PIK3CA-related overgrowth spectrum (PROS) refers to a collection of related but very different disorders that lead to overgrowth of various body parts.

These conditions may be present at birth, or they may develop later, typically during early childhood.

It’s a rare group of conditions, but it’s hard to estimate the number of people who are affected because PROS encompasses so many different disorders.

Learn more about PROS and its subtypes, including causes, symptoms, potential treatment options, and more.

PROS is caused by changes in the PIK3CA gene. This gene is responsible for the production of the catalytic subunit of the PI3K enzyme. In healthy cells, PI3K is responsible for regulating cell growth and division.

In PROS, alterations in the PIK3CA gene cause changes to PI3K that result in the enzyme being continuously turned “on.” That means that cells continue to grow when they shouldn’t, leading to the overgrowth symptoms that are characteristic of the disease.

PROS is considered a genetic disorder, but it’s not inherited. The changes that occur in the PIK3CA gene happen during prenatal development (before birth). They’re not passed down from either parent; they happen due to chance during development. These types of genetic changes are known as de novo.

Because these genetic changes happen after development has already begun, not every cell in the body carries them. This results in the diverse spectrum of symptoms associated with various PROS subtypes.

Symptoms of PROS vary widely based on the types of cells and tissues that are affected. Alterations in PIK3CA can affect almost any tissue in the body. The areas most commonly affected are the:

  • trunk (abdomen and chest)
  • limbs, including fingers and toes
  • face
  • brain

Different types of tissues in these areas can be affected, which can lead to even more diverse symptoms. Possible effects of PROS include:

  • skeletal abnormalities or overgrowth
  • fatty masses or fluid-filled cysts
  • dry, rough patches of skin
  • blood clots or bleeding
  • pain or muscle weakness
  • cognitive or behavioral problems
  • seizures
  • heart problems, such as arrhythmia

PROS is divided into several types based on the body systems that are affected. The various types are not mutually exclusive, and some people may have overlapping forms of PROS. A few of these types are discussed below.

CLOVES syndrome

CLOVES syndrome is named for the most common symptoms seen with this condition:

  • Congenital lipomatous overgrowth: Fatty masses are present at birth, typically on the trunk or buttocks. They may appear on one or both sides of the body.
  • Vascular malformations: These may include red or purplish birthmarks, prominent veins, or problems with blood clots. Problems with blood vessels can lead to pain and inflammation in the affected areas, as well as bleeding in the skin, stomach, intestines, or bladder.
  • Epidermal nevi: These are also known as moles.
  • Scoliosis/skeletal/spinal abnormalities: Limb overgrowth (often uneven), wide hands or feet, large fingers or toes, and curving of the spine are common.

People with CLOVES syndrome may have several or only a couple of the symptoms described above. They may also have other symptoms, such as kidney or spleen problems, joint dislocations, or seizures. The severity of symptoms can vary as well.

Fibroadipose hyperplasia (FAH)

Also known as fibroadipose overgrowth (FAO), this condition is characterized by overgrowth in connective tissues like fat, skin, ligaments, and blood.

Most commonly, overgrowth of fatty tissue below the skin leads to enlargement of the trunk or limbs. People with FAH may have extra fingers or toes at birth, but other symptoms may develop over time.

As body parts become more enlarged, it can lead to problems with movement.

Megalencephaly-capillary malformation (MCAP) syndrome

Many different types of tissues are affected with MCAP syndrome, including the brain, skin, blood vessels, and connective tissues.

Many people with this condition have a disproportionately large head and discoloration of the skin. Enlargement of the brain, known as megalencephaly, can lead to problems such as headaches, seizures, behavioral problems, and trouble breathing.

In some infants with MCAP, body growth may stabilize over time, but it may happen unevenly — that is, one side of the body may grow faster than the other.

Hemihyperplasia-multiple lipomatosis (HHML) syndrome

HHML syndrome is characterized by the presence of many fatty masses, known as lipomas, that develop all over the body.

People with HHML syndrome also typically have enlargement of the trunk or limbs on one side of the body. This enlargement may become worse over time if the affected side grows faster than the other half of the body.

Facial infiltrating lipomatosis (FIL)

In this type of PROS, overgrowth of fat cells in the face leads to swelling, typically on one side of the face. Fatty masses can also develop in nerves around the lips and tongue. Teeth may develop early or become enlarged.

Other types of PROS

A variety of other types of PROS exist that may occur separately or in conjunction with any of those described above. These include:

  • diffuse capillary malformation with overgrowth (DCMO), characterized by blotchy networks of birthmarks
  • hemimegalencephaly (HME) and dysplastic megalencephaly (DMEG), which cause enlargement of one or both sides of the brain, respectively
  • macrodactyly, meaning unusually large fingers or toes

In most people with PROS, the goal of treatment is to manage symptoms. The type of treatment used will depend on the symptoms and how bothersome they are. Treatment plans for PROS may include:

  • medications
  • laser ablation
  • surgery
  • assistive devices
  • physical, occupational, or speech therapy

For some people with severe complications, targeted therapy — aimed at treating the underlying causes of disease — may be needed.

In 2022, alpelisib (Vijoice) became the first medication specifically approved for treatment of PROS in adults and children 2 years of age or older with severe complications.

Alpelisib is a PI3K inhibitor and works to block the activity of the overactive enzyme that leads to overgrowth in PROS. Studies of alpelisib use in people with PROS have found that treatment leads to improved symptoms and reductions in mass size.

The outlook with PROS varies depending on type and the severity of symptoms. In some cases, symptoms may be progressive and get worse over time. Other types of PROS tend to stabilize as children get older. In general, people with brain involvement tend to have worse outcomes than those with other types of PROS.

For some people, continued overgrowth of muscle, bone, or brain tissue can lead to additional complications like mobility problems or seizures. Regular monitoring is typically recommended to help avoid problems or to ensure they are treated quickly if they arise.

Because PROS develops from de novo alterations during development, siblings of people with PROS are no more likely to develop the condition than the general population.

The risk for PROS in future children of affected individuals depends on the types of genetic changes that lead to disease. A genetic counselor can help adults with PROS understand the likelihood of their children developing PROS and assist with family planning if needed.

PROS is a collection of conditions characterized by overgrowth of diverse tissue types, which can lead to a wide range of symptoms and complications. Symptoms of PROS most often appear in infancy, but others may not develop until early childhood.

Management of these conditions depends on the manifestations of the disease — which can vary dramatically from person to person — and requires an individualized approach to treatment. A team of healthcare professionals specializing in the various complications of PROS can help manage symptoms and address complications as they arise.