CLOVES Syndrome: Causes, Symptoms, Diagnosis & Care Guide

CLOVES syndrome is a rare, sporadic overgrowth disorder characterised by a combination of congenital lipomatous overgrowth, vascular malformations, , and scoliosis/skeletal or spinal anomalies. It belongs to the spectrum of PIK3CA-related overgrowth syndromes (PROS), resulting from postzygotic somatic mosaic mutations in the PIK3CA gene. These mutations lead to dysregulated cell growth, affecting multiple tissues including fat, blood/lymph vessels, skin, bones, and spine. Symptoms vary widely in severity, from mild fatty overgrowth to life-threatening vascular complications. Fewer than 200 cases have been reported worldwide, highlighting its ultra-rare nature. Early diagnosis and multidisciplinary management are crucial to address complications like thrombosis, scoliosis, and organ involvement.

What is the cause of CLOVES syndrome?

CLOVES syndrome arises from gain-of-function mutations in the PIK3CA gene on chromosome 3q26.32, occurring postzygotically during embryonic development. These somatic mosaic mutations are not inherited but happen sporadically in some cells, explaining asymmetric overgrowth. The PIK3CA gene encodes the p110α catalytic subunit of phosphatidylinositol 3-kinase (PI3K), a key enzyme in the PI3K/AKT/mTOR pathway regulating cell proliferation, survival, and metabolism. Mutated PI3K causes constitutive pathway activation, leading to tissue overgrowth. Common hotspots include c.3140A>G (p.His1047Arg) and c.1633G>A (p.Glu542Lys). Mosaicism results in variable phenotypes; affected cells drive localised hyperplasia of adipose tissue, vessels, and bones. No germline mutations are reported, and parents are unaffected. Diagnosis is confirmed via targeted sequencing of affected tissues, as blood tests may miss low-level mosaicism.

Clinical features

CLOVES syndrome presents with hallmark features encapsulated in its acronym, though not all are present in every patient. Features are congenital or appear in early childhood, with asymmetric overgrowth often progressing slowly.

• Congenital lipomatous overgrowth: Soft, fatty masses (lipomas) typically on the trunk (back, abdomen, chest), often asymmetric and extending into body cavities. These can cause mass effect, compressing organs.
• Vascular malformations: Predominantly low-flow (venous, lymphatic, capillary), including phlebectasia (dilated veins), port-wine stains, and lymphatic vesicles prone to leakage, infection, or bleeding. High-flow arteriovenous malformations (AVMs) occur rarely but pose thrombosis or neurological risks. Common sites: trunk, limbs, spinal region.
• Epidermal naevi: Benign, warty or hyperpigmented skin lesions, often linear along Blaschko lines, reflecting mosaicism.
• Scoliosis/skeletal/spinal anomalies: Spinal curvature, tethered cord, vertebral anomalies; limb asymmetry with macrodactyly (enlarged digits), wide hands/feet, sandal-gap toe.

Additional features include:

• Neurological: Tethered cord, ventriculomegaly, hemimegalencephaly, seizures (50% cases).
• Renal: Hypoplasia/agenesis (unilateral), cysts, Wilms tumour risk.
• Other: Splenomegaly, intestinal bleeding, bladder hematuria, ptosis, dental hypoplasia.

Differential diagnosis

Key differentials include Proteus syndrome (progressive, distorting overgrowth), Klippel-Trenaunay syndrome (limb overgrowth with vascular stains), and other PROS. CLOVES lacks Proteus’ progressive cerebriform connective tissue nevi and has truncal predominance.

Diagnosis

Diagnosis is clinical, supported by imaging and genetics. Criteria require characteristic triad plus anomalies.

• History/exam: Document asymmetry, lipomas, nevi, vascular lesions, scoliosis.
• Imaging: MRI for lipomas/spinal cord; ultrasound/MRI for vascular/renal anomalies; X-ray for skeletal changes.
• Genetics: Next-generation sequencing of lesional tissue for PIK3CA variants (sensitivity >90% in affected areas).

Treatment and management

No cure exists; management is symptomatic and multidisciplinary (genetics, vascular surgery, orthopaedics, neurology).

• Vascular: Compression garments, sclerotherapy (bleomycin/CO2 laser for vesicles), anticoagulation for thrombosis risk.
• Orthopaedic: Bracing/surgery for scoliosis; debulking lipomas.
• Neurological: Spinal cord untethering if symptomatic.
• Emerging: PI3K/mTOR inhibitors (e.g., alpelisib) show promise in reducing overgrowth in PROS trials.
• Supportive: Pain management, physiotherapy, monitoring for Wilms tumour.

Prognosis

Variable; mild cases allow normal life, severe ones risk complications like coagulopathy, organ failure, or paralysis from spinal AVMs. Survival improved with early intervention; long-term follow-up essential.

Frequently asked questions

Is CLOVES syndrome inherited?

No, it results from de novo somatic mutations, not passed from parents.

Can CLOVES syndrome be cured?

Not currently, but targeted therapies like PI3K inhibitors offer hope.

What is the life expectancy with CLOVES syndrome?

Varies widely; many live into adulthood with proper management.

Does CLOVES affect intelligence?

Typically not; neurological issues are structural, not cognitive.

How is CLOVES diagnosed prenatally?

Challenging; ultrasound may detect overgrowth, but genetic confirmation postnatally.

Similar Articles

Alarming Rise in Self-Harm in Young People

Alarming Rise in Self-Harm in Young People

Skin Signs Of Non-Accidental Injury: Expert Guide For Clinicians

Lichen Simplex Of The Scrotum: Diagnosis And Treatment

Labial Adhesion In Prepubertal Girls: What Parents Need To Know

Thrush In Men: 5 Signs, Causes, And Treatment Options

Author

medha deb

 

Medha Deb is an editor with a master's degree in Applied Linguistics from the University of Hyderabad. She believes that her qualification has helped her develop a deep understanding of language and its application in various contexts.

Read full bio of medha deb