CLOVES syndrome is a rare, complex overgrowth disorder belonging to the PIK3CA-Related Overgrowth Spectrum (PROS). While chronic and potentially severe, it is generally not considered immediately fatal. The long-term prognosis depends on the location and magnitude of high-risk complications, particularly those affecting the vascular and spinal systems. Advances in targeted therapies and multidisciplinary care are steadily improving the outlook for individuals with CLOVES syndrome.
Understanding CLOVES Syndrome
CLOVES syndrome is a congenital condition, present at birth, named for its characteristic features. The acronym stands for:
- Congenital (C).
- Lipomatous overgrowth (L), which are soft, fatty masses often found on the torso.
- Overgrowth (O), typically involving asymmetrical growth of body parts.
- Vascular malformations (V), including capillary, venous, and lymphatic abnormalities.
- Epidermal nevi (E), which are non-cancerous skin lesions.
- Spinal or Skeletal anomalies (S), frequently involving scoliosis or a tethered spinal cord.
The abnormal growth pattern is rooted in a somatic, mosaic gain-of-function mutation in the PIK3CA gene. This gene provides instructions for a protein that regulates cell growth and survival. The mutation occurs spontaneously during early embryonic development, resulting in some cells having the mutation while others do not. This explains the mosaic, localized nature of the overgrowth. The overactivity of the mutated protein drives the abnormal development of fatty tissue, blood vessels, and bones that define the syndrome.
Determining the Severity and Risks
The prognosis for CLOVES syndrome is highly variable, depending on the affected body systems and the extent of malformations. Severity correlates directly with the involvement of truncal structures, as these malformations pose the most significant risk to life and function. While the syndrome is not inherently life-ending, specific, severe complications can be life-threatening if left unmanaged.
Vascular malformations, particularly large ones or those involving high-flow dynamics, pose a major danger. Extensive venous and lymphatic malformations in the chest or abdomen can lead to life-threatening blood clotting issues, such as deep vein thrombosis and pulmonary embolism. Large, fast-flow arteriovenous malformations (AVMs)—abnormal connections between arteries and veins—can severely strain the heart, potentially leading to high-output cardiac failure.
Spinal and skeletal complications also contribute significantly to morbidity. Lipomatous overgrowth in the paraspinal region can infiltrate the spinal canal and compress the spinal cord, causing neurological deficits. Severe scoliosis can progress rapidly, leading to restrictive lung disease as the curved spine limits the expansion of the chest cavity. Respiratory failure due to this restriction or from large intrathoracic masses is a severe cause of premature death in the most severe cases.
A less common but serious concern involves the renal and urological systems, which may present with structural anomalies of the kidneys. In rare instances, uncontrolled cellular growth is associated with an increased risk for specific types of tumors, such as Wilms tumor. The overall risk of severe complications is highest in the neonatal period for those with extensive truncal involvement, but for most individuals, the condition becomes a chronic, manageable disorder.
Management and Long-Term Prognosis
Managing CLOVES syndrome requires a coordinated multidisciplinary approach involving specialists like vascular experts, geneticists, and orthopedic surgeons. Traditional treatments focus on symptomatic relief, including surgical debulking to remove large fatty masses that interfere with function. Sclerotherapy, which involves injecting a solution to shrink a vascular malformation, is frequently used to manage blood vessel anomalies.
Significant advancements have been made with targeted pharmaceutical treatments that address the underlying genetic cause. These therapies inhibit the overactive signaling pathway caused by the PIK3CA mutation. Drugs like alpelisib, a selective PIK3CA inhibitor, stabilize or shrink the abnormal overgrowth in patients with PROS, including CLOVES syndrome.
Alpelisib acts by blocking the specific protein subunit that is excessively active due to the mutation, slowing the progression of existing lesions and potentially preventing new ones. Studies show this targeted therapy reduces the volume of affected lesions and significantly improves symptoms, even in patients who did not respond to older treatments. The US Food and Drug Administration (FDA) approved alpelisib for patients two years and older with PROS, marking a major breakthrough in treatment.
With specialized, proactive care and the availability of these targeted therapies, the long-term outlook for many individuals with CLOVES syndrome is much more favorable. Patients will likely require lifelong management to address chronic conditions and monitor for complications, but the goal is a normal or near-normal lifespan. Targeting the root genetic cause has fundamentally shifted the prognosis toward long-term disease control and improved quality of life.