View source for Waardenburg syndrome

{{Short description|Genetic condition involving hearing loss and depigmentation}}
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<!-- Definition and symptoms -->
'''Waardenburg syndrome''' is a group of rare [[genetic conditions]] characterised by at least some degree of congenital hearing loss and pigmentation deficiencies, which can include bright blue eyes (or [[Heterochromia iridum|one blue eye and one brown eye]]), a [[white forelock]] or patches of light skin. These basic features constitute type 2 of the condition; in type 1, there is also a wider gap between the inner corners of the eyes called [[telecanthus|telecanthus, or dystopia canthorum]].<ref name=":132" /> In type 3, which is rare, the arms and hands are also malformed, with [[Camptodactyly|permanent finger contractures]] or [[fused fingers]], while in type 4, the person also has [[Hirschsprung's disease]].<ref name=":62" /><ref name=":23" /> There also exist at least two types (2E and PCWH) that can result in [[central nervous system]] (CNS) symptoms such as developmental delay and [[muscle tone]] abnormalities.<ref name=":52" />

<!-- Cause and diagnosis -->
The syndrome is caused by mutations in any of several genes that affect the [[Cell division|division]] and [[Cell migration|migration]] of [[neural crest cells]] during [[embryonic development]] (though some of the genes involved also affect the [[neural tube]]).<ref name=":3" /> Neural crest cells are [[stem cells]] left over after the [[Neurulation|closing]] of the neural tube that go on to form diverse non-CNS cells in different parts of the body, including [[melanocytes]], various bones and cartilage of the face and [[inner ear]] and the peripheral [[Myenteric plexus|nerves of the intestines]].<ref name=":5" /> Type 1 is caused by a mutation in the ''[[PAX3]]'' gene, while the gene that most often causes type 2 when mutated is ''[[MITF]]''.<ref name=":132" /><ref name=":03" /> Type 3 is a more severe presentation of type 1 and is caused by a mutation in the same gene, while type 4 is most often caused by a mutation in ''[[SOX10]]''.<ref name=":62" /><ref name=":122" /> Mutations in other genes can also cause the different types, and some of these have been given their own lettered subtypes. Most types are [[autosomal dominant]].

<!-- Management and prognosis -->
<!--Epidemiology and history -->The estimated prevalence of Waardenburg syndrome is 1 in 42,000.<ref name=":3" /><ref name=":122" /> Types 1 and 2 are the most common, comprising approximately half and a third of cases, respectively, while type 4 comprises a fifth and type 3 less than 2% of cases.<ref name=":122" /> An estimated 2–5% of congenitally deaf people have Waardenburg syndrome.<ref name=":122" /> Descriptions of the syndrome date back to at least the first half of the 20th century, however it is named after Dutch ophthalmologist and geneticist [[Petrus Johannes Waardenburg]], who described it in 1951.<ref name=":4" /><ref name="Waardenburg19513">{{Cite journal |last=Waardenburg PJ |date=September 1951 |title=A New Syndrome Combining Developmental Anomalies of the Eyelids, Eyebrows and Noseroot with Pigmentary Anomalies of the Iris and Head Hair and with Congenital Deafness; ''Dystopia canthi medialis et punctorum lacrimalium lateroversa, Hyperplasia supercilii medialis et radicis nasi, Heterochromia iridum totalis sive partialis, Albinismus circumscriptus (leucismus, poliosis) et Surditas congenita (surdimutitas)'' |journal=Am. J. Hum. Genet. |volume=3 |issue=3 |pages=195–253 |pmc=1716407 |pmid=14902764}}</ref> Its subtypes were progressively discovered in the following decades and had genes attributed to them mostly in the 1990s and 2000s.

== Signs and symptoms ==
[[File:Waardenburg syndrome type 1.png|thumb|Facial appearance of a boy from China with Waardenburg syndrome type 1]]

Waardenburg syndrome has multiple different types with some variations in symptoms, and symptoms can vary among those with the same type. The two features consistent across all types of Waardenburg syndrome are some degree of congenital [[sensorineural hearing loss]] and some degree of pigmentation deficiencies, most consistently in the eyes.<ref name=":15">{{Cite web |title=Waardenburg syndrome {{!}} Genetic and Rare Diseases Information Center (GARD) – an NCATS Program |url=https://rarediseases.info.nih.gov/diseases/5525/waardenburg-syndrome |access-date=2018-04-17 |website=rarediseases.info.nih.gov |language=en}}</ref>

=== Type 1 ===
{{Main|Waardenburg syndrome type 1}}
Type 1 is characterised by congenital [[sensorineural hearing loss]], pigmentary deficiencies of the hair such as a white lock of hair ([[poliosis]]) in the front-centre of the head or premature greying, pigmentary deficiencies of the eyes such as different-coloured eyes (complete [[heterochromia iridum]]), multiple colours in an eye (sectoral heterochromia iridum) or brilliant blue eyes, patches of skin depigmentation, and a wider gap between the inner corners of the eyes called [[telecanthus]] or dystopia canthorum. Other facial features associated with type 1 can include a high nasal bridge, a flat nose tip, a [[unibrow]] (synophrys), smaller edges of the nostrils (alae) or a smooth [[philtrum]].<ref name=":132">{{Cite web |title=OMIM Entry - # 193500 - WAARDENBURG SYNDROME, TYPE 1; WS1 |url=https://omim.org/entry/193500 |access-date=2019-12-07 |website=omim.org}}</ref>

=== Type 2 ===
[[File:Waardenburg Syndrome 1.jpg|thumb|Woman with Waardenburg syndrome type 2, showing heterochromia and white forelock]]
The difference that defines type 2 from type 1 is that patients do not have the wider gap between the inner corners of the eyes (telecanthus/dystopia canthorum). Sensorineural hearing loss tends to be more common and more severe in this type.<ref name=":03">{{Cite web |title=OMIM Entry - # 193510 - WAARDENBURG SYNDROME, TYPE 2A; WS2A |url=https://omim.org/entry/193510 |access-date=2019-12-07 |website=omim.org}}</ref><ref name="ghr3">{{Cite web |date=October 2012 |title=Waardenburg syndrome |url=https://medlineplus.gov/genetics/condition/waardenburg-syndrome/ |website=Genetics Home Reference}}</ref> By far the most common gene to cause this type when mutated is ''[[MITF]]'' (classified as type 2A). If two individuals with a mutation in this gene ([[heterozygous]]) have a child carrying both mutations ([[homozygous]]), for which there is a 25% chance, additional symptoms are present in the child, such as a hole in the iris ([[coloboma]]), small eyes ([[microphthalmia]]), hardened bones ([[osteopetrosis]]), [[macrocephaly]], [[Albinism in humans|albinism]] and deafness.<ref name=":03" /> One study documented a rare case of a child with combined type 1 and type 2A mutations (''PAX3'' and ''MITF''), from parents having only single mutations in ''MITF'' or ''PAX3''. The child had increased pigment-related symptoms.<ref name="pmid223202383">{{Cite journal |vauthors=Yang T, Li X, Huang Q, Li L, Chai Y, Sun L, Wang X, Zhu Y, Wang Z, Huang Z, Li Y, Wu H |date=January 2013 |title=Double heterozygous mutations of MITF and PAX3 result in Waardenburg syndrome with increased penetrance in pigmentary defects |journal=Clin. Genet. |volume=83 |issue=1 |pages=78–82 |doi=10.1111/j.1399-0004.2012.01853.x |pmid=22320238 |s2cid=34173541 |doi-access=free}}</ref>

There have been two known patients identified with mutations in both copies of ''[[SNAI2]]'' (classified as [[Waardenburg syndrome type 2D|type 2D]]); these individuals presented with Waardenburg syndrome type 2 but did not have hair pigmentation deficiencies.<ref name=":42">{{Cite web |title=OMIM Entry - # 608890 - WAARDENBURG SYNDROME, TYPE 2D; WS2D |url=https://omim.org/entry/608890 |access-date=2019-12-07 |website=omim.org}}</ref>

When Waardenburg syndrome type 2 is caused by a mutation in ''[[SOX10]]'' (classified as type 2E), it can on some occasions present with multiple neurological symptoms. These can include developmental delay, early childhood [[nystagmus]], [[Hypertonia|increased muscle tone]], [[white matter]] anomalies or [[Myelin|hypomyelination]] in the brain, [[autistic]]-like behaviour and the underdevelopment or complete absence of many [[Inner ear|inner-ear]] structures such as the [[vestibular system]] or [[cochlea]]. Lack of a sense of smell ([[anosmia]]) due to a missing [[olfactory bulb]] in the brain may also be present.<ref name=":52">{{Cite web |title=OMIM Entry - # 611584 - WAARDENBURG SYNDROME, TYPE 2E; WS2E |url=https://omim.org/entry/611584 |access-date=2019-12-07 |website=omim.org}}</ref>

=== Type 3 ===
Also known as '''Klein–Waardenburg syndrome''', or Waardenburg–Klein syndrome, type 3 has the same symptoms as type 1 (and is caused by mutations in the same gene) but has additional symptoms that affect the arms and hands. These can include joint [[contractures]] of the fingers ([[camptodactyly]]), due to underdeveloped muscles, as well as fused digits ([[syndactyly]]) or [[winged scapulae]]. Microcephaly and developmental delay are also possible.<ref name=":62">{{Cite web |title=OMIM Entry - # 148820 - WAARDENBURG SYNDROME, TYPE 3; WS3 |url=https://omim.org/entry/148820 |access-date=2019-12-07 |website=omim.org}}</ref>

=== Type 4 ===
Also known as '''Shah–Waardenburg syndrome''', or Waardenburg–Shah syndrome, type 4 has most of the same features as type 2 (i.e. no telecanthus, or apparent wider eye gap), but with the addition of [[Hirschsprung's disease]], which is a congenital lack of nerves in the intestines leading to [[Intestinal pseudo-obstruction|bowel dysfunction]].<ref name=":23">{{Cite web |title=OMIM Entry - # 277580 - WAARDENBURG SYNDROME, TYPE 4A; WS4A |url=https://omim.org/entry/277580 |access-date=2019-12-07 |website=omim.org}}</ref><ref name="baral3">{{Cite journal |vauthors=Baral V, Chaoui A, Watanabe Y, Goossens M, Attie-Bitach T, Marlin S, Pingault V, Bondurand N |date=2012 |title=Screening of MITF and SOX10 regulatory regions in Waardenburg syndrome type 2 |journal=PLOS ONE |volume=7 |issue=7 |article-number=e41927 |bibcode=2012PLoSO...741927B |doi=10.1371/journal.pone.0041927 |pmc=3407046 |pmid=22848661 |doi-access=free}}</ref> Additionally, hearing loss is not as common as in type 2.<ref name=":23" /> Rarely, [[cleft lip]] has been reported in this form of Waardenburg syndrome.<ref name=":72">{{Cite journal |last1=Pierpont |first1=J. W. |last2=St Jacques |first2=D. |last3=Seaver |first3=L. H. |last4=Erickson |first4=R. P. |date=March 1995 |title=A family with unusual Waardenburg syndrome type I (WSI), cleft lip (palate), and Hirschsprung disease is not linked to PAX 3 |journal=Clinical Genetics |volume=47 |issue=3 |pages=139–143 |doi=10.1111/j.1399-0004.1995.tb03946.x |issn=0009-9163 |pmid=7634536 |s2cid=24530898}}</ref>

Type 4 can also be caused by a mutation in ''SOX10'' (the same gene as in type 2E), in which it is known as type 4C; hearing loss is very common and severe in this type.<ref name=":92">{{Cite web |title=OMIM Entry - # 613266 - WAARDENBURG SYNDROME, TYPE 4C; WS4C |url=https://omim.org/entry/613266 |access-date=2019-12-07 |website=omim.org}}</ref>

=== PCWH ===
A mutation in ''SOX10'', the gene involved in type 2E and type 4C, can sometimes result in the symptoms of both types (neurological symptoms, as sometimes seen in type 2E, and Hirschsprung's disease, as seen in type 4). When this happens, it is called peripheral demyelinating neuropathy–central dysmyelinating leukodystrophy–Waardenburg syndrome–Hirschsprung disease (PCWH).<ref>{{Cite web |title=Orphanet: Search a disease |url=https://www.orpha.net/consor/cgi-bin/Disease_Search.php?lng=EN&data_id=17538 |access-date=2019-12-10 |website=www.orpha.net |language=en}}</ref><ref>{{Cite journal |last1=Verheij |first1=Johanna B. G. M. |last2=Sival |first2=Deborah A. |last3=van der Hoeven |first3=Johannes H. |last4=Vos |first4=Yvonne J. |last5=Meiners |first5=Linda C. |last6=Brouwer |first6=Oebele F. |last7=van Essen |first7=Anthonie J. |date=January 2006 |title=Shah-Waardenburg syndrome and PCWH associated with SOX10 mutations: a case report and review of the literature |journal=European Journal of Paediatric Neurology |volume=10 |issue=1 |pages=11–17 |doi=10.1016/j.ejpn.2005.10.004 |issn=1090-3798 |pmid=16504559}}</ref>

== Cause ==
[[File:Neural crest (Horizontal).svg|thumb|Formation of the [[neural crest]] and [[neural tube]] ([[neurulation]]), around week 4 of [[embryonic development]]|391x391px|alt=]]
[[File:GRN Crest.png|thumb|391x391px|A 2004 model of some of the genes involved in regulating neural crest cells, including some involved in Waardenburg syndrome]]
{{Multiple image
| align =
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| total_width = 400
| image1 = Autosomal dominant - en.svg
| alt1 =
| caption1 = Waardenburg syndrome is usually inherited in an autosomal-dominant pattern.
| image2 = Autosomal recessive - en.svg
| caption2 = Types 2D, 3, 4A, and 4B may sometimes have an autosomal-recessive pattern of inheritance.
}}

Waardenburg syndrome is caused by mutations in any of several genes that affect the operation of [[neural crest]] cells in [[embryonic development]]. Most types of Waardenburg syndrome are caused by [[autosomal dominant]] mutations. The few that are autosomal recessive are rare. In most cases, an affected person has inherited it from one parent with one of the dominant forms of the condition. A small percentage of cases result from spontaneous new mutations in the gene, where no family history of the condition exists.{{citation needed|date=September 2021}}

The neural crest is a group of temporary migratory cells that are left over after the [[neural tube]] has closed ([[neurulation]]), around the fourth week of embryonic development. They are responsible for differentiating into a diverse group of cells that reach different areas of the body. The neural tube and neural crest are derived from the [[ectoderm]]; the neural tube goes on to form the brain and [[spinal cord]], while the neural crest cells eventually go on to form various bones and cartilage of the skull and face by migrating through the [[pharyngeal arches]]. They also differentiate into the [[stria vascularis]] of the [[cochlea]], the nerves and [[glia]] of the intestines ([[myenteric plexus]]), [[Schwann cells]], which [[myelinate]] the [[peripheral nervous system]] to allow sufficient conductivity, [[odontoblasts]], which produce [[dentin]] deep in the teeth, some [[neuroendocrine cells]], connective tissue around the [[Salivary gland|salivary]], [[Lacrimal gland|lacrimal]], [[Pituitary gland|pituitary]], [[thymus]] and [[thyroid]] glands, connective tissue of the eye, such as the [[Stroma of iris|stroma of the iris]] and [[Stroma of cornea|cornea]] and the [[trabecular meshwork]],<ref>{{Cite journal |last1=Williams |first1=Antionette L. |last2=Bohnsack |first2=Brenda L. |date=June 2015 |title=Neural Crest Derivatives in Ocular Development: Discerning the Eye of the Storm |journal=Birth Defects Research Part C: Embryo Today: Reviews |volume=105 |issue=2 |pages=87–95 |doi=10.1002/bdrc.21095 |issn=1542-975X |pmc=5262495 |pmid=26043871}}</ref> and [[melanocytes]], including those in the stroma of the iris that give rise to brown eye colour through [[melanin]]. Neural crest cells also have a role in muscle formation, including the wall muscle of certain cardiac arteries.<ref name=":5">{{Cite web |title=Neural Crest Development - Embryology |url=https://embryology.med.unsw.edu.au/embryology/index.php/Neural_Crest_Development |access-date=2019-12-13 |website=embryology.med.unsw.edu.au}}</ref>

=== Causes of subtypes ===
* Type 1 is caused by an autosomal dominant mutation in the gene ''[[PAX3]]''.<ref name=":132" /> PAX3, or [[paired box]] 3, is a [[transcription factor]] that has a role in maintaining an open window of time for certain neural crest cells (such as those of the head and eyes) to divide and migrate before their [[terminal differentiation]] (i.e. to maintain them in the [[stem-cell]] state). Mutations in this gene therefore prematurely arrest their division and migration, resulting in a minor lack of development of certain face cartilage and bones, as well as underdeveloped inner-ear structures and a lack of melanocytes in the iris stroma. Some evidence shows that PAX3 also regulates cells from before the neural crest forms, i.e. the neural tube, since mice with loss-of-function mutations in one of the copies of ''PAX3'' have [[neural tube defects]] such as [[spina bifida]] or [[exencephaly]].<ref name=":3" />
* Type 2 is caused by a mutation in any of a range of genes, the most common being ''MITF'', when it is classed as type 2A.
** Type 2A is caused by an autosomal dominant mutation in the gene ''MITF''.<ref name=":03" /> MITF, or microphthalmia-associated transcription factor, has a more specialised role in the neural crest and is more strictly involved after the neural crest forms (PAX3 and SOX10 have been found to activate ''MITF'').<ref>{{Cite journal |last1=Kawakami |first1=Akinori |last2=Fisher |first2=David E. |date=June 2017 |title=The master role of microphthalmia-associated transcription factor in melanocyte and melanoma biology |journal=Laboratory Investigation; A Journal of Technical Methods and Pathology |volume=97 |issue=6 |pages=649–656 |doi=10.1038/labinvest.2017.9 |issn=1530-0307 |pmid=28263292 |doi-access=free}}</ref> It is known to allow melanocytes, [[osteoclasts]], [[mast cells]] and [[retinal pigment epithelial]] cells to divide and migrate. The involvement in osteoclasts explains why mutations in both copies of ''MITF'' can lead to bone hardening ([[osteopetrosis]]), as the osteoclasts are responsible for breaking down bone. ''MITF'' also activates transcription of [[tyrosinase]], the enzyme that performs the first step in the creation of melanin (oxidising [[tyrosine]]). A mutation in a copy of ''MITF'' can also lead to [[Tietz syndrome]], which is distinguished from Waardenburg syndrome by uniform albinism instead of patchy depigmentation.<ref name=":3" />
** Type 2B is caused by an autosomal dominant mutation in an unknown gene on chromosome 1 in the locus range of 1p21–1p13.3. The gene has been provisionally termed ''[[WS2B]]''.<ref name=":6">{{Cite web |title=OMIM Entry - % 600193 - WAARDENBURG SYNDROME, TYPE 2B; WS2B |url=https://www.omim.org/entry/600193 |access-date=2019-12-23 |website=www.omim.org}}</ref><ref name=":102">{{Cite journal |last1=Lalwani |first1=A. K. |last2=San Agustin |first2=T. B. |last3=Wilcox |first3=E. R. |date=1994-09-01 |title=A locus for Waardenburg syndrome type II maps to chromosome 1p13.3-2.1 |journal=American Journal of Human Genetics |language=en |volume=55 |issue=Suppl.3 |osti=133315}}</ref>
** Type 2C is caused by an autosomal dominant mutation in an unknown gene on chromosome 8 in the locus of 8p23. The gene has been provisionally termed ''[[WS2C]]''.<ref name=":32">{{Cite web |title=OMIM Entry - % 606662 - WAARDENBURG SYNDROME, TYPE 2C; WS2C |url=https://omim.org/entry/606662 |access-date=2019-12-07 |website=omim.org}}</ref><ref name=":112">{{Cite journal |last1=Selicorni |first1=Angelo |last2=Guerneri |first2=Silvana |last3=Ratti |first3=Antonia |last4=Pizzuti |first4=Antonio |date=January 2002 |title=Cytogenetic mapping of a novel locus for type II Waardenburg syndrome |journal=Human Genetics |volume=110 |issue=1 |pages=64–67 |doi=10.1007/s00439-001-0643-9 |issn=0340-6717 |pmid=11810298 |s2cid=24411957}}</ref>
** Type 2D is caused by an autosomal recessive mutation in both copies of the gene ''[[SNAI2]]''. The study that discovered this association found that ''SNAI2'' is activated by ''MITF'' as part of neural crest development, and this explained why mutations in ''MITF'' cause Waardenburg syndrome, as it results in a lack of activation of ''SNAI2''. Mutations in a single copy of ''SNAI2'' have also been found to cause patches of hair depigmentation ([[piebaldism]]) without any other symptoms.<ref>{{Cite journal |last1=Sánchez-Martín |first1=Manuel |last2=Pérez-Losada |first2=Jesús |last3=Rodríguez-García |first3=Arancha |last4=González-Sánchez |first4=Belén |last5=Korf |first5=Bruce R. |last6=Kuster |first6=W. |last7=Moss |first7=Celia |last8=Spritz |first8=Richard A. |last9=Sánchez-García |first9=I. |date=2003 |title=Deletion of the SLUG (SNAI2) gene results in human piebaldism |journal=American Journal of Medical Genetics Part A |language=en |volume=122A |issue=2 |pages=125–132 |doi=10.1002/ajmg.a.20345 |issn=1552-4833 |pmid=12955764 |s2cid=33811699}}</ref>
** Type 2E is caused by an autosomal dominant mutation in the gene ''SOX10''.<ref name=":52" />
** Rarely, a mutation in a gene other than those currently known may be responsible for a Waardenburg syndrome with features of type 2. This is usually initially classified as simply type 2 but may be given its own subtype once a gene or locus is identified and established.<ref name=":03" />
* Type 3 is caused by a mutation in the gene ''[[PAX3]]'', the same gene as in type 1.<ref name=":62" /> It can be inherited in an autosomal dominant or autosomal recessive manner; it is possible for two parents with Waardenburg syndrome type 1 to have a child carrying both mutated copies of the ''PAX3'' gene (25% chance) and present with Waardenburg syndrome type 3. A [[missense mutation]] has been documented to have this effect. However, it is also possible for Waardenburg syndrome type 3 to present spontaneously with just one mutated copy of ''PAX3''. A deletion of the [[paired domain]] region of the gene has been documented to have this effect.<ref>{{Cite journal |last1=Tekin |first1=M. |last2=Bodurtha |first2=J. N. |last3=Nance |first3=W. E. |last4=Pandya |first4=A. |date=2001 |title=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? |journal=Clinical Genetics |language=en |volume=60 |issue=4 |pages=301–304 |doi=10.1034/j.1399-0004.2001.600408.x |issn=1399-0004 |pmid=11683776 |s2cid=24025063}}</ref><ref name=":3" /> However, no major correlation has been found between type of mutation and disease severity. Severity tends to be dictated by mutations in other genes ([[epistasis]]), as evidenced by distinct familial patterns in severity not tied to Waardenburg mutation type.<ref name=":3" /> Mutations in both copies of ''PAX3'' have sometimes led to death before or shortly after birth, and mice with loss-of-function mutations in both copies of the gene do not survive.<ref name=":3" />
* Type 4 is caused by a mutation in any of a range of genes, the most common being ''SOX10'', when it is classed as type 4C.
** [[Waardenburg syndrome type 4A|Type 4A]] is caused by an autosomal dominant or autosomal-recessive mutation in the gene ''[[EDNRB]]''.<ref name=":72" />
** Type 4B is caused by an autosomal dominant or autosomal-recessive mutation in the gene ''[[EDN3]]''.<ref name=":82">{{Cite web |title=OMIM Entry - # 613265 - WAARDENBURG SYNDROME, TYPE 4B; WS4B |url=https://omim.org/entry/613265 |access-date=2019-12-07 |website=omim.org}}</ref>
** Type 4C is caused by an autosomal dominant or autosomal-recessive mutation in the gene ''SOX10'', the same gene as in type 2E.<ref name=":92" />

=== Classification table ===
{| class="wikitable"
!Type
![[OMIM]]
!Gene
![[Locus (genetics)|Locus]]
!Inheritance
|-
|Type 1 (WS1)
|{{OMIM|193500||none}}
|''[[PAX3]]''
|2q36.1<ref name="pmid75459133">{{Cite journal |vauthors=Tsukamoto K, Nakamura Y, Niikawa N |date=March 1994 |title=Isolation of two isoforms of the PAX3 gene transcripts and their tissue-specific alternative expression in human adult tissues |journal=Hum. Genet. |volume=93 |issue=3 |pages=270–4 |doi=10.1007/bf00212021 |pmid=7545913 |s2cid=36749688}}</ref>
|Autosomal dominant
|-
|Type 2A (WS2A, originally WS2)
|{{OMIM|193510||none}}
|''[[Microphthalmia-associated transcription factor|MITF]]''
|3p14.1–p12.3
|Autosomal dominant
|-
|Type 2B (WS2B)
|{{OMIM|600193||none}}
|''[[WS2B]]''
|1p21–p13.3
|Autosomal dominant
|-
|Type 2C (WS2C)
|{{OMIM|606662||none}}
|''[[WS2C]]''
|8p23
|Autosomal dominant
|-
|Type 2D (WS2D)
|{{OMIM|608890||none}}
|''[[SNAI2]]''
|8q11
|Autosomal recessive
|-
|Type 2E (WS2E)
|{{OMIM|611584||none}}
|''[[SOX10]]''
|22q13.1
|Autosomal dominant
|-
|Type 3 (WS3)
|{{OMIM|148820||none}}
|''[[PAX3]]''
|2q36.1
|Autosomal dominant or autosomal recessive
|-
|Type 4A (WS4A)
|{{OMIM|277580||none}}
|''[[EDNRB]]''
|13q22
|Autosomal dominant or autosomal recessive
|-
|Type 4B (WS4B)
|{{OMIM|613265||none}}
|''[[EDN3]]''
|20q13
|Autosomal dominant or autosomal recessive
|-
|Type 4C (WS4C)
|{{OMIM|613266||none}}
|''[[SOX10]]''
|22q13.1
|Autosomal dominant
|}

== Treatment ==
There is currently no treatment or cure for Waardenburg syndrome. The symptom most likely to be of practical importance is deafness, and this is treated as any other irreversible deafness would be. In marked cases, there may be cosmetic issues. Other abnormalities (neurological, structural, Hirschsprung's disease) associated with the syndrome are treated symptomatically.{{cn|date=November 2024}}

== Epidemiology ==
The prevalence of all types of Waardenburg syndrome is estimated at 1 in 42,000.<ref name=":3">{{Cite journal |last1=Pingault |first1=Véronique |last2=Ente |first2=Dorothée |last3=Moal |first3=Florence Dastot-Le |last4=Goossens |first4=Michel |last5=Marlin |first5=Sandrine |last6=Bondurand |first6=Nadège |date=2010 |title=Review and update of mutations causing Waardenburg syndrome |journal=Human Mutation |language=en |volume=31 |issue=4 |pages=391–406 |doi=10.1002/humu.21211 |issn=1098-1004 |pmid=20127975 |s2cid=12278025 |doi-access=free}}</ref><ref name=":122" /> Types 1 and 2 are by far the most common, with type 1 appearing to be slightly more common.<ref>{{Cite web |title=Orphanet: Waardenburg syndrome type 1 |url=https://www.orpha.net/consor/cgi-bin/OC_Exp.php?Lng=EN&Expert=894 |access-date=2019-12-10 |website=www.orpha.net |language=en}}</ref><ref>{{Cite web |date=2005 |title=Waardenburg syndrome type II |url=https://www.orpha.net/data/patho/GB/uk-WS2(05).pdf |archive-url=https://web.archive.org/web/20210424161849/https://www.orpha.net/data/patho/GB/uk-WS2(05).pdf |archive-date=24 April 2021 |access-date=10 December 2019 |website=Orphanet}}</ref> In a 2015 review looking at 417 patients, type 1 was found to be the most common type, encompassing around half of all cases (47%), while type 2 was the second-most common type, encompassing around a third (33%).<ref name=":122">{{Cite journal |last1=Song |first1=J. |last2=Feng |first2=Y. |last3=Acke |first3=F. R. |last4=Coucke |first4=P. |last5=Vleminckx |first5=K. |last6=Dhooge |first6=I. J. |date=2016 |title=Hearing loss in Waardenburg syndrome: a systematic review |journal=Clinical Genetics |language=en |volume=89 |issue=4 |pages=416–425 |doi=10.1111/cge.12631 |issn=1399-0004 |pmid=26100139 |s2cid=23834634}}</ref> The vast majority (around 85%) of type 2 cases are type 2A.<ref name=":122" /> The prevalence of type 2B is unknown, as it was only reported in one 1996 study.<ref name=":102" /> Type 2C has so far only been found in one Italian family,<ref name=":32" /><ref name=":112" /> and type 2D had only been found in 2 unrelated patients {{As of|2018||df=|lc=y}}.<ref name=":42" /><ref name=":122" /><ref>{{Cite journal |last=Saleem |first=Mohammed D. |date=2019 |title=Biology of human melanocyte development, Piebaldism, and Waardenburg syndrome |journal=Pediatric Dermatology |language=en |volume=36 |issue=1 |pages=72–84 |doi=10.1111/pde.13713 |issn=1525-1470 |pmid=30561083}}</ref> The number of known cases of type 2E that involved neurological abnormalities was reported to be 23 {{As of|2017||df=|lc=y}},<ref>{{Cite journal |last1=Bogdanova-Mihaylova |first1=Petya |last2=Alexander |first2=Michael D. |last3=Murphy |first3=Raymond P. J. |last4=Murphy |first4=Sinéad M. |date=2017 |title=Waardenburg syndrome: a rare cause of inherited neuropathy due to SOX10 mutation |journal=Journal of the Peripheral Nervous System |language=en |volume=22 |issue=3 |pages=219–223 |doi=10.1111/jns.12221 |issn=1529-8027 |pmid=28544110 |s2cid=13676694}}</ref> while the number of the rest is unknown. Type 3 is rarer than types 1, 2 and 4,<ref>{{Cite web |title=Orphanet: Waardenburg syndrome type 3 |url=https://www.orpha.net/consor/cgi-bin/OC_Exp.php?Lng=EN&Expert=896 |access-date=2019-12-10 |website=www.orpha.net |language=en}}</ref> comprising less than 2% of cases.<ref name=":122" /> Type 4 appears to encompass around a fifth of cases (19%). Of its subtypes, type 4C is by far the most common (about 71% of type 4), followed by type 4A (19%) and type 4B (10%).<ref name=":122" />

It is estimated that Waardenburg syndrome is present in 2–5% of congenitally deaf people. Congenital deafness comprises around half of deafness as a whole.<ref name=":122" /> About 1 in 30 students in schools for the deaf have Waardenburg syndrome. The variable presentation of the syndrome makes it difficult to arrive at precise figures for its prevalence.<ref name=":122" />

== History ==

=== Early descriptions ===
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| footer = [[Facies (medical)|Facial features]] of Waardenburg syndrome type 1 (from [[Jan van der Hoeve|Jan van der Hoeve's]] description, 1916)
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In 1916, Dutch ophthalmologist [[Jan van der Hoeve]] (1878–1952) described a pair of twin girls with deafness and a particular type of [[blepharophimosis]], believed to be the dystopia canthorum found in Waardenburg syndrome types 1 and 3.<ref name=":122" /><ref name=":0">{{Cite journal |last1=De Haas |first1=E. B. H. |last2=Tan |first2=K. E. W. P. |date=1966-01-01 |title=Waardenburg's syndrome |journal=Documenta Ophthalmologica |language=en |volume=21 |issue=1 |pages=239–282 |doi=10.1007/BF00184136 |issn=1573-2622 |s2cid=10163905 |quote=Waardenburg (1951, 1957, 1961) has expressed the belief that all these cases of uncomplicated blepharophimosis do in fact belong to his syndrome and that this type of dystopia canthorum does not occur as a separate trait. ... With regard to Mende's cases, [Waardenburg] believes that the 'mongoloid component' in these patients was in actuality due to dystopia canthorum.}}</ref> Blepharophimosis describes eyelids which are underdeveloped such that they permanently cover part of the eyes.<ref>{{Cite web |title=Blepharophimosis, ptosis, and epicanthus inversus syndrome (Concept Id: C0220663) - MedGen - NCBI |url=https://www.ncbi.nlm.nih.gov/medgen/66312 |access-date=2025-08-23 |website=www.ncbi.nlm.nih.gov |language=en}}</ref>

In 1926, German physician Irmgard Mende described a family of four generations in which five children had symptoms of depigmentation of hair, skin and eyes, deafness and a "[[mongoloid]]" appearance. (Waardenburg later attributed this description to the dystopia canthorum.)<ref name=":1">{{Cite journal |last=Klein |first=D. |date=February 1983 |title=Historical background and evidence for dominant inheritance of the Klein-Waardenburg syndrome (type III) |journal=American Journal of Medical Genetics |volume=14 |issue=2 |pages=231–239 |doi=10.1002/ajmg.1320140205 |issn=0148-7299 |pmid=6340503}}</ref><ref name=":0" /> This later led to the synonym Mende syndrome being recorded in some databases.<ref name=":15" /><ref>{{Cite book |last=Stedman |first=Thomas Lathrop |url=https://books.google.com/books?id=isqcnR6ryz0C&pg=PA474 |title=Stedman's Medical Eponyms |date=2005 |publisher=Lippincott Williams & Wilkins |isbn=978-0-7817-5443-9 |language=en}}</ref>

In 1929, Dutch physician K. T. A. [[Halbertsma]] described a familial pattern to dystopia canthorum,<ref>{{Cite web |date=2009-12-02 |title=Over twee op elkaar gelijkende, in wezen echter verschillende aangeboren oogafwijkingen |url=https://www.ntvg.nl/artikelen/over-twee-op-elkaar-gelijkende-wezen-echter-verschillende-aangeboren-oogafwijkingen |access-date=2019-12-10 |website=Nederlands Tijdschrift voor Geneeskunde |language=nl}}</ref><ref name=":0" /> and in 1930, Italian physician Vincenzo Gualdi<ref>{{Cite book |url=https://books.google.com/books?id=niGVVFNDkzkC&pg=PA142 |title=Annuario del Ministero dell'Educazione nazionale |date=1935 |publisher=Provveditorato generale dello Stato |page=142 |language=it}}</ref> (1891–1976) also confirmed a hereditary pattern to dystopia canthorum.<ref name=":1" /> This later led to the synonym Van der Hoeve–Halbertsma–Waardenburg–Gualdi syndrome being recorded in some databases.<ref name=":15" />

In 1947, Swiss ophthalmologist [[David Klein (ophthalmologist)|David Klein]] (1908–1993) first reported a patient with bilateral deafness, pigmentation deficiencies, characteristic facial features and malformation of the arms. Although this was the first full description of a patient with Waardenburg syndrome type 3, contemporary clinicians did not consider the syndrome he described to be the same as that described by Waardenburg four years later, in part due to how severe the arm malformations were in his patient.<ref name=":2" />

The syndrome was first fully formalised and described by Dutch ophthalmologist and geneticist [[Petrus Johannes Waardenburg]] (1886–1979) in 1951.<ref name=":4">{{Cite journal |last=Chandra Mohan |first=Setty. L. N. |date=2018-09-01 |title=Case of Waardenburg Shah syndrome in a family with review of literature |journal=Journal of Otology |volume=13 |issue=3 |pages=105–110 |doi=10.1016/j.joto.2018.05.005 |issn=1672-2930 |pmc=6291636 |pmid=30559775 |doi-access=free}}</ref><ref name="Waardenburg19513" /> The condition he described is now categorised as Waardenburg syndrome type 1.{{cn|date=November 2024}}

=== Descriptions of subtypes ===
Type 2 was first established in 1971 when a study noticed that some Waardenburg syndrome patients did not have dystopia canthorum.<ref name=":03" /><ref>{{Cite journal |last=Arias |first=S. |date=March 1971 |title=Genetic heterogeneity in the Waardenburg syndrome |journal=Birth Defects Original Article Series |volume=07 |issue=4 |pages=87–101 |issn=0547-6844 |pmid=5006208}}</ref> A 1977 study confirmed a familial pattern to this other presentation.<ref name=":03" /> Two 1994 studies first confirmed a link between this type of Waardenburg syndrome and mutations in the ''MITF'' gene (now classed as type 2A), located on chromosome 3 at locus 3p14.1–p12.3.<ref name=":03" />

Type 2B was first established in 1994 when the same study which found mutations in ''MITF'' in patients with Waardenburg syndrome type 2 also found that some patients did not have any mutations in this region.<ref name=":6" /><ref>{{Cite journal |last1=Hughes |first1=A. E. |last2=Newton |first2=V. E. |last3=Liu |first3=X. Z. |last4=Read |first4=A. P. |date=August 1994 |title=A gene for Waardenburg syndrome type 2 maps close to the human homologue of the microphthalmia gene at chromosome 3p12-p14.1 |journal=Nature Genetics |volume=7 |issue=4 |pages=509–512 |doi=10.1038/ng0894-509 |issn=1061-4036 |pmid=7951321 |s2cid=2913481}}</ref> A second 1994 study found a link to chromosome 1 in the locus 1p21–p13.3. This became known as type 2B of the condition (with the gene designated ''[[WS2B]]''), however it has not been documented since, and the gene responsible remains unknown.<ref name=":6" /><ref name=":102" />

Type 2C was established in 2001 when a study of an Italian family with Waardenburg syndrome type 2 features found that they were due to an unknown gene on chromosome 8 at locus 8q23 that had been broken by a [[chromosomal translocation]]. The study established a provisional name for the gene, ''WS2C''. However, mutations in this region in Waardenburg syndrome patients have not been found since.<ref name=":32" /><ref name=":112" />

Type 2D was established in 2002 when a study looking to find mutations in the human version of the ''SNAI2'' gene, known to cause depigmentation in mice, found deletions of both copies of this gene in two unrelated individuals with Waardenburg syndrome type 2. Mutations in both copies of this gene have not been found in those with Waardenburg syndrome type 2 since.<ref name=":122" />

Type 2E was first established in 1996 when a study identified a girl with symptoms of Waardenburg syndrome type 2 but with additional underdevelopment of the [[Anterior segment of eyeball|front of the eye]], leading to blindness. In 1999, it was found that she had a mutation in her ''SOX10'' gene, and later studies confirmed the association between mutations in this gene and this phenotype, as well as neurological symptoms such as developmental delay.<ref name=":52" />

Type 3 was first given its name by Goodman ''et al.'' in 1981, in collaboration with Klein, in which they established the association with arm abnormalities first reported by Klein in 1947.<ref name=":2">{{Cite journal |last1=Goodman |first1=R. M. |last2=Lewithal |first2=I. |last3=Solomon |first3=A. |last4=Klein |first4=D. |date=April 1982 |title=Upper limb involvement in the Klein-Waardenburg syndrome |journal=American Journal of Medical Genetics |volume=11 |issue=4 |pages=425–433 |doi=10.1002/ajmg.1320110407 |issn=0148-7299 |pmid=7091186}}</ref> Mutations in ''PAX3'' were first linked to this phenotype in 1992.<ref name=":62" />

The comorbidity with Hirschsprung's disease, which would later constitute type 4, was first noticed in various studies in the 1970s. Indian paediatrician Krishnakumar Shah and his associates first outlined the syndrome as a possible variant of Waardenburg syndrome in 1981.<ref>{{Cite journal |last1=Shah |first1=Krishnakumar N. |last2=Dalal |first2=Subhash J. |last3=Desai |first3=Meena P. |last4=Sheth |first4=Prem N. |last5=Joshi |first5=Nana C. |last6=Ambani |first6=Lalit M. |date=1981-09-01 |title=White forelock, pigmentary disorder of irides, and long segment Hirschsprung disease: Possible variant of Waardenburg syndrome |journal=The Journal of Pediatrics |volume=99 |issue=3 |pages=432–435 |doi=10.1016/S0022-3476(81)80339-3 |issn=0022-3476 |pmid=7264803}}</ref> The variant was first attributed to a mutation in ''EDNRB'' in 1994 (now classed as type 4A).<ref name=":23" /> Type 4B was established in 1996 when mutations in ''EDN3'' were found to lead to this type of Waardenburg syndrome,<ref name=":82" /> and type 4C was first established in 1998 when mutations in ''SOX10'' were also found to lead to this type.<ref name=":92" />

==Society and culture==
=== Popular culture ===
* The 2001 novel ''[[Shock (novel)|Shock]]'' by [[Robin Cook (American novelist)|Robin Cook]] mentions a character with the disorder.<ref>{{Cite book |last=Cook |first=Robin |url=https://books.google.com/books?id=H392sxCjazIC&pg=PT175 |title=Shock |date=2011-12-12 |publisher=Pan Macmillan |isbn=978-1-4472-1796-1 |page=175 |language=en}}</ref>
* Enzo MacLeod, protagonist of [[Peter May (writer)|Peter May]]'s 2006–2017 book series ''[[The Enzo Files]]'', has Waardenburg syndrome. His eyes are different colors, and he has a white streak in his hair.<ref>{{Cite book |last=May |first=Peter |url=https://books.google.com/books?id=BiZhBQAAQBAJ&pg=PT32 |title=Extraordinary People: Enzo Macleod 1 |date=2013-05-30 |publisher=Quercus |isbn=978-1-78206-885-3 |page=32 |language=en}}</ref><ref>{{Cite book |last=May |first=Peter |url=https://books.google.com/books?id=uSRhBQAAQBAJ&pg=PT76 |title=Blacklight Blue: Enzo Macleod 3 |date=2013-06-13 |publisher=Quercus |isbn=978-1-78206-887-7 |page=76 |language=en}}</ref>
* In the 2011 [[Bones (season 6)|season 6]] episode of [[Bones (TV Series)|''Bones'']] "The Signs in the Silence", the team must solve a case in which the suspected killer has Waardenburg syndrome.<ref>{{Cite web |title=Bones Recap 6.21 "The Signs in the Silence" – Persephone Magazine |url=http://persephonemagazine.com/2011/05/bones-recap-6-21-the-signs-in-the-silence/ |archive-url=https://web.archive.org/web/20111011133207/http://persephonemagazine.com/2011/05/bones-recap-6-21-the-signs-in-the-silence/ |archive-date=2011-10-11 |access-date=2019-12-14 |language=en-US}}</ref>
* The 2013 book ''[[Reconstructing Amelia]]'' by [[Kimberly McCreight]] features several characters with Waardenburg symptoms.<ref>{{Cite book |last=McCreight |first=Kimberly |url=https://books.google.com/books?id=TsWVmdozoGkC&q=waardenburg |title=Reconstructing Amelia |date=2013-04-01 |publisher=Simon and Schuster |isbn=978-1-4711-2944-5 |language=en}}</ref>
* The 2014 book ''Closer Than You Think'' by [[Karen Rose]] features three characters, siblings, with Waardenburg syndrome.<ref>{{Cite book |last=Rose |first=Karen |url=https://books.google.com/books?id=oqqnAwAAQBAJ&q=waardenburg |title=Closer Than You Think (The Cincinnati Series Book 1) |date=2014-11-06 |publisher=Headline |isbn=978-0-7553-8999-5 |language=en}}</ref>

=== Notable people ===
* Canadian YouTube vlogger [[Stef Sanjati]] has Waardenburg syndrome type 1.<ref>{{Cite news |last=Edwards |first=Lucy |date=2018 |title='I get you're transgender, but what's up with your face?' |url=https://www.bbc.com/news/disability-42751434 |access-date=2018-01-28 |work=BBC News |language=en-GB}}</ref>

== Other animals ==
{{for|further details of other animals|Deaf white cat|Dalmatian (dog)#Deafness|Lethal white syndrome|Ferret health#Congenital sensorineural deafness}}
[[File:Waardenburg Syndrome 5.jpg|thumb|Cat with Waardenburg syndrome]]
Waardenburg syndrome type 2A (with a mutation in ''MITF'') has been found in dogs, [[Fleckvieh cattle]], [[minks]], mice and a [[golden hamster]].<ref>{{Cite journal |last1=MARKAKIS |first1=MARIOS N. |last2=SOEDRING |first2=VIBEKE E. |last3=DANTZER |first3=VIBEKE |last4=CHRISTENSEN |first4=KNUD |last5=ANISTOROAEI |first5=RAZVAN |date=2014-08-01 |title=Association of MITF gene with hearing and pigmentation phenotype in Hedlund white American mink (Neovison vison) |journal=Journal of Genetics |language=en |volume=93 |issue=2 |pages=477–481 |doi=10.1007/s12041-014-0370-3 |issn=0973-7731 |pmid=25189243 |s2cid=16725018 |hdl-access=free |hdl=10067/1211550151162165141}}</ref> Degeneration of the cochlea and [[saccule]], as seen in Waardenburg syndrome, has also been found in deaf white cats, [[Dalmatian (dog)#Deafness|Dalmatians]] and other dog breeds, white minks and mice.<ref>{{Cite journal |last=Strain |first=George M. |date=2015 |title=The Genetics of Deafness in Domestic Animals |journal=Frontiers in Veterinary Science |language=en |volume=2 |page=29 |doi=10.3389/fvets.2015.00029 |issn=2297-1769 |pmc=4672198 |pmid=26664958 |doi-access=free}}</ref>

[[Deaf white cat|Domesticated cats with blue eyes and white coats]] are often completely deaf.<ref name="pmid208085813">{{Cite journal |vauthors=Webb AA, Cullen CL |date=June 2010 |title=Coat color and coat color pattern-related neurologic and neuro-ophthalmic diseases |journal=Can. Vet. J. |volume=51 |issue=6 |pages=653–7 |pmc=2871368 |pmid=20808581}}</ref> Deafness is far more common in white cats than in those with other coat colors. According to the [[ASPCA]] ''Complete Guide to Cats'', "17 to 20 percent of white cats with non-blue eyes are deaf; 40 percent of "odd-eyed" white cats with one blue eye are deaf; and 65 to 85 percent of blue-eyed white cats are deaf."<ref>{{Cite book |last=Richards J |url=https://books.google.com/books?id=7JCTRdg68tIC&pg=PA71 |title=ASPCA Complete Guide to Cats: Everything You Need to Know About Choosing and Caring for Your Pet |publisher=Chronicle Books |year=1999 |isbn=978-0-8118-1929-9 |page=71}}</ref> Although few studies have been done to link this to genes known to be involved in human Waardenburg syndrome, a genetic disruption to neural crest development would lead to this presentation in cats as well.<ref>{{Cite journal |last1=Omenn |first1=Gilbert S. |last2=McKusick |first2=Victor A. |last3=Gorlin |first3=Robert J. |date=1979 |title=The association of Waardenburg syndrome and Hirschsprung megacolon |journal=American Journal of Medical Genetics |language=en |volume=3 |issue=3 |pages=217–223 |doi=10.1002/ajmg.1320030302 |issn=1096-8628 |pmid=484594 |quote=The deaf, blue-eyed, white cat, noted by Bree [1829] and by Darwin [1892] and studied histologically at the turn of the century [Alexander, 1900], has a variable clinical and histologic picture, due to either of two autosomal dominant genes ... These pleiotropic effects of single genes may be explained by effects on the neural crest cells involved in the origin of all the tissues affected in Waardenburg syndrome [Weston, 1969].}}</ref> One of the genes that leads to deafness and a white coat in cats when mutated, ''[[KIT (gene)|KIT]]'',<ref>{{Cite journal |last1=David |first1=Victor A. |last2=Menotti-Raymond |first2=Marilyn |last3=Wallace |first3=Andrea Coots |last4=Roelke |first4=Melody |last5=Kehler |first5=James |last6=Leighty |first6=Robert |last7=Eizirik |first7=Eduardo |last8=Hannah |first8=Steven S. |last9=Nelson |first9=George |last10=Schäffer |first10=Alejandro A. |last11=Connelly |first11=Catherine J. |date=2014-10-01 |title=Endogenous Retrovirus Insertion in the KIT Oncogene Determines White and White spotting in Domestic Cats |journal=G3: Genes, Genomes, Genetics |language=en |volume=4 |issue=10 |pages=1881–1891 |doi=10.1534/g3.114.013425 |issn=2160-1836 |pmc=4199695 |pmid=25085922}}</ref> has been found to increase ''MITF'' expression.<ref>{{Cite journal |last1=Lee |first1=Youl-Nam |last2=Brandal |first2=Stephanie |last3=Noel |first3=Pierre |last4=Wentzel |first4=Erik |last5=Mendell |first5=Joshua T. |last6=McDevitt |first6=Michael A. |last7=Kapur |first7=Reuben |last8=Carter |first8=Melody |last9=Metcalfe |first9=Dean D. |last10=Takemoto |first10=Clifford M. |date=2011-03-31 |title=KIT signaling regulates MITF expression through miRNAs in normal and malignant mast cell proliferation |journal=Blood |volume=117 |issue=13 |pages=3629–3640 |doi=10.1182/blood-2010-07-293548 |issn=0006-4971 |pmc=3072881 |pmid=21273305}}</ref>

[[Lethal white syndrome]] is a syndrome in horses caused by mutations in both copies of ''EDNRB''. It leads to death from intestinal pseudo-obstruction due to Hirschsprung's disease. A mutation in a single copy of ''EDNRB'', however, as in Waardenburg syndrome type 4A, produces the patchy white [[overo]] coat with deafness.<ref>{{Cite journal |last1=Magdesian |first1=K. Gary |last2=Williams |first2=D. Colette |last3=Aleman |first3=Monica |last4=LeCouteur |first4=Richard A. |last5=Madigan |first5=John E. |date=2009-11-15 |title=Evaluation of deafness in American Paint Horses by phenotype, brainstem auditory-evoked responses, and endothelin receptor B genotype |journal=Journal of the American Veterinary Medical Association |volume=235 |issue=10 |pages=1204–1211 |doi=10.2460/javma.235.10.1204 |issn=0003-1488 |pmid=19912043 |doi-access=free}}</ref>

[[Ferret]]s with Waardenburg syndrome have a small white stripe along the top or back of the head and sometimes down the back of the neck (known as a "blaze" coat pattern), or a solid-white head from nose to shoulders (known as a "panda" coat pattern). Affected ferrets often have a very slightly flatter skull and wider-set eyes than healthy ferrets. As healthy ferrets have poor hearing, deafness may only be detected by lack of reaction to loud noises. As this is an inherited disorder, affected animals should not be used for breeding. A study of the correlation between coat variations and deafness in European ferrets found, "All (n=27) panda, American panda, and blaze ferrets were deaf."<ref name="pmid247391143">{{Cite journal |vauthors=Piazza S, Abitbol M, Gnirs K, Huynh M, Cauzinille L |date=May 2014 |title=Prevalence of deafness and association with coat variations in client-owned ferrets |journal=J. Am. Vet. Med. Assoc. |volume=244 |issue=9 |pages=1047–52 |doi=10.2460/javma.244.9.1047 |pmid=24739114 |doi-access=free}}</ref>

== See also ==
* [[Chédiak–Higashi syndrome]], a similar syndrome including immunodeficiency and peripheral neuropathy
<!-- *[[Lethal white syndrome]], a lethal form of Waardenburg syndrome type 4A in horses (caused by mutations in both copies of ''EDNRB'') -->
* [[Tietz syndrome]], a condition similar to Waardenburg syndrome type 2 involving uniform albinism (caused by mutations in ''MITF'')
* [[Vogt–Koyanagi–Harada disease]], an autoimmune disease causing uveitis, patchy depigmentation and inner ear symptoms

== References ==
{{Reflist}}

== External links ==
* [https://www.ncbi.nlm.nih.gov/books/NBK1531/ GeneReviews/NCBI/NIH/UW entry on Waardenburg Syndrome Type I]
* [https://medlineplus.gov/genetics/condition/waardenburg-syndrome/ OMIM Genetic disorder catalog] — Waardenburg syndrome<!--For all types.--><!--For the varieties with pigementary effects; this is not a redundant category in this case!-->
* Yose Mirza, [https://www.atlasofhumanity.org/waardenburg Waardenburg in West Sumatra, Indonesia], 2015 - a webpage within the ''[https://www.atlasofhumanity.org/ Atlas of Humanity]'' website, having photos of several Waardenburg syndrome people with various eye pigmentations.

{{Amino acid metabolic pathology}}{{Pigmentation disorders}}{{Transcription factor deficiencies}}{{Cell surface receptor deficiencies}}{{Extracellular ligand disorders}}
{{Medical resources|DiseasesDB=14021|ICD10={{ICD10|E|70|3|e|70}} ([[ILDS]] E70.32)|ICD9={{ICD9|270.2}}|ICDO=|OMIM=|OMIM_mult=|MedlinePlus=001428|eMedicineSubj=ped|eMedicineTopic=2422|eMedicine_mult={{eMedicine2|derm|690}}|MeshID=D014849}}
{{Authority control}}

[[Category:Amino acid metabolism disorders]]
[[Category:Transcription factor deficiencies]]
[[Category:Disturbances of human pigmentation]]
[[Category:Syndromes affecting hearing]]
[[Category:Syndromes in mammals]]