Noonan syndrome is a condition that affects many areas of the body. It is characterized by mildly unusual facial features, short stature, heart defects, bleeding problems, skeletal malformations, and many other signs and symptoms.

People with Noonan syndrome have distinctive facial features such as a deep groove in the area between the nose and mouth (philtrum), widely spaced eyes that are usually pale blue or blue-green in color, and low-set ears that are rotated backward. Affected individuals may have a high arch in the roof of the mouth (high-arched palate), poor teeth alignment, and a small lower jaw (micrognathia). Many children with Noonan syndrome have a short neck, and both children and adults may have excess neck skin (also called webbing) and a low hairline at the back of the neck.

Between 50 and 70 percent of individuals with Noonan syndrome have short stature. At birth, they are usually a normal length and weight, but growth slows over time. Abnormal levels of growth hormone, a protein that is necessary for the normal growth of the body's bones and tissues, may contribute to the slow growth.

Individuals with Noonan syndrome often have either a sunken chest (pectus excavatum) or a protruding chest (pectus carinatum). Some affected people may also have an abnormal side-to-side curvature of the spine (scoliosis).

Most people with Noonan syndrome have some form of critical congenital heart disease. The most common heart defect in these individuals is a narrowing of the valve that controls blood flow from the heart to the lungs (pulmonary valve stenosis). Some have hypertrophic cardiomyopathy, which enlarges and weakens the heart muscle.

A variety of bleeding disorders have been associated with Noonan syndrome. Some affected individuals have excessive bruising, nosebleeds, or prolonged bleeding following injury or surgery. Rarely, women with Noonan syndrome who have a bleeding disorder have excessive bleeding during menstruation (menorrhagia) or childbirth.

Adolescent males with Noonan syndrome typically experience delayed puberty. They go through puberty starting at age 13 or 14 and have a reduced pubertal growth spurt that results in shortened stature. Most males with Noonan syndrome have undescended testes (cryptorchidism), which may contribute to infertility (inability to father a child) later in life. Females with Noonan syndrome can experience delayed puberty but most have normal puberty and fertility.

Noonan syndrome can cause a variety of other signs and symptoms. Most children diagnosed with Noonan syndrome have normal intelligence, but a few have special educational needs, and some have intellectual disability. Some affected individuals have vision or hearing problems. Affected infants may have feeding problems, which typically get better by age 1 or 2 years. Infants with Noonan syndrome may be born with puffy hands and feet caused by a buildup of fluid (lymphedema), which can go away on its own. Older individuals can also develop lymphedema, usually in the ankles and lower legs.

Some people with Noonan syndrome develop cancer, particularly those involving the blood-forming cells (leukemia). It has been estimated that children with Noonan syndrome have an eightfold increased risk of developing leukemia or other cancers over age-matched peers.

Noonan syndrome is one of a group of related conditions, collectively known as RASopathies. These conditions all have similar signs and symptoms and are caused by changes in the same cell signaling pathway. In addition to Noonan syndrome, the RASopathies include cardiofaciocutaneous syndrome, Costello syndrome, neurofibromatosis type 1, Legius syndrome, and Noonan syndrome with multiple lentigines.

Noonan syndrome is a disorder that involves unusual facial characteristics, short stature, heart defects present at birth, bleeding problems, developmental delays, and malformations of the bones of the rib cage.

What is Noonan Syndrome?

Noonan syndrome is a disorder that involves unusual facial characteristics, short stature, heart defects present at birth, bleeding problems, developmental delays, and malformations of the bones of the rib cage.

Noonan syndrome is caused by changes in one of several autosomal dominant genes. A person who has Noonan syndrome may have inherited an altered (mutated) gene from one of his or her parents, or the gene change may be a new change due to an error carried by the egg or sperm or occurring at conception. Alterations in four genes - PTPN11, SOS1, RAF1 and KRAS - have been identified to date.

Noonan syndrome is present in about 1 in 1,000 to 1 in 2,500 people.

What are the symptoms of Noonan Syndrome?

Symptoms of Noonan syndrome may include the following:

• A characteristic facial appearance.

• Short stature.

• Heart defect present at birth (congenital heart defect).

• A broad or webbed neck.

• Minor eye problems such as strabismus in up to 95 percent of individuals.

• Bleeding problems such as a history of abnormal bleeding or bruising.

• An unusual chest shape with widely-spaced and low set nipples.

• Developmental delay of varying degrees, but usually mild.

• In males, undescended testes (cryptorchidism).

How is Noonan syndrome diagnosed?

The diagnosis of Noonan syndrome is based on the person's clinical symptoms and signs. The specialist examines the person looking for the specific features of Noonan syndrome.

Individuals who have Noonan syndrome have normal chromosome studies. Four genes - PTPN11, SOS1, RADF1and KRAS - are the only genes that are known to be associated with Noonan syndrome. Approximately 50 percent of individuals with Noonan syndrome have mutations in the PTPN11 gene. Twenty percent of those with Noonan Syndrome have mutations in the SOS1. Mutations in the RAF1 gene account for between 10 and 15 percent of Noonan syndrome cases. About 5 percent of people with Noonan syndrome have mutations in the KRAS gene and usually have a more severe or atypical form of the disorder. The cause of Noonan syndrome in the remaining 10 to 15 percent of people with this disorder is not yet known. .

Symptoms of Noonan syndrome may include the following:

• A characteristic facial appearance.

• Short stature.

• Heart defect present at birth (congenital heart defect).

• A broad or webbed neck.

• Minor eye problems such as strabismus in up to 95 percent of individuals.

• Bleeding problems such as a history of abnormal bleeding or bruising.

• An unusual chest shape with widely-spaced and low set nipples.

• Developmental delay of varying degrees, but usually mild.

• In males, undescended testes (cryptorchidism).

What is the treatment for Noonan syndrome?

Treatment for individuals who have Noonan syndrome is based on their particular symptoms. Heart problems are treated in the same way as they are for individuals in the general population. Early intervention programs are used to help with developmental disabilities, when present. Bleeding problems that can be present in Noonan syndrome may have a variety of causes and are treated according to their cause. Growth problems may be caused by lack of growth hormone and may be treated with growth hormone treatment. Symptoms such as heart problems are followed on a regular basis.

Is Noonan syndrome inherited?

Noonan syndrome is inherited in families in an autosomal dominant pattern. This means that a person who has Noonan syndrome has one copy of an altered gene that causes the disorder. In about one-third to two-thirds of families one of the parents also has Noonan syndrome. The parent who has Noonan syndrome has a 1 in 2 (50 percent) chance to pass on the altered gene to a child who will be affected; and a 1 in 2 (50 percent) chance to pass on the normal version of the gene to a child who will not have Noonan syndrome. In many individuals who have Noonan syndrome, the altered gene happens for the first time in them, and neither of the parents has Noonan syndrome. This is called a de novo mutation. The chance for these parents to have another child with Noonan syndrome is very small (less than 1 percent).

Mutations in multiple genes can cause Noonan syndrome. Mutations in the PTPN11 gene cause about half of all cases. SOS1 gene mutations cause an additional 10 to 15 percent, and RAF1 and RIT1 genes each account for about 5 percent of cases. Mutations in other genes each account for a small number of cases. The cause of Noonan syndrome in 15 to 20 percent of people with this disorder is unknown.

The PTPN11, SOS1, RAF1, and RIT1 genes all provide instructions for making proteins that are important in the RAS/MAPK cell signaling pathway, which is needed for cell division and growth (proliferation), the process by which cells mature to carry out specific functions (differentiation), and cell movement (migration). Many of the mutations in the genes associated with Noonan syndrome cause the resulting protein to be turned on (active) longer than normal, rather than promptly switching on and off in response to cell signals. This prolonged activation alters normal RAS/MAPK signaling, which disrupts the regulation of cell growth and division, leading to the characteristic features of Noonan syndrome.

Rarely, Noonan syndrome is associated with genes that are not involved in the RAS/MAPK cell signaling pathway. Researchers are working to determine how mutations in these genes can lead to the signs and symptoms of Noonan syndrome.

Normal Function

The BRAF gene provides instructions for making a protein that helps transmit chemical signals from outside the cell to the cell's nucleus. This protein is part of a signaling pathway known as the RAS/MAPK pathway, which controls several important cell functions. Specifically, the RAS/MAPK pathway regulates the growth and division (proliferation) of cells, the process by which cells mature to carry out specific functions (differentiation), cell movement (migration), and the self-destruction of cells (apoptosis). Chemical signaling through this pathway is essential for normal development before birth.

The BRAF gene belongs to a class of genes known as oncogenes. When mutated, oncogenes have the potential to cause normal cells to become cancerous.

Health Conditions Related to Genetic Changes

Cardiofaciocutaneous syndrome

Mutations in the BRAF gene are the most common cause of cardiofaciocutaneous syndrome. This condition affects many parts of the body, particularly the heart (cardio-), facial features (facio-), and the skin and hair (cutaneous). At least 49 BRAF mutations have been identified in people with this disorder. These mutations change single protein building blocks (amino acids) in the BRAF protein. Almost all of these genetic changes abnormally activate the protein, which disrupts the tightly regulated RAS/MAPK signaling pathway in cells throughout the body. The altered signaling interferes with the normal development of many organs and tissues, resulting in the characteristic features of cardiofaciocutaneous syndrome.

Erdheim-Chester disease

At least one mutation in the BRAF gene has been identified in some people with Erdheim-Chester disease. This rare condition is characterized by the abnormal production and accumulation of immune system cells called histiocytes in many of the body's tissues. The disease most commonly affects the bones, causing bone thickening and pain, but the accumulation of histiocytes can also cause signs and symptoms affecting the brain, eyes, lungs, liver, kidneys, and other organs.

The BRAF gene mutation that causes this condition is somatic, meaning that it occurs during a person's lifetime and is present only in certain cells. The mutation affects a single amino acid in the BRAF protein. Specifically, the mutation replaces the amino acid valine with the amino acid glutamic acid at position 600 (written as Val600Glu or V600E). This mutation leads to production of a BRAF protein that is abnormally active, which disrupts regulation of cell proliferation and may allow histiocytes to grow and divide uncontrollably, leading to the abnormal accumulation of histiocytes that occurs in Erdheim-Chester disease.

Giant congenital melanocytic nevus

The V600E mutation (described above) in the BRAF gene has also 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 (described below). In giant congenital melanocytic nevus, a somatic V600E mutation occurs during embryonic development in cells that will develop into pigment-producing skin cells (melanocytes). This mutation leads to production of a BRAF protein that is abnormally active, which disrupts regulation of cell proliferation. The unregulated cell proliferation of early melanocytes leads to a large patch of darkly pigmented skin characteristic of giant congenital melanocytic nevus. Additional gene mutations in cells within the nevus after birth can lead to melanoma in people with giant congenital melanocytic nevus.

Noonan syndrome

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Noonan syndrome with multiple lentigines

At least two mutations in the BRAF gene have been found to cause Noonan syndrome with multiple lentigines (formerly called LEOPARD syndrome). This condition is characterized by multiple brown skin spots (lentigines), heart defects, short stature, a sunken or protruding chest, and distinctive facial features. The BRAF gene mutations change single amino acids in the BRAF protein: One mutation replaces the amino acid threonine with the amino acid proline at position 241 (written as Thr241Pro or T241P) and the other mutation replaces the amino acid leucine with the amino acid phenylalanine at position 245 (written as Leu245Phe or L245F).

The BRAF gene changes that cause Noonan syndrome with multiple lentigines are believed to abnormally activate the BRAF protein, which disrupts the regulation of the RAS/MAPK signaling pathway that controls cell functions such as proliferation. This misregulation can result in the various features of Noonan syndrome with multiple lentigines.

Cholangiocarcinoma

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Gastrointestinal stromal tumor

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Langerhans cell histiocytosis

Somatic mutations in the BRAF gene, most frequently the V600E mutation (described above), have been identified in some individuals with Langerhans cell histiocytosis. This disorder causes an abnormal accumulation of certain immune cells called Langerhans cells in multiple tissues and organs, which often leads to the formation of tumors called granulomas. Many researchers consider Langerhans cell histiocytosis to be a form of cancer, but this classification is controversial.

The BRAF gene mutations, which are found only in the abnormal Langerhans cells, cause the BRAF protein to be continuously active. The overactive protein may contribute to the development of Langerhans cell histiocytosis by allowing the Langerhans cells to grow and divide uncontrollably.

In some other forms of histiocytosis such as Erdheim-Chester disease (described above), the histiocytes do not include Langerhans cells; a disorder of that type is classified as a non-Langerhans cell histiocytosis. It is not clear why the V600E mutation can cause different forms of histiocytosis.

Lung cancer

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Melanoma

The V600E mutation (described above) in the BRAF gene has also been found in about half of noninherited (sporadic) cases of melanoma. Melanoma is a type of skin cancer that begins in pigment-producing cells called melanocytes. In this cancer, a somatic V600E mutation occurs during a person's lifetime, likely caused by ultraviolet (UV) radiation from the sun or other environmental risk factors. This mutation often leads only to the formation of a noncancerous mole. At least one additional mutation is necessary for the development of melanoma.

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Cancers

Somatic mutations in the BRAF gene are common in several types of cancer. Normally, the BRAF protein is switched on and off in response to signals that control cell growth and development. Somatic mutations cause the BRAF protein to be continuously active and to transmit messages to the nucleus even in the absence of these chemical signals. The overactive protein may contribute to the growth of cancers by allowing abnormal cells to grow and divide without external signals.

The V600E mutation (described above) is the most common BRAF gene mutation found in human cancers. This mutation has frequently been found in cancers of the colon and rectum, ovary, and thyroid gland. Several other somatic mutations in the BRAF gene have also been associated with cancer.

Other Names for This Gene

• 94 kDa B-raf protein
• B-raf 1
• B-Raf proto-oncogene serine/threonine-protein kinase
• BRAF1
• BRAF1_HUMAN
• Murine sarcoma viral (v-raf) oncogene homolog B1
• p94
• RAFB1
• v-raf murine sarcoma viral oncogene homolog B

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

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Autoimmune lymphoproliferative syndrome

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Cholangiocarcinoma

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Core binding factor acute myeloid leukemia

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Epidermal nevus

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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 LZTR1 gene provides instructions for making a protein whose exact function is unknown. The LZTR1 protein is made in cells throughout the body. Within cells, it is found in the Golgi apparatus, which is a structure in which newly produced proteins are modified. Studies suggest that the LZTR1 protein may help stabilize this structure. Researchers suspect that this protein may also be associated with the CUL3 ubiquitin ligase complex, which is part of the cell machinery that breaks down (degrades) unneeded proteins.

Based on its role in several tumor types, the LZTR1 protein is thought to act as a tumor suppressor. Tumor suppressors are proteins that keep cells from growing and dividing too rapidly or in an uncontrolled way.

Health Conditions Related to Genetic Changes

Schwannomatosis

More than 50 different mutations in the LZTR1 gene have been found in people with schwannomatosis, a disorder characterized by multiple noncancerous (benign) tumors called schwannomas that grow on nerves. This type of tumor arises from Schwann cells, which are specialized cells that normally form an insulating layer around the nerve.

LZTR1 gene mutations associated with schwannomatosis lead to production of an altered LZTR1 protein that is less able to control cell growth and division, which allows tumors to develop. It is unknown why these gene mutations are predominantly associated with schwannomas, instead of other types of tumor, in people with schwannomatosis.

It appears that mutations in the LZTR1 gene alone are not enough to trigger the development of schwannomas. Additional genetic changes (somatic mutations) that are acquired during a person's lifetime and are present only in certain cells may also be required for schwannomas to form.

Some people who have a mutation in the LZTR1 gene never develop tumors, which is a situation known as reduced penetrance.

Noonan syndrome

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Cancers

Mutations in the LZTR1 gene have also been found in a type of cancerous (malignant) brain tumor called glioblastoma. These mutations are classified as somatic and are present only in the cells that give rise to the tumor. Scientists believe that somatic changes in the LZTR1 gene, or a loss of this gene, are among the factors that allow certain brain cells to grow and divide uncontrollably to form a tumor.

Other Names for This Gene

• BTBD29
• leucine-zipper-like transcriptional regulator 1
• LZTR-1
• NS10
• SWNTS2

Genomic Location

Normal Function

The MAP2K1 gene provides instructions for making a protein known as MEK1 protein kinase. This protein is part of a signaling pathway called the RAS/MAPK pathway, which transmits chemical signals from outside the cell to the cell's nucleus. RAS/MAPK signaling helps control the growth and division (proliferation) of cells, the process by which cells mature to carry out specific functions (differentiation), cell movement (migration), and the self-destruction of cells (apoptosis). MEK1 protein kinase appears to be essential for normal development before birth and for survival after birth.

Health Conditions Related to Genetic Changes

Cardiofaciocutaneous syndrome

At least 13 mutations in the MAP2K1 gene have been identified in people with cardiofaciocutaneous syndrome. This condition affects many parts of the body, particularly the heart (cardio-), facial features (facio-), and the skin and hair (-cutaneous).

The MAP2K1 gene mutations that cause cardiofaciocutaneous syndrome are germline mutations, which means that they are present in cells throughout the body. Each mutation changes a single protein building block (amino acid) in MEK1 protein kinase. The genetic changes abnormally activate the protein, which disrupts the tightly regulated RAS/MAPK signaling pathway in many types of cells. The altered signaling interferes with the normal development of many organs and tissues, resulting in the characteristic features of cardiofaciocutaneous syndrome.

Melorheostosis

At least three mutations in the MAP2K1 gene have been identified in people with melorheostosis. This rare disease causes the abnormal growth of new bone tissue on the surface of existing bones. The new bone has a characteristic "dripping candle wax" or flowing appearance on x-rays.

The mutations associated with melorheostosis are described as somatic. Somatic mutations occur during a person's lifetime and are present only in certain cells, in this case, bone cells in a particular area of the body. The known mutations change single amino acids in MEK1 protein kinase. The mutations lead to the production of a version of the protein that is overactive, which increases RAS/MAPK signaling in bone tissue. The increased signaling disrupts the regulation of bone cell proliferation and allows new bone to grow abnormally. Studies suggest that increased RAS/MAPK signaling also stimulates excess bone remodeling, a normal process in which old bone is broken down and new bone is created to replace it. These changes in bone growth and turnover underlie the bone abnormalities characteristic of melorheostosis.

Noonan syndrome with multiple lentigines

At least one mutation in the MAP2K1 gene has been found to cause Noonan syndrome with multiple lentigines (formerly called LEOPARD syndrome). This condition is characterized by multiple brown skin spots (lentigines), heart defects, short stature, a sunken or protruding chest, and distinctive facial features.

The identified MAP2K1 gene mutation is a germline mutation that replaces the amino acid glutamic acid with the amino acid glycine at position 102 (written as Glu102Gly or E102G) in MEK1 protein kinase. This change likely results in increased activation of the RAS/MAPK signaling pathway in cells throughout the body. The increased signaling interferes with the normal development of many organs and tissues, resulting in the characteristic features of Noonan syndrome with multiple lentigines.

It is unclear why the E102G mutation causes Noonan syndrome with multiple lentigines and other germline mutations in the MAP2K1 gene cause different disorders, such as cardiofaciocutaneous syndrome (described above).

Langerhans cell histiocytosis

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Lung cancer

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Noonan syndrome

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Other cancers

Mutations in the MAP2K1 gene have also been found in several forms of cancer. Like the mutations that cause melorheostosis (described above), cancer-associated mutations in this gene are somatic. They occur only in the cells that ultimately give rise to cancer. Somatic mutations in the MAP2K1 gene have been reported in several forms of blood cell cancer (leukemia and lymphoma), lung cancer, and a form of skin cancer called melanoma. The genetic changes lead to an overactive MEK1 protein kinase, which increases activation of the RAS/MAPK signaling pathway in particular tissues. The increased signaling allows cells to grow and divide too quickly, leading to cancer.

Other Names for This Gene

• Dual Specificity Mitogen-Activated Protein Kinase Kinase 1
• ERK Activator Kinase 1
• MAP Kinase Kinase 1
• MAPK/ERK kinase 1
• MAPKK1
• MEK-1
• MEK-1 Protein Kinase
• MEK1
• MKK-1 Protein Kinase
• MKK1
• MKK1 Protein Kinase
• MP2K1_HUMAN
• PRKMK1
• protein kinase, mitogen-activated, kinase 1 (MAP kinase kinase 1)

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

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Autoimmune lymphoproliferative syndrome

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Cholangiocarcinoma

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Core binding factor acute myeloid leukemia

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Cytogenetically normal acute myeloid leukemia

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Epidermal nevus

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Lung cancer

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Melanoma

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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 PTPN11 gene provides instructions for making a protein called SHP-2. This protein helps regulate the RAS/MAPK signaling pathway. This pathway is involved in several important cell functions, including the growth and division of cells (proliferation), the process by which cells mature to carry out specific functions (differentiation), cell movement (migration), and the self-destruction of cells (apoptosis). During embryonic development, the SHP-2 protein is critical in the development of the heart, blood cells, bones, and several other tissues.

The PTPN11 gene belongs to a class of genes known as oncogenes. When mutated, oncogenes have the potential to cause normal cells to become cancerous.

Health Conditions Related to Genetic Changes

Noonan syndrome

More than 90 mutations causing Noonan syndrome have been identified in the PTPN11 gene. This condition is characterized by mildly unusual facial characteristics, short stature, heart defects, bleeding problems, skeletal malformations, and many other signs and symptoms. Most of the PTPN11 gene mutations replace single amino acids used to make the SHP-2 protein. The resulting protein is either continuously turned on (active) or has prolonged activation, rather than promptly switching on and off in response to other cellular proteins. This increase in protein activity disrupts the regulation of the RAS/MAPK signaling pathway that controls cell functions such as proliferation. This misregulation can result in the heart defects, growth problems, skeletal abnormalities, and other features of Noonan syndrome.

Rarely, a person with Noonan syndrome caused by PTPN11 gene mutations will also develop juvenile myelomonocytic leukemia, which is a type of blood cancer that typically affects children or adolescents.

Noonan syndrome with multiple lentigines

At least 11 mutations in the PTPN11 gene have been found to cause Noonan syndrome with multiple lentigines (formerly called LEOPARD syndrome). This condition is characterized by multiple brown skin spots (lentigines), heart defects, short stature, a sunken or protruding chest, and distinctive facial features. Two mutations that account for approximately 65 percent of cases of Noonan syndrome with multiple lentigines caused by PTPN11 gene mutations change single protein building blocks (amino acids) in the SHP-2 protein: One mutation replaces the amino acid tyrosine with the amino acid cysteine at position 279 (written Tyr279Cys or Y279C) and the other mutation replaces the amino acid threonine with the amino acid methionine at position 468 (written as Thr468Met or T468M).

All known PTPN11 gene changes that cause Noonan syndrome with multiple lentigines are believed to disrupt the SHP-2 protein's normal function. This decrease in protein function impairs the activation of the RAS/MAPK signaling pathway that controls cell functions such as growth and division. This misregulation can result in the various features of Noonan syndrome with multiple lentigines.

Although the PTPN11 gene is an oncogene, a reduction in this protein's function does not seem to increase cancer risk in people with Noonan syndrome with multiple lentigines.

Cancers

Gene mutations can be acquired during a person's lifetime and are present only in certain cells. This type of mutation is called a somatic mutation, and it is not inherited. Somatic mutations in the PTPN11 gene can increase the risk of developing a type of blood cancer called juvenile myelomonocytic leukemia. These mutations cause the SHP-2 protein to be continuously active. Overactivity of the SHP-2 protein disrupts the regulation of pathways that control the production of immature blood cells. As a result, certain white blood cells are overproduced, leading to this type of leukemia. Somatic mutations in the PTPN11 gene are found in about 35 percent of people with juvenile myelomonocytic leukemia.

Some studies indicate that somatic mutations in the PTPN11 gene are also associated with other blood disorders including chronic myelomonocytic leukemia, myelodysplastic syndrome, nonsyndromic acute myeloid leukemia, and acute lymphocytic leukemia. In rare cases, somatic PTPN11 gene mutations are found in cancers of the lung, colon, brain, thyroid, and in a type of skin cancer called melanoma.

Other disorders

Mutations in the PTPN11 gene can cause a condition called metachondromatosis. This condition is characterized by multiple benign (noncancerous) bone tumors called osteochondromas on the bones of the hands and feet. People with this condition also develop enchondromas, which are benign growths of cartilage. In people with metachondromatosis, the growths form at the ends of the long bones or the sides of the hip bones. The growths characteristic of metachondromatosis typically develop during childhood and for reasons that are not understood, usually disappear over time.

Other Names for This Gene

• BPTP3
• protein tyrosine phosphatase, non-receptor type 11 (Noonan syndrome 1)
• protein-tyrosine phosphatase 2C
• PTN11_HUMAN
• PTP-1D
• PTP2C
• SH protein-tyrosine phosphatase
• SH-PTP2
• SH-PTP3
• SHP2
• SHP2 phosphatase

Genomic Location

Normal Function

The RAF1 gene provides instructions for making a protein that is part of a signaling pathway called the RAS/MAPK pathway, which transmits chemical signals from outside the cell to the cell's nucleus. RAS/MAPK signaling helps control the growth and division (proliferation) of cells, the process by which cells mature to carry out specific functions (differentiation), cell movement (migration), and the self-destruction of cells (apoptosis).

The RAF1 gene belongs to a class of genes known as oncogenes. When mutated, oncogenes have the potential to cause normal cells to become cancerous.

Health Conditions Related to Genetic Changes

Noonan syndrome

More than 25 mutations causing Noonan syndrome have been identified in the RAF1 gene. Noonan syndrome is characterized by mildly unusual facial characteristics, short stature, heart defects, bleeding problems, skeletal malformations, and many other signs and symptoms. The RAF1 gene mutations change single protein building blocks (amino acids) in the RAF1 protein. These changes increase protein activity and disrupt the regulation of the RAS/MAPK signaling pathway causing problems with cell division, apoptosis, cell differentiation, and cell migration. Researchers believe that this disruption in normal cell processes plays a role in the signs and symptoms of Noonan syndrome, specifically cardiac abnormalities. It has been noted that people with Noonan syndrome caused by a RAF1 gene mutation have a greater incidence of heart defects than other people with Noonan syndrome, specifically a condition called hypertrophic cardiomyopathy, which is a thickening of the heart muscle that forces the heart to work harder to pump blood.

Noonan syndrome with multiple lentigines

At least two mutations in the RAF1 gene have been found to cause Noonan syndrome with multiple lentigines (formerly called LEOPARD syndrome). This condition is characterized by multiple brown skin spots (lentigines), heart defects, short stature, a sunken or protruding chest, and distinctive facial features. The RAF1 gene mutations change single amino acids in the RAF1 protein: One mutation replaces the amino acid serine with the amino acid leucine at position 257 (written Ser257Leu or S257L) and the other mutation replaces the amino acid leucine with the amino acid valine at position 613 (written Leu613Val or L613V).

The RAF1 gene changes that cause Noonan syndrome with multiple lentigines are believed to abnormally activate the RAF1 protein, which disrupts the regulation of the RAS/MAPK signaling pathway that controls cell functions such as growth and division. This misregulation can result in the various features of Noonan syndrome with multiple lentigines.

Bladder cancer

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Cancers

Some gene mutations are acquired during a person's lifetime and are present only in certain cells. These changes are called somatic mutations and are not inherited. Somatic mutations in the RAF1 gene are involved in the development of several types of cancer. These mutations lead to a RAF1 protein that is always active and can direct cells to grow and divide uncontrollably. Studies suggest that RAF1 gene mutations may be found in ovarian, lung, and colorectal cancers. Somatic mutations in the RAF1 gene are a rare cause of cancer.

For reasons that are unclear, inherited mutations in the RAF1 gene do not appear to increase the risk of cancer in people with Noonan syndrome with multiple lentigines or Noonan syndrome (described above).

Other Names for This Gene

• c-Raf
• CRAF
• Oncogene RAF1
• raf proto-oncogene serine/threonine protein kinase
• Raf-1
• RAF1_HUMAN

Genomic Location

Normal Function

The RIT1 gene provides instructions for making a protein that helps cells survive during periods of cellular stress, such as unusually high energy demands. As part of a signaling pathway known as the RAS/MAPK pathway, the RIT1 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 RIT1 protein is a GTPase, which means it converts a molecule called GTP into another molecule called GDP. To transmit signals during periods of cellular stress, the RIT1 protein is turned on by attaching (binding) to a molecule of GTP. The RIT1 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 RIT1 gene belongs to a class of genes known as oncogenes. When mutated, oncogenes have the potential to cause normal cells to become cancerous. The RIT1 gene is in the Ras family of oncogenes, which also includes three other genes: KRAS, 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

Noonan syndrome

At least 14 mutations in the RIT1 gene have been found to cause Noonan syndrome. This condition is characterized by mildly unusual facial characteristics, short stature, heart defects, bleeding problems, skeletal malformations, and many other signs and symptoms. People with Noonan syndrome caused by RIT1 gene mutations often have swelling caused by a buildup of fluid (lymphedema). Rarely, people with Noonan syndrome caused by a RIT1 gene mutation develop cancer, including a blood cancer called acute lymphoblastic leukemia.

The RIT1 gene mutations associated with Noonan syndrome change single protein building blocks (amino acids) in the RIT1 protein. The mutations lead to the production of an altered RIT1 protein that is either continuously turned on (active) or has prolonged activation, rather than promptly switching on and off in response to other cellular proteins. The abnormally active protein alters normal RAS/MAPK signaling and leads to abnormal cell proliferation, which disrupts the development of organs and tissues throughout the body, resulting in the signs and symptoms of Noonan syndrome.

Lung cancer

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Cancers

Mutations in the RIT1 gene have been found in several different types of blood cell cancer (leukemia), including acute myeloid leukemia (AML), chronic myelomonocytic leukemia (CMML), and a bone marrow disease called myelodysplastic syndrome (MDS). Similar to the RIT1 gene mutations that cause Noonan syndrome (described above), the mutations involved in these cancers likely result in a constitutively active protein. As a result, cell growth is continuously promoted and cells grow and divide uncontrollably leading to cancer formation. Unlike the Noonan syndrome mutations, the RIT1 gene mutations associated with leukemia are somatic mutations, which means they occur during a person's lifetime and are not inherited.

Other Names for This Gene

• GTP-binding protein Roc1
• MGC125864
• MGC125865
• Ras-like without CAAX 1
• ras-like without CAAX protein 1
• RIBB
• RIT
• ROC1

Genomic Location

Normal Function

The SOS1 gene provides instructions for making a protein that is involved in controlling (regulating) the activation of the RAS/MAPK signaling pathway, which helps control several important cell functions. Specifically, the pathway regulates the growth and division of cells (proliferation), the process by which cells mature to carry out specific functions (differentiation), cell movement (migration), and the self-destruction of cells (apoptosis). Within the RAS/MAPK signaling pathway, the SOS1 protein regulates a protein, called Ras, that stimulates cells to grow and divide. This regulation tightly controls the growth of cells and tissues, and is especially important for proper embryonic development.

Health Conditions Related to Genetic Changes

Noonan syndrome

More than 55 mutations causing Noonan syndrome have been identified in the SOS1 gene. Noonan syndrome is characterized by mildly unusual facial characteristics, short stature, heart defects, bleeding problems, skeletal malformations, and many other signs and symptoms. The SOS1 gene mutations change single protein building blocks (amino acids) in the SOS1 protein. The resulting protein is either continuously turned on (active) or has prolonged activation, rather than promptly switching on and off in response to other cellular proteins. This increase in protein activity disrupts the regulation of the RAS/MAPK signaling pathway that controls cell functions such as growth and division. This misregulation can result in the heart defects, growth problems, skeletal abnormalities, and other features of Noonan syndrome.

Other disorders

Mutations in the SOS1 gene can also cause hereditary gingival fibromatosis type 1. This disorder is characterized by a slowly progressive overgrowth of the tissue of the gums (gingiva). Too much of this tissue can impair teeth from emerging through the gums, which can cause difficulties in speech and chewing food. At least one mutation in the SOS1 gene has been shown to cause hereditary gingival fibromatosis type 1. This mutation is an addition of a single building block of DNA (nucleotide). The mutation inserts the nucleotide cytosine into an area of the gene called exon 21 (written 3248_3249insC) and disrupts the gene's instructions, resulting in a shortened protein. Unlike the normal SOS1 protein, the shortened protein is permanently active because it is missing areas that regulate its activity. Instead of triggering cell growth in response to particular signals from outside the cell, the overactive protein directs cells to grow and divide constantly. It is unclear why the overgrowth of tissue is seen only in the gums.

Other Names for This Gene

• alternate SOS1
• GF1
• GGF1
• GINGF
• gingival fibromatosis
• gingival fibromatosis, hereditary, 1
• HGF
• son of sevenless homolog 1
• son of sevenless homolog 1 (Drosophila)
• SOS1_HUMAN

Genomic Location

Some of the signs and symptoms seen in people with Noonan syndrome (NS) are listed below. Please note that the list below does not include all possible symptoms of NS and that not all people with NS will have all of these the signs and symptoms. In general, the signs and symptoms of NS are more obvious early in life and become less obvious as individuals get older.

• Head/Neck:
  • Widely spaced eyes (hypertelorism)
  • Large ears rotated back
  • Short webbed neck
  • Droopy eyelids (ptosis)
  • Low hairline
  • Multiple giant cell lesions (MGCL): painless, benign growths in the jaw that can lead to dental or orthodontic issues
• Heart:
  • Pulmonary stenosis
  • Aortic regurgitation
  • Atrial septal defect
• Skeletal:
  • Short stature
  • Concave chest (pectus excavatum)
  • Bending or curvature of the finger (clinodactyly)
  • Weak bones (generalized osteopenia)
• Skin:
  • Café au lait spots
  • Hemangioma (raised red birthmark)
• Neurological:
  • Delayed milestones due to low muscle tone
  • Developmental delay
  • Learning disabilities or intellectual impairment
• Bleeding disorder
• Undescended testicles (cryptorchidism)

A syndrome named Noonan-like/multiple giant cell lesion syndrome used to be considered a separate condition from Noonan syndrome. It is now known that multiple giant cell lesions are one of the possible symptoms that can occur in people with Noonan syndrome.