PIK3CA-Related Overgrowth Syndrome (PROS) is a rare genetic condition characterized by the overgrowth of various body parts. This overgrowth can manifest in different tissues and organs, appearing either in localized areas or more broadly across the body. The extent and specific presentation of overgrowth vary significantly among affected individuals.
The Basis of PIK3CA-Related Overgrowth Syndrome
PROS is caused by a somatic mutation in the PIK3CA gene. This gene provides instructions for making a protein known as phosphoinositide 3-kinase catalytic subunit alpha (p110α), which plays a role in regulating cell growth, division, and survival.
A somatic mutation means the genetic change occurs after conception, in only some cells of the body. This leads to a “patchwork” or mosaic distribution of affected and unaffected tissues. The presence of the mutation in only certain cells explains why the overgrowth is often localized and can vary widely in its presentation.
PROS is not inherited from parents, arising spontaneously in the individual. The specific timing of when the mutation occurs during embryonic development and in which cell types can influence the diverse presentations of the syndrome.
The PIK3CA gene is a component of the PI3K-AKT-mTOR pathway, a signaling network within cells. When a mutation occurs in PIK3CA, it leads to overactivation of this pathway. This overactivation results in uncontrolled cell growth and proliferation, causing the characteristic overgrowth of tissues and malformations.
Recognizing Manifestations and Diagnosis
The clinical manifestations of PIK3CA-Related Overgrowth Syndrome are diverse, affecting various body parts and systems, including the limbs, trunk, head, and internal organs. The overgrowth is asymmetric, meaning one side of the body or a specific limb may be larger than the other.
Common presentations include macrodactyly (enlargement of fingers or toes) and hemihyperplasia (one side of the body or a limb noticeably larger). Several specific syndromes are now recognized as part of the broader PROS spectrum, such as CLOVES syndrome.
CLOVES is an acronym for Congenital Lipomatous Overgrowth, Vascular Malformations, Epidermal Nevi, and Spinal/Skeletal Anomalies. Other features include vascular malformations (lymphatic, venous, or arteriovenous), brain overgrowth (megalencephaly), and lipomatous overgrowth (abnormal fatty tissue).
Diagnosis of PROS begins with clinical suspicion based on a physical examination and imaging studies. Magnetic Resonance Imaging (MRI) and Computed Tomography (CT) scans are used to visualize the extent and nature of the overgrowth. These imaging techniques help determine which tissues are affected and the degree of involvement.
Confirmation of PROS relies on genetic testing to identify the PIK3CA gene mutation. Due to the mosaic nature of the mutation, detecting it can be challenging, as it may not be present in all cells. Therefore, genetic testing requires tissue samples from affected areas, such as a skin biopsy or surgical tissue, rather than just a blood sample.
Current Management Strategies
Managing PIK3CA-Related Overgrowth Syndrome is complex and requires a multidisciplinary team approach. This team includes specialists such as geneticists, surgeons, neurologists, dermatologists, oncologists, and physical therapists, all collaborating to address the varied aspects of the condition.
Surgical interventions are a primary part of PROS management. Debulking surgeries remove excess tissue and reduce the size of overgrown areas. Corrective surgeries may be necessary to address skeletal deformities or discrepancies in limb length. For vascular malformations, procedures like sclerotherapy or embolization are employed to reduce their size and associated symptoms.
Medical therapies have emerged as an advancement in PROS management, focusing on targeted inhibitors. Drugs such as sirolimus or alpelisib specifically target the overactive PI3K-AKT-mTOR pathway. These medications work by reducing the growth of affected tissues and alleviating symptoms, offering a non-surgical option for managing the condition.
Supportive care and ongoing monitoring are also important components of management. Physical and occupational therapy are used to maintain function and improve mobility in affected individuals. Pain management strategies address discomfort associated with overgrowth and related complications. Regular monitoring assesses treatment effectiveness and identifies complications.