WS2A
MCID: WRD032
MIFTS: 45

Waardenburg Syndrome, Type 2a (WS2A)

Categories: Ear diseases, Eye diseases, Fetal diseases, Gastrointestinal diseases, Genetic diseases, Rare diseases, Skin diseases

Aliases & Classifications for Waardenburg Syndrome, Type 2a

MalaCards integrated aliases for Waardenburg Syndrome, Type 2a:

Name: Waardenburg Syndrome, Type 2a 56 13 39
Waardenburg Syndrome Type 2a 12 74 29 6 15
Ws2a 56 12 73
Waardenburg Syndrome, Type Iia 56 71
Waardenburg Syndrome Without Dystopia Canthorum 56
Waardenburg Syndrome Type Iia 12
Waardenburg Syndrome 2a 73
Ws2 56

Characteristics:

OMIM:

56
Inheritance:
autosomal dominant

Miscellaneous:
variable expressivity of each feature
genetic heterogeneity of waardenburg syndrome type 2
other variants of waardenburg syndrome include waardenburg syndrome type 1 , waardenburg syndrome type 3 , and waardenburg syndrome type 4


HPO:

31
waardenburg syndrome, type 2a:
Inheritance autosomal dominant inheritance heterogeneous
Onset and clinical course variable expressivity


Classifications:



External Ids:

Disease Ontology 12 DOID:0110950
OMIM 56 193510
OMIM Phenotypic Series 56 PS193500
MeSH 43 D014849
MedGen 41 C1860339
UMLS 71 C1860339

Summaries for Waardenburg Syndrome, Type 2a

OMIM : 56 Waardenburg syndrome type 2 is an autosomal dominant auditory-pigmentary syndrome characterized by pigmentary abnormalities of the hair, skin, and eyes; congenital sensorineural hearing loss; and the absence of 'dystopia canthorum,' the lateral displacement of the ocular inner canthi, which is seen in some other forms of WS (reviews by Read and Newton, 1997 and Pingault et al., 2010). (193510)

MalaCards based summary : Waardenburg Syndrome, Type 2a, also known as waardenburg syndrome type 2a, is related to waardenburg syndrome, type 2b and waardenburg syndrome, type 4c. An important gene associated with Waardenburg Syndrome, Type 2a is MITF (Melanocyte Inducing Transcription Factor), and among its related pathways/superpathways are Transcriptional misregulation in cancer and Neural Crest Differentiation. Affiliated tissues include eye, skin and kidney, and related phenotypes are wide nasal bridge and underdeveloped nasal alae

Disease Ontology : 12 A Waardenburg's syndrome characterized by pigmentary abnormalities of the hair, skin, and eyes, congenital sensorineural hearing loss, and absence of lateral displacement of the inner canthus of each eye that has material basis in heterozygous mutation in the MITF gene on chromosome 3p13.

UniProtKB/Swiss-Prot : 73 Waardenburg syndrome 2A: WS2 is a genetically heterogeneous, autosomal dominant disorder characterized by sensorineural deafness, pigmentary disturbances, and absence of dystopia canthorum. The frequency of deafness is higher in WS2 than in WS1.

Wikipedia : 74 Waardenburg syndrome is a rare genetic condition characterised by at least some degree of congenital... more...

Related Diseases for Waardenburg Syndrome, Type 2a

Diseases in the Waardenburg's Syndrome family:

Waardenburg Syndrome, Type 3 Waardenburg Syndrome, Type 1
Waardenburg Syndrome, Type 2a Waardenburg Syndrome, Type 4a
Waardenburg Syndrome, Type 2b Waardenburg Syndrome, Type 2c
Waardenburg Syndrome, Type 2d Waardenburg Syndrome, Type 2e
Waardenburg Syndrome, Type 4b Waardenburg Syndrome, Type 4c
Waardenburg Syndrome Type 4

Diseases related to Waardenburg Syndrome, Type 2a via text searches within MalaCards or GeneCards Suite gene sharing:

(show top 50) (show all 57)
# Related Disease Score Top Affiliating Genes
1 waardenburg syndrome, type 2b 31.4 SOX10 MITF EDN3
2 waardenburg syndrome, type 4c 30.5 SOX10 POLR2F PAX3 MITF EDNRB EDN3
3 waardenburg syndrome, type 2d 30.4 SOX10 PAX3 MITF EDNRB EDN3
4 tietz albinism-deafness syndrome 30.0 TFEC SOX10 PAX3 MITF EDNRB EDN3
5 waardenburg syndrome, type 4b 29.7 TFEB SOX10 PAX3 MITF EDNRB EDN3
6 waardenburg syndrome type 4 29.4 SOX10 MITF EDNRB EDN3
7 megacolon 28.9 SOX10 PAX3 EDNRB EDN3
8 waardenburg syndrome, type 2c 28.9 TFEC TFEB TFE3 SOX10 PAX3 MITF
9 microphthalmia 28.6 TFEC TFEB TFE3 SOX10 PAX3 MITF
10 waardenburg syndrome, type 2e 28.1 TFEC SOX10 POLR2F PAX3 MITF EDNRB
11 waardenburg's syndrome 27.5 TFEC TFE3 SOX10 POLR2F PAX3 MITF
12 triiodothyronine receptor auxiliary protein 10.4
13 rapidly involuting congenital hemangioma 10.4
14 malignant choroid melanoma 10.3 SOX10 MITF
15 gallbladder melanoma 10.3 SOX10 MITF
16 uterus perivascular epithelioid cell tumor 10.2 TFE3 MITF
17 branchiootic syndrome 1 10.2
18 perivascular epithelioid cell tumor 10.2 TFE3 MITF
19 ataxia, combined cerebellar and peripheral, with hearing loss and diabetes mellitus 10.2
20 clear cell papillary renal cell carcinoma 10.2 TFE3 MITF
21 autosomal dominant non-syndromic intellectual disability 19 10.2 TFE3 MITF
22 hirschsprung disease 2 10.2 EDNRB-AS1 EDNRB
23 abcd syndrome 10.1 EDNRB-AS1 EDNRB
24 albinism, oculocutaneous, type ia 10.1
25 skin/hair/eye pigmentation, variation in, 3 10.1
26 albinism, oculocutaneous, type ib 10.1
27 melanoma, cutaneous malignant 8 10.1
28 ocular albinism 10.1
29 albinism 10.1
30 ocular albinism, x-linked 10.1
31 posttransplant acute limbic encephalitis 10.1
32 fryns microphthalmia syndrome 10.1
33 helix syndrome 10.1
34 malignant spindle cell melanoma 10.1 SOX10 MITF
35 clear cell sarcoma 10.0 TFE3 SOX10 MITF
36 renal cell carcinoma, xp11-associated 10.0 TFEB TFE3
37 ocular albinism with congenital sensorineural deafness 10.0 PAX3 MITF
38 cardiovascular cancer 9.9 TFE3 MITF
39 melanoma, cutaneous malignant 1 9.9 SOX10 MITF EDNRB
40 pycnodysostosis 9.9 TFEB TFE3 MITF
41 epithelial predominant wilms' tumor 9.9 TFEB TFE3
42 renal cell carcinoma, papillary, 1 9.7 TFEB TFE3 MITF
43 cochlear disease 9.7 SOX10 EDNRB EDN3
44 lateral displacement of eye 9.7 SOX10 PAX3 MITF EDNRB
45 intestinal pseudo-obstruction 9.7 SOX10 EDNRB EDN3
46 central hypoventilation syndrome, congenital 9.6 SOX10 EDNRB EDN3
47 albinism, ocular, with late-onset sensorineural deafness 9.6 TFE3 SOX10 PAX3 MITF
48 goldberg-shprintzen syndrome 9.6 EDNRB EDN3 BLOC1S1
49 childhood kidney cell carcinoma 9.6 TFEC TFEB TFE3 MITF
50 mucopolysaccharidosis iii 9.6 TFEB BLOC1S1

Graphical network of the top 20 diseases related to Waardenburg Syndrome, Type 2a:



Diseases related to Waardenburg Syndrome, Type 2a

Symptoms & Phenotypes for Waardenburg Syndrome, Type 2a

Human phenotypes related to Waardenburg Syndrome, Type 2a:

31 (show all 12)
# Description HPO Frequency HPO Source Accession
1 wide nasal bridge 31 HP:0000431
2 underdeveloped nasal alae 31 HP:0000430
3 heterochromia iridis 31 HP:0001100
4 premature graying of hair 31 HP:0002216
5 synophrys 31 HP:0000664
6 white forelock 31 HP:0002211
7 white eyebrow 31 HP:0002226
8 white eyelashes 31 HP:0002227
9 congenital sensorineural hearing impairment 31 HP:0008527
10 partial albinism 31 HP:0007443
11 hypoplastic iris stroma 31 HP:0007990
12 albinism 31 HP:0001022

Symptoms via clinical synopsis from OMIM:

56
Head And Neck Nose:
wide nasal bridge
hypoplastic alae nasi

Skin Nails Hair Hair:
premature graying of hair
white forelock
white eyelashes and eyebrows

Head And Neck Ears:
deafness, congenital sensorineural

Head And Neck Eyes:
heterochromia iridis
synophrys
hypoplastic iris stoma
dystopia canthorum absent

Skin Nails Hair Skin:
congenital partial albinism (leukoderma) on face, trunk, or limbs

Clinical features from OMIM:

193510

MGI Mouse Phenotypes related to Waardenburg Syndrome, Type 2a:

45
# Description MGI Source Accession Score Top Affiliating Genes
1 integument MP:0010771 9.92 EDN3 EDNRB MITF PAX3 SOX10 TFE3
2 embryo MP:0005380 9.91 EDN3 EDNRB MITF PAX3 SOWAHB SOX10
3 limbs/digits/tail MP:0005371 9.65 EDNRB MITF PAX3 SOX10 TFEC
4 normal MP:0002873 9.63 MITF PAX3 SOX10 TFE3 TFEB TFEC
5 pigmentation MP:0001186 9.61 BLOC1S1 EDN3 EDNRB MITF PAX3 SOX10
6 vision/eye MP:0005391 9.17 BLOC1S1 EDNRB MITF PAX3 TFE3 TFEB

Drugs & Therapeutics for Waardenburg Syndrome, Type 2a

Search Clinical Trials , NIH Clinical Center for Waardenburg Syndrome, Type 2a

Genetic Tests for Waardenburg Syndrome, Type 2a

Genetic tests related to Waardenburg Syndrome, Type 2a:

# Genetic test Affiliating Genes
1 Waardenburg Syndrome Type 2a 29 MITF

Anatomical Context for Waardenburg Syndrome, Type 2a

MalaCards organs/tissues related to Waardenburg Syndrome, Type 2a:

40
Eye, Skin, Kidney, Uterus

Publications for Waardenburg Syndrome, Type 2a

Articles related to Waardenburg Syndrome, Type 2a:

(show all 31)
# Title Authors PMID Year
1
Analyses of loss-of-function mutations of the MITF gene suggest that haploinsufficiency is a cause of Waardenburg syndrome type 2A. 61 56 6
8659547 1996
2
Biallelic Mutations in MITF Cause Coloboma, Osteopetrosis, Microphthalmia, Macrocephaly, Albinism, and Deafness. 56 6
27889061 2016
3
Point mutation in the MITF gene causing Waardenburg syndrome type II in a three-generation Indian family. 56 6
9856573 1998
4
Apparent digenic inheritance of Waardenburg syndrome type 2 (WS2) and autosomal recessive ocular albinism (AROA). 56 6
9158138 1997
5
The mutational spectrum in Waardenburg syndrome. 56 6
8589691 1995
6
Waardenburg syndrome type 2 caused by mutations in the human microphthalmia (MITF) gene. 56 6
7874167 1994
7
Heterogeneity in Waardenburg's syndrome. Report of a family with ocular albinism. 56 6
666627 1978
8
Hearing loss in Waardenburg syndrome: a systematic review. 56
26100139 2016
9
Ser298 of MITF, a mutation site in Waardenburg syndrome type 2, is a phosphorylation site with functional significance. 6
10587587 2000
10
Waardenburg syndrome. 56
9279758 1997
11
Ectopic expression of MITF, a gene for Waardenburg syndrome type 2, converts fibroblasts to cells with melanocyte characteristics. 56
8782819 1996
12
Analysis of variability of clinical manifestations in Waardenburg syndrome. 56
7573125 1995
13
Waardenburg syndrome type II: phenotypic findings and diagnostic criteria. 56
7702105 1995
14
Locus heterogeneity for Waardenburg syndrome is predictive of clinical subtypes. 56
7942851 1994
15
A gene for Waardenburg syndrome type 2 maps close to the human homologue of the microphthalmia gene at chromosome 3p12-p14.1. 56
7951321 1994
16
Mutations in the PAX3 gene causing Waardenburg syndrome type 1 and type 2. 56
8490648 1993
17
Waardenburg syndrome (WS) type I is caused by defects at multiple loci, one of which is near ALPP on chromosome 2: first report of the WS consortium. 56
1349198 1992
18
Mouse and hamster mutants as models for Waardenburg syndromes in humans. 56
2246770 1990
19
Waardenburg syndrome--two distinct types. 56
7187610 1980
20
Heterogeneity in Waardenburg syndrome. 56
331943 1977
21
Waardenburg's syndrome with fundus and other anomalies. 56
4958935 1966
22
Bilateral asymmetrical partial heterochromia of iris and fundus in Waardenburg syndrome type 2A with a novel MITF gene mutation. 61
31436206 2019
23
Whole-genome sequencing reveals a large deletion in the MITF gene in horses with white spotted coat colour and increased risk of deafness. 61
30644113 2019
24
Homozygous intronic MITF mutation causes severe Waardenburg syndrome type 2A. 61
30117279 2019
25
Creation of miniature pig model of human Waardenburg syndrome type 2A by ENU mutagenesis. 61
29094203 2017
26
Tietz/Waardenburg type 2A syndrome associated with posterior microphthalmos in two unrelated patients with novel MITF gene mutations. 61
27604145 2016
27
MITF mutations associated with pigment deficiency syndromes and melanoma have different effects on protein function. 61
23787126 2013
28
[Hereditary hypomelanocytoses: the role of PAX3, SOX10, MITF, SNAI2, KIT, EDN3 and EDNRB genes]. 61
24379252 2013
29
Melanocytes and the microphthalmia transcription factor network. 61
15568981 2004
30
Genomic, transcriptional and mutational analysis of the mouse microphthalmia locus. 61
10790403 2000
31
Evidence to suggest that expression of MITF induces melanocyte differentiation and haploinsufficiency of MITF causes Waardenburg syndrome type 2A. 61
9170159 1997

Variations for Waardenburg Syndrome, Type 2a

ClinVar genetic disease variations for Waardenburg Syndrome, Type 2a:

6 (show all 30) ‎‎ ‎‎ ‎‎ ‎‎ ‎‎ ‎‎ ‎‎ ‎‎ ‎‎ ‎‎ ‎‎ ‎‎ ‎‎ ‎‎ ‎‎ ‎‎ ‎‎ ‎‎ ‎‎ ‎‎ ‎‎ ‎‎ ‎‎ ‎‎ ‎‎ ‎‎ ‎‎ ‎‎ ‎‎ ‎‎
# Gene Name Type Significance ClinVarId dbSNP ID GRCh37 Pos GRCh38 Pos
1 MITF NM_000248.3(MITF):c.618G>C (p.Lys206Asn)SNV Pathogenic 375215 rs1057519325 3:70001021-70001021 3:69951870-69951870
2 MITF NM_000248.3(MITF):c.649A>G (p.Arg217Gly)SNV Pathogenic 375216 rs1057519326 3:70005620-70005620 3:69956469-69956469
3 MITF NM_000248.3(MITF):c.635-1G>ASNV Pathogenic 375217 rs1057519327 3:70005605-70005605 3:69956454-69956454
4 MITF NM_000248.3(MITF):c.892T>C (p.Ser298Pro)SNV Pathogenic 14277 rs104893747 3:70014031-70014031 3:69964880-69964880
5 MITF NM_000248.3(MITF):c.33+1G>ASNV Pathogenic 14270 rs1553701477 3:69985907-69985907 3:69936756-69936756
6 MITF NM_000248.3(MITF):c.442-2A>CSNV Pathogenic 14271 rs1553703612 3:69998200-69998200 3:69949049-69949049
7 MITF NM_000248.3(MITF):c.748T>C (p.Ser250Pro)SNV Pathogenic 14273 rs104893744 3:70008461-70008461 3:69959310-69959310
8 MITF NM_000248.3(MITF):c.824del (p.Glu275fs)deletion Pathogenic 14274 rs1553705282 3:70008537-70008537 3:69959386-69959386
9 MITF NM_000248.3(MITF):c.640C>T (p.Arg214Ter)SNV Pathogenic 14276 rs104893746 3:70005611-70005611 3:69956460-69956460
10 MITF NM_000248.3(MITF):c.887del (p.Gly296fs)deletion Pathogenic 236050 rs878853234 3:70014025-70014025 3:69964874-69964874
11 MITF NM_000248.3(MITF):c.676G>T (p.Glu226Ter)SNV Pathogenic 545016 rs147682682 3:70005647-70005647 3:69956496-69956496
12 MITF NM_000248.3(MITF):c.763C>T (p.Arg255Ter)SNV Pathogenic/Likely pathogenic 372755 rs1057517966 3:70008476-70008476 3:69959325-69959325
13 MITF NM_000248.3(MITF):c.710+1G>ASNV Pathogenic/Likely pathogenic 545015 rs1559749017 3:70005682-70005682 3:69956531-69956531
14 MITF NM_000248.3(MITF):c.328C>T (p.Arg110Ter)SNV Pathogenic/Likely pathogenic 488040 rs1553702006 3:69988315-69988315 3:69939164-69939164
15 SOX10 NM_001301130.2(POLR2F):c.293+6635deldeletion Likely pathogenic 488041 rs1555937398 22:38369812-38369812 22:37973805-37973805
16 SOX10 NM_001301130.2(POLR2F):c.294-8020deldeletion Likely pathogenic 488042 rs1555938422 22:38374141-38374141 22:37978134-37978134
17 SOX10 NM_006941.3(SOX10):c.403A>C (p.Ser135Arg)SNV Likely pathogenic 488043 rs1555939415 22:38379389-38379389 22:37983382-37983382
18 SOX10 NM_006941.3(SOX10):c.44_62del (p.Val15fs)deletion Likely pathogenic 488044 rs1555939564 22:38379730-38379748 22:37983723-37983741
19 MITF NM_000248.3(MITF):c.718C>G (p.Arg240Gly)SNV Likely pathogenic 545117 rs1559751245 3:70008431-70008431 3:69959280-69959280
20 MITF NM_000248.3(MITF):c.604G>A (p.Glu202Lys)SNV Likely pathogenic 545452 rs1553704086 3:70001007-70001007 3:69951856-69951856
21 MITF NM_000248.3(MITF):c.409_410delinsCC (p.Leu137Pro)indel Likely pathogenic 547530 rs1553702406 3:69990450-69990451 3:69941299-69941300
22 MITF NM_000248.3(MITF):c.632T>C (p.Leu211Pro)SNV Likely pathogenic 547531 rs1553704097 3:70001035-70001035 3:69951884-69951884
23 MITF NM_000248.3(MITF):c.710+4A>CSNV Likely pathogenic 547534 rs1553704850 3:70005685-70005685 3:69956534-69956534
24 MITF NM_000248.3(MITF):c.952G>A (p.Glu318Lys)SNV Conflicting interpretations of pathogenicity 29792 rs149617956 3:70014091-70014091 3:69964940-69964940
25 MITF NM_000248.3(MITF):c.751G>A (p.Val251Met)SNV Uncertain significance 547535 rs1271000541 3:70008464-70008464 3:69959313-69959313
26 MITF NM_000248.3(MITF):c.666C>A (p.Asp222Glu)SNV Uncertain significance 651681 3:70005637-70005637 3:69956486-69956486
27 MITF NM_000248.3(MITF):c.668G>A (p.Arg223His)SNV Uncertain significance 547532 rs763119975 3:70005639-70005639 3:69956488-69956488
28 MITF NM_000248.3(MITF):c.676G>A (p.Glu226Lys)SNV Uncertain significance 547533 rs147682682 3:70005647-70005647 3:69956496-69956496
29 MITF NM_000248.3(MITF):c.348G>A (p.Met116Ile)SNV Likely benign 547529 rs1032758072 3:69990389-69990389 3:69941238-69941238
30 EDNRB NM_001122659.3(EDNRB):c.914G>A (p.Ser305Asn)SNV Benign/Likely benign 16638 rs5352 13:78475230-78475230 13:77901095-77901095

UniProtKB/Swiss-Prot genetic disease variations for Waardenburg Syndrome, Type 2a:

73
# Symbol AA change Variation ID SNP ID
1 MITF p.Ser357Pro VAR_010300 rs104893744
2 MITF p.Asn385Asp VAR_010301
3 MITF p.Ser405Pro VAR_010302 rs104893747

Expression for Waardenburg Syndrome, Type 2a

Search GEO for disease gene expression data for Waardenburg Syndrome, Type 2a.

Pathways for Waardenburg Syndrome, Type 2a

Pathways related to Waardenburg Syndrome, Type 2a according to GeneCards Suite gene sharing:

# Super pathways Score Top Affiliating Genes
1 11.7 TFE3 PAX3 MITF
2 11.34 SOX10 PAX3 MITF
3 10.94 TFEB TFE3 MITF
4 10.41 SOX10 PAX3 MITF

GO Terms for Waardenburg Syndrome, Type 2a

Cellular components related to Waardenburg Syndrome, Type 2a according to GeneCards Suite gene sharing:

# Name GO ID Score Top Affiliating Genes
1 nuclear chromatin GO:0000790 9.1 TFEC TFEB TFE3 SOX10 PAX3 MITF

Biological processes related to Waardenburg Syndrome, Type 2a according to GeneCards Suite gene sharing:

(show all 13)
# Name GO ID Score Top Affiliating Genes
1 regulation of transcription, DNA-templated GO:0006355 9.93 TFEC TFEB TFE3 SOX10 PAX3 MITF
2 positive regulation of transcription by RNA polymerase II GO:0045944 9.73 TFEC TFEB TFE3 SOX10 PAX3 MITF
3 positive regulation of transcription, DNA-templated GO:0045893 9.72 TFEB TFE3 SOX10 PAX3 MITF
4 regulation of gene expression GO:0010468 9.7 TFEB MITF EDN3
5 pigmentation GO:0043473 9.51 MITF EDNRB
6 peripheral nervous system development GO:0007422 9.49 SOX10 EDNRB
7 lysosome localization GO:0032418 9.48 TFEB BLOC1S1
8 vasoconstriction GO:0042310 9.43 EDNRB EDN3
9 regulation of osteoclast differentiation GO:0045670 9.4 TFE3 MITF
10 enteric nervous system development GO:0048484 9.37 SOX10 EDNRB
11 vein smooth muscle contraction GO:0014826 9.16 EDNRB EDN3
12 neural crest cell migration GO:0001755 9.13 SOX10 EDNRB EDN3
13 melanocyte differentiation GO:0030318 8.92 SOX10 MITF EDNRB EDN3

Molecular functions related to Waardenburg Syndrome, Type 2a according to GeneCards Suite gene sharing:

# Name GO ID Score Top Affiliating Genes
1 DNA binding GO:0003677 9.8 TFEC TFEB TFE3 SOX10 POLR2F PAX3
2 RNA polymerase II proximal promoter sequence-specific DNA binding GO:0000978 9.67 TFEC TFE3 SOX10 MITF
3 DNA-binding transcription factor activity, RNA polymerase II-specific GO:0000981 9.63 TFEC TFEB TFE3 SOX10 PAX3 MITF
4 DNA-binding transcription activator activity, RNA polymerase II-specific GO:0001228 9.62 TFEC TFE3 SOX10 MITF
5 transcription regulatory region DNA binding GO:0044212 9.58 TFEB TFE3 SOX10
6 protein dimerization activity GO:0046983 9.26 TFEC TFEB TFE3 MITF
7 DNA-binding transcription factor activity GO:0003700 9.1 TFEC TFEB TFE3 SOX10 PAX3 MITF

Sources for Waardenburg Syndrome, Type 2a

3 CDC
7 CNVD
9 Cosmic
10 dbSNP
11 DGIdb
17 EFO
18 ExPASy
19 FMA
28 GO
29 GTR
30 HMDB
31 HPO
32 ICD10
33 ICD10 via Orphanet
34 ICD9CM
35 IUPHAR
36 KEGG
37 LifeMap
39 LOVD
41 MedGen
43 MeSH
44 MESH via Orphanet
45 MGI
48 NCI
49 NCIt
50 NDF-RT
53 NINDS
54 Novoseek
56 OMIM
57 OMIM via Orphanet
61 PubMed
63 QIAGEN
68 SNOMED-CT via HPO
69 TGDB
70 Tocris
71 UMLS
72 UMLS via Orphanet
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