in severity not tied to waardenburg mutation type. 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. 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. type 4b is caused by an autosomal dominant or autosomal-recessive mutation in the gene edn3. type 4c is caused by an autosomal dominant or autosomal-recessive mutation in the gene sox10, the same gene as in type 2e. a study was done on a rare case of a double heterozygous child with each parent having only single mutations in mitf or pax3. the effect of double heterozygous mutations in the genes mitf and pax3 in ws1 and ws2 can increase the pigment-affected symptoms. it leads to the conclusion that the double mutation of mitf is associated with the extremity of waardenburg syndrome and may affect the phenotypes or symptoms of the syndrome. classification table type omim gene locus inheritance type 1 (ws1) 193500 pax3 2q36.1 autosomal dominant type 2a (ws2a, originally ws2) 193510 mitf 3p14.1–p12.3 autosomal dominant type 2b (ws2b) 600193 ws2b 1p21–p13.3 autosomal dominant type 2c (ws2c) 606662 ws2c 8p23 autosomal dominant type 2d (ws2d) 608890 snai2 8q11 autosomal recessive type 2e (ws2e) 611584 sox10 22q13.1 autosomal dominant type 3 (ws3) 148820 pax3 2q36.1 autosomal dominant or autosomal recessive type 4a (ws4a) 277580 ednrb 13q22 autosomal dominant or autosomal recessive type 4b (ws4b) 613265 edn3 20q13 autosomal dominant or autosomal recessive type 4c (ws4c) 613266 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. epidemiology the prevalence of all types of waardenburg syndrome is estimated at around 1 in 42,000. types 1 and 2 are by far the most common, with type 1 appearing to be slightly more common. 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%). the vast majority (around 85%) of type 2 cases are type 2a. the prevalence of type 2b is unknown, as it was only reported in one 1996 study. type 2c has so far only been found in one italian family, and type 2d had only been found in 2 unrelated patients as of 2018. the number of known cases of type 2e that involved neurological abnormalities was reported to be 23 as of 2017, while the number of the rest is unknown. type 3 is rarer than types 1, 2 and 4, comprising less than 2% of cases. 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%). 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. 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. history early descriptions 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. blepharophimosis describes eyelids which are underdeveloped such that they permanently cover part of the eyes. 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.) this later led to the synonym mende syndrome being recorded in some databases. in 1929, dutch physician k. t. a. halbertsma described a familial pattern to dystopia canthorum, and in 1930, italian physician vincenzo gualdi (1891–1976) also confirmed a hereditary pattern to dystopia canthorum. this later led to the synonym van der hoeve–halbertsma–waardenburg–gualdi syndrome being recorded in some databases. 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. the syndrome was first fully formalised and described by dutch ophthalmologist and geneticist petrus johannes waardenburg (1886–1979) in 1951. the condition he described is now categorised as waardenburg syndrome type 1. descriptions of subtypes type 2 was first established in 1971 when a study noticed that some waardenburg syndrome patients did not have dystopia canthorum. a 1977 study confirmed a familial pattern to this other presentation. 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. 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. 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. 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. 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. 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. 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. mutations in pax3 were first linked to this phenotype in 1992. 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. the variant was first attributed to a mutation in ednrb in 1994 (now classed as type 4a). type 4b was established in 1996 when mutations in edn3 were found to lead to this type of waardenburg syndrome, and type 4c was first established in 1998 when mutations in sox10 were also found to lead to this type. society and culture popular culture the 2001 novel shock by robin cook mentions a character with the disorder. 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. 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. the 2013 book reconstructing amelia by kimberly mccreight features several characters with waardenburg symptoms. the 2014 book closer than you think by karen rose features three characters, siblings, with waardenburg syndrome. the 2017 book murder at the mayan temple by m.j. mandrake features several characters with waardenburg syndrome. the 2019 novel the whisper network by chandler baker uses the syndrome as a plot point. notable people canadian youtube vlogger stef sanjati has waardenburg syndrome type 1. other animals for further details of other animals, see deaf white cat, dalmatian (dog) § deafness, lethal white syndrome, and ferret health § congenital sensorineural deafness. deaf white cat with heterochromia waardenburg syndrome type 2a (with a mutation in mitf) has been found in dogs, fleckvieh cattle, minks, mice and a golden hamster. 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. domesticated cats with blue eyes and white coats are often completely deaf. 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." 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. one of the genes that leads to deafness and a white coat in cats when mutated, kit, has been found to increase mitf expression. 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. 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."