PIK3CA-related overgrowth spectrum (PROS) refers to a group of rare genetic conditions characterized by excessive and abnormal growth of various body parts or tissues. PROS is not contagious, nor is it acquired through environmental factors.
What is PIK3CA-Related Overgrowth Spectrum?
PROS is an umbrella term encompassing multiple distinct conditions, linked by genetic changes. The “spectrum” aspect means that the overgrowth can vary greatly in degree and location. For example, some individuals might experience overgrowth in a single limb, while others could have more widespread involvement affecting multiple body regions.
This overgrowth is not uniform across the body; it often appears as patchy or irregular tissue enlargement. The affected tissues can include fat, muscle, nerve, or bone, and blood vessels. While present at birth or appearing in early childhood, the extent of overgrowth can progress over time.
The PIK3CA Gene and Its Role
The PIK3CA gene provides instructions for making the p110 alpha (p110α) protein, part of the enzyme phosphatidylinositol 3-kinase (PI3K). This enzyme plays a fundamental role in regulating cell activities, including growth, division, survival, movement, and protein production.
In PROS, specific changes, known as activating mutations, occur in the PIK3CA gene. These mutations lead to an overactive PI3K enzyme, which triggers uncontrolled chemical signaling within cells. This unregulated signaling causes affected cells to grow and divide more rapidly, resulting in tissue overgrowth. The predominant reason for these mutations is “mosaicism,” where the genetic change is present in only some cells of the body. This occurs when the mutation arises randomly in a single cell during early embryonic development, leading to a mixture of cells with and without the mutation.
Common Manifestations of PROS
PROS can manifest in various physical signs and symptoms, reflecting the diverse tissues influenced by the PIK3CA gene. Overgrowth can occur in various body parts, such as disproportionate growth of limbs, the trunk, or the head. This can result in one arm or leg being larger than the other, or an enlarged head, sometimes due to brain overgrowth (megalencephaly).
Overgrowth of fatty tissue, known as lipomatosis, is common, appearing as soft, fatty masses often on the trunk. Vascular malformations, which are atypical growths of blood vessels, may also occur, including capillary malformations (port-wine stains), venous malformations, and lymphatic malformations. Other manifestations include:
- Changes in bones, such as scoliosis
- Enlarged fingers or toes (macrodactyly)
- Skin abnormalities, such as epidermal nevi
- Neurological symptoms, such as seizures and developmental delays, particularly with brain involvement
Diagnosing and Managing PROS
Diagnosing PROS begins with a clinical evaluation based on observable physical signs, often appearing at birth or in early childhood. A specialist will assess symptoms such as patchy, irregular tissue overgrowth, or vascular malformations. Imaging studies like MRI, ultrasound, or CT scans are used to visualize internal overgrowth or abnormalities in tissues, bones, or the brain.
Diagnosis of PROS relies on genetic testing to identify specific PIK3CA mutations. It often involves targeted sequencing of DNA obtained from a biopsy of the affected tissue, as the mosaic nature of the mutation means it may not be detectable in blood samples for most forms of PROS. For some conditions within the spectrum, such as megalencephaly-capillary malformation (MCAP) syndrome, blood or saliva samples may be sufficient for testing.
Managing PROS involves a multidisciplinary approach tailored to individual symptoms and affected areas. While there is no cure, various strategies aim to manage symptoms and improve quality of life. Surgical interventions, such as debulking surgery, can reduce the size of overgrown tissues or correct skeletal abnormalities like scoliosis. However, tissues may regrow, necessitating repeat procedures.
Alpelisib (Vijoice), a PI3K alpha-selective inhibitor, is approved for patients aged two years and older with severe manifestations of PROS requiring systemic therapy. This medication works by inhibiting the overactive PI3K protein, thereby reducing abnormal cell growth. Clinical studies have shown alpelisib can reduce the volume of target lesions and improve PROS-related symptoms.
Other medications, like sirolimus, which inhibits the mTOR pathway downstream of PI3K, may also be used for vascular malformations. Supportive care, including physical, occupational, and speech therapy, is also provided.
Genetic Considerations for Families
The vast majority of PROS cases are sporadic, meaning they occur randomly and are not inherited from parents. This is due to the mosaic nature of the PIK3CA mutations, which arise in a single cell during early development after fertilization. Consequently, these mutations are typically not passed on to offspring.
While germline (inherited) PIK3CA mutations have been reported, these are rare. The risk for siblings of an affected individual with somatic mosaicism for a PIK3CA mutation is the same as in the general population. Genetic counseling is recommended for affected individuals and their families. This allows for a thorough understanding of the specific genetic risks, implications for family planning, and discussion of available testing options.