Formation of the neural crest and neural tube (neurulation),alt A 2004 model of some of the genes involved in regulating neural crest cells, including some involved in<unk> <unk>  is caused by mutations in any of several genes that affect the operation of neural crest cells in embryonic development. Most types of<unk>  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. 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. * 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. 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). 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<unk>  by uniform albinism instead of patchy depigmentation. * 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<unk> 2B. * 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<unk> 2C. * 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<unk> , 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. * Rarely, a mutation in a gene other than those currently known may be responsible for a<unk>  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. * Type 3 is caused by a mutation in the gene PAX3, the same gene as in type 1. It can be inherited in an autosomal dominant or autosomal recessive manner; it is possible for two parents with<unk>  type 1 to have a child carrying both mutated copies of the PAX3 gene (25% chance) and present with<unk>  type 3. A missense mutation has been documented to have this effect. However, it is also possible for<unk>  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. 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<unk>  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<unk> 1 and<unk> 2 can increase the pigment-affected symptoms. It leads to the conclusion that the double mutation of MITF is associated with the extremity of<unk>  and may affect the phenotypes or symptoms of the syndrome. Classification table Type OMIM Gene Locus Inheritance Type 1 <unk> 1) PAX3 2q36.1 Autosomal dominant Type 2A <unk> 2A, originally<unk> 2) MITF 3p14.1–p12.3 Autosomal dominant Type 2B <unk> 2B)<unk> 2B 1p21–p13.3 Autosomal dominant Type 2C <unk> 2C)<unk> 2C 8p23 Autosomal dominant Type 2D <unk> 2D) SNAI2 8q11 Autosomal recessive Type 2E <unk> 2E) SOX10 22q13.1 Autosomal dominant Type 3 <unk> 3) PAX3 2q36.1 Autosomal dominant or autosomal recessive Type 4A <unk> 4A) EDNRB 13q22 Autosomal dominant or autosomal recessive Type 4B <unk> 4B) EDN3 20q13 Autosomal dominant or autosomal recessive Type 4C <unk> 4C) SOX10 22q13.1 Autosomal dominant
Waardenburg syndrome
Van Den Bosch syndrome
Alder–Reilly anomaly
Wildervanck syndrome
Aagenaes syndrome
Pelger–Huët anomaly
Singleton Merten syndrome
Koolen–De Vries syndrome