An epidermal nevus (plural: nevi) is an abnormal, noncancerous (benign) patch of skin caused by an overgrowth of cells in the outermost layer of skin (epidermis). Epidermal nevi are typically seen at birth or develop in early childhood. Affected individuals have one or more nevi that vary in size.

There are several types of epidermal nevus that are defined in part by the type of epidermal cell involved. The epidermis is composed primarily of a specific cell type called a keratinocyte. One group of epidermal nevi, called keratinocytic or nonorganoid epidermal nevi, includes nevi that involve only keratinocytes. Keratinocytic epidermal nevi are typically found on the torso or limbs. They can be flat, tan or brown patches of skin or raised, velvety patches. As affected individuals age, the nevi can become thicker and darker and develop a wart-like (verrucous) appearance. Often, keratinocytic epidermal nevi follow a pattern on the skin known as the lines of Blaschko. The lines of Blaschko, which are normally invisible on skin, are thought to follow the paths along which cells migrate as the skin develops before birth. Keratinocytic epidermal nevi are also known as linear epidermal nevi or verrucous epidermal nevi, based on characteristics of their appearance.

Other types of epidermal nevi involve additional types of epidermal cells, such as the cells that make up the hair follicles, the sweat glands, or the sebaceous glands (glands in the skin that produce a substance that protects the skin and hair). These nevi comprise a group called organoid epidermal nevi. A common type of organoid epidermal nevus is called nevus sebaceous. Nevi in this group are waxy, yellow-orange patches of skin, usually on the scalp or face. The patch is typically hairless, leaving a distinct region of baldness (alopecia). Similar to keratinocytic epidermal nevi, nevi sebaceous can become thicker and more verrucous over time. In about one-quarter of people with a nevus sebaceous, a tumor forms in the same region as the nevus. The tumor is usually benign, although rarely cancerous (malignant) tumors develop.

Some affected individuals have only an epidermal nevus and no other abnormalities. However, sometimes people with an epidermal nevus also have problems in other body systems, such as the brain, eyes, or bones. In these cases, the affected individual has a condition called an epidermal nevus syndrome. There are several different epidermal nevus syndromes characterized by the type of epidermal nevus involved.

Several genes have been associated with different types of epidermal nevus. Mutations in the FGFR3 gene and PIK3CA gene account for about forty percent of keratinocytic epidermal nevi. Mutations in the HRAS gene are found in a majority of people with a nevus sebaceous and are also associated with keratinocytic epidermal nevi. Genes related to HRAS (called KRAS and NRAS) are less commonly involved in nevi sebaceous or keratinocytic epidermal nevi. Other genes, some of which have not been identified, are also involved in epidermal nevi.

FGFR3, PIK3CA, HRAS, and other related RAS genes provide instructions for making proteins that are involved in cellular signaling. This signaling helps direct several important cellular processes, including regulation of growth and division of skin cells. In order to relay signals, the proteins must be turned on (activated), which triggers a cascade of chemical reactions inside the cell that control growth and other cellular functions.

Mutations in the genes mentioned above lead to proteins that are constantly turned on. Studies suggest that cells with a mutation in one of these genes grow and divide more than normal cells. This uncontrolled cell division results in overgrowth of skin cells, leading to epidermal nevi.

Mutations associated with an epidermal nevus are present only in the cells of the nevus, not in the normal skin cells surrounding it. Because the mutation is found in some of the body's cells but not in others, people with an epidermal nevus are said to be mosaic for the mutation.

Normal Function

The FGFR2 gene provides instructions for making a protein called fibroblast growth factor receptor 2 (FGFR2). Fibroblast growth factor receptors are related proteins that are involved in important processes such as cell growth and division (proliferation), cell maturation (differentiation), bone development, formation of blood vessels (angiogenesis), wound healing, and embryonic development.

The FGFR2 protein spans the outer membrane surrounding cells, so that one end of the protein remains inside the cell and the other end projects from the outer surface of the cell. This positioning allows the FGFR2 protein to interact with specific growth factors outside the cell and to receive signals that help the cell respond to its environment. When growth factors attach to the FGFR2 protein, the receptor triggers a series of chemical reactions inside the cell that instruct the cell to undergo certain changes, such as maturing to take on specialized functions.

The FGFR2 protein plays an important role in bone growth, particularly during development before birth (embryonic development). For example, this protein signals certain immature cells in the developing embryo to become bone cells and form the head, hands, feet, and other tissues. The protein is also involved in bone remodeling, a normal process in which old bone is broken down and new bone is created to replace it.

There are several slightly different versions (isoforms) of the FGFR2 protein. Specific patterns of these isoforms are found in the body's tissues, and these patterns may change throughout growth and development.

Health Conditions Related to Genetic Changes

Apert syndrome

At least ten mutations in the FGFR2 gene have been found to cause Apert syndrome. This condition causes premature closure of the bones of the skull (craniosynostosis), leading to a misshapen head, distinctive facial features, and brain abnormalities. Affected individuals often have abnormalities of the fingers and toes, hearing and vision problems, and other signs and symptoms.

More than 98 percent of cases of Apert syndrome are caused by one of two mutations in the FGFR2 gene. These mutations change single protein building blocks (amino acids) in the FGFR2 protein. One mutation replaces the amino acid serine with the amino acid tryptophan at protein position 252 (written as Ser252Trp). The other mutation replaces the amino acid proline with the amino acid arginine at position 253 (written as Pro253Arg). These changes are described as "gain-of-function" because they increase the activity of the protein, leading to stronger signaling, which causes cells to mature too quickly. As a result, structures in the body develop abnormally, leading to premature fusion of bones in the skull, hands, and feet and other characteristic features of Apert syndrome.

Beare-Stevenson cutis gyrata syndrome

At least three mutations in the FGFR2 gene have been found to cause Beare-Stevenson cutis gyrata syndrome, a condition that causes craniosynostosis, leading to a misshapen head and distinctive facial features, and a skin abnormality called cutis gyrata. The most common mutation replaces the amino acid tyrosine with the amino acid cysteine at position 375 in the protein (written as Tyr375Cys). The FGFR2 gene mutations that cause Beare-Stevenson cutis gyrata syndrome appear to overactivate signaling by the FGFR2 protein, which promotes the premature fusion of bones in the skull and alters skin development.

Crouzon syndrome

At least 60 mutations in the FGFR2 gene can cause Crouzon syndrome, a condition that causes craniosynostosis, leading to a misshapen head and distinctive facial features. Affected individuals can have vision, hearing, and dental problems related to abnormal skull development. Most of the mutations that cause Crouzon syndrome change single DNA building blocks (nucleotides) in the FGFR2 gene. Insertions and deletions of a small number of nucleotides are also known to cause the disorder. These mutations in the FGFR2 gene appear to overactivate signaling by the FGFR2 protein, which promotes premature fusion of bones in the skull.

Jackson-Weiss syndrome

At least six mutations in the FGFR2 gene have been found to cause Jackson-Weiss syndrome. This condition causes craniosynostosis, leading to a misshapen head and distinctive facial features. Affected individuals also have foot abnormalities. Each of the mutations associated with Jackson-Weiss syndrome changes a single amino acid in a region of the FGFR2 protein known as the IgIII domain, which is critical for receiving signals and interacting with growth factors. The mutations appear to overactivate signaling by the FGFR2 protein, which promotes premature fusion of skull bones and affects development of bones in the feet.

Lacrimo-auriculo-dento-digital syndrome

At least two mutations in the FGFR2 gene have been found to cause lacrimo-auriculo-dento-digital (LADD) syndrome. The main features of LADD syndrome are abnormal tear production, malformed ears with hearing loss, decreased saliva production, small teeth, and hand deformities. A mutation that occurs in some people with LADD syndrome replaces the amino acid alanine with the amino acid threonine at position 628 in the FGFR2 protein (written as Ala628Thr or A628T).

The FGFR2 gene mutations that cause LADD syndrome reduce the FGFR2 protein's ability to trigger chemical signaling within cells when it binds to its growth factor. These defects in cell signaling disrupt cell maturation and development, which results in abnormal formation of glands in the eyes and mouth, the ears, and the skeleton in people with LADD syndrome.

Pfeiffer syndrome

More than 25 mutations in the FGFR2 gene can cause Pfeiffer syndrome, a condition that causes craniosynostosis, leading to a misshapen head and distinctive facial features. People with this condition can also have elbow, hand, or foot abnormalities. The severity of this condition varies widely among affected individuals. Several of the mutations that cause this condition change the number of cysteine amino acids in a critical region of the FGFR2 protein known as the IgIII domain. The remaining mutations affect amino acids other than cysteine or result in an FGFR2 protein that is missing one or more amino acids. These mutations appear to overactivate signaling by the FGFR2 protein, which promotes premature fusion of skull bones and affects the development of bones in the hands and feet.

Breast cancer

MedlinePlus Genetics provides information about Breast cancer

Cholangiocarcinoma

MedlinePlus Genetics provides information about Cholangiocarcinoma

Epidermal nevus

MedlinePlus Genetics provides information about Epidermal nevus

Prostate cancer

MedlinePlus Genetics provides information about Prostate cancer

Other disorders

Mutations in the FGFR2 gene can cause other disorders that affect bone development. FGFR2 gene mutations have been found in individuals with conditions called bent bone dysplasia syndrome and Antley-Bixler syndrome.

Bent bone dysplasia syndrome is characterized by the underdevelopment of certain bones, bent long bones in the arms and legs, low bone mineral density (osteopenia), and distinctive facial features. Signs and symptoms of Antley-Bixler syndrome typically include craniosynostosis, distinctive facial features, arm and leg malformations, and genitourinary abnormalities.

The FGFR2 gene mutations that cause these conditions appear to overactivate signaling by the FGFR2 protein, leading to skeletal abnormalities and other characteristic features of the conditions.

The particular condition that results from FGFR2 gene mutations may be determined by the region of the gene in which the mutation occurs. It is likely that mutations in different regions of the FGFR2 gene have varied effects on the protein, resulting in a range of protein activity and signaling. Changes in other genes or modifications of DNA that do not alter the DNA sequence (epigenetic changes) may also help determine the resulting signs and symptoms. The different factors lead to similar but distinct features of the many conditions associated with FGFR2 gene mutations.

Cancers

Alterations in the activity (expression) of the FGFR2 gene are associated with certain cancers. The altered gene expression may enhance several cancer-promoting cell functions such as cell division (proliferation), cell movement, and the formation of new blood vessels (angiogenesis) that nourish a growing tumor.

The FGFR2 gene is abnormally active (overexpressed) in certain types of stomach (gastric) cancers, and this amplification is associated with a poor disease outcome. Abnormal expression of the FGFR2 gene is also found in patients with prostate cancer. A shift in the expression of two specific FGFR2 isoforms, IIIb and IIIc, appears to correlate with prostate cancer progression. This change in expression is complex, however, and varies depending on the type of prostate tumor. More advanced tumors may show an increase in the IIIb isoform, while other prostate tumors show a decrease in IIIb but an increase in IIIc. Altered FGFR2 gene expression is also associated with ovarian, breast, cervical, endometrial, pancreatic, lung, and head and neck cancers.

Other Names for This Gene

• bacteria-expressed kinase
• BEK
• BEK fibroblast growth factor receptor
• BEK protein tyrosine kinase
• BFR-1
• CD332
• CEK3
• CFD1
• ECT1
• FGF receptor
• FGFR2_HUMAN
• K-SAM
• keratinocyte growth factor receptor
• KGFR
• protein tyrosine kinase, receptor like 14
• TK14
• TK25
• tyrosylprotein kinase

Genomic Location

Normal Function

The FGFR3 gene provides instructions for making a protein called fibroblast growth factor receptor 3. This protein is part of a family of four fibroblast growth factor receptors that share similar structures and functions. These proteins play a role in several important cellular processes, including regulation of cell growth and division (proliferation), determination of cell type, formation of blood vessels (angiogenesis), wound healing, and embryo development.

The FGFR3 protein spans the cell membrane, so that one end of the protein remains inside the cell and the other end projects from the outer surface of the cell. This allows the protein to interact with specific growth factors outside the cell and receive signals that control growth and development. When these growth factors attach to the FGFR3 protein, the protein is turned on (activated). This triggers a cascade of chemical reactions inside the cell that instruct the cell to undergo certain changes, such as maturing to take on specialized functions (differentiation).

Several versions (isoforms) of the FGFR3 protein are produced from the FGFR3 gene. The different isoforms are found in various tissues of the body, and they interact with a variety of growth factors. Many isoforms are found in the cells that form bones. Researchers believe that the FGFR3 protein regulates bone growth by limiting the formation of bone from cartilage. Cartilage is a tough but flexible tissue that makes up much of the skeleton during early development. The process of converting cartilage to bone is called ossification. One particular isoform of the FGFR3 protein is found specifically in cells that line the surfaces of the body (epithelial cells), including the cells that form the outermost layer of skin, called the epidermis.

Health Conditions Related to Genetic Changes

Achondroplasia

Two variants (also called mutations) in the FGFR3 gene cause more than 99 percent of cases of achondroplasia, which is the most common form of short-limbed dwarfism. Both variants lead to the same change in the FGFR3 protein. This change replaces the protein building block (amino acid) glycine with the amino acid arginine at a specific location within the FGFR3 protein. This genetic change causes the receptor to be overly active, which leads to the disturbances in bone growth that occur in people with this disorder.

Crouzon syndrome with acanthosis nigricans

A single FGFR3 gene variant has been identified in people with Crouzon syndrome with acanthosis nigricans. This rare condition causes premature joining of the bones of the skull (craniosynostosis), leading to a misshapen head and distinctive facial features. It also causes a skin abnormality called acanthosis nigricans that is characterized by thick, dark, velvety skin in body folds and creases.

The genetic change that causes Crouzon syndrome with acanthosis nigricans replaces the amino acid alanine with the amino acid glutamic acid at a specific position in the FGFR3 protein (known as A391E). The altered protein is activated more easily than normal, and this overactivity disrupts the normal growth of the skull bones and skin, leading to features of Crouzon syndrome with acanthosis nigricans.

Epidermal nevus

Variants in the FGFR3 gene have been found in approximately 30 percent of people with a certain type of epidermal nevus (plural: nevi). Specifically, FGFR3 gene variants are associated with some keratinocytic epidermal nevi, which are abnormal skin growths that are composed of skin cells called keratinocytes. FGFR3 gene variants have not been found in people with other types of epidermal nevi.

The most common FGFR3 gene variant in people with epidermal nevi changes a single amino acid in the FGFR3 protein. This variant creates a protein that turns on without the help of a growth factor, which means that the FGFR3 protein is constantly active. Studies suggest that cells with this FGFR3 gene variant grow larger and divide more often than normal cells. The resulting overgrowth of skin cells leads to epidermal nevi.

The FGFR3 gene variant found in people with epidermal nevi also occur in people with another skin abnormality called seborrheic keratosis and in people with skeletal disorders known as thanatophoric dysplasia, Crouzon syndrome with acanthosis nigricans, and severe achondroplasia with developmental delay and acanthosis nigricans (SADDAN). However, in contrast to the skeletal conditions, the variants associated with epidermal nevi (and seborrheic keratosis) are somatic variants. Somatic gene variants are not inherited; they are acquired during a person's lifetime and are present only in certain cells. In epidermal nevi, the variants occur during the early stages of development and are present only in the cells of the nevus, not in the normal skin cells surrounding it.

Hypochondroplasia

Multiple variants in the FGFR3 gene have been identified in people with hypochondroplasia, another form of short-limbed dwarfism that is milder than achondroplasia. Many cases are caused by one of two specific FGFR3 gene variants, both of which lead to the same change in the FGFR3 protein. This change replaces the amino acid asparagine with the amino acid lysine at a specific position in the FGFR3 protein (known as N540K). Other FGFR3 gene variants probably cause a small number of cases of hypochondroplasia. These hypochondroplasia-associated variants probably cause the receptor to be mildly overactive, which leads to the disturbances in bone growth that occur in people with this disorder.

Lacrimo-auriculo-dento-digital syndrome

At least one variant in the FGFR3 gene has been found to cause lacrimo-auriculo-dento-digital (LADD) syndrome. The main features of LADD syndrome are abnormal tear production, malformed ears with hearing loss, decreased saliva production, small teeth, and hand deformities. The FGFR3 gene variant that causes LADD syndrome replaces the amino acid aspartic acid with the amino acid asparagine at a specific position in the receptor protein (known as D513N). When a growth factor attaches to this modified version of FGFR3 receptor protein, the protein has difficulty triggering the normal chemical signals within the cell. These defects in cell signaling disrupt cell maturation and development, which results in abnormal formation of the ears, the skeleton, and the glands in the eyes and mouth in people with LADD syndrome.

Muenke syndrome

A single variant in the FGFR3 gene has been shown to cause Muenke syndrome, which is a condition that causes craniosynostosis and leads to a misshapen head and distinctive facial features. Additional signs and symptoms can include hearing loss, subtle hand and foot abnormalities, and developmental delays. The variant that causes Muenke syndrome substitutes the amino acid arginine for the amino acid proline at a specific position in the FGFR3 protein (known as P250R). This variant results in the production of a receptor that is overly active, which allows the bones of the skull to fuse sooner than normal.

The FGFR3 gene variant that causes Muenke syndrome has also been identified in some people with isolated coronal craniosynostosis. This condition is characterized by a premature fusion of the growth line that runs across the top of the head from ear to ear (the coronal suture). People with isolated coronal craniosynostosis do not have the other features that are sometimes associated with Muenke syndrome (such as hand and foot abnormalities).

SADDAN

One variant in the FGFR3 gene has been identified in people with SADDAN (severe achondroplasia with developmental delay and acanthosis nigricans). SADDAN is characterized by short-limb dwarfism (achondroplasia); profound developmental delay; and thick, dark, velvety skin. The genetic change that causes this condition substitutes the amino acid methionine for the amino acid lysine at a specific position in the FGFR3 protein (known as K650M). Researchers believe that this variant strongly overactivates the FGFR3 protein, which leads to severe problems with bone growth. It remains uncertain how the variant causes developmental delays or acanthosis nigricans.

Thanatophoric dysplasia

Variants in the FGFR3 gene have been identified in people with thanatophoric dysplasia, which is a severe skeletal disorder characterized by extremely short limbs and a narrow chest. Most individuals with thanatophoric dysplasia are stillborn or die shortly after birth.

Most of these FGFR3 gene variants change a single amino acid in the FGFR3 protein or create a protein that is longer than normal. These variants cause type I thanatophoric dysplasia.

Only one FGFR3 gene variant has been shown to cause type II thanatophoric dysplasia. This variant affects a different part of the FGFR3 protein than the variants that cause type I thanatophoric dysplasia.

The genetic changes responsible for both types of thanatophoric dysplasia cause the FGFR3 receptor to be overactive, which leads to the severe problems with bone growth that occur in people with this condition.

Bladder cancer

Somatic variants in the FGFR3 gene have been found in some cases of bladder cancer. Bladder cancer is a disease in which certain cells in the bladder multiply uncontrollably to form a tumor. Bladder cancer may cause blood in the urine, pain during urination, frequent urination, the feeling of needing to urinate without being able to, or lower back pain.

Bladder cancer is generally divided into two types, non-muscle invasive bladder cancer (NMIBC) and muscle-invasive bladder cancer (MIBC), based on where in the bladder the tumor is located. Approximately 80 percent of NMIBC tumors have FGFR3 gene variants. FGFR3 gene variants change single amino acids in the FGFR3 protein, which appears to overactivate protein signaling. As a result, bladder cells are likely directed to grow and divide abnormally. This uncontrolled cell division leads to bladder cancer.

Multiple myeloma

MedlinePlus Genetics provides information about Multiple myeloma

Other disorders

At least two FGFR3 gene variants have been found to cause a rare disorder called camptodactyly, tall stature, hearing loss (CATSHL) syndrome. Individuals with this condition are taller than average and typically have hearing loss. They can also have permanently bent fingers or toes (camptodactyly) and other skeletal abnormalities. Researchers suggest that the FGFR3 gene variants involved in CATSHL syndrome reduce the function of the FGFR3 protein, although it is unclear how the variants cause the signs and symptoms of the condition.

Variants in the FGFR3 gene have been found in 30 to 70 percent of people with seborrheic keratoses, which are small, dark, noncancerous (benign) tumors of the skin caused by overgrowth of skin cells. Seborrheic keratoses develop in adulthood and are seen in a majority of people older than age 50. The FGFR3 gene variants associated with seborrheic keratoses are somatic variants, which means that they are only found in the tumors and are not inherited. These variants change single amino acids in the FGFR3 protein. The altered FGFR3 proteins are abnormally active, which results in the overgrowth of skin cells. It has been suggested that the variants involved in seborrheic keratosis may be caused by exposure to ultraviolet light.

A somatic FGFR3 gene mutation that causes epidermal nevus can also cause Garcia-Hafner-Happle syndrome (also known as fibroblast growth factor receptor 3 epidermal nevus syndrome). This condition is characterized by a soft, velvety keratinocytic epidermal nevus and neurological problems, such as seizures, intellectual disability, underdevelopment of the tissue that connects the two halves of the brain (corpus callosum), and a loss of brain cells (cortical atrophy). It is thought that the neurological problems occur because the somatic variant affects brain cells in addition to cells in the skin.

Other cancers

In addition to bladder cancer, somatic variants in the FGFR3 gene have been associated with a cancer of white blood cells (multiple myeloma) and cervical cancer. Some cases of multiple myeloma are related to rearrangements (translocations) of genetic material between chromosome 14 and the region of chromosome 4 that contains the FGFR3 gene. Variants that have been associated with cervical cancer are changes in single DNA building blocks (nucleotides) in the FGFR3 gene.

FGFR3 gene variants that lead to multiple myeloma and cervical cancer are thought to overactivate the FGFR3 protein in certain cells. The mutated receptor directs the cells to grow and divide in the absence of signals from outside the cell. This uncontrolled division can lead to the overgrowth of cancer cells.

Other Names for This Gene

• ACH
• CD333
• CEK2
• FGFR-3
• FGR3_HUMAN
• fibroblast growth factor receptor 3 (achondroplasia, thanatophoric dwarfism)
• HBGFR
• hydroxyaryl-protein kinase
• JTK4
• tyrosine kinase JTK4

Genomic Location

Normal Function

The HRAS gene provides instructions for making a protein called H-Ras that is involved primarily in regulating cell division. Through a process known as signal transduction, the H-Ras protein relays signals from outside the cell to the cell's nucleus. These signals instruct the cell to grow or divide. The H-Ras protein is a GTPase, which means it converts a molecule called GTP into another molecule called GDP. The H-Ras protein acts like a switch, and it is turned on and off by GTP and GDP molecules. To transmit signals, the protein must be turned on by attaching (binding) to a molecule of GTP. The H-Ras protein is turned off (inactivated) when it converts GTP to GDP. When the protein is bound to GDP, it does not relay signals to the cell's nucleus.

The HRAS gene belongs to a class of genes known as oncogenes. When mutated, oncogenes have the potential to cause normal cells to become cancerous. The HRAS gene is in the Ras family of oncogenes, which also includes two other genes: KRAS and NRAS. The proteins produced from these three genes are GTPases. These proteins play important roles in cell division, the process by which cells mature to carry out specific functions (cell differentiation), and the self-destruction of cells (apoptosis).

Health Conditions Related to Genetic Changes

Costello syndrome

At least 15 mutations in the HRAS gene have been identified in people with Costello syndrome, a rare condition that affects many parts of the body and increases the risk of developing cancerous and noncancerous tumors. The mutations change single protein building blocks (amino acids) in a critical region of the H-Ras protein. The most common mutation accounts for more than 80 percent of all cases of Costello syndrome; it replaces the amino acid glycine with the amino acid serine at protein position 12 (written as Gly12Ser or G12S).

The HRAS gene mutations that cause Costello syndrome lead to the production of an H-Ras protein that is abnormally turned on (active) in cells throughout the body. Instead of triggering cell growth in response to signals from outside the cell, the overactive protein directs cells to grow and divide constantly. This uncontrolled cell division can result in the formation of noncancerous and cancerous tumors. Researchers are uncertain how mutations in the HRAS gene cause the other features of Costello syndrome (such as intellectual disability, distinctive facial features, and heart problems), but many of the signs and symptoms probably result from cell overgrowth and abnormal cell division.

Epidermal nevus

Mutations in the HRAS gene are involved in the development of abnormal, noncancerous patches of skin called epidermal nevi (singular: nevus). These patches are caused by an overgrowth of cells in the outer layer of skin (the epidermis).

HRAS gene mutations have been found in a majority of people with a certain type of epidermal nevus called a nevus sebaceous. This type is classified as an organoid epidermal nevus because it involves cells that make up structures (or organs) in the skin, usually the hair follicles, the sweat glands, or the sebaceous glands (glands in the skin that produce a substance that protects the skin and hair). Additional tumors often develop in the region of the nevus sebaceous. In rare cases, these tumors are cancerous.

HRAS gene mutations are less commonly found in keratinocytic epidermal nevi, a type of epidermal nevus that involves a particular type of epidermal cell called a keratinocyte. Keratinocytic epidermal nevi are not typically associated with additional tumors.

Epidermal nevi are caused by gene mutations that are acquired during the early stages of development before birth. The mutations are present only in the cells of the nevus and not the normal skin cells surrounding it. These changes, which are called somatic mutations, are not inherited. The somatic HRAS gene mutations involved in epidermal nevi, change single amino acids in the H-Ras protein. The most common mutation replaces the amino acid glycine with the amino acid valine at protein position 12 (written as Gly12Val or G12V). These mutations lead to production of an H-Ras protein that is always turned on. The affected skin cells grow and divide more than normal cells, resulting in epidermal nevi.

Bladder cancer

MedlinePlus Genetics provides information about Bladder cancer

Head and neck squamous cell carcinoma

MedlinePlus Genetics provides information about Head and neck squamous cell carcinoma

Other disorders

Somatic HRAS gene mutations are also involved in development of Schimmelpenning syndrome, which is a type of epidermal nevus syndrome. Affected individuals have a type of epidermal nevus called nevus sebaceous (described above) in addition to abnormalities of the brain, eyes, or bones. Problems with these other systems can include seizures, intellectual disability, extra or missing pieces of tissue in eye structures (choristomas or colobomas), underdeveloped bones, and a disorder called rickets that leads to softening and weakening of the bones. Schimmelpenning syndrome is caused by the same gene mutations involved in epidermal nevus. It is thought that the additional signs and symptoms occur because the somatic mutation affects other tissues in addition to the skin.

Other cancers

Somatic mutations in the HRAS gene are probably involved in the development of several additional types of cancer. These mutations lead to a version of the H-Ras protein that is always active and can direct cells to grow and divide without control. Studies suggest that HRAS gene mutations may be common in thyroid and kidney cancers. Increased activity (expression) of the HRAS gene has also been reported in other types of cancer.

Other Names for This Gene

• C-H-RAS
• Harvey murine sarcoma virus oncogene
• Harvey rat sarcoma viral oncogene homolog
• HRAS1
• Oncogene, G-RAS
• RASH1
• RASH_HUMAN
• Transformation gene: Oncogene HaMSV
• Transforming protein P21/H-RAS-1 (C-H-RAS)
• v-Ha-ras Harvey rat sarcoma viral oncogene homolog

Genomic Location

Normal Function

The KRAS gene provides instructions for making a protein called K-Ras that is part of a signaling pathway known as the RAS/MAPK pathway. The protein relays signals from outside the cell to the cell's nucleus. These signals instruct the cell to grow and divide (proliferate) or to mature and take on specialized functions (differentiate). The K-Ras protein is a GTPase, which means it converts a molecule called GTP into another molecule called GDP. In this way the K-Ras protein acts like a switch that is turned on and off by the GTP and GDP molecules. To transmit signals, it must be turned on by attaching (binding) to a molecule of GTP. The K-Ras protein is turned off (inactivated) when it converts the GTP to GDP. When the protein is bound to GDP, it does not relay signals to the cell's nucleus.

The KRAS gene belongs to a class of genes known as oncogenes. When mutated, oncogenes have the potential to cause normal cells to become cancerous. The KRAS gene is in the Ras family of oncogenes, which also includes two other genes: HRAS and NRAS. These proteins play important roles in cell division, cell differentiation, and the self-destruction of cells (apoptosis).

Health Conditions Related to Genetic Changes

Cardiofaciocutaneous syndrome

Mutations in the KRAS gene are an uncommon cause of cardiofaciocutaneous syndrome, accounting for less than 5 percent of cases. Several mutations in the KRAS gene have been identified in people with characteristic features of the disorder, which include heart defects, distinctive facial features, and skin abnormalities. These mutations are present in all of the body's cells and are known as germline mutations. The mutations change single protein building blocks (amino acids) in the K-Ras protein. The altered protein shows increased GTP binding and a decreased ability to convert GTP to GDP. These effects lead to prolonged activation of the K-Ras protein, which alters tightly regulated RAS/MAPK signaling during development. The altered signaling interferes with the development of organs and tissues throughout the body, leading to the varied signs and symptoms of cardiofaciocutaneous syndrome.

Noonan syndrome

MedlinePlus Genetics provides information about Noonan syndrome

Autoimmune lymphoproliferative syndrome

MedlinePlus Genetics provides information about Autoimmune lymphoproliferative syndrome

Cholangiocarcinoma

MedlinePlus Genetics provides information about Cholangiocarcinoma

Core binding factor acute myeloid leukemia

MedlinePlus Genetics provides information about Core binding factor acute myeloid leukemia

Epidermal nevus

MedlinePlus Genetics provides information about Epidermal nevus

Lung cancer

At least three mutations in the KRAS gene have been associated with lung cancer. Lung cancer is a disease in which certain cells in the lungs become abnormal and multiply uncontrollably to form a tumor. Lung cancer may not cause signs or symptoms in its early stages. These KRAS gene mutations are somatic, which means they are acquired during a person's lifetime and are present only in tumor cells. Somatic mutations are not inherited. Nearly all of the KRAS gene mutations associated with lung cancer change the amino acid glycine at position 12 or 13 (Gly12 or Gly13) or change the amino acid glutamine at position 61 (Gln61) in the K-Ras protein. These mutations result in a K-Ras protein that is constantly turned on (constitutively activated) and directing cells to proliferate in an uncontrolled way, which leads to tumor formation. When these genetic changes occur in cells in the lungs, lung cancer can develop.

KRAS gene mutations are found in 15 to 25 percent of all lung cancer cases but are more frequent in white populations than in Asian populations; 25 to 50 percent of whites with lung cancer have KRAS gene mutations, whereas 5 to 15 percent of Asians with lung cancer have KRAS gene mutations.

KRAS gene mutations are much more common in long-term tobacco smokers with lung cancer than in nonsmokers. Lung cancers with KRAS gene mutations typically indicate a poor prognosis and are associated with resistance to several cancer treatments.

Other cancers

Somatic mutations in the KRAS gene are involved in the development of several types of cancer, particularly pancreatic and colorectal cancers. These mutations lead to a K-Ras protein that is more strongly overactivated than the mutations that cause cardiofaciocutaneous syndrome (described above). The abnormal K-Ras protein is always active and can direct cells to proliferate in an uncontrolled way.

Other disorders

Germline mutations in the KRAS gene also cause a disorder whose major features overlap with those of cardiofaciocutaneous syndrome (described above) and two related disorders called Noonan syndrome and Costello syndrome. This condition has been described as the KRAS mutation-associated phenotype. People with this condition have variable signs and symptoms that include mild to moderate intellectual disability, distinctive facial features, short stature, an unusually large head (macrocephaly), and hair that is sparse and thin.

At least nine mutations in the KRAS gene have been reported in people with this disorder. Each of these mutations changes single amino acids in the K-Ras protein. These genetic changes abnormally activate the protein, which alters chemical signaling in cells throughout the body. The altered signaling interferes with the normal development of many organs and tissues, resulting in the characteristic features of the KRAS mutation-associated phenotype.

Other Names for This Gene

• C-K-RAS
• c-K-ras protein
• c-K-ras2 protein
• c-Kirsten-ras protein
• cellular c-Ki-ras2 proto-oncogene
• K-ras p21 protein
• KI-RAS
• Kirsten rat sarcoma viral oncogene homolog
• KRAS1
• PR310 c-K-ras oncogene
• RASK2
• RASK_HUMAN
• transforming protein p21
• v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog

Genomic Location

Normal Function

The NRAS gene provides instructions for making a protein called N-Ras that is involved primarily in regulating cell division. Through a process known as signal transduction, the protein relays signals from outside the cell to the cell's nucleus. These signals instruct the cell to grow and divide (proliferate) or to mature and take on specialized functions (differentiate). The N-Ras protein is a GTPase, which means it converts a molecule called GTP into another molecule called GDP. The N-Ras protein acts like a switch, and it is turned on and off by the GTP and GDP molecules. To transmit signals, the N-Ras protein must be turned on by attaching (binding) to a molecule of GTP. The N-Ras protein is turned off (inactivated) when it converts the GTP to GDP. When the protein is bound to GDP, it does not relay signals to the cell's nucleus.

The NRAS gene belongs to a class of genes known as oncogenes. When mutated, oncogenes have the potential to cause normal cells to become cancerous. The NRAS gene is in the Ras family of oncogenes, which also includes two other genes: HRAS and KRAS. The proteins produced from these three genes are GTPases. These proteins play important roles in cell division, cell differentiation, and the self-destruction of cells (apoptosis).

Health Conditions Related to Genetic Changes

Giant congenital melanocytic nevus

At least two mutations in the NRAS gene have been found to cause giant congenital melanocytic nevus. This condition is characterized by a large, noncancerous patch of abnormally dark skin that is present from birth and an increased risk of a type of skin cell cancer called melanoma. The NRAS gene mutations that cause this condition are somatic, meaning that they occur during a person's lifetime and are present only in certain cells. The mutations occur during embryonic development in cells that will develop into pigment-producing skin cells (melanocytes). The mutations that cause this condition affect a single protein building block (amino acid) in the N-Ras protein. Specifically, the mutations replace the amino acid glutamine at position 61 with either lysine or arginine (written as Gln61Lys or Q61K and Gln61Arg or Q61R). These mutations lead to production of an N-Ras protein that is constantly turned on (constitutively active). Instead of triggering cell growth in response to particular signals from outside the cell, the overactive protein directs cells to grow and divide constantly. The uncontrolled cell growth of early melanocytes leads to a large patch of darkly pigmented skin characteristic of giant congenital melanocytic nevus. Uncontrolled cell growth of melanocytes after birth contributes to the risk of developing melanoma in people with giant congenital melanocytic nevus.

Noonan syndrome

MedlinePlus Genetics provides information about Noonan syndrome

Autoimmune lymphoproliferative syndrome

MedlinePlus Genetics provides information about Autoimmune lymphoproliferative syndrome

Cholangiocarcinoma

MedlinePlus Genetics provides information about Cholangiocarcinoma

Core binding factor acute myeloid leukemia

MedlinePlus Genetics provides information about Core binding factor acute myeloid leukemia

Cytogenetically normal acute myeloid leukemia

MedlinePlus Genetics provides information about Cytogenetically normal acute myeloid leukemia

Epidermal nevus

MedlinePlus Genetics provides information about Epidermal nevus

Lung cancer

MedlinePlus Genetics provides information about Lung cancer

Melanoma

MedlinePlus Genetics provides information about Melanoma

Cancers

Somatic mutations in the NRAS gene are involved in the development of several types of cancer. These mutations lead to an N-Ras protein that is constitutively active and can direct cells to grow and divide without control. Studies suggest that NRAS gene mutations are common in the aggressive skin cancer melanoma, including individuals without giant congenital melanocytic nevus (described above). Mutations in the NRAS gene have also been found in other types of cancer.

For reasons that are unclear, inherited mutations in the NRAS gene do not appear to increase the risk of cancer in people with Noonan syndrome.

Other Names for This Gene

• GTPase NRas
• GTPase NRas precursor
• N-ras
• N-ras protein part 4
• neuroblastoma RAS viral (v-ras) oncogene homolog
• neuroblastoma RAS viral oncogene homolog
• NRAS1
• NS6
• RASN_HUMAN
• transforming protein N-Ras
• v-ras neuroblastoma RAS viral oncogene homolog

Genomic Location

Normal Function

The PIK3CA gene provides instructions for making the p110 alpha (p110α) protein, which is one piece (subunit) of an enzyme called phosphatidylinositol 3-kinase (PI3K). The p110α protein is called the catalytic subunit because it performs the action of PI3K, while the other subunit (produced by a different gene) regulates the enzyme's activity.

Like other kinases, PI3K adds a cluster of oxygen and phosphorus atoms (a phosphate group) to other proteins through a process called phosphorylation. PI3K phosphorylates certain signaling molecules, which triggers a series of additional reactions that transmit chemical signals within cells. PI3K signaling is important for many cell activities, including cell growth and division (proliferation), movement (migration) of cells, production of new proteins, transport of materials within cells, and cell survival. Studies suggest that PI3K signaling may be involved in the regulation of several hormones and may play a role in the maturation of fat cells (adipocytes).

Health Conditions Related to Genetic Changes

Bladder cancer

Somatic mutations in the PIK3CA gene have been found in some cases of bladder cancer. Bladder cancer is a disease in which certain cells in the bladder become abnormal and multiply uncontrollably to form a tumor. Bladder cancer may cause blood in the urine, pain during urination, frequent urination, the feeling of needing to urinate without being able to, or lower back pain.

Bladder cancer is generally divided into two types, non-muscle invasive bladder cancer (NMIBC) and muscle-invasive bladder cancer (MIBC), based on where in the bladder the tumor is located. A PIK3CA gene mutation has been found in about half of NMIBC tumors. These mutations change single amino acids in the p110α protein. The altered p110α subunit appears to allow PI3K to become overactive. The increased signaling by PI3K likely contributes to uncontrolled cell growth and division and the formation of bladder cancer.

Epidermal nevus

Mutations in the PIK3CA gene have been found in up to a quarter of people with a certain type of epidermal nevus (plural: nevi). Specifically, PIK3CA gene mutations are associated with some keratinocytic epidermal nevi, which are abnormal skin growths that are composed of skin cells called keratinocytes. PIK3CA gene mutations have not been found in other types of epidermal nevi.

The most common PIK3CA gene mutation found in epidermal nevi replaces the protein building block (amino acid) glutamic acid with the amino acid glycine at position 545 of the p110α protein (written as Glu545Gly or E545G). Studies suggest that this mutation causes cells to grow and divide more than normal. The resulting overgrowth of skin cells leads to formation of epidermal nevi. The genetic changes associated with this condition are somatic mutations and are present only in the cells of the nevus.

Despite the involvement of PIK3CA gene mutations in many cancers (described above) and the overgrowth of cells caused by changes in this gene, individuals with an epidermal nevus do not appear to have an elevated risk of developing cancer.

Klippel-Trenaunay syndrome

At least five mutations in the PIK3CA gene have been found to cause Klippel-Trenaunay syndrome. This condition is characterized by a red birthmark called a port-wine stain, abnormal overgrowth of soft tissues (such as skin and muscles) and bones, and vein malformations. The PIK3CA gene mutations associated with this condition arise randomly in one cell during the early stages of development before birth. These changes, which are called somatic mutations, are not inherited. As cells continue to divide during development, cells arising from the first abnormal cell will have the mutation, and other cells will not. This mixture of cells with and without a genetic mutation is known as mosaicism.

The PIK3CA gene mutations associated with Klippel-Trenaunay syndrome change single protein building blocks (amino acids) in the p110α protein. These changes lead to production of an altered p110α subunit that makes PI3K abnormally active. The altered enzyme triggers unregulated chemical signaling in cells, which allows cells to grow and divide continuously. Increased cell proliferation leads to abnormal growth of the bones, soft tissues, and blood vessels.

Despite the involvement of PIK3CA gene mutations in cancer (described below) and the overgrowth of cells caused by changes in this gene, individuals with Klippel-Trenaunay syndrome do not appear to have an elevated risk of developing cancer.

Megalencephaly-capillary malformation syndrome

At least 15 mutations in the PIK3CA gene have been found to cause a condition known as megalencephaly-capillary malformation syndrome (MCAP), which is characterized by overgrowth of the brain (megalencephaly) and abnormalities caused by enlargement of small blood vessels in the skin (capillary malformations). The mutations that cause MCAP overlap with those that cause Klippel-Trenaunay syndrome (described above). These mutations are not inherited from a parent; they arise randomly in one cell during the early stages of development before birth and lead to mosaicism. The presence of the mutation in different tissues helps explain why multiple conditions can be caused by the same gene mutations.

Most PIK3CA gene mutations involved in MCAP change single amino acids in the p110α protein. These mutations lead to the production of an altered p110α subunit that makes PI3K abnormally active. The resulting unregulated signaling allows cells to grow and divide continuously. Increased cell proliferation in the brain and other tissues and organs leads to the overgrowth characteristic of MCAP.

Despite the involvement of the PIK3CA gene mutations in many cancers (described below) and the overgrowth of cells caused by changes in this gene, individuals with MCAP do not appear to have an elevated risk of developing cancer.

Cholangiocarcinoma

MedlinePlus Genetics provides information about Cholangiocarcinoma

Cowden syndrome

MedlinePlus Genetics provides information about Cowden syndrome

Head and neck squamous cell carcinoma

MedlinePlus Genetics provides information about Head and neck squamous cell carcinoma

Lung cancer

MedlinePlus Genetics provides information about Lung cancer

Ovarian cancer

MedlinePlus Genetics provides information about Ovarian cancer

Other disorders

Mutations in the PIK3CA gene, including those found in some cancers, have been found to cause several other conditions related to overgrowth of tissues. These conditions include hemimegalencephaly; fibroadipose hyperplasia; and a condition called congenital lipomatous overgrowth, vascular malformations, epidermal nevi, and skeletal or spinal abnormalities (CLOVES) syndrome. Hemimegalencephaly is characterized by enlargement of one side of the brain and can cause seizures and intellectual disability. Fibroadipose hyperplasia causes overgrowth of fibrous and fatty (adipose) tissues in various regions of the body, which leads to enlargement of different portions of the body, such as the lower body, an individual arm or leg, or one or more fingers or toes. CLOVES syndrome has multiple features, including an overgrowth of adipose tissue in the abdomen that is often associated with a reddish birthmark on the skin over it, in addition to blood vessel, skin, and bone abnormalities. It is unknown whether individuals with these disorders have an elevated risk of developing cancer.

As in Klippel-Trenaunay syndrome, MCAP, and epidermal nevus (each described above), the genetic changes involved in these disorders occur early in development and are found in only some of the body's cells. This mosaicism helps explain why different conditions involving different parts of the body can be caused by the same gene mutations. Together, the overgrowth disorders caused by PIK3CA gene mutations are known as the PIK3CA-related overgrowth spectrum (PROS).

Cancers

Somatic mutations in the PIK3CA gene are found in many other types of cancer, including cancer of the ovary, breast, lung, brain, and stomach. These mutations are also involved in cancer of the colon (large intestine) and rectum, which are collectively referred to as colorectal cancer. These mutations change single amino acids in the p110α protein. Two common mutations occur in the same region and change the amino acid glutamate at position 542 or at position 545 of the p110α protein to the amino acid lysine (written as Glu542Lys and Glu545Lys, respectively). Two other common mutations occur in another region, changing the amino acid histidine at position 1047 of p110α to the amino acid arginine or leucine (written as His1047Arg and His1047Leu, respectively).

Cancer-associated PIK3CA gene mutations result in production of an altered p110α subunit that allows PI3K to signal without regulation. The increased signaling can contribute to an uncontrolled proliferation of cells, leading to the development of cancer. However, PIK3CA gene mutations may not cause cancer by themselves. Researchers suspect that some cases of cancer likely result from a combination of mutations in PIK3CA and mutations in other genes that influence cancer risk.

Other Names for This Gene

• p110-alpha
• phosphatidylinositol 3-kinase, catalytic, 110-KD, alpha
• phosphatidylinositol 3-kinase, catalytic, alpha polypeptide
• phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform
• phosphatidylinositol-4,5-bisphosphate 3-kinase 110 kDa catalytic subunit alpha
• phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit alpha
• phosphoinositide-3-kinase, catalytic, alpha polypeptide
• PI3-kinase p110 subunit alpha
• PI3K
• PI3K-alpha
• PK3CA_HUMAN
• ptdIns-3-kinase subunit p110-alpha
• serine/threonine protein kinase PIK3CA

Genomic Location

This condition is generally not inherited but arises from mutations in the body's cells that occur after conception. This type of alteration is called a somatic mutation.

Occasionally, a somatic FGFR3 gene mutation occurs in an affected parent's reproductive cells (sperm or eggs) and is passed to the next generation. When this occurs, the gene mutation is found in every cell in the child's body, which results in skeletal abnormalities rather than epidermal nevus.

Epidermal nevi are estimated to occur in 1 to 3 in 1,000 people.