PIK3CA-Related Overgrowth Spectrum

PROS

PIK3CA-related overgrowth spectrum (PROS) is a group of rare conditions that cause unusual growth in different parts of the body. These conditions share a common cause: changes in a gene called PIK3CA that controls how cells grow and divide.

Table of contents

• What is PIK3CA-Related Overgrowth Spectrum?
• Conditions Included in PROS
• What Causes PROS?
• Symptoms and Features
• How PROS is Diagnosed
• Treatment Options
• Living with PROS
• What to Expect

What is PIK3CA-Related Overgrowth Spectrum?

PIK3CA-related overgrowth spectrum, also known as PROS, is an umbrella term for a group of rare conditions that all share the same root cause^[1]. The name comes from a specific gene called PIK3CA, which gives instructions for making a protein that controls how cells grow, divide, and survive in the body^[3].

The main feature that all PROS conditions have in common is overgrowth—when certain parts of the body grow too much or develop unusual shapes. This overgrowth usually appears at birth or during early childhood^[1]. The overgrowth can happen in many different tissues, including skin, blood vessels, bones, fat, muscles, and even the brain^[3].

Before doctors understood that these conditions were all related to the PIK3CA gene, they were thought of as separate diseases. Each was named based on which body parts were affected^[1]. Now doctors know that these conditions are part of one spectrum because they all result from changes in the same gene^[4].

Conditions Included in PROS

PROS includes many different conditions, each with its own set of symptoms and characteristics. The specific condition a person has depends on which body parts are affected by the overgrowth^[4].

Some of the conditions grouped under PROS include:

• CLOVES syndrome, which stands for Congenital Lipomatous asymmetric Overgrowth, Vascular malformations, Epidermal nevi, and Skeletal and spinal anomalies. This condition includes fatty tissue overgrowth, unusual blood vessels, skin marks called nevi (moles), and problems with bones and the spine^[2].
• Fibroadipose hyperplasia (FH), which causes patchy overgrowth of a limb or part of the body due to fatty, fibrous, or blood vessel tissue growing too much. This overgrowth typically gets worse over time^[2].
• Megalencephaly-Capillary Malformation (MCAP) syndrome, characterized by overgrowth of all or part of the brain and head, along with overgrowth of other body parts. The brain overgrowth can lead to seizures, low muscle tone, developmental delays, and intellectual disabilities^[2].
• Klippel-Trenaunay Syndrome (KTS)^[4]
• Isolated Lymphatic Malformation (ILM)^[4]
• HemiHyperplasia-Multiple Lipomatosis (HHML), which often affects the growth of arms and legs and causes slow-growing, painless fatty masses under the skin^[3]
• Macrodactyly, which causes enlarged fingers or toes^[4]

Other conditions may be identified and characterized as PROS over time^[4].

What Causes PROS?

PROS is caused by changes, or mutations, in the PIK3CA gene^[3]. This gene normally provides instructions for making a protein that acts as an important signal in your body. These signals help make sure that cells grow, divide, move, and die when they should^[3].

When the PIK3CA gene has a mutation, the protein it makes doesn’t work correctly. This leads to mistakes in cell growth, causing cells to grow and divide too fast or live too long. This results in overgrowth or unusual shapes in the parts of the body where the mutation is present^[3].

An important feature of PROS is mosaicism—the mutation is only present in some cells of the body, not all of them^[4]. Which body parts are affected depends on which cells have the genetic change in PIK3CA^[2]. Different parts of the body affected by the mutation developed at different times during embryonic development, which explains why PROS diseases can look very different from each other^[5].

Unlike many other genetic conditions, PROS is not passed from parent to child. The mutation happens during development, so if your child has PROS, it doesn’t mean that you have it or that your other children will develop it^[3].

Symptoms and Features

PROS conditions can cause a wide variety of symptoms depending on which type a person has and which parts of the body are affected^[3]. Some people have only mild symptoms, while others have more severe disease that causes problems in day-to-day life^[12].

The overgrowth in PROS most commonly affects the brain, limbs (including fingers and toes), trunk (including abdomen and chest), and face, usually in an uneven or asymmetric pattern^[1].

Common features driven by the PIK3CA mutation include^[4]:

• Enlarged digits: one or more unusually large fingers or toes
• Scoliosis: a sideways curvature of the spine caused by abnormal growth
• Abnormal growth: when certain parts of the body grow too much or too little, which may occur in muscles, fatty tissue, organs, the spine, or skeleton, and may also affect the surface of the skin
• Vascular malformations: when blood vessels like veins, arteries, and capillaries grow in abnormal ways
• Lymphatic malformations: when vessels that contain clear fluid called lymph grow abnormally
• Enlarged head: when brain complications such as hydrocephalus (fluid in the brain) or seizures cause overgrowth in the brain

When the brain is affected, there may be generalized brain overgrowth accompanied by overgrowth of specific brain structures. This can result in ventriculomegaly (enlarged fluid-filled spaces in the brain), a markedly thick corpus callosum (the structure connecting the two sides of the brain), and crowding of the posterior fossa (the back part of the skull)^[1].

Vascular malformations may include capillary, venous, and less frequently, arterial or mixed types^[1]. Lymphatic malformations may be in various locations, both internal and external, and can cause swelling, pain, and occasionally bleeding if injured^[1].

The overgrowth of fatty tissue, called lipomatous overgrowth, may occur on the same side or opposite side of a vascular malformation if one is present^[1].

Many children with PROS have feeding difficulties that are often due to multiple factors. Poor muscle tone can make it hard for some babies to eat or swallow, and they may be slower to sit up and move around on their own than other children^[12].

The degree of intellectual disability appears to be mostly related to the presence and severity of seizures, cortical dysplasia (abnormal development of the brain’s outer layer), and hydrocephalus^[1].

A small number of individuals develop endocrine (hormone) problems, most commonly including low blood sugar (hypoglycemia), hypothyroidism (underactive thyroid), and growth hormone deficiency^[1].

How PROS is Diagnosed

Children are often born with a PROS condition, and symptoms are typically visible when a baby is born or appear during early childhood, which is when doctors can make a diagnosis^[3]. However, some overgrowth is not evident at birth and may develop over time^[2].

The diagnosis may be suspected based on physical examination and imaging studies such as Magnetic Resonance Imaging (MRI) or Computed Tomography (CT)^[2].

To confirm the diagnosis, genetic testing is needed. The diagnosis of PROS is established when a person with suggestive symptoms is found to have a heterozygous mosaic (or rarely, present in all cells) activating pathogenic variant (disease-causing change) in the PIK3CA gene^[1].

Because the PIK3CA mutation may not affect all cells in the body due to mosaicism, a positive mutation can be difficult to detect^[4]. For this reason, testing DNA from clinically affected tissue samples is recommended. The best samples come from freshly obtained skin biopsy overlying an affected area, from surgical removal of the overgrown tissue, or from uncultured tissues such as skin fibroblasts or other tissues^[1].

Specialized genetic testing techniques are used, including targeted capture of the entire PIK3CA coding region followed by next-generation sequencing at very deep coverage. This approach allows for detection of very low levels of mosaicism throughout the gene^[1].

Treatment Options

There is no cure for PROS, but various treatments can help manage symptoms and make it easier to live with the condition^[9]. The wide range of PROS conditions means there is a similarly wide range of treatments. Treatment depends on the type and location of symptoms^[9].

Medications to Treat Symptoms

Children may take medications to help with specific symptoms^[9]:

• For children whose PROS affects their brain and causes seizures, doctors might prescribe epilepsy medications^[9]
• If overgrowth of skin cells causes lesions or skin growths that are painful or itchy, doctors might prescribe steroids or antihistamines as pills or creams^[9]
• Anti-inflammatory medications like aspirin can help with pain and swelling^[9]
• Anticoagulant therapy, such as blood thinners, may be used to prevent blood clots^[10]
• Antibiotics may be needed for people with lymphatic complications^[10]
• Growth hormone therapy, medications for hypothyroidism, or treatments for hypoglycemia may be prescribed for endocrine problems^[10]

Surgery

It’s common for people with PROS to need surgery, especially if they have growths that make it hard to move around^[9]. Surgery can help correct problems with bones, such as scoliosis or legs that are different lengths. If there is overgrowth in the limbs that involves many layers of tissue, treatment happens in stages, and multiple surgeries over time may be needed^[9].

For skin lesions, laser treatment can help reduce them, but surgery might be the best option to get rid of them completely^[9].

With severe brain overgrowth, medications may not be enough to stop seizures. In these cases, surgery can be more successful. It can also help if growths are putting physical pressure on the brain or spinal cord^[9].

Other procedures that may be used include sclerotherapy, a treatment for vascular malformations^[5].

Targeted Therapy

For people with severe symptoms of PROS, targeted therapy may be recommended. In 2022, the U.S. Food and Drug Administration (FDA) approved a medication called alpelisib for use in adults and children with severe PROS requiring systemic therapy^[6]. This medication works by blocking the overactive PI3K enzyme that causes the overgrowth, reducing excessive cell signaling and helping to regulate cell growth^[6].

This type of treatment targets the root cause of PROS rather than just managing symptoms. Research has shown it can be effective in relieving pain and reducing malformations^[5].

Supportive Therapies

Many children benefit from additional supportive therapies and assistive devices^[10]:

• Physical, occupational, or speech therapy
• Mobility aids such as wheelchairs, walkers, braces, or shoe lifts
• Assistive devices to help with daily tasks

Working with a physical therapist or occupational therapist can help a child adapt their movements to do more tasks at home or school^[12].

Living with PROS

PROS can affect many aspects of daily life, but with proper support and accommodations, people with PROS can adapt and thrive.

Eating and Nutrition

PROS conditions may make it hard for some children to eat and swallow foods, making it difficult to get enough nutrition to stay healthy^[12]. A nutritionist can work with families to create a plan that helps children stay at a healthy weight. With nutritional counseling and support, children with PROS often reach a healthy weight^[12].

Walking and Movement

Some children or teens with PROS may have difficulty walking or moving around because of loose or unstable joints, uneven leg lengths, large or unusually shaped feet, or overgrowth of tissues^[12]. Children often learn to adapt to their changing bodies so they can walk, play, and perform daily activities. Sometimes surgeries to remove extra tissue can make it easier to move^[12].

Clothing and Shoes

Some children with PROS may have very wide or large feet or toes, making it challenging to find shoes that fit^[12]. Families can try larger shoes or sandals that can be adapted to fit changing feet. Some children may prefer to walk or play barefoot or in just their socks. If a child’s legs are different lengths, a shoe lift may help even out the difference^[12].

Children or teens who have hand mobility problems may want to wear clothes that pull on and off easily, such as T-shirts, pullovers, and elastic-waist pants^[12].

School

Some children with PROS have intellectual or developmental delays, as well as speech or hearing impairment. Many benefit from speech therapy, physical therapy, occupational therapy, or special education at their school^[12]. Some children or teens have an individualized education plan (IEP) or 504 Plan—legal documents that describe the accommodations a child needs from their public school^[12].

Emotional Support

Beyond physical complications, PROS can also affect the psychosocial health of patients and lead to increased stress, anxiety, and depression^[7]. Support groups for families living with PROS can be great places to learn practical tips for everyday life and connect with others facing similar challenges^[12].

What to Expect

The outlook for someone with PROS depends on many factors that vary from person to person^[6]. Individual factors such as the type of PROS, the affected tissues and organs, the time of diagnosis, and the presence of complications all contribute to the overall outlook^[6].

Some people who receive diagnoses of isolated, mild forms of PROS in childhood can live typical life spans. In some cases, symptoms that were initially progressive can lessen with age. However, not all mild cases stabilize^[6].

For people who experience systemic involvement, brain enlargement, mobility challenges, or cardiovascular complications, PROS can cause significant long-term health concerns^[6]. PROS that leads to brain enlargement is associated with developmental and cognitive delays, seizures, and neurological deficits^[6].

In some cases, symptoms may be progressive and get worse over time. Other types of PROS tend to stabilize as children get older^[14]. If the overgrowth of various tissues worsens, it may lead to complications such as mobility problems, seizures, and difficulty completing day-to-day activities. This type of progression may happen slowly or quickly, depending on the type of PROS^[14].

Early intervention and treatment can improve the outlook and prevent complications^[6]. With proper medical care, supportive therapies, and accommodations, many people with PROS can manage their symptoms and maintain quality of life.