Costello syndrome is a rare disorder that affects many parts of the body. This condition is characterized by delayed development, loose folds of skin (which are especially noticeable on the hands and feet), unusually flexible joints, heart problems, short stature, and distinctive facial features.

Children with Costello syndrome are often delayed in reaching developmental milestones, such as speaking, sitting, and walking. Affected individuals may also have intellectual disabilities that can vary in severity.

Distinctive facial features in people with Costello syndrome typically include a prominent forehead, full cheeks, and full lips. Infants with Costello syndrome may be larger than average at birth, but most have difficulty eating and grow more slowly than other children. Affected individuals may have gastrointestinal problems that include constipation or a backflow of stomach acids into the esophagus (gastroesophageal reflux or GERD). People with this condition have short stature compared to their family and peers and may have reduced growth hormone levels.

Heart problems are common, including an abnormal heartbeat (arrhythmia), structural heart defects, and a type of heart disease that enlarges and weakens the heart muscle (hypertrophic cardiomyopathy). Neurological problems in people with Costello syndrome include seizures, weak muscle tone (hypotonia), and a structural abnormality of the brain called a Chiari I malformation. Costello syndrome can cause vision problems, such as nearsightedness (myopia), farsightedness (hyperopia), or eyes that do not point in the same direction (strabismus). Hearing loss may also occur.

Other signs and symptoms of Costello syndrome can include tight Achilles tendons (which connect the calf muscles to the heel), recurrent respiratory infections, dry and thickened skin, skeletal abnormalities, and dental problems.

Beginning in early childhood, people with Costello syndrome have a higher risk of developing certain cancerous and noncancerous tumors compared to the general population. The most common noncancerous tumors associated with this condition are papillomas, which are small, wart-like growths that usually develop around the nose and mouth or near the anus. The most common cancerous tumor associated with Costello syndrome is a childhood cancer called rhabdomyosarcoma, which begins in muscle tissue. Neuroblastoma, a tumor that arises in developing nerve cells, has also been reported in children and adolescents with this syndrome. In addition, some teenagers with Costello syndrome have developed transitional cell carcinoma, a form of bladder cancer that is usually seen in older adults.

The signs and symptoms of Costello syndrome overlap significantly with those of two other genetic conditions, cardiofaciocutaneous syndrome (CFC syndrome) and Noonan syndrome. In affected infants, it can be difficult to tell the three conditions apart based on their physical features. However, the conditions can be distinguished by their genetic causes and by the specific patterns of signs and symptoms that develop later in childhood.

Variants (also called mutations) in the HRAS gene cause Costello syndrome. This gene provides instructions for making a protein called H-Ras, which is part of a pathway that helps control cell growth and division. Variants that cause Costello syndrome lead to the production of an H-Ras protein that is abnormally turned on (active). The overactive protein directs cells to grow and divide constantly, which can lead to the development of tumors. It is unclear how variants in the HRAS gene cause the other features of Costello syndrome, but many of the signs and symptoms probably result from cell overgrowth and abnormal cell division.

Some people with signs and symptoms like those of Costello syndrome do not have an identified variant in the HRAS gene. These individuals may actually have CFC syndrome or Noonan syndrome, which are caused by variants in related genes. The proteins produced from these genes interact with one another and with the H-Ras protein as part of the same cell growth and division pathway. This pathway is called the RAS/MAPK signaling pathway, so these three conditions are sometimes referred to as RASopathies. These interactions help explain why variants in different genes can cause conditions with overlapping signs and symptoms.

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

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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

This condition is inherited in an autosomal dominant pattern, which means one copy of the altered gene in each cell is sufficient to cause the disorder. Most cases of this condition result from new (de novo) variants in the gene that occur during the formation of reproductive cells (eggs or sperm) in an affected individual's parent or in early embryonic development. These affected individuals have no history of the disorder in their family.

This condition is very rare; it probably affects 100 to 1,500 people worldwide. The estimates of Costello syndrome prevalence range from 1 in 300,000 to 1 in 1.25 million people.