CLOVE Syndrome: Facts, Symptoms, and Management Approaches

CLOVE syndrome (Congenital Lipomatous Overgrowth, Vascular malformations, Epidermal nevi, Scoliosis/Skeletal anomalies) is a rare congenital disorder now classified under PIK3CA-Related Overgrowth Spectrum (PROS). This non-hereditary condition results from somatic PIK3CA gene mutations, causing asymmetric overgrowth and vascular anomalies typically apparent at birth. Medical management focuses on symptom-specific interventions and multidisciplinary care.

Understanding CLOVE syndrome requires recognizing its evolution in medical classification. Once considered a distinct entity, current medical consensus places CLOVE syndrome within the broader PIK3CA-Related Overgrowth Spectrum (PROS), reflecting advances in genetic understanding. This reclassification emerged after researchers identified somatic mutations in the PIK3CA gene as the common molecular basis for several previously separate overgrowth conditions.

Genetic Basis and Pathophysiology

CLOVE syndrome stems from post-zygotic mutations in the PIK3CA gene, which encodes a critical component of the PI3K-AKT-mTOR signaling pathway. These spontaneous mutations occur during embryonic development, creating a mosaic pattern where only certain body tissues are affected. The mutation leads to constitutive activation of the PI3K pathway, resulting in uncontrolled cellular growth and proliferation.

Unlike inherited genetic disorders, CLOVE syndrome occurs sporadically with no family history. The mosaic nature explains the variable presentation between patients—some experience mild manifestations while others face significant medical challenges. Recent research has identified specific PIK3CA mutation hotspots correlating with particular clinical features, advancing targeted treatment approaches.

Clinical Features and Diagnostic Criteria

The acronym CLOVE represents the core clinical features:

Feature	Manifestations
Congenital Lipomatous Overgrowth	Asymmetric fatty tissue overgrowth, typically affecting one side of the body
Vascular Malformations	Capillary, venous, or lymphatic abnormalities, sometimes with slow-flow characteristics
Epidermal Nevi	Skin lesions following Blaschko's lines, often on the torso or limbs
Skeletal Anomalies	Scoliosis, limb length discrepancies, widened metaphyses, or spinal canal enlargement

Additional common findings include:

• Connective tissue nevi
• Kidney abnormalities
• Neurological complications from spinal involvement
• Increased risk of deep vein thrombosis

Diagnosis relies on clinical evaluation by specialists familiar with overgrowth syndromes. Genetic testing through next-generation sequencing of affected tissues confirms PIK3CA mutations. Differential diagnosis must exclude other overgrowth conditions like Proteus syndrome, Klippel-Trénaunay syndrome, and fibroadipose hyperplasia.

Medical Management Approaches

Effective clove syndrome treatment requires a multidisciplinary team addressing specific manifestations:

Vascular Management

Interventional radiology techniques provide minimally invasive options for problematic vascular malformations. Sclerotherapy and embolization can reduce lesion size and associated pain. For complex cases, specialized centers may offer sirolimus (an mTOR inhibitor) as an off-label treatment showing promising results in reducing overgrowth progression.

Skeletal and Orthopedic Care

Management of skeletal anomalies often involves:

• Custom orthotics for limb length discrepancies
• Bracing for scoliosis management
• Guided growth procedures in pediatric patients
• Reconstructive surgery for severe deformities

Early intervention by orthopedic specialists familiar with rare overgrowth conditions significantly improves long-term mobility outcomes for patients with clove syndrome and skeletal involvement.

Prognosis and Quality of Life Considerations

CLOVE syndrome prognosis varies significantly based on mutation burden and affected systems. Most patients experience normal cognitive development but face physical challenges requiring ongoing care. Life expectancy depends on complication management—particularly neurological and vascular issues.

Comprehensive care coordination through specialized vascular anomalies centers provides the best outcomes. Emerging targeted therapies like alpelisib (a PI3Kα inhibitor) show potential for modifying disease progression in clinical trials, representing hope for future clove syndrome management strategies.

Support Resources and Community

Families navigating clove syndrome diagnosis benefit from connecting with specialized support networks. Organizations like the Lymphatic Education & Research Network (LE&RN) and the MAGIC Foundation provide educational materials and community connections. Participation in patient registries contributes to advancing research while connecting families with clinical trial opportunities.

Is CLOVE syndrome hereditary?

No, CLOVE syndrome is not hereditary. It results from spontaneous somatic mutations in the PIK3CA gene that occur after conception, meaning it's not passed from parents to children. The mosaic nature of the mutation explains why affected individuals have varying presentations.

What's the difference between CLOVE syndrome and PROS?

CLOVE syndrome is now considered part of the broader PIK3CA-Related Overgrowth Spectrum (PROS). PROS encompasses several previously separate conditions including CLOVE syndrome, fibroadipose hyperplasia, and others, all sharing the same genetic cause - PIK3CA mutations. The reclassification reflects our improved understanding of the genetic basis of these overgrowth disorders.

At what age is CLOVE syndrome typically diagnosed?

CLOVE syndrome is usually apparent at birth or during early infancy when characteristic physical features become noticeable. Some cases may be detected prenatally through ultrasound showing asymmetric growth. However, milder presentations might not be diagnosed until later childhood when symptoms progress or complications arise.

Are there specialized treatments for CLOVE syndrome symptoms?

Yes, specialized treatments include targeted therapies like alpelisib (a PI3Kα inhibitor) currently in clinical trials, customized orthotics for limb discrepancies, interventional radiology procedures for vascular malformations, and multidisciplinary surgical approaches. Management focuses on specific symptoms rather than a cure, requiring coordination between vascular anomalies specialists, orthopedists, and other relevant specialists.

How common is CLOVE syndrome?

CLOVE syndrome is extremely rare, with only several hundred documented cases worldwide. Its rarity contributes to diagnostic challenges, as many healthcare providers may never encounter a patient with this condition during their careers.