WS3
MCID: WRD031
MIFTS: 45

Waardenburg Syndrome, Type 3 (WS3)

Categories: Ear diseases, Eye diseases, Fetal diseases, Gastrointestinal 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 56 52 13 39
Klein-Waardenburg Syndrome 56 12 52 58 73 54
Waardenburg Syndrome Type 3 12 74 52 58 15
Ws3 56 12 52 58 73
Waardenburg Syndrome with Upper Limb Anomalies 56 12 52 73
Waardenburg Syndrome Type Iii 12 58
White Forelock Syndrome with Multiple Congenital Malformations 52
Waardenburg Syndrome with Limb Anomalies 58
White Forelock with Malformations 73
Waardenburg Syndrome, Type Iii 56
Waardenburg Syndrome 3 73
Klein's Syndrome 71

Characteristics:

Orphanet epidemiological data:

58
waardenburg syndrome type 3
Inheritance: Autosomal dominant,Autosomal recessive; Age of onset: Neonatal; Age of death: normal life expectancy;

OMIM:

56
Inheritance:
autosomal recessive
autosomal dominant

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


HPO:

31
waardenburg syndrome, type 3:
Inheritance autosomal recessive inheritance autosomal dominant contiguous gene syndrome
Onset and clinical course variable expressivity


Classifications:

Orphanet: 58  
Rare eye diseases
Rare otorhinolaryngological diseases
Rare skin diseases
Developmental anomalies during embryogenesis


Summaries for Waardenburg Syndrome, Type 3

NIH Rare Diseases : 52 The following summary is from Orphanet , a European reference portal for information on rare diseases and orphan drugs. Orpha Number: 896 Definition A very rare subtype of Waardenburg syndrome (WS) that is characterized by limb anomalies in association with congenital hearing loss , minor defects in structures arising from neural crest, resulting in pigmentation anomalies of eyes, hair, and skin. Epidemiology Incidence is unknown, but WS3 is the rarest form of all Waardenburg syndrome types. Clinical description WS3 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. Etiology WS3 is caused by heterozygous or homozygous mutations in the PAX3 (2q36.1) gene . Diagnostic methods Diagnosis 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 diagnosis Antenatal diagnosis is possible for affected parents. Genetic counseling The defects are more severe in homozygous than heterozygous forms. Genetic counseling is recommended. Management and treatment Hearing 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). Prognosis Due 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 2b and waardenburg syndrome, type 2c. 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 Melanocyte Development and Pigmentation. Affiliated tissues include eye, skin and bone, 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 : 56 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 : 73 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 : 74 Waardenburg syndrome is a group of rare genetic conditions characterised by at least some degree of... 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 42)
# Related Disease Score Top Affiliating Genes
1 waardenburg syndrome, type 2b 32.1 SOX10 MITF EDN3
2 waardenburg syndrome, type 2c 31.7 SOX10 PAX3 MITF EDNRB EDN3
3 waardenburg syndrome, type 4c 31.6 SOX10 PAX3 MITF EDNRB EDN3
4 waardenburg syndrome, type 2d 31.6 SOX10 SNAI2 PAX3 MITF EDNRB
5 waardenburg syndrome, type 2e 31.3 SOX10 SNAI2 PAX3 MITF EDNRB EDN3
6 waardenburg syndrome, type 4b 31.3 SOX10 SNAI2 PAX3 MITF EDNRB EDN3
7 waardenburg syndrome, type 4a 29.9 SOX10 SNAI2 PAX3 MITF EDNRB EDN3
8 waardenburg's syndrome 29.7 SOX10 SNAI2 PAX3 MITF EDNRB EDN3
9 waardenburg syndrome, type 1 28.7 SOX10 SNAI2 PAX3 MITF MED20 EDNRB
10 white forelock with malformations 12.9
11 pulmonary hypertension, primary, 4 10.4
12 gallbladder melanoma 10.3 SOX10 MITF
13 ocular albinism with congenital sensorineural deafness 10.3 PAX3 MITF
14 pulmonary hypertension, primary, 3 10.3
15 malignant choroid melanoma 10.3 SOX10 MITF
16 craniofacial-deafness-hand syndrome 10.2
17 chromosome 2q35 duplication syndrome 10.2
18 telecanthus 10.2
19 pallister w syndrome 10.2
20 sensorineural hearing loss 10.2
21 blepharophimosis 10.2
22 achalasia 10.2
23 albinism 10.2
24 malignant spindle cell melanoma 10.2 SOX10 MITF
25 albinism, ocular, with late-onset sensorineural deafness 10.2 SOX10 PAX3 MITF
26 intestinal pseudo-obstruction 10.2 SOX10 EDN3
27 cochlear disease 10.2 SOX10 EDNRB EDN3
28 central hypoventilation syndrome, congenital 10.1 SOX10 EDNRB EDN3
29 charge syndrome 10.1 SOX10 SNAI2 PAX3
30 waardenburg syndrome, type 2a 10.1 SOX10 PAX3 MITF EDNRB
31 waardenburg syndrome type 4 10.0 SOX10 MITF EDNRB EDN3
32 goldberg-shprintzen syndrome 10.0 EDNRB EDN3
33 rare genetic deafness 10.0 SOX10 PAX3 MITF EDNRB
34 neural tube defects 10.0
35 myelomeningocele 10.0
36 coloboma of macula 9.9 SOX10 MITF BMP7
37 lentigines 9.9 MITF EDNRB
38 peripheral demyelinating neuropathy, central dysmyelination, waardenburg syndrome, and hirschsprung disease 9.9 SOX10 PAX3 MITF EDNRB EDN3
39 megacolon 9.9 SOX10 PAX3 MITF EDNRB EDN3
40 tietz albinism-deafness syndrome 9.7 SOX10 SNAI2 PAX3 MITF EDNRB EDN3
41 piebald trait 9.7 SOX10 SNAI2 PAX3 MITF EDNRB EDN3
42 hirschsprung disease 1 9.6 SOX10 SNAI2 PAX3 MITF EDNRB EDN3

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:

58 31 (show all 39)
# Description HPO Frequency Orphanet Frequency HPO Source Accession
1 hearing impairment 58 31 hallmark (90%) Very frequent (99-80%) HP:0000365
2 joint stiffness 58 31 hallmark (90%) Very frequent (99-80%) HP:0001387
3 microcephaly 58 31 hallmark (90%) Very frequent (99-80%) HP:0000252
4 thick eyebrow 58 31 hallmark (90%) Very frequent (99-80%) HP:0000574
5 downslanted palpebral fissures 58 31 hallmark (90%) Very frequent (99-80%) HP:0000494
6 blepharophimosis 58 31 hallmark (90%) Very frequent (99-80%) HP:0000581
7 narrow nasal bridge 58 31 hallmark (90%) Very frequent (99-80%) HP:0000446
8 synostosis of carpal bones 58 31 hallmark (90%) Very frequent (99-80%) HP:0005048
9 cutaneous finger syndactyly 58 31 hallmark (90%) Very frequent (99-80%) HP:0010554
10 tented upper lip vermilion 58 31 hallmark (90%) Very frequent (99-80%) HP:0010804
11 atelectasis 58 31 frequent (33%) Frequent (79-30%) HP:0100750
12 telecanthus 58 31 frequent (33%) Frequent (79-30%) HP:0000506
13 white hair 58 31 frequent (33%) Frequent (79-30%) HP:0011364
14 intellectual disability 58 31 occasional (7.5%) Occasional (29-5%) HP:0001249
15 acrocyanosis 58 31 occasional (7.5%) Occasional (29-5%) HP:0001063
16 atrial septal defect 58 31 occasional (7.5%) Occasional (29-5%) HP:0001631
17 camptodactyly of finger 58 31 occasional (7.5%) Occasional (29-5%) HP:0100490
18 spastic paraplegia 58 31 occasional (7.5%) Occasional (29-5%) HP:0001258
19 tracheomalacia 58 31 occasional (7.5%) Occasional (29-5%) HP:0002779
20 mandibular prognathia 31 HP:0000303
21 wide nasal bridge 31 HP:0000431
22 sensorineural hearing impairment 31 HP:0000407
23 hypopigmented skin patches 31 HP:0001053
24 scapular winging 31 HP:0003691
25 abnormality of the face 58 Very frequent (99-80%)
26 blue irides 31 HP:0000635
27 premature graying of hair 31 HP:0002216
28 brachydactyly 31 HP:0001156
29 aganglionic megacolon 31 HP:0002251
30 heterochromia iridis 31 HP:0001100
31 prominent nasal bridge 31 HP:0000426
32 white forelock 31 HP:0002211
33 abnormality of finger 58 Very frequent (99-80%)
34 abnormality of the upper limb 58 Very frequent (99-80%)
35 synophrys 31 HP:0000664
36 partial albinism 31 HP:0007443
37 carpal synostosis 31 HP:0009702
38 clinodactyly 31 HP:0030084
39 joint contracture of the hand 31 HP:0009473

Symptoms via clinical synopsis from OMIM:

56
Skin Nails Hair Skin:
hypopigmented skin patches
congenital partial albinism (leukoderma) on face, trunk, or limbs

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

Head And Neck Face:
prognathism

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

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

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

Head And Neck Ears:
sensorineural deafness

Head And Neck Nose:
prominent nasal root
hypoplastic alae

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:

45
# Description MGI Source Accession Score Top Affiliating Genes
1 behavior/neurological MP:0005386 10.11 BCKDHA BMP7 CMBL EDN3 EDNRB METTL21C
2 embryo MP:0005380 9.92 BMP7 EDN3 EDNRB MED20 MITF PAX3
3 integument MP:0010771 9.91 BMP7 EDN3 EDNRB GP6 MITF PAX3
4 limbs/digits/tail MP:0005371 9.63 BMP7 CMBL EDNRB MITF PAX3 SOX10
5 pigmentation MP:0001186 9.5 BMP7 EDN3 EDNRB MITF PAX3 SNAI2
6 vision/eye MP:0005391 9.23 BCKDHA BMP7 EDNRB GP6 MED20 MITF

Drugs & Therapeutics for Waardenburg Syndrome, Type 3

Search Clinical Trials , 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:

40
Eye, Skin, Bone

Publications for Waardenburg Syndrome, Type 3

Articles related to Waardenburg Syndrome, Type 3:

(show all 26)
# Title Authors PMID Year
1
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? 61 54 56 6
11683776 2001
2
Homozygous and heterozygous inheritance of PAX3 mutations causes different types of Waardenburg syndrome. 6 56 61
12949970 2003
3
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). 56 61 6
8447316 1993
4
Autosomal dominant inheritance of Klein-Waardenburg syndrome. 61 6 56
1536170 1992
5
Upper limb involvement in the Klein-Waardenburg syndrome. 61 56 6
7091186 1982
6
Homozygosity for Waardenburg syndrome. 6 56
7726174 1995
7
Waardenburg syndrome. 56 61
9279758 1997
8
Historical background and evidence for dominant inheritance of the Klein-Waardenburg syndrome (type III). 61 56
6340503 1983
9
Hearing loss in Waardenburg syndrome: a systematic review. 56
26100139 2016
10
Screening program for Waardenburg syndrome in Colombia: clinical definition and phenotypic variability. 56
18241065 2008
11
The mutational spectrum in Waardenburg syndrome. 56
8589691 1995
12
Possible homozygous Waardenburg syndrome in a fetus with exencephaly. 56
8588597 1995
13
Discordant phenotype of two overlapping deletions involving the PAX3 gene in chromosome 2q35. 56
8103404 1993
14
Splotch (Sp2H), a mutation affecting development of the mouse neural tube, shows a deletion within the paired homeodomain of Pax-3. 56
1682057 1991
15
A new white forelock (poliosis) syndrome with multiple congenital malformations in two sibs. 56
7398117 1980
16
[A case of Waardenburg-Klein syndrome]. 56
5759294 1968
17
First report of Klein-Waardenburg Syndrome in Iran and a novel pathogenic splice site variant in PAX3 gene. 61
30173992 2018
18
Congenital stapes malformation: Rare conductive hearing loss in a patient with Waardenburg syndrome. 61
26152551 2016
19
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. 61
9482647 1998
20
Missense mutation in the paired domain of PAX3 causes craniofacial-deafness-hand syndrome. 61
8664898 1996
21
Physiopathological investigations in a family with a history of unilateral hereditary deafness. 61
7610804 1995
22
[Hereditary unilateral deaf-mutism as a variable manifestation of bilateral deaf-mutism or hearing loss]. 61
1616543 1992
23
[Klein-Waardenburg syndrome. Report of 3 cases in a family with a review of the literature]. 61
4010406 1985
24
Anal atresia and the Klein-Waardenburg syndrome. 61
7241550 1981
25
[Klein-Waardenburg syndrome]. 61
5628551 1967
26
[New observation of the severe form of the Klein-Waardenburg syndrome]. 61
5899973 1964

Variations for Waardenburg Syndrome, Type 3

ClinVar genetic disease variations for Waardenburg Syndrome, Type 3:

6 ‎‎ ‎‎ ‎‎ ‎‎ ‎‎ ‎‎ ‎‎
# Gene Name Type Significance ClinVarId dbSNP ID GRCh37 Pos GRCh38 Pos
1 PAX3 NM_181458.4(PAX3):c.251C>T (p.Ser84Phe)SNV Pathogenic 4212 rs104893651 2:223161767-223161767 2:222297048-222297048
2 PAX3 NM_181458.4(PAX3):c.139A>C (p.Asn47His)SNV Pathogenic 4214 rs104893653 2:223161879-223161879 2:222297160-222297160
3 PAX3 NM_181458.4(PAX3):c.386_398del (p.Phe129fs)deletion Pathogenic 4215 rs1559318494 2:223160300-223160312 2:222295581-222295593
4 PAX3 NM_181458.4(PAX3):c.268T>C (p.Tyr90His)SNV Pathogenic 4216 rs104893654 2:223161750-223161750 2:222297031-222297031
5 PAX3 NM_181458.4(PAX3):c.246C>G (p.Cys82Trp)SNV Likely pathogenic 547736 rs777297575 2:223161772-223161772 2:222297053-222297053
6 PAX3 NM_181458.4(PAX3):c.580G>A (p.Glu194Lys)SNV Conflicting interpretations of pathogenicity 504786 rs148454691 2:223158892-223158892 2:222294173-222294173
7 PAX3 NM_181458.4(PAX3):c.540C>G (p.Ser180Arg)SNV Uncertain significance 504788 rs200679164 2:223158932-223158932 2:222294213-222294213

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

73
# 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

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 11.03 SOX10 SNAI2 PAX3 MITF BMP7
2 10.74 SOX10 PAX3 MITF

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 neural crest cell migration GO:0001755 9.43 SOX10 EDNRB EDN3
2 peripheral nervous system development GO:0007422 9.4 SOX10 EDNRB
3 vasoconstriction GO:0042310 9.37 EDNRB EDN3
4 enteric nervous system development GO:0048484 9.32 SOX10 EDNRB
5 vein smooth muscle contraction GO:0014826 9.16 EDNRB EDN3
6 pigmentation GO:0043473 9.13 SNAI2 MITF EDNRB
7 melanocyte differentiation GO:0030318 8.92 SOX10 MITF EDNRB EDN3

Sources for Waardenburg Syndrome, Type 3

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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