CLOVES Syndrome: Comprehensive Imaging Guide and Clinical Overview
Overview
CLOVES syndrome is an acronym for congenital lipomatous overgrowth (CLO), vascular malformations (V), epidermal nevi (E), and spinal/skeletal anomalies including scoliosis (S). It is a rare, sporadic, non-hereditary overgrowth syndrome detected typically at birth or early infancy. The syndrome manifests as asymmetric, segmental overgrowth predominantly involving soft tissues and bones alongside complex vascular malformations. The pathogenesis is linked to somatic activating mutations in the PIK3CA gene, resulting in mosaic distribution of affected tissues. Clinical features include truncal lipomatous masses, limb anomalies like large or wide fingers and toes, epidermal nevi, and skeletal deformities such as scoliosis or abnormal vertebrae.
Key Imaging Features
- Subcutaneous fatty overgrowth: Predominantly midline truncal lipomatous masses visible on MRI and ultrasound, sometimes invading deeper structures.
- Complex vascular malformations: Capillary, venous, and lymphatic malformations seen as slow-flow lesions; arteriovenous malformations (fast-flow) are rare but may be detected with MR angiography or Doppler ultrasound.
- Musculoskeletal anomalies: Skeletal deformities on X-ray and CT include scoliosis, abnormal vertebral segmentation, and limb length discrepancies.
- Soft tissue swelling: Ultrasound characterization demonstrates heterogeneous echogenicity reflecting fatty and vascular components with possible phleboliths.
- Skin and epidermal changes: Epidermal nevi and lymphatic vesicles may be visible as superficial lesions correlating with cutaneous abnormalities.
- Renal anomalies: Occasionally small or absent kidneys identified on ultrasound, warranting surveillance for Wilms tumor.
Pathophysiology
CLOVES syndrome arises due to somatic mosaicism involving activating mutations in the PIK3CA gene, which encodes a subunit of the phosphatidylinositol-3-kinase, a critical component in cellular growth and proliferation pathways. This results in localized cellular overgrowth, abnormal angiogenesis, and aberrant lymphatic development manifesting as diffuse fatty hypertrophy and complex vascular anomalies. The patchy distribution reflects mosaic involvement, explaining the segmental, asymmetric overgrowth detected by imaging. Vascular malformations consist mainly of capillary, venous, and lymphatic channels, contributing to the soft tissue heterogeneity and slow-flow characteristics on Doppler and MR angiography. Skeletal abnormalities stem from abnormal bone growth and segmentation anomalies induced by the same dysregulated pathways.
Differential Diagnosis
- Proteus syndrome: Characterized by progressive asymmetric overgrowth including cerebriform connective tissue nevi, differing by more widespread and rapidly progressive skeletal anomalies visible on imaging.
- Klippel-Trenaunay syndrome: Presents with capillary-venous-lymphatic malformations and limb overgrowth, but without truncal lipomatous masses; vascular malformations are similar but less complex.
- Parkes Weber syndrome: Notable for high-flow arteriovenous malformations; imaging reveals prominent AV shunts absent in typical CLOVES cases.
- Other PROS disorders: Share PIK3CA mutations but differ by extent and pattern of overgrowth and vascular anomalies, requiring genetic correlation and detailed imaging for identification.
Imaging Protocols and Techniques
Accurate diagnosis and assessment of CLOVES syndrome require a multimodal imaging approach:
- Ultrasound is first-line for evaluating superficial soft tissue masses and characterizing vascular malformations with Doppler assessment, useful also for Wilms tumor screening during follow-up.
- Magnetic Resonance Imaging (MRI) with fat-suppression sequences provides detailed soft tissue contrast for delineating the extent of lipomatous overgrowth and vascular anomalies. MR angiography is essential for evaluating vascular flow characteristics.
- Computed Tomography (CT) may be employed for detailed evaluation of skeletal anomalies, bony overgrowth, and surgical planning.
- X-rays are used for initial skeletal survey assessing scoliosis, vertebral anomalies, and limb discrepancies.
- Employing serial imaging is advised to monitor progression or complications such as thrombosis or tumor development.
Imaging pearls include recognizing the typical midline truncal fatty mass with associated vascular slow-flow malformations, differentiating these from fast-flow lesions, and careful skeletal evaluation for subtle segmentation defects. Pitfalls include mistaking lipomatous overgrowth for neoplastic masses and underestimating the complexity of combined vascular anomalies without multimodal imaging.
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