CLOVES syndrome

Overview

CLOVES syndrome is a rare congenital disorder characterized by a combination of tissue overgrowth, vascular malformations, and skin anomalies. The name CLOVES is an acronym that stands for Congenital Lipomatous Overgrowth, Vascular malformations, Epidermal nevi, and Scoliosis or spinal deformities. It is part of a group of overgrowth syndromes associated with somatic mutations in the PIK3CA gene. The condition is typically present at birth and varies widely in severity and symptoms depending on which parts of the body are affected.

Causes

CLOVES syndrome is caused by a somatic mutation in the PIK3CA gene, which plays a key role in cell growth, proliferation, and survival. This mutation is not inherited but occurs spontaneously during early embryonic development. Because it is a somatic (non-germline) mutation, it affects only certain parts of the body, leading to segmental or patchy overgrowth. The mutation results in abnormal activation of the PI3K-AKT signaling pathway, contributing to uncontrolled tissue growth and vascular anomalies.

Symptoms

Symptoms of CLOVES syndrome vary widely depending on the size, location, and severity of affected tissues. Common features include:

• Congenital lipomatous overgrowth: Fatty tissue overgrowth, often asymmetrical and located on the trunk, back, or extremities

• Vascular malformations: Including capillary, venous, and lymphatic malformations; may cause swelling, pain, and bleeding

• Epidermal nevi: Thickened, wart-like patches of skin following the lines of Blaschko

• Scoliosis or spinal abnormalities: Curvature of the spine or other vertebral malformations

• Asymmetric limb growth: One arm or leg may be significantly larger than the other

• Neurological involvement: In some cases, patients may have tethered spinal cord or other central nervous system abnormalities

• Increased risk of thrombosis: Due to vascular anomalies and venous stasis

Some individuals may also experience functional impairments, chronic pain, or cosmetic concerns due to visible overgrowth or deformities.

Diagnosis

Diagnosis of CLOVES syndrome is typically based on clinical evaluation, imaging studies, and genetic testing. Key diagnostic steps include:

• Clinical assessment: Identification of characteristic features such as overgrowth, vascular anomalies, and epidermal nevi

• Imaging studies: MRI or ultrasound to evaluate tissue overgrowth, vascular malformations, and spinal involvement

• Genetic testing: Somatic mutation testing of affected tissue (not blood) to identify mutations in the PIK3CA gene

• Differential diagnosis: Rule out similar overgrowth syndromes such as Proteus syndrome, Klippel–Trénaunay syndrome, and other PIK3CA-related overgrowth spectrum (PROS) conditions

Treatment

There is no cure for CLOVES syndrome, but treatment is focused on managing symptoms and improving quality of life. A multidisciplinary approach is usually required, involving specialists in genetics, surgery, dermatology, interventional radiology, neurology, and rehabilitation. Treatment options include:

• Surgical interventions: To remove or reduce overgrown tissue, correct spinal deformities, or treat vascular malformations

• Interventional radiology: Sclerotherapy or embolization for vascular anomalies

• Medications: Targeted therapies such as sirolimus or alpelisib (a PI3K inhibitor) may reduce abnormal growth and inflammation

• Pain management: Physical therapy, medications, or procedures to address chronic pain

• Compression garments: To manage swelling and prevent complications like deep vein thrombosis (DVT)

• Regular monitoring: To watch for complications such as thrombosis, infections, or neurological issues

Prognosis

The prognosis for individuals with CLOVES syndrome varies depending on the extent and severity of the condition. While the syndrome is not typically life-threatening, complications such as vascular malformations, thrombosis, and neurological involvement can pose significant risks. With appropriate medical care and supportive therapies, many individuals can manage symptoms effectively and maintain a good quality of life. Ongoing research into PIK3CA-targeted therapies holds promise for improving long-term outcomes in CLOVES and related disorders.