WS3
MCID: WRD031
MIFTS: 44

Waardenburg Syndrome, Type 3 (WS3)

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

Aliases & Classifications for Waardenburg Syndrome, Type 3

MalaCards integrated aliases for Waardenburg Syndrome, Type 3:

Name: Waardenburg Syndrome, Type 3 58 54 13 41
Klein-Waardenburg Syndrome 58 12 54 60 76 56
Waardenburg Syndrome Type 3 12 77 54 60 15
Ws3 58 12 54 60 76
Waardenburg Syndrome with Upper Limb Anomalies 58 12 54 76
Waardenburg Syndrome Type Iii 12 60
White Forelock Syndrome with Multiple Congenital Malformations 54
Waardenburg Syndrome with Limb Anomalies 60
White Forelock with Malformations 76
Waardenburg Syndrome, Type Iii 58
Waardenburg Syndrome 3 76
Klein's Syndrome 74

Characteristics:

Orphanet epidemiological data:

60
waardenburg syndrome type 3
Inheritance: Autosomal dominant,Autosomal recessive; Age of onset: Neonatal; Age of death: normal life expectancy;

OMIM:

58
Inheritance:
autosomal recessive
autosomal dominant

Miscellaneous:
variable severity
both heterozygous and homozygous pax3 mutations have been found


HPO:

33
waardenburg syndrome, type 3:
Onset and clinical course variable expressivity
Inheritance autosomal dominant contiguous gene syndrome autosomal recessive inheritance


Classifications:



Summaries for Waardenburg Syndrome, Type 3

NIH Rare Diseases : 54 The following summary is from Orphanet, a European reference portal for information on rare diseases and orphan drugs.Orpha Number: 896Disease definitionWaardenburg syndrome type 3 (WS3) is a very rare subtype of Waardenburg syndrome (WS; see this term) that is characterized by limb anomalies in association with congenitalhearing loss, minor defects in structures arising from neural crest, resulting in pigmentation anomalies of eyes, hair, and skin.EpidemiologyIncidence is unknown, but WS3 is the rarest form of all Waardenburg syndrome types.Clinical descriptionWS3 is characterized by the association of limb anomalies (predominantly involving upper limbs, with hypoplasia of the musculoskeletal system, flexion contractures, fusion of the carpal bones, syndactylia) with features of Waardenburg syndrome (see this term), which include congenital sensorineural hearing loss, hypopigmentation abnormalities of irides, hair and skin and minor facial dysmorphism in combination with dystopia canthorum.EtiologyWS3 is caused by heterozygous or homozygousmutations in the PAX3 (2q36.1) gene.Diagnostic methodsDiagnosis is made through criteria of the association of WS1 manifestations with limb anomalies. PAX3 gene analysis confirms diagnosis resulting in an abnormality of melanocytes of skin, ears and hair.Antenatal diagnosisAntenatal diagnosis is possible for affected parents.Genetic counselingThe defects are more severe in homozygous than heterozygous forms. Genetic counseling is recommended.Management and treatmentHearing aids to counter hearing loss, effective therapy to improve language, communication, and cognitive skill and limbs physiotherapy are recommended. Associated manifestations are treated as appropriate (e.g. skin and eyes protection from the sun).PrognosisDue to the very few number of cases described so far, information on prognosis and quality of life is limited. Disease progression is variable, with symptoms being more severe in homozygous than in heterozygous forms.Visit the Orphanet disease page for more resources.

MalaCards based summary : Waardenburg Syndrome, Type 3, also known as klein-waardenburg syndrome, is related to waardenburg syndrome, type 2e and waardenburg syndrome, type 4b. An important gene associated with Waardenburg Syndrome, Type 3 is PAX3 (Paired Box 3), and among its related pathways/superpathways are Neural Crest Differentiation and Regulation of retinoblastoma protein. Affiliated tissues include skin, eye and kidney, and related phenotypes are hearing impairment and joint stiffness

Disease Ontology : 12 A Waardenburg's syndrome characterized by upper limb anomalies, congenital hearing loss, dystopia canthorum and pigmentation anomalies of eyes, hair, and skin that has material basis in heterozygous or homozygous mutation in the PAX3 gene on chromosome 2q36.

OMIM : 58 Waardenburg syndrome type 3 is an auditory-pigmentary syndrome characterized by pigmentary abnormalities of the hair, skin, and eyes; congenital sensorineural hearing loss; presence of 'dystopia canthorum,' the lateral displacement of the ocular inner canthi; and upper limb abnormalities (reviews by Read and Newton, 1997 and Pingault et al., 2010). WS type 3 is also referred to as 'Klein-Waardenburg syndrome' (Gorlin et al., 1976). (148820)

UniProtKB/Swiss-Prot : 76 Waardenburg syndrome 3: WS3 is an autosomal dominant disorder characterized by sensorineural deafness, pigmentary disturbances, dystopia canthorum and limb anomalies such as hypoplasia of the musculoskeletal system, flexion contractures, fusion of the carpal bones, syndactylies.

Wikipedia : 77 Waardenburg syndrome is a rare genetic disorder most often characterized by varying degrees of deafness,... more...

Related Diseases for Waardenburg Syndrome, Type 3

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 3 via text searches within MalaCards or GeneCards Suite gene sharing:

(show all 29)
# Related Disease Score Top Affiliating Genes
1 waardenburg syndrome, type 2e 31.6 MITF SOX10
2 waardenburg syndrome, type 4b 30.8 EDN3 MITF PAX3 SOX10
3 waardenburg syndrome, type 1 29.6 EDN3 MITF PAX3 SOX10
4 waardenburg's syndrome 29.4 EDN3 MITF PAX3 SOX10
5 white forelock with malformations 12.6
6 waardenburg syndrome, type 2b 11.1
7 waardenburg syndrome, type 2c 11.1
8 waardenburg syndrome, type 2d 11.1
9 waardenburg syndrome, type 4c 11.1
10 pulmonary hypertension, primary, 4 10.3
11 childhood kidney cell carcinoma 10.1 MITF PAX3
12 albinism, ocular, with late-onset sensorineural deafness 10.0 MITF SOX10
13 malignant spindle cell melanoma 10.0 MITF SOX10
14 breast angiosarcoma 10.0 MITF SOX10
15 hermansky-pudlak syndrome 1 10.0 PAX3 SOX10
16 cellular schwannoma 10.0 PAX3 SOX10
17 myelomeningocele 10.0
18 piebald trait 10.0 MITF PAX3
19 neurofibroma 9.9 MITF SOX10
20 tietz albinism-deafness syndrome 9.8 MITF PAX3 SOX10
21 megacolon 9.7 EDN3 SOX10
22 waardenburg syndrome type 4 9.7 EDN3 MITF SOX10
23 cochlear disease 9.7 EDN3 MITF SOX10
24 waardenburg syndrome, type 4a 9.7 EDN3 MITF SOX10
25 waardenburg syndrome, type 2a 9.7 EDN3 MITF SOX10
26 colonic disease 9.6 EDN3 SOX10
27 peripheral demyelinating neuropathy, central dysmyelination, waardenburg syndrome, and hirschsprung disease 9.5 EDN3 MITF PAX3 SOX10
28 dyschromatosis symmetrica hereditaria 9.5 EDN3 MITF PAX3 SOX10
29 hirschsprung disease 1 9.5 EDN3 MITF PAX3 SOX10

Graphical network of the top 20 diseases related to Waardenburg Syndrome, Type 3:



Diseases related to Waardenburg Syndrome, Type 3

Symptoms & Phenotypes for Waardenburg Syndrome, Type 3

Human phenotypes related to Waardenburg Syndrome, Type 3:

60 33 (show all 39)
# Description HPO Frequency Orphanet Frequency HPO Source Accession
1 hearing impairment 60 33 hallmark (90%) Very frequent (99-80%) HP:0000365
2 joint stiffness 60 33 hallmark (90%) Very frequent (99-80%) HP:0001387
3 microcephaly 60 33 hallmark (90%) Very frequent (99-80%) HP:0000252
4 thick eyebrow 60 33 hallmark (90%) Very frequent (99-80%) HP:0000574
5 downslanted palpebral fissures 60 33 hallmark (90%) Very frequent (99-80%) HP:0000494
6 blepharophimosis 60 33 hallmark (90%) Very frequent (99-80%) HP:0000581
7 narrow nasal bridge 60 33 hallmark (90%) Very frequent (99-80%) HP:0000446
8 synostosis of carpal bones 60 33 hallmark (90%) Very frequent (99-80%) HP:0005048
9 cutaneous finger syndactyly 60 33 hallmark (90%) Very frequent (99-80%) HP:0010554
10 tented upper lip vermilion 60 33 hallmark (90%) Very frequent (99-80%) HP:0010804
11 telecanthus 60 33 frequent (33%) Frequent (79-30%) HP:0000506
12 atelectasis 60 33 frequent (33%) Frequent (79-30%) HP:0100750
13 white hair 60 33 frequent (33%) Frequent (79-30%) HP:0011364
14 intellectual disability 60 33 occasional (7.5%) Occasional (29-5%) HP:0001249
15 acrocyanosis 60 33 occasional (7.5%) Occasional (29-5%) HP:0001063
16 atrial septal defect 60 33 occasional (7.5%) Occasional (29-5%) HP:0001631
17 spastic paraplegia 60 33 occasional (7.5%) Occasional (29-5%) HP:0001258
18 tracheomalacia 60 33 occasional (7.5%) Occasional (29-5%) HP:0002779
19 camptodactyly of finger 60 33 occasional (7.5%) Occasional (29-5%) HP:0100490
20 clinodactyly 33 HP:0030084
21 mandibular prognathia 33 HP:0000303
22 wide nasal bridge 33 HP:0000431
23 sensorineural hearing impairment 33 HP:0000407
24 scapular winging 33 HP:0003691
25 hypopigmented skin patches 33 HP:0001053
26 prominent nasal bridge 33 HP:0000426
27 heterochromia iridis 33 HP:0001100
28 premature graying of hair 33 HP:0002216
29 aganglionic megacolon 33 HP:0002251
30 abnormality of the face 60 Very frequent (99-80%)
31 blue irides 33 HP:0000635
32 brachydactyly 33 HP:0001156
33 white forelock 33 HP:0002211
34 abnormality of finger 60 Very frequent (99-80%)
35 abnormality of the upper limb 60 Very frequent (99-80%)
36 synophrys 33 HP:0000664
37 partial albinism 33 HP:0007443
38 carpal synostosis 33 HP:0009702
39 joint contracture of the hand 33 HP:0009473

Symptoms via clinical synopsis from OMIM:

58
Skeletal Hands:
clinodactyly
brachydactyly
syndactyly, cutaneous
finger contractures
hypoplasia of the hand muscles

Head And Neck Eyes:
blepharophimosis
synophrys
dystopia canthorum
heterochromia iridis (complete or partial)
hypopigmented iris
more
Skeletal Feet:
syndactyly

Head And Neck Nose:
prominent nasal root
hypoplastic alae

Skeletal Limbs:
contractures of the upper limb joints
hypoplasia of the bones of the upper limbs and wrists

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

Skin Nails Hair Hair:
white forelock
premature graying of the hair

Head And Neck Face:
prognathism

Head And Neck Ears:
sensorineural deafness

Neurologic Central Nervous System:
mental retardation (reported in 1 patient)
spasticity (reported in 1 patient)

Clinical features from OMIM:

148820

MGI Mouse Phenotypes related to Waardenburg Syndrome, Type 3:

47
# Description MGI Source Accession Score Top Affiliating Genes
1 embryo MP:0005380 9.46 EDN3 MITF PAX3 SOX10
2 integument MP:0010771 9.26 EDN3 MITF PAX3 SOX10
3 pigmentation MP:0001186 8.92 EDN3 MITF PAX3 SOX10

Drugs & Therapeutics for Waardenburg Syndrome, Type 3

Interventional clinical trials:


# Name Status NCT ID Phase Drugs
1 Pathway Study WS3 - Home Based Metacognitive Therapy for Cardiac Rehabilitation Patients Recruiting NCT03129282 Not Applicable

Search NIH Clinical Center for Waardenburg Syndrome, Type 3

Genetic Tests for Waardenburg Syndrome, Type 3

Anatomical Context for Waardenburg Syndrome, Type 3

MalaCards organs/tissues related to Waardenburg Syndrome, Type 3:

42
Skin, Eye, Kidney, Colon

Publications for Waardenburg Syndrome, Type 3

Articles related to Waardenburg Syndrome, Type 3:

# Title Authors Year
1
First report of Klein-Waardenburg Syndrome in Iran and a novel pathogenic splice site variant in PAX3 gene. ( 30173992 )
2018
2
Waardenburg syndrome type 3 (Klein-Waardenburg syndrome) segregating with a heterozygous deletion in the paired box domain of PAX3: a simple variant or a true syndrome? ( 11683776 )
2001
3
Myelomeningocele and Waardenburg syndrome (type 3) in patients with interstitial deletions of 2q35 and the PAX3 gene: possible digenic inheritance of a neural tube defect. ( 9482647 )
1998
4
Mutations in the paired domain of the human PAX3 gene cause Klein-Waardenburg syndrome (WS-III) as well as Waardenburg syndrome type I (WS-I). ( 8447316 )
1993
5
Autosomal dominant inheritance of Klein-Waardenburg syndrome. ( 1536170 )
1992
6
Historical background and evidence for dominant inheritance of the Klein-Waardenburg syndrome (type III). ( 6340503 )
1983
7
Upper limb involvement in the Klein-Waardenburg syndrome. ( 7091186 )
1982
8
Anal atresia and the Klein-Waardenburg syndrome. ( 7241550 )
1981

Variations for Waardenburg Syndrome, Type 3

UniProtKB/Swiss-Prot genetic disease variations for Waardenburg Syndrome, Type 3:

76
# Symbol AA change Variation ID SNP ID
1 PAX3 p.Asn47His VAR_003791 rs104893653
2 PAX3 p.Ser84Phe VAR_003801 rs104893651
3 PAX3 p.Arg270Cys VAR_013619 rs122859019
4 PAX3 p.Tyr90His VAR_017535 rs104893654

ClinVar genetic disease variations for Waardenburg Syndrome, Type 3:

6 (show all 14)
# Gene Variation Type Significance SNP ID Assembly Location
1 PAX3 NM_001127366.2(PAX3): c.251C> T (p.Ser84Phe) single nucleotide variant Pathogenic rs104893651 GRCh37 Chromosome 2, 223161767: 223161767
2 PAX3 NM_001127366.2(PAX3): c.251C> T (p.Ser84Phe) single nucleotide variant Pathogenic rs104893651 GRCh38 Chromosome 2, 222297048: 222297048
3 PAX3 NM_181457.3(PAX3): c.139A> C (p.Asn47His) single nucleotide variant Pathogenic rs104893653 GRCh37 Chromosome 2, 223161879: 223161879
4 PAX3 NM_181457.3(PAX3): c.139A> C (p.Asn47His) single nucleotide variant Pathogenic rs104893653 GRCh38 Chromosome 2, 222297160: 222297160
5 PAX3 NM_181457.3(PAX3): c.386_398delTCAGCTGGGAAAT (p.Phe129Serfs) deletion Pathogenic GRCh37 Chromosome 2, 223160300: 223160312
6 PAX3 NM_181457.3(PAX3): c.386_398delTCAGCTGGGAAAT (p.Phe129Serfs) deletion Pathogenic GRCh38 Chromosome 2, 222295581: 222295593
7 PAX3 NM_181457.3(PAX3): c.268T> C (p.Tyr90His) single nucleotide variant Pathogenic rs104893654 GRCh37 Chromosome 2, 223161750: 223161750
8 PAX3 NM_181457.3(PAX3): c.268T> C (p.Tyr90His) single nucleotide variant Pathogenic rs104893654 GRCh38 Chromosome 2, 222297031: 222297031
9 PAX3 NM_181457.3(PAX3): c.540C> G (p.Ser180Arg) single nucleotide variant Uncertain significance rs200679164 GRCh38 Chromosome 2, 222294213: 222294213
10 PAX3 NM_181457.3(PAX3): c.540C> G (p.Ser180Arg) single nucleotide variant Uncertain significance rs200679164 GRCh37 Chromosome 2, 223158932: 223158932
11 PAX3 NM_181457.3(PAX3): c.580G> A (p.Glu194Lys) single nucleotide variant Uncertain significance rs148454691 GRCh37 Chromosome 2, 223158892: 223158892
12 PAX3 NM_181457.3(PAX3): c.580G> A (p.Glu194Lys) single nucleotide variant Uncertain significance rs148454691 GRCh38 Chromosome 2, 222294173: 222294173
13 PAX3 NM_181457.3(PAX3): c.246C> G (p.Cys82Trp) single nucleotide variant Likely pathogenic rs777297575 GRCh38 Chromosome 2, 222297053: 222297053
14 PAX3 NM_181457.3(PAX3): c.246C> G (p.Cys82Trp) single nucleotide variant Likely pathogenic rs777297575 GRCh37 Chromosome 2, 223161772: 223161772

Expression for Waardenburg Syndrome, Type 3

Search GEO for disease gene expression data for Waardenburg Syndrome, Type 3.

Pathways for Waardenburg Syndrome, Type 3

Pathways related to Waardenburg Syndrome, Type 3 according to GeneCards Suite gene sharing:

# Super pathways Score Top Affiliating Genes
1 11.14 MITF PAX3 SOX10
2 10.9 MITF PAX3
3 10.41 MITF PAX3 SOX10

GO Terms for Waardenburg Syndrome, Type 3

Biological processes related to Waardenburg Syndrome, Type 3 according to GeneCards Suite gene sharing:

# Name GO ID Score Top Affiliating Genes
1 positive regulation of transcription, DNA-templated GO:0045893 9.43 MITF PAX3 SOX10
2 neural crest cell migration GO:0001755 9.16 EDN3 SOX10
3 transcription, DNA-templated GO:0006351 8.96 MITF POLR1D
4 melanocyte differentiation GO:0030318 8.8 EDN3 MITF SOX10

Sources for Waardenburg Syndrome, Type 3

3 CDC
7 CNVD
9 Cosmic
10 dbSNP
11 DGIdb
17 EFO
18 ExPASy
20 FMA
29 GO
30 GTR
31 HGMD
32 HMDB
33 HPO
34 ICD10
35 ICD10 via Orphanet
36 ICD9CM
37 IUPHAR
38 KEGG
39 LifeMap
41 LOVD
43 MedGen
45 MeSH
46 MESH via Orphanet
47 MGI
50 NCI
51 NCIt
52 NDF-RT
55 NINDS
56 Novoseek
58 OMIM
59 OMIM via Orphanet
63 PubMed
65 QIAGEN
70 SNOMED-CT via HPO
71 SNOMED-CT via Orphanet
72 TGDB
73 Tocris
74 UMLS
75 UMLS via Orphanet
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