Epidermal nevus (Epidermal Nevus) - Genes FGFR2, FGFR3, HRAS, KRAS, NRAS and PIK3CA


The epidermal nevus is a benign anomaly in the development of the epidermis caused by excessive growth of skin cells. Generally, these anomalies are manifested at birth or develop in early childhood. They can be flat or raised spots, skin tanning or velvety patches. As the age of affected individuals progresses, the nevus can become thicker and darker and develop a warty appearance. Often nevus epidermal follow a pattern in the skin known as Blaschko lines.

They described various types of epidermal nevus defined in part by the type of skin cell involved. A group of epidermal nevus, called keratinocyte epidermal nevus, nevus involving only includes keratinocytes. Other types of epidermal nevus involving other types of epidermal, such as the cells that make up hair follicles or sebaceous gland cells. These comprise a group nevus called organoid epidermal nevus. Some affected individuals have only epidermal nevus no other abnormalities. However, people with an epidermal nevus sometimes also have problems in other organs such as the brain, eyes and bones. In these cases, the affected individual has a condition called epidermal nevus syndrome. There are different types of epidermal nevus syndromes that are characterized by the type of epidermal nevus involved.

Several genes have been associated with different types of epidermal nevus. Mutations in the FGFR3 (fibroblast growth factor receptor 3) and PIK3CA gene (phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha) represent about 40 percent of keratinocyte epidermal nevus. Mutations in the HRAS gene (H - ras proto-oncogene, GTPase) are in most people with a sebaceous naevus and also associated with keratinocyte epidermal nevus. HRAS related genes (KRAS and NRAS) less frequently involved in epidermal nevus sebaceous or keratinocyte. Other genes, some of which have not been identified, are also involved in the development of epidermal nevus. FGFR3, PIK3CA, HRAS, and other related genes RAS genes encode proteins that are involved in cell signaling. This signal helps direct several important cellular processes, including regulation of growth and division of skin cells. In order to transmit signals, the proteins must be activated, which triggers a cascade of chemical reactions inside the cell that control growth and other cellular functions.

FGFR3 (fibroblast growth factor receptor 3) gene, located on the short arm of chromosome 4 (4p16.3), encodes a protein called receptor fibroblast growth factor 3. This protein is part of a family of receptors factor fibroblast growth that share similar structures and functions. These proteins play a role in several important cellular processes, including the regulation of growth and cell division, determining the cell type, the formation of blood vessels, wound healing and embryonic development. The FGFR3 protein across the cell membrane, so that one end of the protein remains inside the cell and the other end remains on the outer surface. This positioning of the protein allows it to interact with specific growth factors outside the cell and receive signals that control growth and development. Several isoforms encoded from the FGFR3 gene are found in various tissues of the body and interact with a variety of growth factors. Many isoforms are found in the cells that form bones. It is believed that bone cells, the protein FGFR3 regulates bone growth by ossification, particularly of long bones. One particular isoform of FGFR3 protein is specifically in epithelial cells, including the cells that form the epidermis.

Mutations in the FGFR3 gene have been identified in approximately 30% of people with type epidermal nevus called keratinocyte epidermal nevus. The most frequent mutation of FGFR3 gene replaces the amino acid arginine by the amino acid cysteine at position 248 in the FGFR3 (Arg248Cys or R248C) protein. This mutation creates a protein that is activated without binding of a growth factor, which means that the FGFR3 protein is constantly active. As a result, cells with this mutation grow and divide more than normal cells. Furthermore, the mutated cells initiate apoptosis as easily as normal cells. These effects result in excessive growth of skin cells, resulting in epidermal nevus. Mutations in the FGFR3 gene associated with epidermal nevus also occur in people with seborrheic keratosis, thanatophoric dysplasia, SADDAN Crouzonodermoskeletal syndrome and syndrome.

FGFR2 (Fibroblast growth factor receptor 2) gene, located on the long arm of chromosome 10 (10q26), encoding the protein receptor fibroblast growth factor-2. La proteína FGFR2 interactúa con factores de crecimiento específicos externos a célula y recibe señales que ayudan a la célula a responder a su medio ambiente. Cuando los factores de crecimiento se unen a la proteína FGFR2, el receptor desencadena una cascada de reacciones químicas en el interior de la célula que hacen que la célula asuma la realización de ciertos cambios, como asumir funciones especializadas. to Cuando los factores de crecimiento se unen a la proteína FGFR2, el receptor desencadena una cascada de reacciones químicas en el interior de la célula que hacen que la célula asuma la realización de ciertos cambios, como asumir funciones especializadas. La proteína FGFR2 juega un papel importante en el crecimiento óseo, particularmente durante el desarrollo embrionario. Hay varias isoformas de la proteína FGFR2. Los patrones específicos de estas isoformas se encuentran en los tejidos del organismo, y estos patrones pueden cambiar a lo largo del crecimiento y el desarrollo.

RAS genes (HRAS, KRAS and NRAS) encode highly similar G proteins involved in signal transduction of growth and differentiation. The NRAS (Neuroblastoma RAS viral oncogene homolog) gene is located on the short arm of chromosome 1 (1p13.2), while HRAS (H - ras proto-oncogene, GTPase) and KRAS (KRAS proto-oncogene, GTPase) are in the short arm of chromosomes 11 (11p15.5) and 12 (12p12.1), respectively. The coding sequence of the three genes RAS is equally distributed in four exons except KRAS, the fourth exon has two alternative forms transcribed (K-RASA and RASB K-). Under normal conditions, Ras proteins are in equilibrium between the active (GTP - bound) form and the inactive (GDP - bound). However, the mutated forms of Ras lose the ability to hydrolyze GTP and always remain in its active form.

HRAS gene mutations found in most people with type called epidermal nevus sebaceous nevus. This type is classified as an organoid epidermal nevus. Often, additional tumors develop in the region of sebaceous nevus. In rare cases, these tumors are cancerous. HRAS gene mutations are less frequently in keratinocyte epidermal nevus. Epidermal keratinocyte nevi are not generally associated with the development of additional tumors. Somatic mutations of genes involved in the development HRAS epidermal nevus, change amino acids in the H-Ras protein. The most frequent mutation replaces the amino acid glycine with the amino acid valine at position 12 protein (Gly12Val or G12V). Mutations in the gene NRAS, as mutations in the KRAS and HRAS, lead to the synthesis of proteins that are continuously active. The skin cells grow and multiply affected more than normal cells, resulting in the development of epidermal nevus.

The PIK3CA gene (phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha), located on the long arm of chromosome 3 (3q26.3), encoding the p110 protein, a subunit of the enzyme phosphatidylinositol 3-kinase (PI3K ). The p110 catalytic subunit protein is because performing the action of PI3K, while the other subunit (encoded by a different gene) regulates the activity of the enzyme. Like other kinases, PI3K add a phosphate group to other proteins through phosphorylation. PI3K plays a role in chemical signaling within cells. PI3K signaling is important for many cellular activities, including growth and proliferation, cell migration, encoding new proteins, transport materials within cells, and cell survival. These functions are important for the development of tissues throughout the body, including the brain and blood vessels. It is believed that PI3K signaling may be involved in the regulation of various hormones and may play a role in the maturation of adipocytes.

Mutations in PIK3CA gene have been found in up to 25% of people with keratinocyte epidermal nevus, without having so far found in other types of epidermal nevus. The most frequent mutation of PIK3CA gene replaces the amino acid glutamic acid for glycine at amino acid position 545 p110 protein (Glu545Gly or E545G). Studies suggest that this mutation causes the cells to grow and divide more than usual. Despite the involvement of the PIK3CA gene mutations in many cancers and overgrowth of cells, individuals with epidermal nevi appear to have an elevated risk of developing cancer.

Overall, the epidermal nevus is not inherited but arises from mutations that occur in the body 's cells after conception. This alteration is called a somatic mutation. Occasionally, the somatic mutation occurs in reproductive cells and passed to the next generation. An inherited mutation of FGFR3 gene is found in every cell in the body, resulting in skeletal abnormalities rather than epidermal nevus.

Tests in IVAMI: in IVAMI perform detection of mutations associated with epidermal nevus, by complete PCR amplification of the exons of FGFR2, FGFR3, HRAS, KRAS, NRAS and PIK3CA, respectively, and subsequent sequencing genes.

Samples recommended: fresh or paraffin - embedded biopsy tissue from affected.