The term "PIK3CA-related overgrowth spectrum" (PROS) describes a group of closely connected but distinctly distinct illnesses that cause overgrowth in diverse body areas.
These problems might arise later, usually in early childhood, or they can exist from birth.
It's a rare category of illnesses, but because PROS includes so many distinct problems, it's difficult to determine how many people are affected.
Find out more about the causes, symptoms, possible treatments, and other aspects of PROS and its subtypes.
PIK3CA and PROS
Modifications in the PIK3CA gene result in PROS. This gene is in charge of producing the PI3K enzyme's catalytic subunit. PI3K controls cell division and proliferation in healthy cells.
In PROS, mutations in the PIK3CA gene lead to modifications in PI3K, which keep the enzyme perpetually "on." This implies that cells continue to grow when they shouldn't, which causes the disease's hallmark overgrowth symptoms.
Although it is not hereditary, PROS is seen as a genetic illness. The PIK3CA gene undergoes modifications throughout prenatal development, or before birth. They occur by accident throughout development; neither parent passes them on. We refer to these kinds of genomic alterations as "de novo."
These genetic alterations are not present in every cell in the body because they occur after development has started. As a result, different PROS subtypes are linked to a wide range of symptoms.
Signs and symptoms
The sorts of cells and tissues that are damaged by PROS can cause a wide range of symptoms. Almost every tissue in the body can be impacted by changes in PIK3CA. The most often impacted areas are the:
- trunk (abdomen and chest)
- limbs, including fingers and toes
- face
- brain
In certain regions, several tissue types may be impacted, which may result in an even wider range of symptoms. PROS may have the following effects:
- anomalies or overgrowth of the skeleton
- fat deposits or cysts filled with fluid
- dry, rough skin areas
- haemorrhage or blood clots
- discomfort or weakened muscles
- behavioural or cognitive issues
- cardiac issues, like arrhythmias
- seizures
Types of PROS
PROS is classified into multiple forms according to the afflicted body systems. The several kinds do not preclude one another, and some individuals may have more than one type of PROS. We go over a couple of these varieties below.
CLOVES syndrome
The symptoms that are most frequently associated with CLOVES syndrome are listed below:
- Congenital lipomatous overgrowth: At birth, there are usually fatty lumps on the trunk or buttocks. They could show up on one or both of the body's sides.
- Vascular malformations: These could be birthmarks that are red or purplish, noticeable veins, or issues with blood clots. Blood artery issues can cause bleeding in the skin, stomach, intestines, or bladder in addition to pain and inflammation in the affected areas.
- Epidermal nevi: These are also known as moles.
- Scoliosis/skeletal/spinal abnormalities: Wide hands or feet, big fingers or toes, and uneven limb overgrowth are typical. The spine also frequently curves.
Individuals who have CLOVES syndrome may exhibit multiple symptoms or only a few of the ones listed above. Other symptoms including joint dislocations, convulsions, or issues with the kidneys or spleen could also be present. The degree of symptoms can also differ.
Fibroadipose hyperplasia (FAH)
This disorder, often referred to as fibroadipose overgrowth (FAO), is typified by the overabundance of connective tissues, such as skin, ligaments, fat, and blood.
Most often, enlargement of the trunk or limbs results from an overabundance of fatty tissue beneath the skin. Although extra fingers or toes may be present at birth in people with FAH, other symptoms may eventually appear.
Increased body part enlargement may result in mobility issues.
Megalencephaly-capillary malformation (MCAP) syndrome
MCAP syndrome affects a wide range of tissues, including connective tissues, blood vessels, the brain, and skin.
Skin darkening and an abnormally big head are common symptoms of this illness. Megalencephaly, or enlargement of the brain, can cause issues like migraines, seizures, behavioural issues, and breathing difficulties.
A baby's body may eventually stabilise in certain MCAP cases, but it may do so unevenly—that is, one side of the body may grow more quickly than the other.
Hemihyperplasia-multiple lipomatosis (HHML) syndrome
A common feature of HHML syndrome is the development of many lipomas, or fatty lumps, throughout the body.
Additionally, expansion of the trunk or limbs on one side of the body is common in people with HHML syndrome. If the damaged side of the body grows more quickly than the other, this enlargement could eventually get worse.
Facial infiltrating lipomatosis (FIL)
Swelling, usually on one side of the face, is caused by the development of fat cells in the face in this kind of PROS. Additionally, the nerves surrounding the lips and tongue may develop fatty masses. Teeth may expand or develop prematurely.
Other types of PROS
There are numerous other kinds of PROS that can happen on their own or in combination with any of the previously mentioned sorts.
These include:
- The hallmark of diffuse capillary malformation with overgrowth (DCMO) is blotchy birthmark networks.
- one or both sides of the brain grow in hemimegalencephaly (HME) and dysplastic megalencephaly (DMEG), respectively.
- macrodactyly, which denotes abnormally huge toes or fingers
Treatment
The aim of treatment for the majority of PROS patients is symptom management. The severity of the symptoms will determine the kind of treatment that is administered. Plans for treating PROS may include of:
- medications
- laser ablation
- surgery
- assistive devices
- speech, physical, or occupational therapy
Targeted therapy, which tries to treat the disease's underlying causes, might be necessary for some patients who have serious consequences.
The first drug particularly approved for the treatment of PROS in adults and children two years of age or older with severe consequences was alpelisib, also known as vibrace. This approval occurred in 2022.
PI3K inhibitor alpelisib functions by inhibiting the hyperactive enzyme that causes PROS to proliferate excessively. Research on the usage of alpelisib in patients with PROS has revealed that the medication improves symptoms and reduces mass.
Outlook
Depending on the kind and intensity of symptoms, there are different prognoses for PROS. Certain patients may have progressive symptoms that worsen with time. When children get older, other sorts of PROS typically stabilise. People who experience brain involvement typically experience worse outcomes than people who experience other forms of PROS.
In certain individuals, persistent hypertrophy of the brain, bones, or muscles might result in further difficulties such as seizures or impaired movement. It's usually advised to do routine monitoring to assist prevent issues or make sure they are promptly addressed in the event they do occur.
Siblings of individuals with PROS do not have a higher risk of developing the disorder than the general population since PROS results from de novo mutations made during development.
Future offspring of afflicted persons may be at risk for PROS depending on the specific genetic alterations causing the illness. When it comes to family planning, a genetic counsellor can help adults with PROS determine the probability that their offspring will also develop PROS.
The takeaway
The overgrowth of several tissue types that characterises PROS is a group of disorders that can cause a wide range of symptoms and problems. Some PROS symptoms may not manifest until early childhood, but the majority do so in infancy.
The way these disorders are managed is determined by the disease's symptoms, which can differ greatly from person to person and necessitate a customised treatment plan. Symptom management and timely resolution of problems might be facilitated by a group of medical specialists who specialise in the many consequences associated with PROS.
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