Piebaldism is a condition characterized by the absence of cells called melanocytes in certain areas of the skin and hair. Melanocytes produce the pigment melanin, which contributes to hair, eye, and skin color. The absence of melanocytes leads to patches of skin and hair that are lighter than normal. Approximately 90 percent of affected individuals have a white section of hair near their front hairline (a white forelock). The eyelashes, the eyebrows, and the skin under the forelock may also be unpigmented.

People with piebaldism usually have other unpigmented patches of skin, typically appearing symmetrically on both sides of the body. There may be spots or patches of pigmented skin within or around the borders of the unpigmented areas.

In most cases, the unpigmented areas are present at birth and do not increase in size or number. The unpigmented patches are at increased risk of sunburn and skin cancer related to excessive sun exposure. Some people with piebaldism are self-conscious about the appearance of the unpigmented patches, which may be more noticeable in darker-skinned people. Aside from these potential issues, this condition has no effect on the health of the affected individual.

Piebaldism can be caused by mutations in the KIT and SNAI2 genes. Piebaldism may also be a feature of other conditions, such as Waardenburg syndrome; these conditions have other genetic causes and additional signs and symptoms.

The KIT gene provides instructions for making a protein that is involved in signaling within cells. KIT protein signaling is important for the development of certain cell types, including melanocytes. The KIT gene mutations responsible for piebaldism lead to a nonfunctional KIT protein. The loss of KIT signaling is thought to disrupt the growth and division (proliferation) and movement (migration) of melanocytes during development, resulting in patches of skin that lack pigmentation.

The SNAI2 gene (often called SLUG) provides instructions for making a protein called snail 2. 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 melanocytes. The snail 2 protein probably plays a role in the formation and survival of melanocytes. SNAI2 gene mutations that cause piebaldism probably reduce 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.

Piebaldism is sometimes mistaken for another condition called vitiligo, which also causes unpigmented patches of skin. People are not born with vitiligo, but acquire it later in life, and it is not caused by specific genetic mutations. For unknown reasons, in people with vitiligo the immune system appears to damage the melanocytes in the skin.

Normal Function

The KIT gene provides instructions for making a member of a protein family called receptor tyrosine kinases. Receptor tyrosine kinases transmit signals from the cell surface into the cell through a process called signal transduction. The KIT protein is found in the cell membrane of certain cell types where a specific protein, called stem cell factor, attaches (binds) to it. This binding turns on (activates) the KIT protein, which then activates other proteins inside the cell by adding a cluster of oxygen and phosphorus atoms (a phosphate group) at specific positions. This process, called phosphorylation, leads to the activation of a series of proteins in multiple signaling pathways.

The signaling pathways stimulated by the KIT protein control many important cellular processes such as cell growth and division (proliferation), survival, and movement (migration). KIT protein signaling is important for the development and function of certain cell types, including reproductive cells (germ cells), early blood cells (hematopoietic stem cells), white blood cells called mast cells, cells in the gastrointestinal tract called interstitial cells of Cajal (ICCs), and cells called melanocytes. Melanocytes produce the pigment melanin, which contributes to hair, eye, and skin color.

Health Conditions Related to Genetic Changes

Piebaldism

At least 69 KIT gene mutations have been identified in people with piebaldism. This condition is characterized by white patches of skin and hair caused by a lack of melanocytes in those areas. The mutations responsible for piebaldism lead to a nonfunctional KIT protein. The loss of KIT signaling is thought to disrupt melanocyte migration and proliferation during development, resulting in patches of skin that lack pigmentation.

Gastrointestinal stromal tumor

Mutations in the KIT gene are the most common genetic changes associated with gastrointestinal stromal tumors (GISTs). GISTs are a type of tumor that occurs in the gastrointestinal tract, most commonly in the stomach or small intestine. In most cases, these KIT gene mutations are acquired during a person's lifetime and are called somatic mutations. Somatic mutations, which lead to sporadic GISTs, are present only in the tumor cells and are not inherited. Less commonly, KIT gene mutations that increase the risk of developing GISTs are inherited from a parent, which can lead to familial GISTs.

KIT gene mutations associated with GISTs create a protein that no longer requires binding of the stem cell factor protein to be activated. As a result, the KIT protein and the signaling pathways are constantly turned on (constitutively activated), which increases the proliferation and survival of ICCs, leading to GIST formation.

Systemic mastocytosis

Somatic mutations in the KIT gene have been found to play a role in systemic mastocytosis. This condition is a blood disorder that typically appears after adolescence, varies in severity, and can affect many different body systems. Systemic mastocytosis occurs when mast cells abnormally accumulate in tissues. Mast cells normally trigger inflammation during an allergic reaction and signal an immune response when they are activated by an environmental trigger.

In most cases of systemic mastocytosis, the accumulated mast cells have a KIT gene mutation. More than 80 percent of individuals with systemic mastocytosis have a mutation in the KIT gene that replaces the protein building block (amino acid) aspartic acid with the amino acid valine at position 816 in the protein (Asp816Val or D816V). This and other KIT gene mutations result in production of altered proteins that are constitutively activated. As a result, signaling pathways that promote the proliferation of cells are overactive, which leads to increased production of mast cells and accumulation of the cells in various tissues. Cells with altered KIT proteins are more active than normal, leading to increased immune responses and signs and symptoms of systemic mastocytosis. In systemic mastocytosis, the excess mast cells lead to an increased immune response and signs and symptoms similar to an allergic reaction, such as skin redness and warmth (flushing), nausea, abdominal pain, nasal congestion, low blood pressure (hypotension), and headache.

Core binding factor acute myeloid leukemia

MedlinePlus Genetics provides information about Core binding factor acute myeloid leukemia

Other cancers

Somatic mutations in the KIT gene have been identified in several cancers. KIT gene mutations are involved in some cases of acute myeloid leukemia, which is a cancer of a type of blood cell known as myeloid cells, and sinonasal natural killer/T-cell lymphoma (NKTCL), another blood cell cancer that occurs in the nasal passages. In addition, some people with seminoma, a type of testicular cancer, have a somatic KIT gene mutation. The genetic changes involved in acute myeloid leukemia and seminomas lead to a KIT protein that is constitutively activated. The constant signaling causes overproliferation of the cells that make up these tumors. It is unclear how the KIT mutations in NKTCL are involved in the condition.

Other Names for This Gene

• C-Kit
• CD117
• KIT_HUMAN
• mast/stem cell growth factor receptor Kit
• p145 c-kit
• PBT
• piebald trait protein
• proto-oncogene c-Kit
• proto-oncogene tyrosine-protein kinase Kit
• SCFR
• tyrosine-protein kinase Kit
• v-kit Hardy-Zuckerman 4 feline sarcoma viral oncogene homolog
• v-kit Hardy-Zuckerman 4 feline sarcoma viral oncogene-like protein

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

This condition is inherited in an autosomal dominant pattern, which means one copy of the altered gene in each cell is sufficient to cause the disorder.

The prevalence of piebaldism is unknown.