CLOVES disease is a rare, complex congenital disorder characterized by the overgrowth of various tissues and abnormal blood vessel development. The syndrome is a multisystem condition present at birth that impacts the skin, vascular system, and musculoskeletal structure. The variable presentation of CLOVES syndrome necessitates specialized care and early identification for effective management. Understanding the defining features, genetic origin, and comprehensive treatment approach is fundamental to addressing this condition.
Defining CLOVES Syndrome
CLOVES syndrome is classified as a sporadic, non-hereditary disorder, meaning the condition arises spontaneously during early development rather than being passed down through families. The name is an acronym describing the primary features: Congenital Lipomatous Overgrowth, Vascular malformations, Epidermal nevi, and Spinal/Skeletal anomalies/scoliosis. This grouping indicates the disease affects multiple body systems simultaneously from birth.
The disorder is categorized under the umbrella term PIK3CA-Related Overgrowth Spectrum (PROS), which includes a range of rare overgrowth conditions caused by a specific genetic mutation. CLOVES syndrome is considered to be one of the more extensive manifestations within the PROS group due to the widespread nature of the affected tissues. The congenital nature of the condition means that some asymmetrical, disproportionate growth may even be detectable during prenatal scans.
CLOVES syndrome is distinct from similar overgrowth disorders because of its specific combination of fatty masses and complex vascular anomalies, often affecting the trunk and spine. This classification helps clinicians differentiate it from other syndromes like Proteus syndrome or Klippel-Trénaunay syndrome.
Recognizing the Physical Signs
The physical presentation of CLOVES syndrome is highly variable, but it involves an asymmetrical overgrowth pattern noticeable at birth. A defining feature is the presence of localized lipomatous masses, which are soft, fatty tissue growths frequently found on the trunk, back, or abdomen. These masses can be extensive, sometimes invading deeper structures, including the spinal canal, potentially leading to neurological complications.
Patients exhibit complex vascular malformations, which include various types of abnormal blood vessels. These malformations may be low-flow (capillary, venous, and lymphatic malformations) or, less commonly, high-flow arteriovenous malformations. Low-flow malformations often present as enlarged veins or port-wine stains on the skin overlying the fatty mass, while high-flow malformations are more aggressive and can occur near the spine.
Skeletal abnormalities are another consistent component, often manifesting as spinal issues like scoliosis or a tethered spinal cord. Limb involvement is common and includes overgrowth of the extremities, resulting in large, wide hands or feet, and sometimes macrodactyly (enlargement of fingers or toes).
The “E” in CLOVES refers to Epidermal nevi, which are benign, sharply defined skin lesions. These skin anomalies can appear as raised, warty, or flesh-colored patches, often following specific linear patterns on the body. Serious internal complications can include heart failure due to severe vascular involvement and issues with kidney size or function.
The Underlying Genetic Cause
CLOVES syndrome is caused by a somatic mosaic gain-of-function mutation in the PIK3CA gene. The PIK3CA gene provides instructions for making the p110α subunit of an enzyme called phosphoinositide 3-kinase (PI3K). This enzyme acts as a master regulator in a crucial signaling pathway within cells known as the PI3K/AKT/mTOR pathway.
The mutation is described as “gain-of-function” because it causes the PI3K enzyme to be overactive, essentially putting the cell’s growth signals into overdrive. The PI3K/AKT/mTOR pathway is responsible for controlling cell proliferation, maturation, survival, and blood vessel formation, which directly explains the overgrowth and vascular anomalies seen in CLOVES syndrome.
The term “mosaicism” is fundamental to understanding the disease’s localized nature, meaning the mutation is not present in every cell of the body. This genetic change occurs spontaneously in a single cell early in embryonic development, post-fertilization. As the embryo develops, only the cells that descended from that original mutated cell will carry the genetic change, leading to the localized, asymmetrical pattern of overgrowth. Because the mutation is somatic (present only in body cells), the condition is typically not inherited from the parents.
Multidisciplinary Treatment Strategies
The management of CLOVES syndrome requires a comprehensive and highly specialized approach involving a multidisciplinary team of specialists. Treatment focuses on managing the specific manifestations, improving function, and reducing the risk of complications. Specialists frequently involved include interventional radiologists, orthopedic surgeons, plastic surgeons, and geneticists.
Surgical intervention is a common strategy, often used for debulking the large, localized lipomatous masses that can compress nearby structures. Orthopedic surgeons address skeletal anomalies like scoliosis or limb overgrowth through corrective surgeries aimed at improving mobility and correcting asymmetry. However, surgery on the soft tissue masses can be challenging due to the highly vascular nature of the overgrown tissue.
Interventional radiology techniques are routinely employed to treat the vascular malformations component of the syndrome. Sclerotherapy involves injecting a solution directly into the abnormal vascular channels to cause them to shrink and scar down. Embolization is another technique used to block the blood supply to aggressive malformations, particularly those that are high-flow or located near the spine.
Targeted medical therapy represents a significant advance in treating CLOVES syndrome and other PROS disorders. These treatments specifically inhibit the overactive PI3K/AKT/mTOR pathway that drives the abnormal growth. Drugs like alpelisib (BYL719), which is a selective PIK3CA inhibitor, have shown promising results in clinical studies. This targeted approach can reduce the size of vascular tumors, improve heart function, and lessen the severity of hemihypertrophy and scoliosis.