Congenital Lipomatous Overgrowth-Vascular Malformation-Epidermal Nevi-Skeletal Anomaly Syndrome

Congenital lipomatous overgrowth-vascular malformation-epidermal nevi-skeletal anomaly syndrome is usually called CLOVES syndrome. It is a very rare birth problem. Babies are born with too much soft fatty tissue, abnormal blood and lymph vessels, special birthmarks on the skin, and bone or spine changes such as scoliosis. The extra tissue often affects the trunk (back, chest, belly) and sometimes the arms, legs, face, or organs. The condition is part of a group of disorders called PIK3CA-related overgrowth spectrum (PROS), which all come from changes in the same gene.

Congenital lipomatous overgrowth–vascular malformation–epidermal nevi–skeletal anomaly syndrome (CLOVES syndrome) is a very rare genetic overgrowth and vascular anomaly disorder present from birth. It causes patches of fatty overgrowth, complex vascular malformations, birth-mark–like skin changes (epidermal nevi), and bone or spine problems such as scoliosis or leg-length difference. [1] CLOVES belongs to the PIK3CA-related overgrowth spectrum (PROS), a group of conditions caused by changes (mutations) in the PIK3CA gene that over-activate a growth pathway in cells. [2] There is no simple cure, but careful long-term care can improve comfort, function, and appearance. [3]

In CLOVES syndrome, a spelling change (mutation) happens in the PIK3CA gene during early development in the womb. This mutation is somatic and mosaic, which means only some cells carry the change, so overgrowth and malformations appear in certain body segments, not everywhere. [2] The faulty PIK3CA gene keeps the PI3K–AKT–mTOR pathway switched “on,” telling cells to grow, divide, and make blood and lymph vessels even when the body does not need it. [4] This leads to fatty tissue overgrowth, abnormally formed veins and lymph vessels, and bone or spine changes. [5]

CLOVES syndrome happens because of a change (mutation) in a gene called PIK3CA. This change does not come from the parents. It happens by chance in some cells of the baby after the egg and sperm join. Doctors call this somatic mosaic mutation. Because only some cells carry the gene change, only certain parts of the body grow too much or in the wrong way.

People with CLOVES syndrome can have very different problems. Some have mild fatty lumps and birthmarks. Others have large overgrowths, serious blood-vessel malformations, bone deformity, and nerve or brain problems. Symptoms often get worse slowly over time because the abnormal tissues keep growing. There is no simple cure, so care focuses on watching the child, treating symptoms, and preventing complications such as bleeding, infection, or blood clots.

Other names

Doctors use several names for this condition. One long name is “congenital lipomatous overgrowth, vascular malformations, epidermal nevi, scoliosis/skeletal/spinal anomalies syndrome”. The short name is CLOVES syndrome, made from the first letters of the main features. Earlier papers sometimes wrote “CLOVE syndrome” without the final “S”. All of these names describe the same rare overgrowth disorder.

CLOVES syndrome is also described as one type of PIK3CA-related overgrowth spectrum (PROS). PROS is an umbrella group that includes several disorders that all come from PIK3CA gene changes and share tissue overgrowth and vascular malformations. In this group, CLOVES is the pattern with big fatty masses on the trunk, complex blood-vessel problems, skin birthmarks, and spine or bone abnormalities.

Doctors sometimes talk about clinical patterns or “types” of CLOVES syndrome. These are not strict official types, but they help describe how the disease looks:

1. Classic truncal CLOVES pattern – main fatty mass on the back or side of the trunk, with birthmarks and limb changes.

2. CLOVES with strong spinal involvement – large vascular malformations and fatty masses around the spine, with scoliosis or tethered cord.

3. CLOVES with major limb overgrowth – very wide hands or feet, big fingers or toes, and big difference between right and left limbs.

4. CLOVES with brain or nerve problems – overgrowth of brain areas, seizures, or developmental delay in addition to body overgrowth.

5. Overlap with other PROS conditions – signs of CLOVES together with features similar to other PIK3CA overgrowth disorders, such as strong facial or brain involvement.

Causes

The main real cause of this syndrome is one gene problem. Many of the “20 causes” below are different ways of explaining how that gene problem works in the body.

1. PIK3CA gene mutation
   The central cause is a mutation (change) in the PIK3CA gene. This gene controls a protein that helps cells grow and survive. When the gene changes in a harmful way, the protein becomes too active, and cells grow too much or in the wrong pattern, leading to overgrowth and malformations.

2. Somatic mosaicism
   The mutation happens after the baby starts to form, so only some cells carry the change. This is called somatic mosaicism. Body parts that come from mutated cells become overgrown, while other parts that do not have the mutation stay normal size.

3. Overactive PI3K-AKT-mTOR pathway
   The PIK3CA gene is part of a signaling chain called the PI3K-AKT-mTOR pathway. When this pathway is too active, it sends constant “grow and divide” signals to cells. This leads to thick fatty tissue, enlarged bones, and abnormal vessels in affected areas.

4. Abnormal fat cell growth
   The gene change makes fat cells grow too many and too large in certain zones, especially on the trunk. This causes big soft “lipomatous” masses under the skin that are typical in this syndrome.

5. Abnormal blood vessel formation (angiogenesis)
   The same pathway also affects how blood and lymph vessels form. The mutation leads to twisted, enlarged, or mis-connected vessels, creating venous, capillary, lymphatic, or arteriovenous malformations in skin, muscles, and organs.

6. Abnormal lymphatic vessel development
   Lymph vessels can become wide and leaky, forming cyst-like spaces. This is called a lymphatic malformation. These spaces can fill with fluid, swell, and sometimes get infected, adding to pain and swelling in affected areas.

7. Disorganized bone growth
   The mutation in bone-forming cells causes uneven bone growth. Some bones become thick, curved, or too long. This can lead to scoliosis of the spine, limb length difference, and deformity in hands, feet, or ribs.

8. Early fetal developmental error
   The gene change happens very early in pregnancy, while the baby’s tissues are being laid down. Because of this early timing, large body segments, such as one side of the trunk or one limb, can be affected.

9. Segmental distribution of mutated cells
   Mutated cells often follow embryonic “segments” of skin and body called dermatomes or growth segments. This is why overgrowth and skin changes in CLOVES often follow a streaky or patchy pattern.

10. Local pressure and blood-flow changes
    Abnormal vessels and extra tissue can change local blood flow and pressure. Over time, this can worsen the malformations and make some areas grow even more, adding to swelling and deformity.

11. Abnormal nerve and spinal development
    If the mutation affects cells in the spine or nervous system, the spinal cord may be tethered or compressed by abnormal tissue or vessels. This can cause nerve symptoms and further skeletal changes.

12. Abnormal brain development in some patients
    In some people, the overgrowth pathway affects the brain. This can lead to brain overgrowth, cortical malformations, and seizures. These changes come from the same gene problem affecting brain cells.

13. No inherited cause (sporadic disease)
    CLOVES is usually not inherited. Parents typically have normal genes. The mutation appears by chance in the baby. This kind of “new” mutation is called sporadic.

14. Persistent activation of cell survival signals
    The overactive pathway tells cells not only to grow but also to avoid normal cell death. This makes abnormal tissues stay in the body longer than they should, so excess tissue builds up over time.

15. Disruption of normal skeletal patterning
    Because bone-forming cells in some areas carry the mutation, normal bone shapes and alignment are disturbed. This can lead to bowing of long bones, abnormal vertebrae, and chest wall changes.

16. Increased risk of vascular complications
    Abnormal vessels created by the mutation can favor clot formation and poor blood return. This can cause deep vein thrombosis, pulmonary embolism, or bleeding in the gut or lungs in some people.

17. Soft-tissue overgrowth around joints
    Overgrowth of fat and vessels near joints can change joint alignment and movement. Over time, this may result in joint dislocation, uneven wear, and pain, which become part of the clinical picture.

18. Secondary muscle and tendon changes
    As bones and soft tissues grow unevenly, muscles and tendons must adapt. They can become tight or weak in some areas, which can worsen limb deformity and walking problems.

19. Chronic inflammation in abnormal tissues
    Abnormal lymphatic and venous channels can lead to chronic low-grade inflammation. This may contribute to pain, swelling, and skin changes over time.

20. Possible tumor risk in some tissues
    Long-term overactivation of growth pathways can slightly increase the risk of benign or sometimes malignant tumors in affected tissues, although this risk is still being studied and seems low.

Symptoms and signs

1. Soft fatty masses on the trunk
   Many babies are born with large, soft, fatty lumps on the back, side, chest, belly, or buttocks. These masses feel like soft cushions under the skin and can grow over time.

2. Birthmarks and skin color changes
   The skin over the fatty masses often has flat red or purple patches called capillary malformations or “port-wine stains”. These are caused by abnormal small blood vessels near the skin surface.

3. Epidermal nevi (skin streaks or plaques)
   Some patients have raised, thick, or warty skin streaks or patches called epidermal nevi. They often follow a line or band and can appear brown or flesh-colored.

4. Limb overgrowth and wide hands or feet
   Arms or legs on one side may be larger or longer than the other. Hands and feet can be broad, with big or extra fingers or toes, or wide gaps between toes.

5. Body asymmetry
   Because only some body segments are affected, the body can look uneven. One side of the trunk, one leg, or one arm may be clearly larger, causing difficulties in walking or posture.

6. Scoliosis and spinal deformity
   Many people develop a curved spine (scoliosis) or other spine shape problems. These changes come from abnormal bone growth and soft-tissue masses around the vertebrae.

7. Vascular malformations (abnormal vessels)
   Patients often have unusual veins, lymph vessels, and sometimes arteries. These can appear as visible blue or purple veins, swelling from lymph fluid, or more serious arteriovenous malformations that can cause pain and high-flow blood shunts.

8. Swelling and limb heaviness
   Because lymph and venous vessels do not drain properly, affected limbs or areas can swell. The limb may feel heavy, tight, or uncomfortable, especially after standing or walking.

9. Pain and discomfort
   Pain can come from swollen tissues, nerve compression, joint strain, or infection in lymphatic malformations. Pain may be mild and chronic or sometimes severe and sudden if a complication occurs.

10. Bleeding or clotting problems from vessels
    Fragile abnormal vessels can bleed into skin, muscles, or organs. Slow blood flow in abnormal veins can favor blood clots, which may travel to the lungs and cause serious problems.

11. Walking and posture problems
    Spine curves, limb-length differences, and joint deformity can cause limping, uneven hips, and difficulty standing straight. Children may need braces or mobility aids as they grow.

12. Neurologic symptoms (in some patients)
    If the spine or brain is involved, patients may have weakness, numbness, bladder problems, headaches, or seizures. These symptoms depend on where the abnormal tissue or vessels press on nerves.

13. Developmental delay (in some)
    Some children with brain involvement or severe physical problems may show delays in movement, speech, or learning. Not all patients have this, and severity can vary widely.

14. Recurrent infections of lymphatic malformations
    Fluid-filled lymphatic spaces, especially in the skin or deeper tissues, can get infected. This causes redness, warmth, fever, and increased pain in that area, and often needs antibiotics.

15. Emotional and social impact
    Visible body differences, chronic pain, and repeated treatments can cause emotional stress, anxiety, or low mood for patients and families. Support from a multidisciplinary team and peer groups is important.

Diagnostic tests

Physical examination

General physical examination
A detailed physical exam from head to toe is the first and most important test. The doctor looks at body shape, size differences between sides, skin changes, and the location of fatty masses and visible veins. This helps them suspect CLOVES and decide which further tests are needed.

Skin examination
The skin is checked for port-wine stains, other birthmarks, and epidermal nevi. The doctor notes their shape, color, and pattern, which can match the typical look of CLOVES syndrome and helps distinguish it from other overgrowth disorders.

Spine and posture examination
The doctor inspects and feels the spine for curves, humps, or uneven shoulders and hips. They may ask the child to bend forward or walk. These simple checks reveal scoliosis or other spinal deformities linked to the disease.

Neurological examination
Basic tests of strength, reflexes, sensation, and balance help find any nerve or spinal cord problems. Weakness, abnormal reflexes, or loss of feeling can suggest spinal cord compression or brain involvement and guide imaging choices.

Manual and bedside tests

Limb length measurements
The doctor measures both arms and both legs with a tape measure or special tools. They compare lengths and circumferences. A clear difference in length or girth supports the diagnosis of segmental overgrowth as seen in CLOVES.

Joint range-of-motion testing
The examiner gently bends and straightens joints in affected limbs to see how far they move and whether movement causes pain. Stiffness or limited motion may show joint deformity or soft-tissue tightness due to overgrowth.

Gait (walking) assessment
The child is observed while walking, running, or climbing. The doctor watches for limping, dragging of a leg, or imbalance. This simple test reveals functional impact of limb asymmetry and spinal curves.

Developmental and functional screening
For young children, simple checklists and tasks (such as sitting, standing, speaking, drawing) help see whether development is on track for age. Any delay, together with brain or spine findings, can be part of the overall syndrome picture.

Laboratory and pathological tests

Complete blood count (CBC)
A basic blood test called CBC measures red cells, white cells, and platelets. In CLOVES syndrome, CBC is often normal, but it can show anemia from chronic bleeding or changes linked to infection or clot problems. It helps assess general health and surgical risk.

Coagulation and clotting tests
Tests such as prothrombin time, activated partial thromboplastin time, and sometimes D-dimer help check the blood’s clotting system. Because abnormal vessels can lead to clots or bleeding, these tests are useful before operations or when clot complications are suspected.

Inflammatory markers
Blood tests like C-reactive protein and erythrocyte sedimentation rate may be done when infection of a lymphatic malformation or other inflammation is suspected. Raised values support a diagnosis of infection and guide antibiotic treatment.

Biopsy of skin or soft tissue
Sometimes a small sample of skin, epidermal nevus, or fatty tissue is removed under local anesthesia and examined under the microscope. Pathologists can see characteristic patterns of overgrown fat, vessels, and skin layers, which support the diagnosis.

Targeted PIK3CA genetic testing on tissue
A very important modern test is genetic testing on a biopsy from affected tissue. Because the mutation is mosaic, it may not appear in blood but can be found in skin or fat from the abnormal area. Finding a PIK3CA mutation confirms that the condition is part of PIK3CA-related overgrowth spectrum and fits CLOVES.

Expanded genetic panel or exome (in special cases)
If the picture is not clear, doctors may order wider genetic tests that look at many genes linked to overgrowth and vascular malformations. This helps rule out other syndromes and supports the final diagnosis.

Electrodiagnostic tests

Electroencephalogram (EEG)
If a person has seizures or unusual spells, an EEG may be done. This test records the brain’s electrical activity through small electrodes on the scalp. Abnormal brain waves can point to seizure disorders related to brain malformations in CLOVES.

Electromyography and nerve conduction studies (EMG/NCS)
When there is weakness, numbness, or pain in limbs, EMG and nerve conduction tests can measure how well nerves and muscles work. They help show whether symptoms are from nerve damage, spinal cord compression, or only from bone and joint problems.

Imaging tests

Ultrasound and Doppler studies
Ultrasound uses sound waves to look at soft tissues and vessels. Doppler ultrasound can show blood flow inside veins and arteries. In CLOVES, it helps map venous and lymphatic malformations, see blood clots, and guide treatment plans.

X-rays of bones and spine
Simple X-rays are used to see bone shape, limb length, and spine curves. They show scoliosis, abnormal vertebrae, bone thickening, and joint misalignment that are common in this syndrome.

Magnetic resonance imaging (MRI)
MRI is a key imaging test in CLOVES. It gives detailed pictures of soft tissues, vessels, and the spine without radiation. MRI can show the size and depth of fatty overgrowth, lymphatic cysts, venous malformations, and any effect on the spinal cord or brain.

Magnetic resonance angiography or venography (MRA/MRV)
These are special MRI methods that focus on blood vessels. They map arteries, veins, and sometimes lymphatic channels in three dimensions. In CLOVES, they are very helpful to understand complex vascular malformations and to plan surgery or embolization.

Computed tomography (CT) scan (selected cases)
CT scans use X-rays to create detailed cross-section pictures of bones, lungs, or other organs. They may be used when MRI is not enough or when bone structure and lung problems need closer study. CT can also show some vascular malformations but is used carefully to limit radiation in children.

Prenatal ultrasound and fetal MRI (before birth)
In some pregnancies, large masses or abnormal vessels can be seen on ultrasound before the baby is born. Fetal MRI may then be used to better define the overgrowth and plan delivery at a center with experienced specialists. These tests can suggest the diagnosis of CLOVES even before birth.

Non-pharmacological treatments (therapies and other approaches)

Below are key non-drug treatments used in CLOVES. Exact plans are individualized and managed by a multidisciplinary team (vascular anomalies, orthopedics, dermatology, interventional radiology, pain, rehabilitation). [3]

1. Regular specialist follow-up
   Children and adults with CLOVES need frequent review by a specialized vascular anomalies or PROS clinic. [1] Regular visits allow early detection of blood-clot risk, breathing problems, or fast-growing vascular malformations. Doctors can order imaging, blood tests, and physical exams to track overgrowth. Ongoing follow-up also helps time surgery, interventional procedures, or new medications, and offers psychological support for the family. Consistent monitoring is one of the strongest tools to protect long-term health. [2]

2. Compression garments and bandaging
   Custom-made compression stockings or sleeves gently squeeze the limb or trunk where vascular malformations and swelling occur. [1] This can reduce pain, heaviness, and leakage of lymph fluid, and may lower the risk of superficial blood clots. Garments must be fitted by trained therapists so they are firm but not too tight. Families are taught how long to wear them each day and how to watch for skin irritation, especially in children. [2]

3. Physiotherapy and occupational therapy
   Overgrowth, scoliosis, and joint deformities can limit walking, hand use, and balance. [1] Physiotherapists design exercises to maintain muscle strength and joint range of motion. Occupational therapists help with daily tasks, school activities, and specialized aids, such as adapted pens or seating. Therapy can also reduce pain and stiffness and can delay or improve the outcome of surgeries by keeping muscles and joints as healthy as possible. [2]

4. Orthotic devices and shoe lifts
   Braces, insoles, and shoe lifts help manage limb-length differences, joint instability, and foot deformities caused by asymmetrical overgrowth. [1] Correctly fitted orthotics can improve walking pattern, reduce joint stress, and lower the chance of long-term arthritis. They are often adjusted as the child grows, and combined with physiotherapy and, when needed, orthopedic surgery for best results. [2]

5. Psychological counseling and family support
   CLOVES syndrome often changes body shape and appearance, leading to bullying, low self-esteem, or anxiety. [1] Psychologists and social workers support the child and family by teaching coping strategies, supporting school communication, and guiding parents on how to explain the condition in age-appropriate language. Group support or online communities can reduce feelings of isolation and help families learn from others living with PROS. [2]

6. Pain management strategies (non-drug)
   Chronic pain from vascular malformations, nerve compression, or orthopedic problems is common. [1] Non-drug methods such as heat or cold packs, relaxation breathing, mindfulness, distraction, gentle stretching, and graded activity can reduce pain levels and improve function. Pain specialists may also teach cognitive behavioral techniques to reframe pain and help the child stay active and engaged in life. [2]

7. Sclerotherapy (interventional radiology)
   Sclerotherapy is a minimally invasive procedure where a doctor injects a special chemical into abnormal veins or lymphatic malformations under imaging guidance. [1] The drug damages the inner lining of the malformed vessel, causing it to shrink and scar down over time. This can reduce swelling, pain, and leakage. Sclerotherapy is often repeated in stages and combined with compression for best results. [2]

8. Laser and ablative skin treatments
   Vascular birthmarks and epidermal nevi may be treated with different types of lasers or ablative devices. [1] The laser light targets blood vessels or pigmented cells, reducing redness, thickness, or hair growth. Several sessions are usually needed. While these treatments are mainly cosmetic, improving appearance can strongly support mental health and self-confidence. [2]

9. Weight management and healthy activity
   Extra body weight can worsen limb pain, joint stress, venous problems, and breathing symptoms. [1] A dietitian and physiotherapist can help design safe activity plans and nutrition strategies to maintain a healthy weight. In many patients, light to moderate exercise actually improves fatigue and circulation when done carefully under medical advice. [2]

10. Lymphedema care and skin hygiene
    Some patients develop lymphatic swelling, skin thickening, and leaking fluid. [1] Gentle manual lymphatic drainage, compression, careful skin moisturizing, and fast treatment of small wounds lower the risk of cellulitis (skin infection). Trained therapists teach families daily routines and warning signs that need urgent medical assessment. [2]

(Clinics may use more specialized non-drug methods, but the above are the most common foundations of care.)

---

Drug treatments (medical therapy)

Important safety note: All medicines for CLOVES or PROS must be prescribed and closely monitored by experienced specialists. Many are off-label or newly approved for PROS and can have serious side effects. Never start, stop, or change doses without your doctor.

Below are key drug types used in or studied for CLOVES and related PROS conditions. Information about dosing and safety comes from official FDA prescribing information and clinical studies; however, doses for PROS are individualized and may differ from those for transplant or cancer. [1]

1. Alpelisib (Vijoice / Piqray) – PI3Kα inhibitor
   Alpelisib is an oral PI3K-alpha inhibitor that directly blocks the overactive PIK3CA pathway. [1] It received FDA approval as Vijoice for selected patients with PIK3CA-related overgrowth spectrum, based on data showing reduction in overgrowth and symptoms including CLOVES-type features. [2] Dose is weight-based and adjusted for side effects like high blood sugar, diarrhea, rash, and lowered blood counts; careful lab monitoring is required. [3] Although alpelisib targets the root pathway, it does not “cure” CLOVES and is used as part of a comprehensive plan. [4] [1]

2. Sirolimus (Rapamune; including albumin-bound sirolimus) – mTOR inhibitor
   Sirolimus is an mTOR inhibitor approved for organ transplant and some tumors, but widely studied off-label in vascular malformations and PROS, including CLOVES. [1] It works downstream of PI3K, slowing cell growth and abnormal lymphatic or venous vessel formation. Case reports and series show improvements in lesion size, pain, and function, though side effects (infections, high lipids, mouth ulcers, low blood counts) are common. [2] Doses are tailored to body surface area and blood trough levels, guided by transplant and LAM experience from FDA labels. [3] [2]

3. Pain control medicines (paracetamol, NSAIDs, sometimes stronger analgesics)
   Many patients have chronic or episodic pain from vascular lesions, nerve pressure, or joint deformity. [1] Doctors may use paracetamol (acetaminophen) as first-line, with cautious use of non-steroidal anti-inflammatory drugs (NSAIDs) like ibuprofen when kidney function and bleeding risk allow. In severe cases, short courses of opioids or adjuvant drugs such as gabapentin can be used under strict supervision. [2] These drugs do not treat the cause of CLOVES, but they improve quality of life while other treatments address underlying problems. [3]

4. Anticoagulants or antiplatelet drugs (e.g., low-dose aspirin, heparin, DOACs)
   Large venous malformations and sluggish blood flow increase risk of local clots and, rarely, pulmonary embolism. [1] Depending on imaging and blood clotting tests, doctors may prescribe low-dose aspirin, low-molecular-weight heparin, or direct oral anticoagulants (DOACs) to reduce clot risk. These medicines thin the blood and must be balanced against bleeding risk, especially in children and around surgeries. [2] Treatment is always individualized and monitored by hematology and vascular specialists. [3]

5. Antibiotics for skin and soft tissue infections
   Because of abnormal vessels, swelling, and skin changes, people with CLOVES may have recurrent cellulitis or wound infections. [1] Prompt antibiotic therapy based on local guidelines reduces the risk of sepsis and further tissue damage. Long-term low-dose antibiotics are sometimes used in patients with very frequent infections, but only after specialist review to avoid resistance. [2] Good skin care and lymphedema treatment help lower the need for repeated antibiotics. [3]

6. Corticosteroids (short, targeted use)
   Steroids like prednisolone may occasionally be used short-term to treat severe inflammation, airway swelling, or certain acute complications of vascular malformations. [1] They reduce immune and inflammatory activity but are not a chronic solution for CLOVES because long-term use can worsen weight gain, bone thinning, and infection risk. [2] Decisions about steroids are made by specialists and often linked to specific crisis situations or procedures. [3]

7. Topical sirolimus for skin and mucosal lesions (investigational)
   Small studies suggest that topical sirolimus gels or solutions may improve superficial lymphatic and vascular lesions while limiting systemic side effects. [1] Research is ongoing in lymphatic malformations of the head and neck and may be relevant to some CLOVES lesions in the future. [2] Dosing, formulations, and long-term safety are still being studied, so use is restricted to research settings or highly specialized centers. [3]

8. Other pathway-targeted or cancer drugs (research use only)
   In a few complex PROS cases, doctors and researchers have explored other targeted drugs (for example, AKT or MEK inhibitors) borrowed from cancer medicine. [1] These treatments are experimental, given only in clinical trials or under strict compassionate-use programs, and are not standard care for CLOVES at this time. [2] Families should discuss any new drug idea with a specialist center; never use cancer medicines outside supervised protocols. [3]

---

Dietary molecular supplements

Supplements do not treat the genetic cause of CLOVES, but they can support bone health, immunity, and overall wellbeing when used under medical guidance. Always discuss supplements with your doctor, especially if your child is taking sirolimus, alpelisib, or blood thinners, because of possible interactions.

1. Vitamin D
   Vitamin D supports bone strength, immune function, and muscle health. [1] Children with mobility limits or those on long-term steroids or mTOR inhibitors may have higher risk of low vitamin D and fragile bones. Supplements are usually dosed based on blood levels and age. Correcting deficiency can improve fatigue and reduce fracture risk, especially when combined with calcium and weight-bearing activity. [2]

2. Calcium
   Calcium is essential for bones and teeth. In patients with scoliosis, limb deformity, or limited movement, good calcium intake supports bone remodeling and strength. [1] Intake often comes from food (milk, yogurt, cheese, fortified drinks), but supplements may be used when diet is insufficient. Doctors avoid very high doses if there is kidney disease or certain drugs on board. [2]

3. Omega-3 fatty acids (fish oil)
   Omega-3 fatty acids have mild anti-inflammatory and possibly anti-thrombotic (anti-clot) effects. [1] They may help support cardiovascular health and reduce inflammation-related discomfort, though evidence specifically in CLOVES is limited. Doses are adjusted for age and weight and must be used cautiously in patients already on blood thinners, because they can slightly increase bleeding tendency. [2]

4. Multivitamin with trace elements
   A balanced multivitamin can help children with poor appetite, feeding difficulties, or repeated infections meet daily nutrient needs. [1] It should not replace a healthy diet but can fill small gaps, especially for iron, zinc, and B vitamins. Over-the-counter products should be used within recommended age-appropriate doses to avoid toxicity. [2]

5. Probiotics (with medical guidance)
   Some patients receiving long-term antibiotics or targeted therapies have gut side effects like diarrhea. [1] Selected probiotic strains may support gut microbiome balance and reduce antibiotic-associated diarrhea. However, in people on strong immunosuppressants (such as sirolimus), probiotics should be used cautiously and only on specialist advice because of rare infection risks. [2]

6. Protein-rich nutritional supplements
   When surgeries, pain, or feeding problems reduce food intake, high-protein oral nutrition drinks can help maintain muscle mass and wound healing. [1] Dietitians choose formulas suitable for age and any kidney or liver problems. These drinks support recovery after major interventions such as debulking surgery or sclerotherapy. [2]

---

Immune-booster, regenerative and stem-cell-related therapies

There are no standard or FDA-approved “stem cell drugs” specifically for CLOVES syndrome. Research into regenerative and gene-targeted approaches is at an early stage. [1]

1. Careful vaccination and infection prevention
   Because drugs like sirolimus and alpelisib can lower immune defenses, up-to-date routine vaccines, plus flu and COVID-19 vaccines where recommended, act as safe “immune support.” [1] Doctors may avoid live vaccines in patients on strong immunosuppressants and tailor schedules individually. [2]

2. Optimizing sleep, nutrition, and exercise
   Basic pillars of health—good sleep, balanced diet, and regular gentle activity—are powerful natural immune boosters. [1] They help the body tolerate surgeries and drug treatments better and lower infection risk. [2]

3. Intravenous immunoglobulin (IVIG) – rare situations
   In special cases with immune deficiency or severe recurrent infections, specialists may consider IVIG, a purified antibody infusion. [1] This is not specific to CLOVES but may support immunity in selected patients, always in hospital settings due to cost and infusion reactions. [2]

4. Future gene and cell-based therapies (experimental)
   Scientists are exploring ways to target PIK3CA-mutated cells more precisely, possibly using gene-editing or highly targeted pathway drugs. [1] At present, these approaches are research only and not available as routine care. Families interested in research can ask their specialist about clinical trial registries, but should be cautious of unregulated “stem cell clinics.” [2]

---

Surgical treatments

Surgery in CLOVES is complex and must be planned by highly experienced teams. It aims to improve function, reduce pain or complication risk, and, when possible, improve appearance. [1]

1. Debulking surgery for fatty and soft-tissue overgrowth
   Surgeons may remove portions of overgrown fatty and fibrous tissue to reduce bulk, improve movement, and ease pain. [1] These operations are carefully planned to protect nerves and blood vessels, and may be staged over time. Overgrowth can recur, so surgery is often combined with medical therapy such as sirolimus or alpelisib to limit regrowth. [2]

2. Orthopedic surgery for skeletal deformities
   Procedures may include correcting scoliosis, stabilizing joints, or equalizing leg length using growth-plate surgery or bone shortening/lengthening techniques. [1] The goal is to improve walking, reduce back and hip pain, and prevent long-term joint damage. These surgeries are typically done in late childhood or adolescence after detailed imaging and gait analysis. [2]

3. Vascular surgery or embolization
   Some large or deep vascular malformations may need open surgery or catheter-based embolization, where materials are used to block abnormal vessels. [1] This can reduce bleeding, swelling, and heart strain. These procedures require careful risk–benefit discussions because of the chance of recurrence or damage to nearby structures. [2]

4. Skin and soft-tissue reconstruction
   After debulking or treatment of ulcerated lesions, plastic surgeons may use skin grafts or flaps to close wounds and restore contour. [1] The aim is to protect deeper tissues, lower infection risk, and improve appearance, which can strongly affect self-esteem. [2]

5. Airway or organ-relief procedures
   If overgrowth or lymphatic malformations compress the airway, chest, or abdominal organs, emergency or planned surgery may be needed to relieve pressure. [1] These high-risk operations are done only in expert centers and often combined with intensive care support and long-term follow-up. [2]

---

Prevention and lifestyle

You cannot prevent the genetic cause of CLOVES, but you can reduce complications:

1. Keep all specialist appointments for ongoing monitoring. [1]

2. Use compression garments exactly as prescribed. [2]

3. Maintain good skin hygiene and moisturize daily to prevent cracks and infections. [3]

4. Treat small cuts or insect bites quickly and watch for redness or fever. [4]

5. Encourage regular gentle physical activity, avoiding prolonged immobility. [5]

6. Maintain healthy body weight with balanced nutrition. [6]

7. Stay up to date with vaccinations after discussing immunosuppressive drugs with your doctor. [7]

8. Avoid smoking and second-hand smoke, which harm blood vessels and healing. [8]

9. Plan surgeries and long trips with your care team to manage clot risk and pain. [9]

10. Seek psychological support early for body image, anxiety, or bullying issues. [10]

---

When to see doctors urgently

Seek urgent medical care if you notice:

• Sudden swelling, redness, or severe pain in a limb or lesion (possible infection or blood clot). [1]

• Shortness of breath, chest pain, or coughing up blood (possible pulmonary embolism). [2]

• Rapid increase in size of a vascular or fatty mass, especially with fever. [3]

• New weakness, loss of sensation, or bladder/bowel problems suggesting spinal compression. [4]

• Any severe drug side effects such as high fever, mouth ulcers, severe diarrhea, extreme fatigue, or very high blood sugar. [5]

Regular (non-emergency) visits are needed for medication monitoring, imaging follow-up, planning surgeries, and psychological support. [6]

---

What to eat and what to avoid

1. Focus on a balanced plate with vegetables, fruits, whole grains, lean protein, and healthy fats to support growth and healing. [1]

2. Include calcium- and vitamin-D-rich foods like dairy or fortified plant milks to protect bones. [2]

3. Choose lean proteins (fish, poultry, beans, lentils) to maintain muscle and help wounds heal after procedures. [3]

4. Use healthy fats (olive oil, nuts, seeds, avocado) rather than trans-fats and deep-fried foods that worsen inflammation. [4]

5. Limit sugary drinks and sweets, which promote weight gain and may worsen alpelisib-related high blood sugar. [5]

6. Moderate salt intake to avoid extra swelling in limbs with venous or lymphatic problems. [6]

7. Avoid crash diets or extreme supplements that promise “cure”; they can be unsafe and interact with medicines. [7]

8. Limit alcohol in adults, especially if taking liver-metabolized drugs or blood thinners. [8]

9. Stay well hydrated, unless your doctor gives different fluid advice. [9]

10. Work with a dietitian at a vascular anomalies/PROS center for tailored plans, especially if appetite is poor or many drugs are used. [10]

---

Frequently asked questions (FAQs)

1. Is CLOVES syndrome cancer?
   No. CLOVES is an overgrowth and vascular malformation condition caused by an overactive growth pathway, but it is not a classic cancer. [1] However, because the same pathway is involved in some cancers, doctors monitor patients carefully and borrow some targeted drugs from oncology to control overgrowth. [2]

2. Is CLOVES syndrome inherited?
   In almost all known cases, CLOVES is not inherited. [1] The PIK3CA mutation happens randomly in the embryo after conception, so parents and siblings usually do not have the same mutation. Genetic counseling can explain this in more detail and discuss rare exceptions. [2]

3. Can CLOVES be cured?
   At present, there is no cure that removes the mutation from all affected cells. [1] Treatment focuses on controlling symptoms, preventing complications, and improving function and appearance. Targeted drugs like alpelisib and sirolimus offer stronger control than before and may further improve outcomes as research grows. [2]

4. What is PROS and how is it related to CLOVES?
   PROS stands for PIK3CA-related overgrowth spectrum, a group of conditions caused by PIK3CA mutations, which includes CLOVES, some forms of Klippel-Trénaunay syndrome, and other segmental overgrowth disorders. [1] They share similar genetic and pathway changes, so treatments such as alpelisib and sirolimus may help several PROS diagnoses. [2]

5. What is the role of alpelisib in CLOVES?
   Alpelisib directly targets PI3K-alpha, the enzyme over-activated by PIK3CA mutations. [1] The FDA has approved alpelisib (Vijoice) for selected PROS patients with documented PIK3CA mutations, including some with CLOVES-like features. [2] Studies show reductions in lesion size, pain, and need for invasive procedures, but side effects require close monitoring and it is not suitable for everyone. [3]

6. Why is sirolimus still used if alpelisib exists?
   Sirolimus acts further down the PI3K–AKT–mTOR pathway and has been used longer in vascular anomalies. [1] It may be preferred when access to alpelisib is limited, when side-effect profiles differ, or when clinicians have more experience with sirolimus in that center. In some complex cases, treatment may start with sirolimus and later switch to or combine with other approaches based on response. [2]

7. What are the main risks of sirolimus and alpelisib?
   Both medicines can increase infection risk and affect blood counts and metabolic health. [1] Sirolimus often causes high cholesterol and triglycerides, mouth ulcers, and delayed wound healing. Alpelisib commonly causes high blood sugar, diarrhea, rash, and sometimes severe allergic-type skin reactions. [2] Regular blood tests and specialist follow-up are essential, and families should report unusual symptoms promptly. [3]

8. Will my child always need surgery?
   Not every child with CLOVES needs surgery. [1] Decisions depend on the severity of overgrowth, pain, function, and risks. Some problems can be managed mainly by medical therapy, compression, and physiotherapy. When surgery is needed, it is usually staged and combined with other treatments to limit regrowth and complications. [2]

9. Can CLOVES affect internal organs?
   Yes. Depending on where the mutated cells are, CLOVES can involve chest, abdomen, spinal canal, or pelvic structures. [1] This is why detailed imaging (MRI, CT, ultrasound) and long-term monitoring are so important, even if the main visible problems seem to be in the limbs or skin. [2]

10. Is pregnancy possible for someone with CLOVES?
    Many people with CLOVES can become pregnant, but it requires high-risk obstetric and vascular anomalies care. [1] Pregnancy changes blood volume and clot risk, which may worsen vascular malformations. Some medicines, like alpelisib and sirolimus, are not safe in pregnancy, so treatment plans must be adjusted well before conception. [2]

11. Can CLOVES be detected before birth?
    Sometimes, large overgrowths or vascular malformations are seen on prenatal ultrasound or MRI, but a definite diagnosis of CLOVES usually needs postnatal assessment and sometimes genetic testing of affected tissue. [1] Prenatal detection often leads to planned delivery in a center with neonatal intensive care and surgical expertise. [2]

12. Does every hospital know how to manage CLOVES?
    No. CLOVES is very rare, so expertise is concentrated in a few specialized vascular anomalies and PROS centers. [1] Families often travel to these centers for initial assessment, treatment planning, and complex procedures, while local hospitals help with day-to-day care. [2]

13. What is the long-term outlook?
    The outlook varies widely. Some people have mild disease with few complications, while others face major orthopedic, vascular, or organ challenges. [1] Early diagnosis, access to expert care, and newer targeted treatments are improving function and quality of life for many patients. [2]

14. Can lifestyle alone control CLOVES?
    No. Healthy lifestyle choices (diet, activity, skin care) are very important but cannot replace medical and surgical care. [1] CLOVES is a structural and genetic condition; lifestyle helps reduce complications and support mental health, but the underlying malformations usually need specialist treatments. [2]

15. Where can families find reliable information and support?
    Reliable information usually comes from major children’s hospitals with vascular anomaly centers, national rare disease organizations, and published medical reviews on CLOVES and PROS. [1] Patient advocacy groups and PROS support networks can also provide emotional help and practical tips. Always check that online information is medically reviewed and not promising unproven “cures.” [2]

Disclaimer: Each person’s journey is unique, treatment plan, life style, food habit, hormonal condition, immune system, chronic disease condition, geological location, weather and previous medical  history is also unique. So always seek the best advice from a qualified medical professional or health care provider before trying any treatments to ensure to find out the best plan for you. This guide is for general information and educational purposes only. Regular check-ups and awareness can help to manage and prevent complications associated with these diseases conditions. If you or someone are suffering from this disease condition bookmark this website or share with someone who might find it useful! Boost your knowledge and stay ahead in your health journey. We always try to ensure that the content is regularly updated to reflect the latest medical research and treatment options. Thank you for giving your valuable time to read the article.

The article is written by Team RxHarun and reviewed by the Rx Editorial Board Members

Last Updated: January 31, 2025.