Waardenburg syndrome

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. 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. Type 2 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. 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. 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. 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. 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. 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. Additionally, hearing loss is not as common as in type 2. 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. 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). == Cause ==

and neural tube (neurulation), around week 4 of embryonic development|391x391px|alt= 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. 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, 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. Causes of subtypes • Type 1 is caused by an autosomal dominant mutation in the gene PAX3. 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. • 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. • 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. • Type 2E is caused by an autosomal dominant mutation in the gene SOX10. • Type 4C is caused by an autosomal dominant or autosomal-recessive mutation in the gene SOX10, the same gene as in type 2E. Classification table == 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 1 in 42,000. 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 number of known cases of type 2E that involved neurological abnormalities was reported to be 23 , 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.) In 1929, Dutch physician K. T. A. Halbertsma described a familial pattern to dystopia canthorum, (1891–1976) also confirmed a hereditary pattern to dystopia canthorum. A 1977 study confirmed a familial pattern to this other presentation. 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. Mutations in PAX3 were first linked to this phenotype in 1992. 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. Notable people • Canadian YouTube vlogger Stef Sanjati has Waardenburg syndrome type 1. == Other animals ==

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 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." == See also ==