Waardenburg syndrome is a group of genetic conditions that can cause hearing loss and changes in coloring (pigmentation) of the hair, skin, and eyes. Although most people with Waardenburg syndrome have normal hearing, moderate to profound hearing loss can occur in one or both ears. The hearing loss is present from birth (congenital). People with this condition often have very pale blue eyes or different colored eyes, such as one blue eye and one brown eye. Sometimes one eye has segments of two different colors. Distinctive hair coloring (such as a patch of white hair or hair that prematurely turns gray) is another common sign of the condition. The features of Waardenburg syndrome vary among affected individuals, even among people in the same family.

There are four recognized types of Waardenburg syndrome, which are distinguished by their physical characteristics and sometimes by their genetic cause. Types I and II have very similar features, although people with type I almost always have eyes that appear widely spaced and people with type II do not. In addition, hearing loss occurs more often in people with type II than in those with type I. Type III (sometimes called Klein-Waardenburg syndrome) includes abnormalities of the arms and hands in addition to hearing loss and changes in pigmentation. Type IV (also known as Waardenburg-Hirschsprung disease or Waardenburg-Shah syndrome) has signs and symptoms of both Waardenburg syndrome and Hirschsprung disease, an intestinal disorder that causes severe constipation or blockage of the intestine.

Variants (also known as mutations) in the EDN3, EDNRB, MITF, PAX3, SNAI2, and SOX10 genes can cause Waardenburg syndrome. These genes are involved in the formation and development of several types of cells, including pigment-producing cells called melanocytes. Melanocytes make a pigment called melanin, which contributes to skin, hair, and eye color and plays an essential role in the normal function of the inner ear. Variants in any of these genes disrupt the normal development of melanocytes, leading to abnormal pigmentation of the skin, hair, and eyes and problems with hearing.

Waardenburg syndrome types I and III are caused by variants in the PAX3 gene. Variants in the MITF or SNAI2 gene can cause Waardenburg syndrome type II.

Variants in the SOX10, EDN3, or EDNRB gene can cause Waardenburg syndrome type IV. In addition to melanocyte development, these genes are important for the development of nerve cells in the large intestine. Variants in any of these genes result in hearing loss, changes in pigmentation, and intestinal problems related to Hirschsprung disease.

In some cases, the genetic cause of Waardenburg syndrome has not been identified.

Normal Function

The EDN3 gene provides instructions for making a protein called endothelin 3. Proteins in the endothelin family are produced in various cells and tissues, where they are involved in the development and function of blood vessels, the production of certain hormones, and the stimulation of cell growth and division (proliferation).

Endothelin 3 functions by interacting with another protein, endothelin receptor type B (produced from the EDNRB gene), on the surface of cells. During early development before birth, endothelin 3 and endothelin receptor type B together play an important role in neural crest cells. These cells migrate from the developing spinal cord to specific regions in the embryo, where they give rise to many different types of cells. In particular, endothelin 3 and its receptor are essential for the formation of nerves in the intestine (enteric nerves) and for the production of specialized cells called melanocytes. Melanocytes produce melanin, a pigment that contributes to skin, hair, and eye color. Melanin is also involved in the normal function of the inner ear.

Health Conditions Related to Genetic Changes

Hirschsprung disease

Variants (also known as mutations) in the EDN3 gene have been found to cause Hirschsprung disease, a disorder that causes severe constipation or blockage of the intestine. Although Hirschsprung disease is a feature of another disorder called Waardenburg syndrome type IV (described below), EDN3 gene variants can also cause Hirschsprung disease in people without Waardenburg syndrome. These variants change one DNA building block (nucleotide) or insert an additional nucleotide in the gene. Changes in the EDN3 gene disrupt the normal function of endothelin 3, preventing it from playing its usual role in the development of enteric nerves. As a result, these cells do not form normally during embryonic development. A lack of enteric nerves prevents stool from being moved through the intestine normally, leading to severe constipation or intestinal blockage.

Waardenburg syndrome

Variants in the EDN3 gene have been identified in people with Waardenburg syndrome type IV (also known as Waardenburg-Hirschsprung disease or Waardenburg-Shah syndrome). This type of Waardenburg syndrome is characterized by changes in skin, hair, and eye coloring; hearing loss; and Hirschsprung disease (described above). EDN3 gene variants change single nucleotides in the gene, preventing the production of a functional endothelin 3 protein. Because active endothelin 3 is necessary for the formation of enteric nerves and melanocytes, these cell types do not form normally during embryonic development. Missing enteric nerves in certain parts of the intestine cause the signs and symptoms of Hirschsprung disease. A lack of melanocytes affects the coloring of skin, hair, and eyes and causes the hearing loss characteristic of Waardenburg syndrome.

Other Names for This Gene

• EDN3_HUMAN
• endothelin 3 precursor
• ET3
• HSCR4
• PPET3
• Preproendothelin-3
• RP4-614C15.1
• WS4B

Genomic Location

Normal Function

The EDNRB gene provides instructions for making a protein called endothelin receptor type B. This protein is located on the surface of cells and functions as a signaling mechanism, transmitting information from outside the cell to inside the cell. The receptor interacts with proteins called endothelins to regulate several critical biological processes, including the development and function of blood vessels, the production of certain hormones, and the stimulation of cell growth and division (proliferation).

Endothelin 3 (produced from the EDN3 gene) is one of the proteins that interacts with endothelin receptor type B. During early development before birth (embryonic development), endothelin 3 and endothelin receptor type B together play an important role in neural crest cells. These cells migrate from the developing spinal cord to specific regions in the embryo, where they give rise to many different types of cells. In particular, endothelin 3 and endothelin receptor type B are essential for the formation of nerves in the intestine (enteric nerves) and for the production of specialized cells called melanocytes. Melanocytes produce melanin, a pigment that contributes to skin, hair, and eye color. Melanin is also involved in the normal function of the inner ear.

Health Conditions Related to Genetic Changes

Hirschsprung disease

Variants (also known as mutations) in the EDNRB gene have been found to cause Hirschsprung disease, a disorder that causes severe constipation or blockage of the intestine. Although Hirschsprung disease is a feature of another condition called Waardenburg syndrome type IV (described below), EDNRB gene variants can also cause Hirschsprung disease in people without Waardenburg syndrome. People with a variant in one of the two copies of the EDNRB gene tend to develop Hirschsprung disease, while people with variants in both copies of the gene usually develop Waardenburg syndrome type IV. Most of these variants change single DNA building blocks (nucleotides) in the gene. Changes in the EDNRB gene disrupt the normal function of endothelin receptor type B, preventing it from playing its usual role in the development of enteric nerves. As a result, these cells do not form normally during embryonic development. A lack of enteric nerves prevents stool from being moved through the intestine normally, leading to severe constipation or intestinal blockage.

Waardenburg syndrome

Variants in the EDNRB gene have been identified in people with Waardenburg syndrome type IV (also known as Waardenburg-Hirschsprung disease or Waardenburg-Shah syndrome). This type of Waardenburg syndrome is characterized by changes in skin, hair, and eye coloring; hearing loss; and Hirschsprung disease (described above). Variants in the EDNRB gene disrupt the normal function of endothelin receptor type B or lead to the production of an abnormally small, nonfunctional version of the protein. Because the receptor is necessary for the formation of enteric nerves and melanocytes, these cell types do not form normally during embryonic development. Missing enteric nerves in certain parts of the intestine cause the signs and symptoms of Hirschsprung disease. A lack of melanocytes affects the coloring of skin, hair, and eyes and causes the hearing loss characteristic of Waardenburg syndrome.

Cancers

Several studies have suggested that inherited variations in the EDNRB gene may be associated with an increased risk of melanoma, a common form of skin cancer that begins in melanocytes. However, other studies have not shown this association, and this gene's role in cancer risk remains unclear.

Other Names for This Gene

• ABCDS
• EDNRB_HUMAN
• endothelin receptor, non-selective type
• ETB
• ETBR
• ETRB
• HSCR
• HSCR2
• RP11-318G21.1
• WS4A

Genomic Location

Normal Function

The MITF gene provides instructions for making a protein called melanocyte inducing transcription factor. This protein plays a role in the development, survival, and function of certain types of cells. To carry out this role, the protein attaches to specific areas of DNA and helps control the activity of particular genes. On the basis of this action, the protein is called a transcription factor.

Melanocyte inducing transcription factor helps control the development and function of pigment-producing cells called melanocytes. Within these cells, this protein controls production of the pigment melanin, which contributes to hair, eye, and skin color. Melanocytes are also found in the inner ear and play an important role in hearing. Additionally, melanocyte inducing transcription factor regulates the development of specialized cells in the eye called retinal pigment epithelial cells. These cells nourish the retina, the part of the eye that detects light and color. Some research indicates that melanocyte inducing transcription factor also regulates the development of cells that break down and remove bone (osteoclasts) and cells that play a role in allergic reactions (mast cells).

The structure of melanocyte inducing transcription factor includes three critically important regions. Two of the regions, called the helix-loop-helix motif and the leucine-zipper motif, are critical for protein interactions. These motifs allow molecules of melanocyte inducing transcription factor to interact with each other or with other proteins that have a similar structure, creating a two-protein unit (dimer) that functions as a transcription factor. The other region, known as the basic motif, binds to specific areas of DNA, allowing the dimer to control gene activity.

Health Conditions Related to Genetic Changes

Melanoma

MITF gene variants (also called mutations) have also been found in people with an aggressive form of skin cancer called melanoma. Most of these variants are somatic, meaning that they occur during a person's lifetime and are present only in cells that give rise to the melanoma. Occasionally the variant is inherited and is found in every cell of the body (known as a germline variant).

Some of the MITF gene variants associated with melanoma increase cell growth and division (proliferation) directly. Other variants have an indirect effect, increasing the activity (expression) of other genes involved in proliferation and resulting in the abnormal cell growth that occurs in melanoma.

Tietz syndrome

MITF gene variants have been identified in people with Tietz syndrome, which is characterized by profound hearing loss from birth, fair skin, and light-colored hair. Researchers suggest that Tietz syndrome may be a severe form of Waardenburg syndrome (described below).

The MITF gene variants that cause Tietz syndrome either delete or change a single protein building block (amino acid) in the basic motif region of the melanocyte inducing transcription factor structure. Dimers incorporating the abnormal melanocyte inducing transcription factor cannot be transported into the cell nucleus to bind with DNA. As a result, most of the dimers are unavailable to bind to DNA, which affects the development of melanocytes and the production of melanin. The resulting reduction or absence of melanocytes in the inner ear leads to hearing loss. Decreased melanin production (hypopigmentation) accounts for the light skin and hair color that are characteristic of Tietz syndrome.

Waardenburg syndrome

Variants in the MITF gene have been identified in people with Waardenburg syndrome type II, a disorder that can cause hearing loss and changes in coloring (pigmentation) of the hair, skin, and eyes. Some MITF gene variants change the amino acids used to make melanocyte inducing transcription factor, which alters the helix-loop-helix or leucine-zipper motif. Other variants result in an abnormally small version of the protein. Researchers believe that both types of variant disrupt the formation of dimers. Although some dimers are produced, the amount is insufficient for full development of melanocytes. As a result, there is a shortage of melanocytes in certain areas of the skin, hair, eyes, and inner ear. This shortage leads to hearing loss and the patchy loss of pigmentation associated with Waardenburg syndrome.

Other Names for This Gene

• homolog of mouse microphthalmia
• melanogenesis associated transcription factor
• microphthalmia-associated transcription factor
• MITF_HUMAN
• WS2A

Genomic Location

Normal Function

The PAX3 gene belongs to a family of PAX genes that plays a critical role in the formation of tissues and organs during embryonic development. The PAX gene family is also important for maintaining the normal function of certain cells after birth. To carry out these roles, the PAX genes provide instructions for making proteins that attach (bind) to specific areas of DNA. By attaching to critical DNA regions, PAX proteins help control the activity of particular genes. On the basis of this action, PAX proteins are called transcription factors.

During embryonic development, the PAX3 gene is active in cells called neural crest cells. These cells migrate from the developing spinal cord to specific regions in the embryo. The protein made from the PAX3 gene directs the activity of other genes that signal neural crest cells to form specialized tissues or cell types such as some nerve tissue and pigment-producing cells called melanocytes. Melanocytes produce the pigment melanin, which contributes to hair, eye, and skin color. Melanocytes are also found in certain regions of the brain and inner ear.

Studies suggest that the PAX3 protein is also necessary for the normal development of bones in the face and skull (craniofacial bones) and elsewhere in the body, and for the formation of muscle tissue (myogenesis).

Health Conditions Related to Genetic Changes

Craniofacial-deafness-hand syndrome

At least one PAX3 gene variant (also known as a mutation) has been identified in individuals with craniofacial-deafness-hand syndrome, a condition characterized by distinctive facial features, profound hearing loss, and abnormalities of the hand muscles that can restrict movement. The variant replaces a single protein building block (amino acid) called asparagine with another amino acid called lysine at position 47 in the PAX3 protein (written as Asn47Lys or N47K). This variant appears to affect the ability of the PAX3 protein to bind to DNA. As a result, the PAX3 protein cannot control the activity of other genes and cannot direct the neural crest cells to form specialized tissues. A lack of specialization of neural crest cells leads to the impaired growth of craniofacial bones, nerve tissue, and muscles seen in craniofacial-deafness-hand syndrome.

Waardenburg syndrome

PAX3 gene variants have been identified in people with Waardenburg syndrome, a group of genetic conditions that can cause hearing loss and changes in coloring (pigmentation) of the hair, skin, and eyes. Specifically, PAX3 gene variants can cause Waardenburg syndrome types I and III.

Some of these variants change single amino acids in the PAX3 protein. Other variants lead to an abnormally small version of the PAX3 protein. Researchers believe that all PAX3 gene variants have the same effect: they prevent the PAX3 protein from binding to DNA and regulating the activity of other genes. As a result, melanocytes do not develop in certain areas of the skin, hair, eyes, and inner ear, leading to hearing loss and the patchy loss of pigmentation that are characteristic features of Waardenburg syndrome. Additionally, loss of PAX3 protein function disrupts development of certain bones and muscles, producing abnormalities of the arms and hands in people with Waardenburg syndrome type III.

Cancers

Rearrangements of genetic material involving the PAX3 gene are associated with a cancer of muscle tissue called alveolar rhabdomyosarcoma, which typically affects adolescents and young adults. This genetic change is somatic, which means that it is not inherited and occurs only in the cells that give rise to cancer. The rearrangements cause the PAX3 gene to be fused with another gene, most commonly the FOXO1A gene (also called FKHR) on chromosome 13. The protein produced from the fused PAX3-FOXO1A gene has an increased ability to activate genes involved in myogenesis and can prevent cell death. As a result, muscle cell growth becomes uncontrolled, which can lead to this cancer of muscle tissue.

Somatic rearrangements involving the PAX3 gene are also associated with a cancer of the nasal passages and sinuses called biphenotypic sinonasal sarcoma. This type of cancer usually occurs in adulthood and affects women more often than men. The genetic rearrangements involved in biphenotypic sinonasal sarcoma fuse the PAX3 gene with another gene, most commonly the MAML3 gene on chromosome 4. The protein produced from the fusion gene is overactive and turns on genes involved in the development of structures in the nasal passages and sinuses abnormally. As a result, cells in these structures can grow without control, forming a tumor.

Other Names for This Gene

• CDHS
• HUP2
• paired box gene 3 (Waardenburg syndrome 1)
• paired box homeotic gene 3
• paired domain gene 3
• paired domain gene HuP2
• PAX3/FKHR fusion gene
• PAX3_HUMAN
• WS1

Genomic Location

Normal Function

The SNAI2 gene (often called SLUG) provides the instructions for making a protein called snail 2. Snail 2 belongs to the snail protein family, which plays a role in the formation of tissues during embryonic development. The snail 2 protein is also found in most adult tissues, so it probably helps maintain the normal function of cells after birth. To carry out these roles, snail 2 attaches to critical regions of DNA and helps control the activity of particular genes. On the basis of this action, the protein is called a transcription factor.

Research indicates that the snail 2 protein is required during embryonic growth for the development of cells called neural crest cells. Neural crest cells migrate from the developing spinal cord to specific regions in the embryo and give rise to many tissues and cell types, including some nerve tissue and pigment-producing cells called melanocytes. Melanocytes produce the pigment melanin, which contributes to hair, eye, and skin color. Melanocytes are also found in certain regions of the brain and inner ear. The snail 2 protein probably plays a role in the formation and survival of melanocytes.

Health Conditions Related to Genetic Changes

Piebaldism

One copy of the SNAI2 gene is missing (deleted) in some cases of piebaldism, a condition characterized by white patches of skin and hair caused by a lack of pigmented cells (melanocytes). Loss of one copy of the gene probably reduces the production of the snail 2 protein. Shortage of the snail 2 protein may disrupt the development of melanocytes in certain areas of the skin and hair, causing the patchy loss of pigment.

Waardenburg syndrome

In some cases of Waardenburg syndrome type II, both copies of the SNAI2 gene are missing. With no copies of the gene, the snail 2 protein is absent. Lack of snail 2 may disrupt the development of melanocytes in certain areas of the skin, hair, eyes, and inner ear, leading to hearing loss and the patchy loss of pigmentation that are characteristic features of Waardenburg syndrome type II.

Other Names for This Gene

• neural crest transcription factor SLUG
• SLUG
• slug homolog, zinc finger protein (chicken)
• SLUG_HUMAN
• SLUGH1
• snail 2
• snail family zinc finger 2
• snail homolog 2 (Drosophila)
• SNAIL2
• WS2D

Genomic Location

Normal Function

The SOX10 gene belongs to a family of genes that plays a critical role in the formation of tissues and organs during embryonic development. The SOX gene family also maintains the normal function of certain cells after birth. To carry out these roles, proteins made by genes in the SOX family bind to specific areas of DNA. By attaching to critical regions near genes, SOX proteins help control the activity of those genes. SOX proteins are called transcription factors on the basis of this action.

During embryonic development, the SOX10 gene is active in cells called neural crest cells. These cells migrate from the developing spinal cord to specific regions in the embryo, where they give rise to many different types of cells. The protein made by the SOX10 gene directs the activity of other genes (such as MITF) that signal neural crest cells to become more specific cell types. In particular, the SOX10 protein is essential for the formation of nerves in the intestine (enteric nerves) and for the production of specialized cells called melanocytes. Melanocytes produce melanin, a pigment that contributes to skin, hair, and eye color. Melanin is also involved in the normal function of the inner ear.

Health Conditions Related to Genetic Changes

Waardenburg syndrome

Variants (also known as mutations) in the SOX10 gene have been identified in people with Waardenburg syndrome type II and type IV (also known as Waardenburg-Hirschsprung disease or Waardenburg-Shah syndrome). Both types of Waardenburg syndrome are characterized by changes in skin, hair, and eye coloring and hearing loss. People with type IV also have an intestinal disorder called Hirschsprung disease that causes severe constipation or intestinal blockage.

Most SOX10 gene variants lead to the production of an abnormal version of the SOX10 protein or prevent the gene from making any protein. An abnormal or missing SOX10 protein cannot control genes that signal neural crest cells to become specific cell types. As a result, enteric nerves and melanocytes do not form normally during embryonic development. Missing enteric nerves in certain parts of the intestine cause the signs and symptoms of Hirschsprung disease. A lack of melanocytes affects the coloring of skin, hair, and eyes and causes the hearing loss characteristic of Waardenburg syndrome.

Researchers have found that variants in the SOX10 gene also cause a similar disorder known as peripheral demyelinating neuropathy, central demyelinating leukodystrophy, Waardenburg syndrome, and Hirschsprung disease (PCWH). This rare condition is a variant of Waardenburg syndrome type IV that also affects other parts of the nervous system. Like variants that cause other types of Waardenburg syndrome, the variants involved in PCWH lead to the production of an abnormal version of the SOX10 protein that is unable to direct the activity of other genes.

Hirschsprung disease

MedlinePlus Genetics provides information about Hirschsprung disease

Kallmann syndrome

MedlinePlus Genetics provides information about Kallmann syndrome

Other Names for This Gene

• DOM
• dominant megacolon, mouse, human homolog of
• SOX10_HUMAN
• SRY (sex determining region Y)-box 10
• SRY box 10
• SRY-related HMG-box gene 10
• transcription factor SOX-10
• WS4

Genomic Location

Waardenburg syndrome is usually inherited in an autosomal dominant pattern, which means one copy of the altered gene in each cell is sufficient to cause the disorder. In most cases, an affected person has one parent with the condition. A small percentage of cases result from new variants in the gene; these cases occur in people with no history of the disorder in their family.

Some cases of Waardenburg syndrome type II and type IV appear to have an autosomal recessive pattern of inheritance, which means both copies of the gene in each cell have variants. Most often, the parents of an individual with an autosomal recessive condition each carry one copy of the altered gene, but do not show signs and symptoms of the condition.

A diagnosis of Waardenburg syndrome (WS) is made based on the presence of signs and symptoms. In 1992, the Waardenburg Consortium proposed diagnostic criteria, which includes both major and minor criteria. A diagnosis of WS type 1 (the most common type) needs 2 major, or 1 major and 2 minor of the following criteria:

Major criteria:

• Congenitalsensorineural hearing loss (present from birth)
• Iris pigmentary (coloration) abnormality, such as heterochromia iridis (complete, partial, or segmental); pale blue eyes (isohypochromia iridis); or pigmentary abnormalities of the fundus (part of the eye opposite the pupil)
• Abnormalities of hair pigmentation, such as white forelock (lock of hair above the forehead), or loss of hair color
• Dystopia canthorum – lateral displacement of inner angles (canthi) of the eyes (in WS types 1 and 3 only)
• Having a 1st degree relative with Waardenburg syndrome

Minor criteria:

• Leukoderma (white patches of skin) present from birth
• Synophrys (connected eyebrows, or "unibrow") or medial eyebrow flare
• Broad or high nasal bridge (uppermost part of the nose)
• Hypoplasia (incomplete development) of the nostrils
• Premature gray hair (under age 30)

WS type 2 has features similar to type 1, but the inner canthi of the eyes are normal (no dystopia canthorum present).

WS type 3 also has similar features to WS type 1, but is additionally characterized by musculoskeletal abnormalities such as muscle hypoplasia; flexion contractures (inability to straighten joints); or syndactyly (webbed or fused fingers or toes).

WS type 4 has similar features to WS type 2, but with Hirschsprung disease (a condition resulting from missing nerve cells in the muscles of part or all of the large intestine).

Waardenburg syndrome affects an estimated 1 in 40,000 people. It accounts for 2 to 5 percent of all cases of congenital hearing loss. Types I and II are the most common forms of Waardenburg syndrome, while types III and IV are rare.