with Ehlers-Danlos syndrome type IV. (19818579)
2009
26
Endovascular treatment for a spontaneous rupture of the posterior tibial artery in a patient with Ehlers-Danlos syndrome Type IV: report of a case. (19468810)
2009
27
Breast calcifications in Ehlers-Danlos syndrome. (18312469)
2008
28
Identification of a novel TGFBR1 mutation in a Loeys-Dietz syndrome type II patient with vascular Ehlers-Danlos syndrome phenotype. (18070134)
2008
29
Absence of apparent disease causing mutations in COL5A3 in 13 patients with hypermobility Ehlers-Danlos syndrome. (19012342)
2008
30
Urological radiographic manifestations of the Ehlers-Danlos syndrome. (17706699)
2007
31
Ultrastructural alterations of elastic fibers and other dermal components in ehlers-danlos syndrome of the hypermobile type. (17667170)
2007
32
Ehlers-Danlos syndrome coexisting with juvenile nephronophtisis. (16669972)
2006
33
Triple-barrelled aortic dissection in Ehlers-Danlos syndrome. (16844880)
2006
34
Current concepts in the diagnosis and management of vascular Ehlers-Danlos syndrome. (17172533)
2006
35
Fatal peritoneal bleeding following embolization of a carotid-cavernous fistula in Ehlers-Danlos syndrome type IV. (16967223)
2006
36
Multiple developmental dental anomalies and hypermobility type Ehlers-Danlos syndrome. (16937863)
2006
37
Total absence of the alpha2(I) chain of collagen type I causes a rare form of Ehlers-Danlos syndrome with hypermobility and propensity to cardiac valvular problems. (16816023)
2006
38
Successful mitral valve replacement in a patient with Ehlers-Danlos syndrome type VI. (15975394)
2005
39
Use of porcine small intestinal submucosa in the surgical treatment of recurrent rectocele in a patient with Ehlers-Danlos syndrome type III. (15645146)
2005
40
Homozygous Gly530Ser substitution in COL5A1 causes mild classical Ehlers-Danlos syndrome. (11992482)
2002
41
Clinical and genetic features of Ehlers-Danlos syndrome type IV, the vascular type. (10706896)
2000
42
New lethal disease involving type I and III collagen defect resembling geroderma osteodysplastica, De Barsy syndrome, and Ehlers-Danlos syndrome IV. (9643297)
1998
43
Ehlers-Danlos syndrome type IV: a single base substitution of the last nucleotide of exon 34 in COL3A1 leads to exon skipping. (7665911)
1995
44
A patient with Ehlers-Danlos syndrome type VI is a compound heterozygote for mutations in the lysyl hydroxylase gene. (8163671)
1994
45
Ehlers-Danlos syndrome type IV. Clinical and molecular aspects and guidelines for diagnosis and management. (7841550)
1994
46
Ehlers-Danlos Syndrome Type IV (20301667)
1993
47
A homozygous stop codon in the lysyl hydroxylase gene in two siblings with Ehlers-Danlos syndrome type VI. (1345174)
1992
48
Cerebrovascular disease in Ehlers-Danlos syndrome type IV. (2326845)
1990
49
Ultrastructural characteristics of the skin in a form of the Ehlers-Danlos syndrome type IV. Storage in the rough endoplasmic reticulum. (7193778)
1981
50
A case of Ehlers-Danlos syndrome (type IV) with persisting vitelline duct cyst. (7363668)
1980

Genetic Variations for Ehlers-Danlos Syndrome

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Expression for genes affiliated with Ehlers-Danlos Syndrome

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1BioGPS, 15Gene Expression Omnibus DataSets
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Expression patterns in normal tissues for genes affiliated with Ehlers-Danlos Syndrome

Search GEO for disease gene expression data for Ehlers-Danlos Syndrome.

Pathways for genes affiliated with Ehlers-Danlos Syndrome

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53Reactome, 37NCBI BioSystems Database, 12EMD Millipore, 29KEGG, 49PharmGKB, 51QIAGEN
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Pathways related to Ehlers-Danlos Syndrome according to GeneCards/GeneDecks:

(show all 26)
idSuper pathways (with members indented)ScoreTop Affiliating Genes
110.4COL1A2, COL1A1
210.4COL1A2, COL1A1
310.4COL1A1, COL1A2
410.4COL1A1, COL1A2
510.4COL1A1, COL1A2
610.3COL1A2, COL1A1, COL3A1
7
Cell adhesion ECM remodeling
Hide members
10.3COL3A1, COL1A2, COL1A1
810.3COL3A1, COL1A1, COL1A2
910.3PLOD1, PLOD2, PLOD3
10
Hide members
10.3COL5A3, COL5A1, COL1A2
11
Hide members
10.3COL5A2, COL5A3, COL5A1
1210.3COL5A1, COL5A3, COL5A2
1310.3COL3A1, COL1A1, COL1A2, CD36
1410.3CD36, COL1A2, COL1A1, COL3A1
15
Hide members
10.2COL3A1, COL5A2, COL5A3, COL5A1
16
Hide members
10.2COL3A1, COL5A2, COL5A3, COL5A1
17
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10.2TNXB, CD36, COL1A1, COL3A1, COL5A2
18
Hide members
10.2COL5A2, COL5A3, COL5A1, COL3A1, CD36
1910.1COL1A1, COL5A2, COL5A3, COL5A1, COL1A2, COL3A1
20
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10.1COL5A2, TNXB, COL5A1, COL5A3, COL1A2, COL3A1
2110.1COL5A1, COL1A2, COL5A2, COL1A1, COL3A1, COL5A3
22
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10.1COL1A2, COL5A1, COL5A3, COL5A2, COL1A1, COL3A1
23
Hide members
10.1COL5A1, COL5A3, COL8A2, COL1A1, COL1A2, COL3A1
24
Hide members
10.1COL5A1, COL1A2, COL8A2, COL5A3, COL5A2, COL1A1
25
Hide members
10.0COL5A3, CD36, COL3A1, COL1A1, COL8A2, COL1A2
26
Hide members
9.8COL5A2, COL5A3, COL1A1, COL3A1, TNXB, PLOD2

Compounds for genes affiliated with Ehlers-Danlos Syndrome

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11DrugBank, 44Novoseek, 59Tocris Bioscience, 28IUPHAR, 49PharmGKB, 24HMDB
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Compounds related to Ehlers-Danlos Syndrome according to GeneCards/GeneDecks:

(show all 22)
idCompoundScoreTop Affiliating Genes
1Collagenase1110.7COL3A1, COL1A2, COL1A1
2nppa4410.7COL1A2, COL1A1, COL3A1
3nppb44 59 2812.7COL3A1, COL1A1, COL1A2
4hydroxylysinonorleucine4410.6PLOD2, PLOD1
5carbodiimide4410.6COL1A1, COL1A2
6vitamin c49 1111.6PLOD2, PLOD3, PLOD1
7hydroxylysine4410.6PLOD1, COL1A1
8l-lysine28 11 2412.6PLOD2, PLOD1, PLOD3
9pyridinoline4410.6PLOD3, CD36, PLOD1, PLOD2
10succinic acid28 11 2412.6PLOD2, PLOD1, PLOD3
11silver nitrate4410.5DSPP, CD36
12calcium carbonate4410.5CD36, DSPP
13procollagen4410.5COL1A1, ADAMTS2, PLOD1, CD36, COL3A1, COL1A2
14aspartate4410.5DSPP, COL3A1, COL1A2, COL1A1, PLOD1
15ascorbic acid44 2411.4DSPP, CD36, PLOD1, PLOD3, PLOD2
16carbon dioxide44 2411.4PLOD2, PLOD3, PLOD1
17tannins4410.4CD36, DSPP
18vitamin d4410.4COL1A2, DSPP, COL1A1, CD36
19xbai4410.4COL1A1, COL1A2
20glycosaminoglycan4410.3COL1A1, B4GALT7, CD36
21tartrate4410.2CD36, DSPP
22polyglycolic acid4410.0CD36, DSPP

GO Terms for genes affiliated with Ehlers-Danlos Syndrome

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16Gene Ontology
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Cellular components related to Ehlers-Danlos Syndrome according to GeneCards/GeneDecks:

idNameGO IDScoreTop Affiliating Genes
1collagen type VGO:00558810.4COL5A3, COL5A1, COL5A2
2rough endoplasmic reticulum membraneGO:03086710.3PLOD2, PLOD1, PLOD3
3collagen type IGO:00558410.3COL1A1, COL1A2
4proteinaceous extracellular matrixGO:00557810.2COL8A2, ADAMTS2, DSPP, TNXB
5extracellular matrixGO:03101210.2TNXB, COL3A1, COL1A1, COL5A2, COL5A1, COL1A2
6endoplasmic reticulum lumenGO:00578810.1FKBP14, COL3A1, COL1A1, COL5A2, COL5A3, COL5A1
7extracellular regionGO:0055769.7ADAMTS2, COL3A1, COL1A1, COL5A2, COL5A3, COL5A1

Biological processes related to Ehlers-Danlos Syndrome according to GeneCards/GeneDecks:

(show all 17)
idNameGO IDScoreTop Affiliating Genes
1collagen biosynthetic processGO:03296410.6COL1A1, COL5A1, COL3A1
2extracellular fibril organizationGO:04320610.5COL3A1, COL5A1, TNXB, B4GALT7
3cellular response to amino acid stimulusGO:07123010.5COL3A1, COL1A1, COL5A2, COL1A2
4eye morphogenesisGO:04859210.5COL5A1, COL5A2
5blood vessel developmentGO:00156810.5COL5A1, COL1A2, COL1A1, COL3A1
6skin developmentGO:04358810.4COL5A3, COL3A1, ADAMTS2, COL5A2, COL5A1
7skin morphogenesisGO:04358910.4COL1A2, COL1A1
8cellular protein modification processGO:00646410.4PLOD3, PLOD2, B4GALT7, PLOD1
9skeletal system developmentGO:00150110.4COL1A2, DSPP, COL5A2, COL1A1, COL3A1
10extracellular matrix disassemblyGO:02261710.3COL3A1, COL5A2, COL5A3, COL8A2, COL1A2, COL5A1
11collagen catabolic processGO:03057410.3ADAMTS2, COL5A2, COL5A3, COL8A2, COL1A2, COL5A1
12platelet activationGO:03016810.3COL3A1, CD36, COL1A1, COL1A2
13collagen fibril organizationGO:03019910.3COL1A2, COL5A1, COL5A3, COL1A1, COL3A1, TNXB
14axon guidanceGO:00741110.2COL5A3, COL5A1, COL5A2, COL3A1
15cell-matrix adhesionGO:00716010.2COL5A3, COL3A1, TNXB
16extracellular matrix organizationGO:03019810.1COL1A2, COL3A1, PLOD2, PLOD1, PLOD3, ADAMTS2
17protein heterotrimerizationGO:07020810.1COL1A2, COL1A1

Molecular functions related to Ehlers-Danlos Syndrome according to GeneCards/GeneDecks:

(show all 10)
idNameGO IDScoreTop Affiliating Genes
1platelet-derived growth factor bindingGO:04840710.5COL1A2, COL5A1, COL1A1, COL3A1
2procollagen-lysine 5-dioxygenase activityGO:00847510.5PLOD3, PLOD1, PLOD2
3L-ascorbic acid bindingGO:03141810.4PLOD3, PLOD1, PLOD2
4SMAD bindingGO:04633210.4COL1A2, COL5A2, COL3A1
5proteoglycan bindingGO:04339410.3COL5A1, COL5A3
6collagen bindingGO:00551810.3DSPP, TNXB, COL5A3
7integrin bindingGO:00517810.2TNXB, COL3A1, COL5A1
8extracellular matrix structural constituentGO:00520110.2DSPP, COL8A2, COL1A2, COL5A1, COL5A3, COL5A2
9metal ion bindingGO:04687210.1ZNF469, B4GALT7, COL3A1, COL1A1, COL5A2, COL5A1
10heparin bindingGO:00820110.0COL5A1, COL5A3, TNXB

Products for genes affiliated with Ehlers-Danlos Syndrome

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  • Antibodies
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Sources for Ehlers-Danlos Syndrome

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3CDC
13ExPASy
14FMA
22GTR
23HGMD
24HMDB
25ICD10
26ICD10 via Orphanet
27ICD9CM
28IUPHAR
29KEGG
34MeSH
35MESH via Orphanet
36MGI
39NCIt
40NDF-RT
43NINDS
44Novoseek
46OMIM
47OMIM via Orphanet
50PubMed
51QIAGEN
57SNOMED-CT via Orphanet
60UMLS
61UMLS via Orphanet