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Waardenburg syndrome type 1(WS1)

MedGen UID:
376211
Concept ID:
C1847800
Disease or Syndrome
Synonyms: Waardenburg Syndrome Type I; WAARDENBURG SYNDROME WITH DYSTOPIA CANTHORUM; Waardenburg's syndrome type 1; WS1
SNOMED CT: Waardenburg syndrome type 1 (1010606009)
Modes of inheritance:
Autosomal dominant inheritance
MedGen UID:
141047
Concept ID:
C0443147
Intellectual Product
Sources: HPO, OMIM
A mode of inheritance that is observed for traits related to a gene encoded on one of the autosomes (i.e., the human chromosomes 1-22) in which a trait manifests in heterozygotes. In the context of medical genetics, an autosomal dominant disorder is caused when a single copy of the mutant allele is present. Males and females are affected equally, and can both transmit the disorder with a risk of 50% for each child of inheriting the mutant allele.
 
Gene (location): PAX3 (2q36.1)
 
Monarch Initiative: MONDO:0008670
OMIM®: 193500
Orphanet: ORPHA894

Disease characteristics

Excerpted from the GeneReview: Waardenburg Syndrome Type I
Waardenburg syndrome type I (WS1) is an auditory-pigmentary disorder comprising congenital sensorineural hearing loss and pigmentary disturbances of the iris, hair, and skin, along with dystopia canthorum (lateral displacement of the inner canthi). The hearing loss in WS1, observed in approximately 60% of affected individuals, is congenital, typically non-progressive, either unilateral or bilateral, and sensorineural. Most commonly, hearing loss in WS1 is bilateral and profound (>100 dB). The majority of individuals with WS1 have either a white forelock or early graying of the scalp hair before age 30 years. The classic white forelock observed in approximately 45% of individuals is the most common hair pigmentation anomaly seen in WS1. Affected individuals may have complete heterochromia iridium, partial/segmental heterochromia, or hypoplastic or brilliant blue irides. Congenital leukoderma is frequently seen on the face, trunk, or limbs. [from GeneReviews]
Authors:
Jeff Mark Milunsky   view full author information

Additional descriptions

From OMIM
Waardenburg syndrome type 1 (WS1) is an autosomal dominant auditory-pigmentary syndrome characterized by pigmentary abnormalities of the hair, skin, and eyes; congenital sensorineural hearing loss; and 'dystopia canthorum,' the lateral displacement of the ocular inner canthi (reviews by Read and Newton, 1997, Tamayo et al., 2008, and Pingault et al., 2010). Clinical Variability of Waardenburg Syndrome Types 1-4 Waardenburg syndrome is an auditory-pigmentary syndrome characterized by pigmentary abnormalities of the hair, including a white forelock and premature graying; pigmentary changes of the iris, such as heterochromia irides and brilliant blue eyes; and congenital sensorineural hearing loss. Waardenburg syndrome has been classified into 4 main phenotypes. WS type 1 is distinguished by the presence of dystopia canthorum. WS type 2 (WS2; see 193510) is distinguished from type 1 by the absence of dystopia canthorum. WS type 3 (WS3; 148820) has dystopia canthorum and upper limb abnormalities. WS type 4 (WS4; see 277580), also known as Waardenburg-Shah syndrome, has the additional feature of Hirschsprung disease (reviews by Read and Newton, 1997 and Tamayo et al., 2008). Genetic Heterogeneity of All Types of Waardenburg Syndrome Waardenburg syndrome is genetically heterogeneous. WS1 and WS3 are both caused by mutation in the PAX3 gene. See WS2A (193510) for a discussion of genetic heterogeneity of WS type 2, and WS4A (277580) for a discussion of genetic heterogeneity of WS type 4.  http://www.omim.org/entry/193500
From MedlinePlus Genetics
There are four recognized types of Waardenburg syndrome, which are distinguished by their physical characteristics and sometimes by their genetic cause. Types I and II have very similar features, although people with type I almost always have eyes that appear widely spaced and people with type II do not. In addition, hearing loss occurs more often in people with type II than in those with type I. Type III (sometimes called Klein-Waardenburg syndrome) includes abnormalities of the arms and hands in addition to hearing loss and changes in pigmentation. Type IV (also known as Waardenburg-Shah syndrome) has signs and symptoms of both Waardenburg syndrome and Hirschsprung disease, an intestinal disorder that causes severe constipation or blockage of the intestine.\n\nWaardenburg syndrome is a group of genetic conditions that can cause hearing loss and changes in coloring (pigmentation) of the hair, skin, and eyes. Although most people with Waardenburg syndrome have normal hearing, moderate to profound hearing loss can occur in one or both ears. The hearing loss is present from birth (congenital). People with this condition often have very pale blue eyes or different colored eyes, such as one blue eye and one brown eye. Sometimes one eye has segments of two different colors. Distinctive hair coloring (such as a patch of white hair or hair that prematurely turns gray) is another common sign of the condition. The features of Waardenburg syndrome vary among affected individuals, even among people in the same family.  https://medlineplus.gov/genetics/condition/waardenburg-syndrome
From MedlinePlus Genetics
Waardenburg syndrome is a group of genetic conditions that can cause hearing loss and changes in coloring (pigmentation) of the hair, skin, and eyes. Although most people with Waardenburg syndrome have normal hearing, moderate to profound hearing loss can occur in one or both ears. The hearing loss is present from birth (congenital). People with this condition often have very pale blue eyes or different colored eyes, such as one blue eye and one brown eye. Sometimes one eye has segments of two different colors. Distinctive hair coloring (such as a patch of white hair or hair that prematurely turns gray) is another common sign of the condition. The features of Waardenburg syndrome vary among affected individuals, even among people in the same family.\n\nThere are four recognized types of Waardenburg syndrome, which are distinguished by their physical characteristics and sometimes by their genetic cause. Types I and II have very similar features, although people with type I almost always have eyes that appear widely spaced and people with type II do not. In addition, hearing loss occurs more often in people with type II than in those with type I. Type III (sometimes called Klein-Waardenburg syndrome) includes abnormalities of the arms and hands in addition to hearing loss and changes in pigmentation. Type IV (also known as Waardenburg-Shah syndrome) has signs and symptoms of both Waardenburg syndrome and Hirschsprung disease, an intestinal disorder that causes severe constipation or blockage of the intestine.  https://medlineplus.gov/genetics/condition/waardenburg-syndrome

Clinical features

From HPO
Aplasia of the vagina
MedGen UID:
330738
Concept ID:
C1841990
Finding
Aplasia of the vagina.
Congenital sensorineural hearing impairment
MedGen UID:
356101
Concept ID:
C1865866
Disease or Syndrome
A type of hearing impairment caused by an abnormal functionality of the cochlear nerve with congenital onset.
Myelomeningocele
MedGen UID:
7538
Concept ID:
C0025312
Congenital Abnormality
Protrusion of the meninges and portions of the spinal cord through a defect of the vertebral column.
Isolated spina bifida
MedGen UID:
38283
Concept ID:
C0080178
Congenital Abnormality
A group of rare neural tube defect disorders characterized by improper closure of the spinal column during embryonal development, not associated with other major congenital malformations nor ventriculomegaly. The extent of the closure defect may vary, ranging from spina bifida occulta, in which the site of the lesion is not exposed (e.g. an isolated posterior vertebral arch defect), to spina bifida aperta, in which the lesion may be conformed of proturding spinal cord and meninges (myelomeningocele) or meninges exposure only (meningocele), with or without a proturding sac at the site of the lesion, to the most severe defect which includes total exposure of the spinal cord along its full length (rachischisis). Depending on the type, size and site of the defect, severe morbidity, typically inlcuding motor, sensory and sphincter dysfunction, and mortality may be associated. Spina bifida occulta may be asymptomatic.
Congenital elevation of scapula
MedGen UID:
56291
Concept ID:
C0152438
Congenital Abnormality
A congenital skeletal deformity characterized by the elevation of one scapula (thus, one scapula is located superior to the other).
Supernumerary vertebrae
MedGen UID:
75583
Concept ID:
C0265681
Congenital Abnormality
Supernumerary ribs
MedGen UID:
83380
Concept ID:
C0345397
Congenital Abnormality
The presence of more than 12 rib pairs.
Mandibular prognathia
MedGen UID:
98316
Concept ID:
C0399526
Finding
Abnormal prominence of the chin related to increased length of the mandible.
Blepharophimosis
MedGen UID:
2670
Concept ID:
C0005744
Congenital Abnormality
A fixed reduction in the vertical distance between the upper and lower eyelids with short palpebral fissures.
Mandibular prognathia
MedGen UID:
98316
Concept ID:
C0399526
Finding
Abnormal prominence of the chin related to increased length of the mandible.
Telecanthus
MedGen UID:
140836
Concept ID:
C0423113
Finding
Distance between the inner canthi more than two standard deviations above the mean (objective); or, apparently increased distance between the inner canthi.
Synophrys
MedGen UID:
98132
Concept ID:
C0431447
Congenital Abnormality
Meeting of the medial eyebrows in the midline.
Smooth philtrum
MedGen UID:
222980
Concept ID:
C1142533
Finding
Flat skin surface, with no ridge formation in the central region of the upper lip between the nasal base and upper vermilion border.
Underdeveloped nasal alae
MedGen UID:
322332
Concept ID:
C1834055
Congenital Abnormality
Thinned, deficient, or excessively arched ala nasi.
White eyelashes
MedGen UID:
332275
Concept ID:
C1836736
Finding
White color (lack of pigmentation) of the eyelashes.
White eyebrow
MedGen UID:
373165
Concept ID:
C1836737
Finding
White color (lack of pigmentation) of the eyebrow.
Wide nasal bridge
MedGen UID:
341441
Concept ID:
C1849367
Finding
Thick eyebrow
MedGen UID:
377914
Concept ID:
C1853487
Finding
Increased density/number and/or increased diameter of eyebrow hairs.
Oral cleft
MedGen UID:
893092
Concept ID:
C4021813
Congenital Abnormality
The presence of a cleft in the oral cavity, the two main types of which are cleft lip and cleft palate. In cleft lip, there is the congenital failure of the maxillary and median nasal processes to fuse, forming a groove or fissure in the lip. In cleft palate, there is a congenital failure of the palate to fuse properly, forming a grooved depression or fissure in the roof of the mouth. Clefts of the lip and palate can occur individually or together. It is preferable to code each defect separately.
Partial albinism
MedGen UID:
36361
Concept ID:
C0080024
Congenital Abnormality
Piebaldism is a rare autosomal dominant trait characterized by the congenital absence of melanocytes in affected areas of the skin and hair. A white forelock of hair, often triangular in shape, may be the only manifestation, or both the hair and the underlying forehead may be involved. The eyebrows and eyelashes may be affected. Irregularly shaped white patches may be observed on the face, trunk, and extremities, usually in a symmetrical distribution. Typically, islands of hyperpigmentation are present within and at the border of depigmented areas (summary by Thomas et al., 2004).
Premature graying of hair
MedGen UID:
75524
Concept ID:
C0263498
Finding
Development of gray hair at a younger than normal age.
White forelock
MedGen UID:
91023
Concept ID:
C0344312
Finding
A triangular depigmented region of white hairs located in the anterior midline of the scalp.
Synophrys
MedGen UID:
98132
Concept ID:
C0431447
Congenital Abnormality
Meeting of the medial eyebrows in the midline.
White eyelashes
MedGen UID:
332275
Concept ID:
C1836736
Finding
White color (lack of pigmentation) of the eyelashes.
White eyebrow
MedGen UID:
373165
Concept ID:
C1836737
Finding
White color (lack of pigmentation) of the eyebrow.
Thick eyebrow
MedGen UID:
377914
Concept ID:
C1853487
Finding
Increased density/number and/or increased diameter of eyebrow hairs.
Hypertelorism
MedGen UID:
9373
Concept ID:
C0020534
Finding
Although hypertelorism means an excessive distance between any paired organs (e.g., the nipples), the use of the word has come to be confined to ocular hypertelorism. Hypertelorism occurs as an isolated feature and is also a feature of many syndromes, e.g., Opitz G syndrome (145410), Greig cephalopolysyndactyly (175700), and Noonan syndrome (163950) (summary by Cohen et al., 1995).
Hypopigmentation of the fundus
MedGen UID:
101805
Concept ID:
C0151891
Disease or Syndrome
Reduced pigmentation of the fundus, typically generalised. Fundoscopy may reveal a low level pigment in both RPE and choroid with clear visibility of choroidal vessels (pale/albinoid) or low pigment level in the RPE with deep pigment in choroid so that visible choroidal vessels are separated by deeply pigmented zones (tesselated/tigroid).
Heterochromia iridis
MedGen UID:
98395
Concept ID:
C0423318
Finding
Asymmetry between the two irides or asymmetry between different parts of one iris.
Blue irides
MedGen UID:
108297
Concept ID:
C0578626
Finding
Hypoplastic iris stroma
MedGen UID:
349788
Concept ID:
C1860344
Finding
Underdevelopment of the stroma of iris.

Term Hierarchy

CClinical test,  RResearch test,  OOMIM,  GGeneReviews,  VClinVar  
Follow this link to review classifications for Waardenburg syndrome type 1 in Orphanet.

Professional guidelines

PubMed

Alford RL, Arnos KS, Fox M, Lin JW, Palmer CG, Pandya A, Rehm HL, Robin NH, Scott DA, Yoshinaga-Itano C; ACMG Working Group on Update of Genetics Evaluation Guidelines for the Etiologic Diagnosis of Congenital Hearing Loss.; Professional Practice and Guidelines Committee.
Genet Med 2014 Apr;16(4):347-55. Epub 2014 Mar 20 doi: 10.1038/gim.2014.2. PMID: 24651602
ACMG.
Genet Med 2002 May-Jun;4(3):162-71. doi: 10.1097/00125817-200205000-00011. PMID: 12180152Free PMC Article

Recent clinical studies

Etiology

Li S, Guo M, Ruan B, Liu Y, Cui X, Han W, Li R
Genet Test Mol Biomarkers 2020 May;24(5):249-255. Epub 2020 Apr 3 doi: 10.1089/gtmb.2019.0231. PMID: 32250160
Hart J, Miriyala K
Am J Med Genet A 2017 Sep;173(9):2472-2477. Epub 2017 Jul 7 doi: 10.1002/ajmg.a.38325. PMID: 28686331
Wang J, Li S, Xiao X, Wang P, Guo X, Zhang Q
Mol Vis 2010 Jun 22;16:1146-53. PMID: 20664692Free PMC Article
Madden C, Halsted MJ, Hopkin RJ, Choo DI, Benton C, Greinwald JH Jr
Laryngoscope 2003 Nov;113(11):2035-41. doi: 10.1097/00005537-200311000-00034. PMID: 14603070
Newton V
J Laryngol Otol 1990 Feb;104(2):97-103. doi: 10.1017/s002221510011196x. PMID: 2324631

Diagnosis

Guo M, Li Q, Jiang C, Li S, Ruan B
Int J Pediatr Otorhinolaryngol 2021 Aug;147:110758. Epub 2021 May 11 doi: 10.1016/j.ijporl.2021.110758. PMID: 34038854
Li S, Guo M, Ruan B, Liu Y, Cui X, Han W, Li R
Genet Test Mol Biomarkers 2020 May;24(5):249-255. Epub 2020 Apr 3 doi: 10.1089/gtmb.2019.0231. PMID: 32250160
Choi EY, Choi W, Lee CS
BMC Ophthalmol 2018 Oct 11;18(1):266. doi: 10.1186/s12886-018-0933-9. PMID: 30314436Free PMC Article
Morimoto N, Mutai H, Namba K, Kaneko H, Kosaki R, Matsunaga T
Auris Nasus Larynx 2018 Apr;45(2):222-226. Epub 2017 May 11 doi: 10.1016/j.anl.2017.03.022. PMID: 28502583
Trabelsi M, Nouira M, Maazoul F, Kraoua L, Meddeb R, Ouertani I, Chelly I, Benoit V, Besbes G, Mrad R
Int J Pediatr Otorhinolaryngol 2017 Dec;103:14-19. Epub 2017 Sep 28 doi: 10.1016/j.ijporl.2017.09.029. PMID: 29224756

Therapy

Morell R, Friedman TB, Asher JH Jr, Robbins LG
J Med Genet 1997 Jun;34(6):447-52. doi: 10.1136/jmg.34.6.447. PMID: 9192262Free PMC Article

Prognosis

Cesca F, Bettella E, Polli R, Cama E, Scimemi P, Santarelli R, Murgia A
Int J Pediatr Otorhinolaryngol 2018 Jan;104:88-93. Epub 2017 Oct 31 doi: 10.1016/j.ijporl.2017.10.042. PMID: 29287889
Morimoto N, Mutai H, Namba K, Kaneko H, Kosaki R, Matsunaga T
Auris Nasus Larynx 2018 Apr;45(2):222-226. Epub 2017 May 11 doi: 10.1016/j.anl.2017.03.022. PMID: 28502583
Morell R, Friedman TB, Moeljopawiro S, Hartono, Soewito, Asher JH Jr
Hum Mol Genet 1992 Jul;1(4):243-7. doi: 10.1093/hmg/1.4.243. PMID: 1303193

Clinical prediction guides

Cesca F, Bettella E, Polli R, Cama E, Scimemi P, Santarelli R, Murgia A
Int J Pediatr Otorhinolaryngol 2018 Jan;104:88-93. Epub 2017 Oct 31 doi: 10.1016/j.ijporl.2017.10.042. PMID: 29287889
Morimoto N, Mutai H, Namba K, Kaneko H, Kosaki R, Matsunaga T
Auris Nasus Larynx 2018 Apr;45(2):222-226. Epub 2017 May 11 doi: 10.1016/j.anl.2017.03.022. PMID: 28502583
Trabelsi M, Nouira M, Maazoul F, Kraoua L, Meddeb R, Ouertani I, Chelly I, Benoit V, Besbes G, Mrad R
Int J Pediatr Otorhinolaryngol 2017 Dec;103:14-19. Epub 2017 Sep 28 doi: 10.1016/j.ijporl.2017.09.029. PMID: 29224756
Soejima H, Fujimoto M, Tsukamoto K, Matsumoto N, Yoshiura KI, Fukushima Y, Jinno Y, Niikawa N
Hum Mutat 1997;9(2):177-80. doi: 10.1002/(SICI)1098-1004(1997)9:2<177::AID-HUMU11>3.0.CO;2-#. PMID: 9067759
Morell R, Friedman TB, Moeljopawiro S, Hartono, Soewito, Asher JH Jr
Hum Mol Genet 1992 Jul;1(4):243-7. doi: 10.1093/hmg/1.4.243. PMID: 1303193

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