Waardenburg syndrome

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 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, or dystopia canthorum.<ref name=":132" /> In type 3, which is rare, the arms and hands are also malformed, with 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" />

The syndrome is caused by mutations in any of several genes that affect the division and 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 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 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.

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">Template:Cite journal</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

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">Template:Cite web</ref>

Type 1

Template:Main 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">Template:Cite web</ref>

Type 2

File:Waardenburg Syndrome 1.jpg

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">Template:Cite web</ref><ref name="ghr3">Template:Cite web</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 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">Template:Cite journal</ref>

There have been two known patients identified with mutations in both copies of SNAI2 (classified as type 2D); these individuals presented with Waardenburg syndrome type 2 but did not have hair pigmentation deficiencies.<ref name=":42">Template:Cite web</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, increased muscle tone, white matter anomalies or hypomyelination in the brain, autistic-like behaviour and the underdevelopment or complete absence of many 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">Template:Cite web</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">Template:Cite web</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 bowel dysfunction.<ref name=":23">Template:Cite web</ref><ref name="baral3">Template:Cite journal</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">Template:Cite journal</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">Template:Cite web</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>Template:Cite web</ref><ref>Template:Cite journal</ref>

Cause

File:Neural crest (Horizontal).svg

Formation of the neural crest and neural tube (neurulation), around week 4 of embryonic development

File:GRN Crest.png

A 2004 model of some of the genes involved in regulating neural crest cells, including some involved in Waardenburg syndrome

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.Template:Citation needed

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, lacrimal, pituitary, thymus and thyroid glands, connective tissue of the eye, such as the stroma of the iris and cornea and the trabecular meshwork,<ref>Template:Cite journal</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">Template:Cite web</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>Template:Cite journal</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">Template:Cite web</ref><ref name=":102">Template:Cite journal</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">Template:Cite web</ref><ref name=":112">Template:Cite journal</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>Template:Cite journal</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>Template:Cite journal</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.
  • 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">Template:Cite web</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

Type	OMIM	Gene	Locus	Inheritance
Type 1 (WS1)	Template:OMIM	PAX3	2q36.1<ref name="pmid75459133">Template:Cite journal</ref>	Autosomal dominant
Type 2A (WS2A, originally WS2)	Template:OMIM	MITF	3p14.1–p12.3	Autosomal dominant
Type 2B (WS2B)	Template:OMIM	WS2B	1p21–p13.3	Autosomal dominant
Type 2C (WS2C)	Template:OMIM	WS2C	8p23	Autosomal dominant
Type 2D (WS2D)	Template:OMIM	SNAI2	8q11	Autosomal recessive
Type 2E (WS2E)	Template:OMIM	SOX10	22q13.1	Autosomal dominant
Type 3 (WS3)	Template:OMIM	PAX3	2q36.1	Autosomal dominant or autosomal recessive
Type 4A (WS4A)	Template:OMIM	EDNRB	13q22	Autosomal dominant or autosomal recessive
Type 4B (WS4B)	Template:OMIM	EDN3	20q13	Autosomal dominant or autosomal recessive
Type 4C (WS4C)	Template:OMIM	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.Template:Cn

Epidemiology

The prevalence of all types of Waardenburg syndrome is estimated at 1 in 42,000.<ref name=":3">Template:Cite journal</ref><ref name=":122" /> Types 1 and 2 are by far the most common, with type 1 appearing to be slightly more common.<ref>Template:Cite web</ref><ref>Template:Cite web</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">Template:Cite journal</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 Template:As of.<ref name=":42" /><ref name=":122" /><ref>Template:Cite journal</ref> The number of known cases of type 2E that involved neurological abnormalities was reported to be 23 Template:As of,<ref>Template:Cite journal</ref> while the number of the rest is unknown. Type 3 is rarer than types 1, 2 and 4,<ref>Template:Cite web</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

Template:Multiple image 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">Template:Cite journal</ref> Blepharophimosis describes eyelids which are underdeveloped such that they permanently cover part of the eyes.<ref>Template:Cite web</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">Template:Cite journal</ref><ref name=":0" /> This later led to the synonym Mende syndrome being recorded in some databases.<ref name=":15" /><ref>Template:Cite book</ref>

In 1929, Dutch physician K. T. A. Halbertsma described a familial pattern to dystopia canthorum,<ref>Template:Cite web</ref><ref name=":0" /> and in 1930, Italian physician Vincenzo Gualdi<ref>Template:Cite book</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 (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">Template:Cite journal</ref><ref name="Waardenburg19513" /> The condition he described is now categorised as Waardenburg syndrome type 1.Template:Cn

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>Template:Cite journal</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>Template:Cite journal</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 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">Template:Cite journal</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>Template:Cite journal</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 by Robin Cook mentions a character with the disorder.<ref>Template:Cite book</ref>
• Enzo MacLeod, protagonist of 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>Template:Cite book</ref><ref>Template:Cite book</ref>
• In the 2011 season 6 episode of Bones "The Signs in the Silence", the team must solve a case in which the suspected killer has Waardenburg syndrome.<ref>Template:Cite web</ref>
• The 2013 book Reconstructing Amelia by Kimberly McCreight features several characters with Waardenburg symptoms.<ref>Template:Cite book</ref>
• The 2014 book Closer Than You Think by Karen Rose features three characters, siblings, with Waardenburg syndrome.<ref>Template:Cite book</ref>

Notable people

• Canadian YouTube vlogger Stef Sanjati has Waardenburg syndrome type 1.<ref>Template:Cite news</ref>

Other animals

File:Waardenburg Syndrome 5.jpg

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>Template:Cite journal</ref> Degeneration of the cochlea and saccule, as seen in Waardenburg syndrome, has also been found in deaf white cats, Dalmatians and other dog breeds, white minks and mice.<ref>Template:Cite journal</ref>

Domesticated cats with blue eyes and white coats are often completely deaf.<ref name="pmid208085813">Template:Cite journal</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>Template:Cite book</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>Template:Cite journal</ref> One of the genes that leads to deafness and a white coat in cats when mutated, KIT,<ref>Template:Cite journal</ref> has been found to increase MITF expression.<ref>Template:Cite journal</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>Template:Cite journal</ref>

Ferrets 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">Template:Cite journal</ref>

See also

• Chédiak–Higashi syndrome, a similar syndrome including immunodeficiency and peripheral neuropathy
• 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

External links

• GeneReviews/NCBI/NIH/UW entry on Waardenburg Syndrome Type I
• OMIM Genetic disorder catalog — Waardenburg syndrome
• Yose Mirza, Waardenburg in West Sumatra, Indonesia, 2015 - a webpage within the Atlas of Humanity website, having photos of several Waardenburg syndrome people with various eye pigmentations.