PIK3CA-related overgrowth spectrum

PIK3CA -related overgrowth spectrum (PROS) is caused by changes in the PIK3CA gene. When a genetic change causes a syndrome, it is also known as a mutation or pathogenic variant. The PIK3CA gene provides instructions to the body to make a protein that helps control the signaling of other proteins. This protein therefore helps many processes occur at the correct times including cell growth and division, cell movement, and cell survival. When there is a change in the PIK3CA gene, the body does not receive instructions to make the signaling protein correctly. This causes mistakes in cell growth and division and how long a cell survives. If cells are dividing too quickly or if they survive longer than they should, overgrowth of that part of the body can occur. This causes the signs and symptoms associated with PROS.

A diagnosis of PIK3CA -related overgrowth spectrum (PROS) is often suspected based on characteristic signs and symptoms of the syndromes. For example, megalencephaly-capillary malformation syndrome (MCAP syndrome) can be diagnosed based on findings of megalencephaly and characteristic malformations of the smallest blood vessels (capillaries). CLOVES syndrome can be similarly diagnosed by observing signs and symptoms such as overgrowth, capillary malformations, skin findings, and skeletal abnormalities.

A diagnosis of PROS can be confirmed with genetic testing of the PIK3CA gene. However, some people with these syndromes may have normal (negative) genetic testing. This is because the genetic changes (mutations or pathogenic variants) are only in some cells of the body. Therefore, multiple samples of different tissues may need to be tested for the PIK3CA genetic changes. In some cases, even if multiple tissues are tested, the diagnosis is not able to be confirmed with genetic testing.

PIK3CA -related overgrowth spectrum (PROS) is not known to be inherited at this time. There are no confirmed reports of transmission of PROS from a parent to a child, and there are no reports of siblings having PROS.

Most people with PROS have a somatic mutation in the PIK3CA gene, which is a genetic change that is not inherited, occurring randomly after fertilization (the joining of the egg and the sperm). Somatic mutations occur in cells other than egg and sperm cells (which are called gametes), and ultimately are only present in the cells that originate from the cell in which the mutation occurred. This is called somatic mosaicism. A person with somatic mosaicism cannot pass the mutation on to his/her children when the mutation is not present in the gametes. The siblings of a person with PROS due to somatic mosaicism also are not thought to have an increased risk to have PROS.

Rarely, a person with PROS has a germline mutation (a genetic change in a person's egg or sperm cell), which means the mutation is present in all of that person's cells. However, in the reported cases of germline mutations causing PROS, the mutations have occurred for the first time in the person with PROS and have not been inherited from either parent. These are called de novo mutations. Each child of a person with a de novo germline mutation has a 50% chance of inheriting the mutation. However as noted above, PROS in both a parent and child has not been reported. Siblings of a person with a de novo germline mutation theoretically have a 1% risk to have PROS, due to the possibility of germline mosaicism in a parent.

People with PIK3CA -related overgrowth syndrome (PROS) may struggle with severe overgrowth. This may mean that they require surgery to help remove some of the extra tissue, especially if it is causing trouble in day-to-day life. Unfortunately, the syndromes can also be associated with other health problems that can make daily life difficult. If overgrowth affects the brain and creates too much pressure, there can be side-effects such as intellectual disability and developmental delay.

Unfortunately, there is no cure for PIK3CA -related overgrowth spectrum (PROS). However, there are treatment options that can help manage symptoms of the syndromes. People with overgrowth may be treated with surgery to remove growths that are impacting movement. Surgery may also be necessary if there is too much pressure on the brain or to treat skeletal symptoms such as scoliosis. Medications may be used to treat seizures (epilepsy). Researchers are investigating other potential medications that may be used to treat PROS.

People with PROS may be followed by a multi-disciplinary team that may include a neurologist, cardiologist, nephrologist (doctor that helps manage kidney problems), and an orthopedist. Other treatment options may include speech therapy, physical therapy, and special education in school.

The University of Cambridge has a resource about segmental overgrowth and opportunities to enroll in a database for future research opportunities.