Bannayan-Riley-Ruvalcaba syndrome is a genetic condition characterized by a large head size (macrocephaly), multiple noncancerous tumors and tumor-like growths called hamartomas, and dark freckles on the penis in males. The signs and symptoms of Bannayan-Riley-Ruvalcaba syndrome are present from birth or become apparent in early childhood.

At least half of affected infants have macrocephaly, and many also have a high birth weight and a large body size (macrosomia). Growth usually slows during childhood, so affected adults are of normal height and body size. About half of all children with Bannayan-Riley-Ruvalcaba syndrome have intellectual disability or delayed development, particularly the development of speech and of motor skills such as sitting, crawling, and walking. These delays may improve with age.

About half of all people with Bannayan-Riley-Ruvalcaba syndrome develop hamartomas in their intestines, known as hamartomatous polyps. Other noncancerous growths often associated with Bannayan-Riley-Ruvalcaba syndrome include fatty tumors called lipomas and angiolipomas that develop under the skin. Some affected individuals also develop hemangiomas, which are red or purplish growths that consist of tangles of abnormal blood vessels. People with Bannayan-Riley-Ruvalcaba syndrome may also have an increased risk of developing certain cancers, although researchers are still working to determine the cancer risks associated with this condition.

Other signs and symptoms that have been reported in people with Bannayan-Riley-Ruvalcaba syndrome include weak muscle tone (hypotonia) and other muscle abnormalities, and seizures. Some affected individuals have thyroid problems, such as an enlargement of the thyroid gland, known as multinodular goiter, or a condition called Hashimoto thyroiditis. Skeletal abnormalities have also been described with this condition, including an unusually large range of joint movement (hyperextensibility), abnormal side-to-side curvature of the spine (scoliosis), and a sunken chest (pectus excavatum).

The features of Bannayan-Riley-Ruvalcaba syndrome overlap with those of another disorder called Cowden syndrome. People with Cowden syndrome develop hamartomas and other noncancerous growths; they also have an increased risk of developing certain types of cancer. Both conditions can be caused by mutations in the PTEN gene. Some people with Bannayan-Riley-Ruvalcaba syndrome have had relatives diagnosed with Cowden syndrome, and other individuals have had the characteristic features of both conditions. Based on these similarities, researchers have proposed that Bannayan-Riley-Ruvalcaba syndrome and Cowden syndrome represent a spectrum of overlapping features known as PTEN hamartoma tumor syndrome instead of two distinct conditions.

About 60 percent of all cases of Bannayan-Riley-Ruvalcaba syndrome result from mutations in the PTEN gene. Another 10 percent of cases are caused by a large deletion of genetic material that includes part or all of this gene. The protein produced from the PTEN gene is a tumor suppressor, which means that it normally prevents cells from growing and dividing (proliferating) too rapidly or in an uncontrolled way. If this protein is missing or defective, cell proliferation is not regulated effectively. Uncontrolled cell division can lead to the formation of hamartomas and other cancerous and noncancerous tumors. The protein produced from the PTEN gene likely has other important functions within cells; however, it is unclear how mutations in this gene can cause the other features of Bannayan-Riley-Ruvalcaba syndrome, such as macrocephaly, developmental delay, and muscle and skeletal abnormalities.

When Bannayan-Riley-Ruvalcaba syndrome is not caused by mutations or deletions of the PTEN gene, the cause of the condition is unknown.

Normal Function

The PTEN gene provides instructions for making an enzyme that is found in almost all tissues in the body. The enzyme acts as a tumor suppressor, which means that it helps regulate cell division by keeping cells from growing and dividing (proliferating) too rapidly or in an uncontrolled way. To function, the PTEN enzyme attaches (binds) to another PTEN enzyme (dimerizes) then binds to the cell membrane. The PTEN enzyme modifies other proteins and fats (lipids) by removing phosphate groups, each of which consists of a cluster of oxygen and phosphorus atoms. Enzymes with this function are called phosphatases.

The PTEN enzyme is part of a chemical pathway that signals cells to stop dividing and triggers cells to self-destruct through a process called apoptosis. Evidence suggests that this enzyme also helps control cell movement (migration), the sticking (adhesion) of cells to surrounding tissues, and the formation of new blood vessels (angiogenesis). Additionally, it likely plays a role in maintaining the stability of a cell's genetic information. All of these functions help prevent uncontrolled cell proliferation that can lead to the formation of tumors.

Health Conditions Related to Genetic Changes

Bannayan-Riley-Ruvalcaba syndrome

More than 30 mutations in the PTEN gene have been found to cause Bannayan-Riley-Ruvalcaba syndrome. Common features of this condition include a large head size (macrocephaly), multiple noncancerous tumors and tumor-like growths called hamartomas, and dark freckles on the penis in males. Bannayan-Riley-Ruvalcaba syndrome is one of several related conditions that are often considered together as PTEN hamartoma tumor syndrome (described below).

Some of the mutations that cause Bannayan-Riley-Ruvalcaba syndrome change single DNA building blocks (base pairs) in the PTEN gene or insert or delete a small number of base pairs. Other mutations result in an abnormally short enzyme or reduce the amount of enzyme that is produced. In about 10 percent of cases, Bannayan-Riley-Ruvalcaba syndrome results from the deletion of a large amount of genetic material that includes part or all of the PTEN gene. All of these genetic changes prevent the PTEN enzyme from regulating cell proliferation effectively, which can lead to uncontrolled cell growth and the formation of hamartomas and other types of tumors. Research is needed to determine what role PTEN gene mutations play in causing macrocephaly and the other features of Bannayan-Riley-Ruvalcaba syndrome.

Breast cancer

Inherited mutations in the PTEN gene increase the risk of developing breast cancer. In many cases, this increased risk occurs as part of Cowden syndrome (described below). Inherited mutations in the PTEN gene are thought to account for only a small fraction of all breast cancer cases.

Noninherited (somatic) PTEN gene mutations occur in some breast cancers in women without a family history of the disease. Somatic mutations are not inherited and do not occur as part of a familial cancer syndrome. They are acquired during a person's lifetime and occur only in certain cells in the breast. These mutations impair the tumor suppressor function of the PTEN enzyme, allowing cells to grow and divide without control or order. This uncontrolled cell growth contributes to the formation of a cancerous tumor. Studies suggest that a loss of functional PTEN enzyme is also related to poor responsiveness to a drug called trastuzumab (Herceptin), which is used to treat breast cancer.

Cowden syndrome

Researchers have identified more than 300 mutations in the PTEN gene that can cause Cowden syndrome or a similar disorder called Cowden-like syndrome. These conditions are characterized by the growth of multiple hamartomas and an increased risk of developing certain cancers, particularly breast cancer (described above), thyroid cancer, and cancer of the uterine lining (endometrial cancer). Cowden syndrome and Cowden-like syndrome are considered to be part of PTEN hamartoma tumor syndrome (described below).

Mutations that cause Cowden syndrome and Cowden-like syndrome include changes in a small number of base pairs and, in some cases, deletions of a larger amount of genetic material from the PTEN gene. These mutations lead to the production of a PTEN enzyme that does not function properly or does not work at all. The altered enzyme is unable to restrain cell division or signal abnormal cells to die, which contributes to the development of hamartomas and cancerous tumors.

Autism spectrum disorder

PTEN gene mutations have been identified in several people who have both an unusually large head size and the characteristic features of autism spectrum disorder, which affects communication and social interaction. Many of these mutations change single protein building blocks (amino acids) in the PTEN enzyme or lead to the production of an abnormally short version of the enzyme. Researchers are studying how changes in the PTEN gene are related to the risk of developing autism spectrum disorder. Some of these mutations have also been reported in families with PTEN hamartoma tumor syndrome (described below), and it is unclear how these mutations can cause different disorders.

Prostate cancer

Studies suggest that somatic mutations in the PTEN gene may be the most frequent genetic changes in prostate cancer. Mutations in the PTEN gene reduce or eliminate the tumor suppressor function of the PTEN enzyme. The loss of this enzyme's function likely permits certain cells to divide uncontrollably, contributing to the growth of cancerous tumors. In some cases, the presence of PTEN gene mutations is associated with more advanced stages of tumor growth.

Bladder cancer

MedlinePlus Genetics provides information about Bladder cancer

Cholangiocarcinoma

MedlinePlus Genetics provides information about Cholangiocarcinoma

Head and neck squamous cell carcinoma

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Lung cancer

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Other disorders

Several related conditions caused by mutations in the PTEN gene, including Bannayan-Riley-Ruvalcaba syndrome and Cowden syndrome (described above), are often considered together as PTEN hamartoma tumor syndrome. The mutations that cause these conditions are present in cells throughout the body and are often inherited from a parent. Some of the mutations that cause PTEN hamartoma tumor syndrome lead to a defective version of the PTEN enzyme that cannot perform its function as a tumor suppressor. Other mutations prevent the PTEN gene from producing any enzyme at all. Without functional PTEN enzyme, cell division is not controlled effectively and damaged cells continue to divide inappropriately, leading to the development of hamartomas and other tumors.

In some published case reports, mutations in the PTEN gene have been associated with Proteus syndrome, a rare condition characterized by asymmetric overgrowth of the bones, skin, and other tissues. However, many researchers now believe that individuals with PTEN gene mutations and asymmetric overgrowth do not meet the strict guidelines for a clinical diagnosis of Proteus syndrome. Instead, these individuals have a condition that is considered part of PTEN hamartoma tumor syndrome. One name that has been proposed for the condition is segmental overgrowth, lipomatosis, arteriovenous malformations, and epidermal nevus (SOLAMEN) syndrome; another is type 2 segmental Cowden syndrome. However, some scientific articles still refer to PTEN-related Proteus syndrome.

Other cancers

Somatic mutations in the PTEN gene are among the most common genetic changes found in human cancers. The cancers associated with somatic mutations are not inherited and do not occur as part of a cancer syndrome. Somatic mutations in the PTEN gene have been reported in many types of cancer, and studies suggest that PTEN may be the most frequently mutated gene in endometrial cancer. PTEN gene mutations are also commonly found in brain tumors called glioblastomas and astrocytomas, and in an aggressive form of skin cancer called melanoma. Mutations in the PTEN gene reduce or eliminate the tumor suppressor function of the PTEN enzyme. The loss of this enzyme's function likely permits certain cells to divide uncontrollably, contributing to the growth of cancerous tumors. In some cases, the presence of PTEN gene mutations is associated with more advanced stages of tumor growth.

Other Names for This Gene

• MMAC1
• mutated in multiple advanced cancers 1
• phosphatase and tensin homolog (mutated in multiple advanced cancers 1)
• phosphatase and tensin homolog deleted on chromosome 10
• protein-tyrosine phosphatase PTEN
• PTEN-MMAC1 protein
• PTEN1
• PTEN_HUMAN
• TEP1
• TEP1 phosphatase

Genomic Location

• Large head size (macrocephaly)
• Increased birth weight,
• Intellectual disability
• Autism spectrum disorder
• Benign skin tumors:
  • Hair follicle tumors (trichilemmomas)
  • Raised bumps on tongue and gums (oral papillomas)
  • Fatty tumors (lipomas)
• Growths in the colon (colon polyps)
• Dark colored freckles on the penis (macular pigmentation)
• Increased risk for cancer, especially thyroid, breast, uterine, and kidney

• Medical geneticist
• Neurologist (nerve specialist)
• Dermatologist (skin specialist)
• Gastroenterologist (digestion specialist)
• Urologist (kidney and bladder specialist)

The prevalence of Bannayan-Riley-Ruvalcaba syndrome is unknown, although it appears to be rare. Several dozen cases have been reported in the medical literature. Researchers suspect that the disorder is underdiagnosed because its signs and symptoms vary and some of them are subtle.