XHIM
MCID: CD4003
MIFTS: 43

Cd40 Ligand Deficiency (XHIM)

Categories: Genetic diseases, Immune diseases

Aliases & Classifications for Cd40 Ligand Deficiency

MalaCards integrated aliases for Cd40 Ligand Deficiency:

Name: Cd40 Ligand Deficiency 12 15 73
Hyperimmunoglobulin M Syndrome 12 29 6 73
X-Linked Hyper Igm Syndrome 12 24 25 15
Hyper-Igm Syndrome 1 24 25
Higm1 24 25
Hyper-Igm Immunodeficiency Syndrome, Type 1 73
Immunodeficiency with Hyper-Igm, Type 1 25
X-Linked Hyper-Igm Immunodeficiency 24
Hyper-Igm Immunodeficiency Syndrome 44
Immunodeficiency, with Hyper Igm 40
X-Linked Hyper-Igm Syndrome 12
Higmx-1 12
Xhim 24

Characteristics:

GeneReviews:

24
Penetrance Penetrance is complete in males with a cd40lg pathogenic variant...

Classifications:



External Ids:

Disease Ontology 12 DOID:0060022 DOID:6620
MeSH 44 D053306
NCIt 50 C3990 C84783
SNOMED-CT 68 82286005

Summaries for Cd40 Ligand Deficiency

Disease Ontology : 12 A combined T cell and B cell immunodeficiency that is a X-linked immunodeficiency with hyperimmunoglobulin M (XHIM) affecting isotype switching and is caused by the absence of CD40 ligand which is normally expressed on activated CD4+ T cells. Individuals with this mutation are unable to switch from IgM to IgG, IgA and IgE.

MalaCards based summary : Cd40 Ligand Deficiency, also known as hyperimmunoglobulin m syndrome, is related to immunodeficiency with hyper-igm, type 1 and immunodeficiency with hyper-igm, type 3, and has symptoms including diarrhea An important gene associated with Cd40 Ligand Deficiency is CD40LG (CD40 Ligand), and among its related pathways/superpathways are NF-kappa B signaling pathway and Apoptosis and survival Anti-apoptotic TNFs/NF-kB/Bcl-2 pathway. The drugs Fludarabine and Vidarabine have been mentioned in the context of this disorder. Affiliated tissues include t cells, b cells and bone.

GeneReviews: NBK1402

Related Diseases for Cd40 Ligand Deficiency

Diseases related to Cd40 Ligand Deficiency via text searches within MalaCards or GeneCards Suite gene sharing:

(show top 50) (show all 67)
# Related Disease Score Top Affiliating Genes
1 immunodeficiency with hyper-igm, type 1 32.2 AICDA CD40 CD40LG UNG
2 immunodeficiency with hyper-igm, type 3 31.5 AICDA CD40 CD40LG
3 immunodeficiency with hyper-igm, type 4 31.2 AICDA CD40 CD40LG UNG
4 immunodeficiency with hyper-igm, type 2 31.2 AICDA CD40 CD40LG UNG
5 light fixation seizure syndrome 30.9 CD40 CD40LG
6 common variable immunodeficiency 30.1 AICDA CD40 CD40LG
7 congenital rubella 30.0 CD40LG UNG
8 immunodeficiency with hyper-igm, type 5 11.1
9 pneumonia 10.3
10 lupus erythematosus 10.3
11 encephalitis 10.3
12 systemic lupus erythematosus 10.2
13 arthritis 10.2
14 crohn's disease 10.2
15 hemophagocytic lymphohistiocytosis 10.2
16 meningoencephalitis 10.2
17 sarcoma 10.2
18 pneumocystosis 10.2
19 cryptococcosis 10.2
20 pulmonary alveolar proteinosis 10.2
21 obstructive jaundice 10.2
22 neuroendocrine tumor 10.2
23 gastroenteritis 10.2
24 progressive multifocal leukoencephalopathy 10.2
25 leishmaniasis 10.2
26 visceral leishmaniasis 10.2
27 bronchiectasis 10.2
28 acute respiratory distress syndrome 10.2
29 autoimmune retinopathy 10.2
30 discoid lupus erythematosus 10.2
31 sulfamethoxazole allergy 10.1 CD40 CD40LG
32 amyloidosis 10.1
33 exanthema subitum 10.1 CD40 CD40LG
34 agammaglobulinemia, x-linked 10.1 CD40 CD40LG
35 hematopoietic stem cell transplantation 10.0
36 neutropenia 10.0
37 immune deficiency disease 10.0 CD40 CD40LG
38 waldenstrom macroglobulinemia 10.0 CD40 CD40LG
39 toxoplasmosis 10.0 CD40 CD40LG
40 lymphoproliferative syndrome, x-linked, 1 10.0
41 liver disease 10.0
42 lymphoproliferative syndrome 10.0
43 dysgammaglobulinemia 10.0
44 megaloblastic anemia 10.0
45 immune system disease 10.0 CD40 CD40LG
46 lipomatosis, multiple 9.9
47 cyclic neutropenia 9.9
48 systemic mastocytosis 9.9
49 pleomorphic lipoma 9.9
50 histoplasmosis 9.9

Graphical network of the top 20 diseases related to Cd40 Ligand Deficiency:



Diseases related to Cd40 Ligand Deficiency

Symptoms & Phenotypes for Cd40 Ligand Deficiency

UMLS symptoms related to Cd40 Ligand Deficiency:


diarrhea

Drugs & Therapeutics for Cd40 Ligand Deficiency

Drugs for Cd40 Ligand Deficiency (from DrugBank, HMDB, Dgidb, PharmGKB, IUPHAR, NovoSeek, BitterDB):

(show all 18)
# Name Status Phase Clinical Trials Cas Number PubChem Id
1
Fludarabine Approved Phase 2,Not Applicable 75607-67-9, 21679-14-1 30751
2
Vidarabine Approved, Investigational Phase 2,Not Applicable 24356-66-9 32326 21704
3
Cyclophosphamide Approved, Investigational Phase 2,Not Applicable 6055-19-2, 50-18-0 2907
4 Antineoplastic Agents, Alkylating Phase 2,Not Applicable
5 Vidarabine Phosphate Phase 2
6 Antiviral Agents Phase 2,Not Applicable
7 Alkylating Agents Phase 2,Not Applicable
8 Antimetabolites, Antineoplastic Phase 2,Not Applicable
9 Antimetabolites Phase 2,Not Applicable
10 Anti-Infective Agents Phase 2,Not Applicable
11 Immunosuppressive Agents Phase 2,Not Applicable
12 Antirheumatic Agents Phase 2,Not Applicable
13 Immunologic Factors Phase 2,Not Applicable
14
Busulfan Approved, Investigational Not Applicable 55-98-1 2478
15
alemtuzumab Approved, Investigational Not Applicable 216503-57-0
16
Mesna Approved, Investigational Not Applicable 3375-50-6 598
17
Melphalan Approved Not Applicable 148-82-3 4053 460612
18 Protective Agents Not Applicable

Interventional clinical trials:


# Name Status NCT ID Phase Drugs
1 Unrelated Hematopoietic Stem Cell Transplantation(HSCT) for Genetic Diseases of Blood Cells Completed NCT00730314 Phase 1, Phase 2
2 Fludarabine Phosphate, Cyclophosphamide, Total Body Irradiation, and Donor Stem Cell Transplant in Treating Patients With Blood Cancer Recruiting NCT03333486 Phase 2 Cyclophosphamide;Fludarabine Phosphate
3 Allogeneic Hematopoietic Stem Cell Transplant for Patients With Primary Immune Deficiencies Recruiting NCT01652092 Not Applicable Alemtuzumab 0.3 mg;Cyclophosphamide;Busulfan;Fludarabine phosphate 40 mg;Melphalan;Alemtuzumab 0.2 mg;Busulfan;Fludarabine phosphate 30 mg;MESNA

Search NIH Clinical Center for Cd40 Ligand Deficiency

Cochrane evidence based reviews: hyper-igm immunodeficiency syndrome

Genetic Tests for Cd40 Ligand Deficiency

Genetic tests related to Cd40 Ligand Deficiency:

# Genetic test Affiliating Genes
1 Hyperimmunoglobulin M Syndrome 29

Anatomical Context for Cd40 Ligand Deficiency

MalaCards organs/tissues related to Cd40 Ligand Deficiency:

41
T Cells, B Cells, Bone, Bone Marrow, Liver, Lymph Node, Small Intestine

Publications for Cd40 Ligand Deficiency

Articles related to Cd40 Ligand Deficiency:

(show all 36)
# Title Authors Year
1
Gastrointestinal histoplasmosis ileal stricture successfully treated with through-the-scope balloon dilation in a patient with hyperimmunoglobulin M syndrome. ( 29340926 )
2018
2
Successful sequential liver and haematopoietic stem cell transplantation in a child with CD40 ligand deficiency and Cryptosporidium-induced liver cirrhosis. ( 29377874 )
2018
3
CD40 ligand deficiency causes functional defects of peripheral neutrophils that are improved by exogenous IFN-I^. ( 29518426 )
2018
4
Human CD40 ligand deficiency dysregulates the macrophage transcriptome causing functional defects that are improved by exogenous IFN-I^. ( 27554817 )
2016
5
Liver Transplantation in a Patient With CD40 Ligand Deficiency and Hyper-IgM Syndrome: Clinical and Immunological Assessments. ( 26762604 )
2016
6
A Case Report of X-Linked Hyperimmunoglobulin M Syndrome with Lipoma Arborescens of Knees. ( 27818686 )
2016
7
Clinical features and hematopoietic stem cell transplantations for CD40 ligand deficiency in Japan. ( 25840720 )
2015
8
Hematopoietic Stem Cell Transplantation for CD40 Ligand Deficiency: Single Institution Experience. ( 26291959 )
2015
9
Identification of germinal centres in the lymph node of a patient with hyperimmunoglobulin M syndrome associated with congenital rubella. ( 25113848 )
2014
10
Immunoglobulin class switch recombination deficiency type 1 or CD40 ligand deficiency: from bedside to bench and back again. ( 24308834 )
2014
11
Transitional cell carcinoma in a patient with X-linked hyperimmunoglobulin M syndrome. ( 25521976 )
2014
12
Atypical combined immunodeficiency due to Artemis defect: a case presenting as hyperimmunoglobulin M syndrome and with LGLL. ( 23911390 )
2013
13
Molecular Diagnostic Challenges and Complex Management of Consecutive Twin Pregnancies in a Family with CD40 Ligand Deficiency. ( 21958324 )
2012
14
Cholangiocarcinoma complicating secondary sclerosing cholangitis from cryptosporidiosis in an adult patient with CD40 ligand deficiency: case report and review of the literature. ( 22678466 )
2012
15
CD40 ligand deficiency with grade III liver fibrosis, transplanted by a treosulphan-based conditioning regimen. ( 21967264 )
2011
16
Nodularity of the small intestine in a child with systemic mastocytosis associated with hyperimmunoglobulin M syndrome. ( 21865968 )
2011
17
CD40 ligand deficiency: neurologic sequelae with radiographic correlation. ( 19931163 )
2009
18
Poorly differentiated gastroenteropancreatic neuroendocrine carcinoma associated with X-linked hyperimmunoglobulin M syndrome. ( 18466034 )
2008
19
JC virus granule cell neuronopathy in a child with CD40 ligand deficiency. ( 17352955 )
2007
20
Successful unrelated cord blood transplantation for a patient with CD40 ligand deficiency. ( 18056008 )
2007
21
Successful management of neutropenia in a patient with CD40 ligand deficiency by immunoglobulin replacement therapy. ( 17303928 )
2007
22
Trans-splicing repair of CD40 ligand deficiency results in naturally regulated correction of a mouse model of hyper-IgM X-linked immunodeficiency. ( 15273748 )
2004
23
Treatment of CD40 ligand deficiency by hematopoietic stem cell transplantation: a survey of the European experience, 1993-2002. ( 14525761 )
2004
24
Bone marrow transplantation for CD40 ligand deficiency: a single centre experience. ( 11369571 )
2001
25
Non-X-linked hyperimmunoglobulin M syndrome with chronic interstitial pneumonitis. ( 11206940 )
2000
26
Host CD40 ligand deficiency induces long-term allograft survival and donor-specific tolerance in mouse cardiac transplantation but does not prevent graft arteriosclerosis. ( 10975872 )
2000
27
Mutation analysis and therapeutic response to granulocyte colony-stimulating factor in a case of hyperimmunoglobulin M syndrome with chronic neutropenia. ( 10864066 )
2000
28
T-cell-depleted bone marrow transplantation from unrelated donor for [correction of allogeneic sibling for] X-linked hyperimmunoglobulin M syndrome. ( 10931436 )
2000
29
A family with hyperimmunoglobulin M syndrome and systemic amyloidosis. ( 10978420 )
2000
30
Thymic lymphoproliferative disease after successful correction of CD40 ligand deficiency by gene transfer in mice. ( 9809548 )
1998
31
The X-linked hyperimmunoglobulin M syndrome. ( 9801261 )
1998
32
Acquired CD40-ligand deficiency in chronic lymphocytic leukemia. ( 9288724 )
1997
33
Mutation analysis in CD40 ligand deficiency leading to X-linked hypogammaglobulinemia with hyper IgM syndrome. ( 8889581 )
1996
34
CD40 ligand deficiency presenting as unresponsive neutropenia. ( 8669967 )
1996
35
[Successful treatment of cyclic neutropenia associated with hyperimmunoglobulin M syndrome using recombinant granulocyte-colony stimulating factor]. ( 7566951 )
1995
36
Hyperimmunoglobulin M syndrome associated with systemic amyloidosis type AA. ( 8801110 )
1995

Variations for Cd40 Ligand Deficiency

ClinVar genetic disease variations for Cd40 Ligand Deficiency:

6 (show top 50) (show all 203)
# Gene Variation Type Significance SNP ID Assembly Location
1 AICDA NM_020661.3(AICDA): c.*1934C> T single nucleotide variant Uncertain significance rs104894981 NCBI36 Chromosome 12, 8646213: 8646213
2 AICDA NM_020661.3(AICDA): c.*1934C> T single nucleotide variant Uncertain significance rs104894981 GRCh37 Chromosome 12, 8754946: 8754946
3 AICDA NM_020661.3(AICDA): c.*1934C> T single nucleotide variant Uncertain significance rs104894981 GRCh38 Chromosome 12, 8602350: 8602350
4 AICDA NM_020661.3(AICDA): c.*446G> A single nucleotide variant Uncertain significance rs104894982 NCBI36 Chromosome 12, 8647701: 8647701
5 AICDA NM_020661.3(AICDA): c.*446G> A single nucleotide variant Uncertain significance rs104894982 GRCh37 Chromosome 12, 8756434: 8756434
6 AICDA NM_020661.3(AICDA): c.*446G> A single nucleotide variant Uncertain significance rs104894982 GRCh38 Chromosome 12, 8603838: 8603838
7 AICDA NM_020661.3(AICDA): c.210A> G (p.Leu70=) single nucleotide variant Benign/Likely benign rs104894984 NCBI36 Chromosome 12, 8649295: 8649295
8 AICDA NM_020661.3(AICDA): c.210A> G (p.Leu70=) single nucleotide variant Benign/Likely benign rs104894984 GRCh37 Chromosome 12, 8758028: 8758028
9 AICDA NM_020661.3(AICDA): c.210A> G (p.Leu70=) single nucleotide variant Benign/Likely benign rs104894984 GRCh38 Chromosome 12, 8605432: 8605432
10 AICDA NM_020661.3(AICDA): c.465C> T (p.His155=) single nucleotide variant Benign rs2028373 GRCh37 Chromosome 12, 8757481: 8757481
11 AICDA NM_020661.3(AICDA): c.465C> T (p.His155=) single nucleotide variant Benign rs2028373 GRCh38 Chromosome 12, 8604885: 8604885
12 AICDA NM_020661.3(AICDA): c.48A> G (p.Lys16=) single nucleotide variant Conflicting interpretations of pathogenicity rs186739900 GRCh37 Chromosome 12, 8759569: 8759569
13 AICDA NM_020661.3(AICDA): c.48A> G (p.Lys16=) single nucleotide variant Conflicting interpretations of pathogenicity rs186739900 GRCh38 Chromosome 12, 8606973: 8606973
14 UNG NM_080911.2(UNG): c.-51A> T single nucleotide variant Uncertain significance rs375712849 GRCh38 Chromosome 12, 109097629: 109097629
15 UNG NM_080911.2(UNG): c.-51A> T single nucleotide variant Uncertain significance rs375712849 GRCh37 Chromosome 12, 109535434: 109535434
16 UNG NM_080911.2(UNG): c.544A> G (p.Ile182Val) single nucleotide variant Uncertain significance rs545691651 GRCh38 Chromosome 12, 109102849: 109102849
17 UNG NM_080911.2(UNG): c.544A> G (p.Ile182Val) single nucleotide variant Uncertain significance rs545691651 GRCh37 Chromosome 12, 109540654: 109540654
18 UNG NM_080911.2(UNG): c.623-9T> A single nucleotide variant Uncertain significance rs745983593 GRCh38 Chromosome 12, 109103424: 109103424
19 UNG NM_080911.2(UNG): c.623-9T> A single nucleotide variant Uncertain significance rs745983593 GRCh37 Chromosome 12, 109541229: 109541229
20 UNG NM_080911.2(UNG): c.*788dupT duplication Likely benign rs886048913 GRCh37 Chromosome 12, 109548562: 109548562
21 UNG NM_080911.2(UNG): c.*788dupT duplication Likely benign rs886048913 GRCh38 Chromosome 12, 109110757: 109110757
22 AICDA NM_020661.3(AICDA): c.*1173C> T single nucleotide variant Uncertain significance rs192088951 GRCh37 Chromosome 12, 8755707: 8755707
23 AICDA NM_020661.3(AICDA): c.*1173C> T single nucleotide variant Uncertain significance rs192088951 GRCh38 Chromosome 12, 8603111: 8603111
24 AICDA NM_020661.3(AICDA): c.*1137A> G single nucleotide variant Uncertain significance rs867594346 GRCh37 Chromosome 12, 8755743: 8755743
25 AICDA NM_020661.3(AICDA): c.*1137A> G single nucleotide variant Uncertain significance rs867594346 GRCh38 Chromosome 12, 8603147: 8603147
26 AICDA NM_020661.3(AICDA): c.*1106A> G single nucleotide variant Uncertain significance rs886049869 GRCh37 Chromosome 12, 8755774: 8755774
27 AICDA NM_020661.3(AICDA): c.*1106A> G single nucleotide variant Uncertain significance rs886049869 GRCh38 Chromosome 12, 8603178: 8603178
28 AICDA NM_020661.3(AICDA): c.*718C> A single nucleotide variant Likely benign rs74372815 GRCh37 Chromosome 12, 8756162: 8756162
29 AICDA NM_020661.3(AICDA): c.*718C> A single nucleotide variant Likely benign rs74372815 GRCh38 Chromosome 12, 8603566: 8603566
30 AICDA NM_020661.3(AICDA): c.*556T> G single nucleotide variant Uncertain significance rs3205190 GRCh37 Chromosome 12, 8756324: 8756324
31 AICDA NM_020661.3(AICDA): c.*556T> G single nucleotide variant Uncertain significance rs3205190 GRCh38 Chromosome 12, 8603728: 8603728
32 AICDA NM_020661.3(AICDA): c.*554T> C single nucleotide variant Uncertain significance rs886049874 GRCh37 Chromosome 12, 8756326: 8756326
33 AICDA NM_020661.3(AICDA): c.*554T> C single nucleotide variant Uncertain significance rs886049874 GRCh38 Chromosome 12, 8603730: 8603730
34 AICDA NM_020661.3(AICDA): c.*288C> T single nucleotide variant Uncertain significance rs886049875 GRCh37 Chromosome 12, 8756592: 8756592
35 AICDA NM_020661.3(AICDA): c.*288C> T single nucleotide variant Uncertain significance rs886049875 GRCh38 Chromosome 12, 8603996: 8603996
36 UNG NM_080911.2(UNG): c.6C> A (p.Ile2=) single nucleotide variant Uncertain significance rs886048905 GRCh38 Chromosome 12, 109097685: 109097685
37 UNG NM_080911.2(UNG): c.6C> A (p.Ile2=) single nucleotide variant Uncertain significance rs886048905 GRCh37 Chromosome 12, 109535490: 109535490
38 UNG NM_080911.2(UNG): c.100G> A (p.Ala34Thr) single nucleotide variant Uncertain significance rs886048906 GRCh38 Chromosome 12, 109097779: 109097779
39 UNG NM_080911.2(UNG): c.100G> A (p.Ala34Thr) single nucleotide variant Uncertain significance rs886048906 GRCh37 Chromosome 12, 109535584: 109535584
40 UNG NM_080911.2(UNG): c.528G> A (p.Pro176=) single nucleotide variant Conflicting interpretations of pathogenicity rs373915335 GRCh38 Chromosome 12, 109101994: 109101994
41 UNG NM_080911.2(UNG): c.528G> A (p.Pro176=) single nucleotide variant Conflicting interpretations of pathogenicity rs373915335 GRCh37 Chromosome 12, 109539799: 109539799
42 UNG NM_080911.2(UNG): c.660C> T (p.Ala220=) single nucleotide variant Uncertain significance rs572632781 GRCh38 Chromosome 12, 109103470: 109103470
43 UNG NM_080911.2(UNG): c.660C> T (p.Ala220=) single nucleotide variant Uncertain significance rs572632781 GRCh37 Chromosome 12, 109541275: 109541275
44 UNG NM_080911.2(UNG): c.*159G> A single nucleotide variant Uncertain significance rs886048907 GRCh37 Chromosome 12, 109547933: 109547933
45 UNG NM_080911.2(UNG): c.*159G> A single nucleotide variant Uncertain significance rs886048907 GRCh38 Chromosome 12, 109110128: 109110128
46 UNG NM_080911.2(UNG): c.*522A> G single nucleotide variant Uncertain significance rs189054927 GRCh37 Chromosome 12, 109548296: 109548296
47 UNG NM_080911.2(UNG): c.*522A> G single nucleotide variant Uncertain significance rs189054927 GRCh38 Chromosome 12, 109110491: 109110491
48 UNG NM_080911.2(UNG): c.*545A> G single nucleotide variant Uncertain significance rs562354759 GRCh37 Chromosome 12, 109548319: 109548319
49 UNG NM_080911.2(UNG): c.*545A> G single nucleotide variant Uncertain significance rs562354759 GRCh38 Chromosome 12, 109110514: 109110514
50 UNG NM_080911.2(UNG): c.*708T> C single nucleotide variant Uncertain significance rs150677845 GRCh37 Chromosome 12, 109548482: 109548482

Expression for Cd40 Ligand Deficiency

Search GEO for disease gene expression data for Cd40 Ligand Deficiency.

Pathways for Cd40 Ligand Deficiency

GO Terms for Cd40 Ligand Deficiency

Cellular components related to Cd40 Ligand Deficiency according to GeneCards Suite gene sharing:

# Name GO ID Score Top Affiliating Genes
1 P-body GO:0000932 8.62 AICDA HAX1

Biological processes related to Cd40 Ligand Deficiency according to GeneCards Suite gene sharing:

# Name GO ID Score Top Affiliating Genes
1 negative regulation of apoptotic process GO:0043066 9.65 CD40LG HAX1 UNG
2 platelet activation GO:0030168 9.46 CD40 CD40LG
3 B cell differentiation GO:0030183 9.43 AICDA CD40LG
4 tumor necrosis factor-mediated signaling pathway GO:0033209 9.4 CD40 CD40LG
5 B cell proliferation GO:0042100 9.37 CD40 CD40LG
6 positive regulation of interleukin-12 production GO:0032735 9.32 CD40 CD40LG
7 positive regulation of endothelial cell apoptotic process GO:2000353 9.26 CD40 CD40LG
8 somatic hypermutation of immunoglobulin genes GO:0016446 9.16 AICDA UNG
9 isotype switching GO:0045190 8.96 AICDA CD40LG
10 regulation of immunoglobulin secretion GO:0051023 8.62 CD40 CD40LG

Sources for Cd40 Ligand Deficiency

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
38 LifeMap
40 LOVD
42 MedGen
44 MeSH
45 MESH via Orphanet
46 MGI
49 NCI
50 NCIt
51 NDF-RT
54 NINDS
55 Novoseek
57 OMIM
58 OMIM via Orphanet
62 PubMed
64 QIAGEN
69 SNOMED-CT via HPO
70 SNOMED-CT via Orphanet
71 TGDB
72 Tocris
73 UMLS
74 UMLS via Orphanet
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