CLOVES Syndrome

CLOVES syndrome is a very rare disease where some parts of the body grow too much and in an uneven way. It usually starts before birth, so the baby is born with these changes. The name “CLOVES” is an English short form made from the first letters of the main problems: Congenital (from birth), Lipomatous overgrowth (too much fatty tissue), Overgrowth, Vascular malformations (abnormal blood and lymph vessels), Epidermal nevi (special birthmarks on the skin), and Spinal or skeletal problems like scoliosis (curved spine).

CLOVES syndrome is a very rare condition that a baby is born with. The name “CLOVES” is an acronym that stands for Congenital Lipomatous Overgrowth, Vascular malformations, Epidermal nevi, and Spinal/skeletal anomalies/scoliosis. In simple words, parts of the body grow too much fatty tissue, there are abnormal blood and lymph vessels, the skin can have thick or bumpy areas, and the bones or spine can grow in an uneven way. CLOVES syndrome is now known to be part of a group of disorders called PIK3CA-related overgrowth spectrum (PROS), which are caused by a change (mutation) in a gene called PIK3CA.

People with CLOVES syndrome usually have these problems on one side or one area of the body more than others, because the gene change happens in only some cells (mosaicism). The condition is not usually inherited from the parents and is considered “sporadic,” meaning it happens by chance very early in baby development. Symptoms can range from mild to very severe and can involve the skin, soft tissue, blood vessels, bones, nerves, and internal organs. Because many body systems are involved, treatment almost always needs a multidisciplinary team that includes pediatricians, dermatologists, surgeons, interventional radiologists, pain specialists, rehabilitation experts, and genetic counselors.

Doctors now know that CLOVES is part of a bigger group of conditions called PIK3CA-related overgrowth spectrum (PROS). In these conditions, a change (mutation) happens in a gene called PIK3CA, which controls how cells grow and divide. Because of this change, cells in some body parts receive strong “grow” signals, so fat, blood vessels, bones, and skin in those areas grow too much and in the wrong way.

CLOVES syndrome is not common. Only a few hundred people have been reported around the world. It does not spread from one person to another. It also usually does not run in families, because the gene change happens after the baby starts to develop in the womb and is present only in some cells (this is called somatic mosaic mutation).

Other names

CLOVES syndrome has a long full medical name: “Congenital Lipomatous Overgrowth, Vascular malformations, Epidermal nevi, Spinal/Skeletal anomalies”. This long name explains the main body changes: present from birth, extra fatty tissue, abnormal vessels, special skin marks, and bone or spine problems.

Some older papers used the name CLOVE syndrome (without the final “S”). Later, doctors added the “S” to stress the importance of spinal and skeletal problems, so “CLOVES” is now the preferred name. CLOVES is also described as a PIK3CA-related overgrowth spectrum (PROS) disorder, because it belongs to the same gene group as some other overgrowth conditions.

Types of CLOVES syndrome

Doctors do not have one strict official “type” system for CLOVES syndrome, but in practice they often talk about different patterns or forms of the disease. These patterns depend on which body parts are affected and how severe the changes are.

Type 1 – Mild localized form.
In this form, only a small area of the body is affected, often with a soft fatty mass and a few abnormal vessels. The child may have small skin birthmarks and mild bone changes. Growth problems are present but usually limited, and the child may have fewer health complications than in more severe forms.

Type 2 – Truncal-predominant form.
Here, most of the problems are on the trunk (back, chest, belly, or sides). There may be large fatty overgrowths on the back or flanks, with complex vascular malformations in the same region. The spine may curve (scoliosis), and some ribs or vertebrae may be abnormal.

Type 3 – Limb-predominant form.
Some people have mainly one or more limbs affected. A leg or arm may be bigger and longer than the other side. The hands or feet may be very wide, with big or extra fingers or toes. There are often abnormal veins and lymph vessels in the limb, which can cause swelling and pain.

Type 4 – Generalized or multi-segment form.
In this more severe pattern, several body regions are affected together, such as trunk, limbs, and sometimes internal organs. There may be large fatty masses, many vascular malformations, marked bone deformities, and skin changes spread over different segments of the body. These children usually need very close medical follow-up and many tests.

Type 5 – Overlap with other PROS conditions.
Some patients have features of CLOVES together with signs seen in other PIK3CA-related overgrowth disorders. In these cases, doctors may describe the condition as “CLOVES within PROS” or “CLOVES-like PROS,” and genetic testing helps to confirm the diagnosis.

Causes

The main and most important cause of CLOVES syndrome is a change (mutation) in the PIK3CA gene in some of the baby’s cells. This change happens after conception, so it is not usually inherited from the parents. Below are 20 simple “cause and mechanism” points that explain how this gene problem leads to the disease.

1. Somatic PIK3CA mutation.
   In CLOVES, a mistake occurs in the PIK3CA gene in some cells while the baby is growing in the womb. This mistake is not present in every cell, only in certain areas, which is why only parts of the body are affected.

2. Mosaicism.
   Because the mutation happens later in development, some cells have the normal gene and some have the changed gene. This “patchy” pattern is called mosaicism and explains why overgrowth occurs only on one side or in one area of the body.

3. Overactive PI3K/AKT/mTOR pathway.
   The PIK3CA gene makes part of a protein called PI3K. When the gene is mutated, this pathway becomes overactive and sends strong “grow and divide” signals to cells. This leads to too much growth of fat, vessels, and bone.

4. Abnormal fat cell growth.
   The overactive growth pathway makes fat cells multiply too much and become larger. This causes the soft, fatty overgrowths or lipomas seen in CLOVES.

5. Abnormal blood vessel formation (angiogenesis).
   The same pathway also affects how blood vessels form. Small vessels may grow in a twisted and disorganized way, leading to venous, capillary, or combined vascular malformations.

6. Abnormal lymph vessel development.
   Lymphatic vessels, which drain fluid from tissues, may also grow abnormally and become enlarged or leaky. This causes lymphatic malformations and swelling in affected areas.

7. Bone and spine overgrowth.
   The PIK3CA mutation in bone cells can cause bones to grow too much or in the wrong shape. This leads to scoliosis, enlarged bones of the limbs, and other skeletal deformities.

8. Skin cell changes leading to epidermal nevi.
   Skin cells with the mutation may grow in thick, raised lines or patches called epidermal nevi. These are harmless but are a visible sign of the gene change in the skin.

9. Timing of the mutation in early development.
   If the mutation happens very early in the embryo, more body segments can be affected, making the disease more severe. If it happens later, fewer areas may be involved and the condition may be milder.

10. Location of mutated cells.
    The body part that ends up abnormal depends on which cell group first received the mutation (for example, cells that will form the back, a leg, or the chest wall). This explains the segmental pattern of overgrowth.

11. Non-inherited, sporadic cause.
    Because the mutation is somatic and mosaic, parents of a child with CLOVES almost never have the same condition themselves, and future children are very unlikely to be affected for genetic reasons.

12. Disturbed balance between cell growth and death.
    The overactive pathway not only makes cells grow faster but may also reduce normal programmed cell death. This means old or damaged cells are not removed in the usual way, adding to tissue build-up.

13. Abnormal blood flow and pressure.
    Large vascular malformations can disturb blood flow and pressure, which in turn may cause veins and surrounding tissues to remodel and grow abnormally over time.

14. Local clot risk in malformed vessels.
    Slow or turbulent blood flow in abnormal vessels can promote small blood clots, which may further damage vessel walls and affect how vessels grow and repair themselves.

15. Pressure effects from fatty masses.
    Big lipomatous masses can press on nearby nerves, muscles, and organs. This pressure may cause pain, weakness, or functional problems, acting as a secondary cause of symptoms even though the gene mutation is the root cause.

16. Effects on nearby organs (for example, kidneys).
    In some patients, overgrowth and vascular malformations near the kidneys or other organs can change their shape or function and lead to organ problems over time.

17. Risk of bleeding from fragile vessels.
    Malformed vessels can have thin or irregular walls, which can bleed more easily with minor injury or surgery. This tendency to bleed becomes another cause of health problems.

18. Risk of infection in swollen tissues.
    Lymphatic malformations and chronic swelling can make it harder for the immune system to clear germs from the tissues, increasing the risk of repeated skin infections and cellulitis.

19. Mechanical strain on joints and spine.
    Uneven growth of limbs and spine changes how weight is carried. Over time, this mechanical strain can cause joint pain, early wear of joints, and worsening of spinal curves.

20. Overlap with other PROS mechanisms.
    Because CLOVES belongs to PROS, it shares many mechanisms with other PIK3CA-related disorders, such as disorganized growth of brain, skin, and vessels. These shared mechanisms help explain the wide range of features seen between different patients.

Symptoms

The signs and symptoms of CLOVES can be very different from one person to another, but some features are common. Most are present at birth or appear in early infancy.

1. Soft fatty overgrowths (lipomatous masses).
   Many babies with CLOVES are born with soft, fatty lumps or masses, often on the back, sides, or belly. These lumps feel like soft cushions under the skin and may slowly grow over time.

2. Asymmetrical body growth.
   One side of the body, or one limb, may be bigger or longer than the other. This uneven growth is a key feature and reflects the mosaic pattern of the gene mutation.

3. Capillary birthmarks (port-wine stains).
   Flat, reddish-purple birthmarks, often called port-wine stains, can appear on the skin over affected areas. They come from abnormal small blood vessels in the skin.

4. Venous malformations (abnormal veins).
   Deeper or enlarged veins may look like soft, bluish swellings. They can cause pain, swelling, or a heavy feeling, especially in the limbs.

5. Lymphatic malformations and swelling.
   Clusters of fluid-filled spaces in the lymph system may appear as soft, spongy areas or cyst-like swellings. They can leak fluid or become infected.

6. Combined complex vascular malformations.
   Some patients have more complex lesions that combine different vessel types and may include fast-flow arteriovenous malformations, especially around the spine or trunk. These can be serious and sometimes cause nerve problems.

7. Epidermal nevi (special skin plaques).
   These are raised, often brown or flesh-colored patches or lines on the skin. They can feel rough or warty and usually follow certain patterns on the body. They are benign but show where the mutated skin cells are located.

8. Wide hands, feet, fingers, or toes.
   Hands and feet may be broad, with big or extra fingers or toes, and wide spaces between them. These changes reflect overgrowth of bones and soft tissues in the extremities.

9. Scoliosis (curved spine).
   The spine may curve sideways due to uneven growth of vertebrae or surrounding tissues. Over time, scoliosis can worsen and may affect posture, balance, and sometimes breathing.

10. Other skeletal deformities.
    Some patients have abnormal ribs, vertebrae, or limb bones, leading to chest wall deformity, leg length difference, or joint misalignment.

11. Pain and discomfort.
    Pain can come from heavy overgrown tissues, stretched skin, joint strain, or problems inside abnormal vessels (such as small clots or bleeding). Pain levels differ from person to person.

12. Recurrent skin infections.
    Because of lymphatic problems and skin changes, some patients get repeated infections like cellulitis in the affected limbs or areas, which may need antibiotics.

13. Neurologic symptoms.
    If vascular malformations or overgrowth press on the spinal cord or nerves, there may be weakness, numbness, or trouble walking. In some cases, seizures or brain involvement have been reported.

14. Kidney or internal organ problems (in some cases).
    Some people have kidney abnormalities, such as a small or missing kidney, or other organ changes related to nearby overgrowth and vascular malformations.

15. Emotional and social impact.
    Visible body differences and chronic medical care can cause emotional stress, anxiety, or low self-confidence. Families often need psychological support alongside physical treatment.

Diagnostic tests

Doctors diagnose CLOVES syndrome by carefully looking at the person, studying images of the inside of the body, and confirming the gene change when possible. No single test is enough; usually a combination of tests is used.

Physical exam tests

1. Whole-body clinical examination.
   The doctor carefully looks at the child from head to toe, checking for fatty masses, birthmarks, skin plaques, and uneven growth. They note which body segments are affected, because CLOVES typically shows patchy, segmental overgrowth.

2. Growth and body measurement check.
   Height, weight, head size, limb length, and body proportions are measured and compared with normal growth charts. This helps show which parts are growing faster than expected.

3. Skin inspection.
   The skin is examined for port-wine stains, epidermal nevi, and any areas of thickening, ulceration, or infection. The pattern and location of skin changes give strong clues to CLOVES and help distinguish it from other overgrowth syndromes.

4. Spine and posture examination.
   The doctor looks at the back from behind and from the side to see if the spine is straight or curved. They may ask the child to bend forward to check for scoliosis and observe how the shoulders and hips line up.

5. Abdominal and chest palpation.
   By gently pressing on the chest and belly, the doctor can feel fatty masses, organ enlargement, or tender areas. This helps decide which areas need imaging tests like ultrasound or MRI.

Manual and bedside functional tests

6. Joint range of motion testing.
   The doctor moves the child’s joints (hips, knees, ankles, shoulders) to see how easily they bend and straighten. Overgrowth and joint misalignment can limit movement, and this test measures that problem.

7. Manual muscle strength testing.
   By asking the child to push or pull against resistance, the doctor checks muscle strength in limbs and trunk. Weakness may show nerve or spine involvement from nearby vascular malformations or bone changes.

8. Gait and walking assessment.
   The child is observed while walking, running, or standing on one leg. A limp, unequal step length, or balance problems can reflect limb length difference, joint deformity, or neurologic involvement.

9. Limb circumference and length measurement.
   Using a tape, doctors compare the thickness and length of both arms and both legs. These manual measurements show the degree of asymmetry and help track changes over time.

10. Bedside neurological exam.
    Simple tests of reflexes, sensation (touch, pain, vibration), and coordination are done to check how well the nerves and spinal cord are working, especially when vascular malformations lie near the spine.

Lab and pathological tests

11. Basic blood tests (CBC and biochemistry).
    A complete blood count and basic blood chemistry help look for anemia, clotting problems, infection, or organ stress. While these tests do not diagnose CLOVES directly, they are important for planning surgery and monitoring complications.

12. Coagulation profile and D-dimer.
    These tests check how well the blood clots and whether there is increased clot breakdown. People with large venous malformations can sometimes have a mild, chronic clotting problem, so this screening is helpful.

13. Kidney function tests and urinalysis.
    Blood creatinine and urea and a urine test are done if there is concern about kidney changes, since some patients with CLOVES have kidney abnormalities or are monitored for kidney tumors in childhood.

14. Biopsy of skin or fatty tissue (when needed).
    Sometimes a small sample of skin, fat, or vessel tissue is taken and examined under the microscope. This can confirm the presence of vascular malformation, abnormal fat, or epidermal nevus and may be used for gene testing.

15. Genetic testing for PIK3CA mutation.
    Special genetic tests look for mutations in the PIK3CA gene in tissue taken from an affected area (and sometimes in blood, although blood can be negative because of mosaicism). Finding a PIK3CA mutation strongly supports the diagnosis and places the patient within the PROS group.

Electrodiagnostic tests

16. Nerve conduction studies (NCS).
    If there are signs of nerve damage, doctors may test how fast and how well electrical signals move along the nerves in the arms or legs. Large vascular or fatty masses pressing on nerves can slow these signals.

17. Electromyography (EMG).
    In EMG, a small needle electrode is placed into muscles to record their electrical activity. This test can show whether weakness is due to nerve compression, muscle problems, or spinal cord involvement. It is not done in every patient but can be useful in selected cases.

Imaging tests

18. Ultrasound (with Doppler).
    Ultrasound uses sound waves to create pictures of soft tissues and vessels. It is often the first imaging test done in children. Doppler ultrasound shows how blood flows through the vessels and helps identify venous or lymphatic malformations in a safe, painless way.

19. Magnetic resonance imaging (MRI and MR angiography).
    MRI gives very detailed images of soft tissues, fat, vessels, and the spine. Special sequences and MR angiography show the exact size and type of vascular malformations and how they relate to nerves and organs. MRI is key for planning surgery or targeted treatments.

20. Computed tomography (CT / CT angiography) and X-rays.
    CT scans provide good pictures of bones and some soft tissues and can highlight complex vessel anatomy when CT angiography is used. Plain X-rays of the spine and limbs show bone deformities, scoliosis, and leg length differences. These imaging tools complete the full picture of the disease.

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Non-pharmacological treatments

Because CLOVES affects many body systems, non-drug therapies are essential. Below are 20 main approaches that doctors may consider as part of an individualized plan.

1. Compression garments
Elastic compression stockings, sleeves or custom garments gently squeeze enlarged limbs or areas with venous and lymphatic malformations. This pressure can lower swelling, reduce the feeling of heaviness and help blood and lymph flow back toward the heart. Compression also helps prevent skin breakdown and may reduce the risk of superficial blood clots. These garments are usually fitted by trained therapists and are worn most of the day, adjusted as the child grows.

2. Physiotherapy (physical therapy)
Physiotherapy uses guided exercises, stretching and movement training to maintain joint range of motion, muscle strength and balance in limbs affected by overgrowth or deformity. In CLOVES, some muscles may be weak while others are overloaded by abnormal anatomy. A physiotherapist designs a programme to protect joints, improve gait, reduce pain from muscle fatigue and delay functional decline. Therapy is often long-term and adapts as surgery or growth changes the limb shape.

3. Occupational therapy
Occupational therapy helps children and adults manage daily tasks such as dressing, writing, using a computer or cooking, even when one limb is larger or less mobile. The therapist may teach energy-saving techniques, suggest alternative ways to perform tasks and recommend adaptive tools (for example, larger handles or modified seating). The goal is to keep the person as independent as possible at home, school and work, while protecting joints and reducing strain on the spine.

4. Custom orthotics and footwear
When one leg is longer, wider or differently shaped, special shoe inserts, braces or custom footwear can help equalize leg length and support the foot. This reduces uneven loading on hips and spine, decreases pain and lowers the chance of developing early arthritis. Orthotists often work with orthopaedic surgeons and physiotherapists to design devices that fit comfortably despite soft-tissue overgrowth or deformity.

5. Posture and scoliosis management
CLOVES can cause spinal curves (scoliosis) or abnormal posture because of uneven growth. Early detection with regular spinal exams and imaging allows timely use of bracing, physiotherapy and, when needed, surgery. Teaching proper sitting, standing and lifting techniques helps reduce back pain and protects the spinal cord from compression. In some cases, neurosurgeons and orthopaedic surgeons coordinate to address spinal tethering or instability.

6. Sclerotherapy (as a procedure but also part of ongoing management)
Sclerotherapy is a minimally invasive treatment where a specialist injects a medicine (sclerosant) into abnormal veins or lymphatic channels to make them shrink and scar closed. For CLOVES, repeated sclerotherapy sessions can reduce the size of painful venous or lymphatic malformations, lower bleeding risk and improve appearance. It is usually done under imaging guidance and may be combined with compression therapy and surgery in a stepwise plan.

7. Endovascular embolization support
Embolization is a catheter-based technique in which tiny coils, plugs or glue-like materials are placed inside abnormal vessels to block blood flow. In CLOVES, this is used for large veins or arteriovenous malformations that cannot be safely removed by surgery alone. Embolization can shrink lesions, reduce heart strain and make later surgery safer. Patients usually need careful imaging follow-up, because new collateral vessels can form over time.

8. Laser therapy for skin and superficial vessels
Laser treatments, such as pulsed dye laser, can lighten capillary malformations and reduce visible small vessels in the skin. This can lessen bleeding episodes, skin irritation and cosmetic distress. Several sessions are usually needed, and results may be partial, but laser can be a helpful adjunct to other vascular treatments when used by experienced teams.

9. Pain management programmes (non-drug)
Chronic pain from overgrowth, nerve compression and vascular malformations is common. Non-drug pain management includes physio-guided exercises, heat and cold therapy, relaxation techniques, breathing exercises and cognitive-behavioural therapy. Learning coping skills and pacing activities can reduce pain flares and improve sleep and mood, especially in teenagers and adults living with long-term symptoms.

10. Skin care and infection prevention routines
Areas with lymphatic leakage or skin folds are at higher risk of infections like cellulitis. Gentle cleansing, keeping skin dry, prompt treatment of small cuts and early recognition of redness or warmth can prevent serious infections. Families are taught to look for warning signs and to seek medical care quickly, because some patients may need early antibiotics to avoid hospitalisation or sepsis.

11. Weight and activity management
Extra body weight puts more strain on enlarged limbs, veins and joints, and can worsen pain and mobility problems. A dietitian and physiotherapist can help design an eating plan and activity programme that maintains a healthy weight, protects joints and supports cardiovascular health. Low-impact exercise such as swimming or cycling is often encouraged, while very high-impact sports may be limited in people with fragile vessels or spine issues.

12. Psychosocial and mental health support
Living with a visible difference, multiple hospital visits and chronic pain can cause anxiety, low mood and social isolation. Psychological counselling, peer support groups and family therapy help patients and caregivers cope emotionally, build resilience and manage school or work challenges. Support from rare-disease communities and online registries also helps families feel less alone and more empowered.

13. Genetic counselling and education
Although CLOVES is caused by a genetic mutation, it is usually not inherited, but arises as a somatic mosaic change. Genetic counselling helps families understand this mechanism, recurrence risk and the relationship to the wider PIK3CA-related overgrowth spectrum. Counsellors also explain the rationale for targeted therapies that block the PI3K/AKT/mTOR pathway.

14. School and workplace accommodations
Children and adults may need extra time to move between classes, adapted seating, permission to elevate a limb, or flexibility for medical appointments. Written letters from specialists and disability coordinators can formalize these accommodations, helping the person stay in mainstream education or employment as much as possible.

15. Respiratory and sleep support when needed
Large truncal or chest wall overgrowth can affect breathing or posture in some patients. Sleep studies, respiratory physiotherapy and, occasionally, non-invasive ventilation or surgery may be considered if airway obstruction or reduced lung capacity is suspected. Careful anaesthesia planning is essential for any procedure in people with chest or airway anomalies.

16. Regular imaging surveillance
MRI, ultrasound and sometimes CT scans are used to monitor vascular malformations, spinal structures and organ involvement. Regular imaging helps detect changes early, such as spinal cord compression, thrombosis or fast-flow arteriovenous malformations, so that doctors can intervene before serious complications appear. The schedule is individualized based on the extent and location of disease.

17. Thrombosis risk assessment and lifestyle measures
CLOVES can be associated with abnormal large veins that increase the risk of blood clots. Lifestyle measures such as staying active within safe limits, avoiding dehydration and using compression garments during long travel are part of non-drug prevention. Doctors will assess when additional medical clot-prevention is needed.

18. Dental and bone health care
Uneven jaw or skull growth and long-term drug therapies can affect dental and bone health. Regular dental visits, attention to calcium and vitamin D intake and monitoring bone density are important, particularly if corticosteroids or other treatments that affect bone are used.

19. Rehabilitation after surgery or interventions
After debulking surgery, orthopaedic procedures or embolization, structured rehabilitation helps restore movement, strength and function. Therapists teach safe ways to move while scars heal, protect new reconstructions and gradually increase activity so that patients can return to daily life more quickly.

20. Participation in registries and clinical studies
Joining natural history registries and clinical studies helps families access expert centres and emerging therapies, and also improves future care by increasing scientific knowledge. The CLOVES Syndrome Registry and PROS research networks collect long-term information on symptoms, treatments and outcomes from patients worldwide.

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Drug treatments

Because CLOVES is ultra-rare, only one medicine is currently approved specifically for the broader PROS group, and many other drugs are used “off label” to control complications like pain, infection and thrombosis. Never start or change any of these medicines without a specialist.

1. Alpelisib (Vijoice®) – targeted PI3K-alpha inhibitor
Alpelisib is an oral medicine that blocks the PI3K-alpha enzyme, which is over-active in PIK3CA-related overgrowth spectrum, including CLOVES. It is approved by the U.S. Food and Drug Administration (FDA) for adults and children ≥2 years with severe PROS who need systemic therapy. The FDA label recommends once-daily dosing with food, typically 50 mg/day in younger children and 250 mg/day in adults, adjusted by age, weight and side-effects like high blood sugar, diarrhoea and rash. In studies and real-world cohorts, alpelisib has reduced overgrowth, pain and vascular malformation volume in many patients, but requires close monitoring of glucose, lipids and kidney function.

2. Sirolimus (Rapamune®) – mTOR inhibitor for vascular anomalies (off-label in CLOVES)
Sirolimus is an oral mTOR inhibitor originally approved to prevent kidney transplant rejection and treat lymphangioleiomyomatosis. It indirectly down-regulates the same PI3K/AKT/mTOR pathway involved in PROS. Case reports and small series show that sirolimus can shrink lymphatic and venous malformations, reduce pain and bleeding and improve quality of life in patients with CLOVES and related vascular anomalies. Doses are individualized and guided by blood level monitoring; common side-effects include mouth ulcers, high cholesterol, lowered blood counts and infection risk.

3. Low-dose aspirin (antiplatelet therapy)
Some patients with CLOVES have large abnormal veins and are at risk for blood clots. Low-dose aspirin is sometimes used to reduce platelet activation and micro-clotting in slow-flow venous malformations. The dose and duration depend on age, weight, bleeding risk and other medications. Aspirin can irritate the stomach and increase bleeding, so specialists carefully weigh benefits and risks and avoid it in children with certain viral illnesses because of Reye’s syndrome risk.

4. Anticoagulants (e.g., low-molecular-weight heparin, direct oral anticoagulants)
In patients with documented thrombosis or very high clot risk, blood thinners such as low-molecular-weight heparin or, in selected older patients, direct oral anticoagulants may be used. These medicines reduce the blood’s ability to form clots, which can protect the lungs and other organs but also increase bleeding risk, especially around large vascular malformations or after surgery. Dosing is strictly individualized, monitored by specialists in haematology or vascular medicine and adjusted before procedures.

5. Analgesics (paracetamol/acetaminophen, NSAIDs with caution)
Basic pain relievers like paracetamol (acetaminophen) are commonly used to control mild to moderate pain related to overgrowth, surgery or procedures. Non-steroidal anti-inflammatory drugs (NSAIDs) such as ibuprofen can help with inflammatory pain but may be used cautiously or avoided in some patients with bleeding risk or kidney problems. Doses follow standard paediatric or adult guidelines, and doctors check that total daily amounts do not exceed safe limits.

6. Neuropathic pain medicines (e.g., gabapentin, pregabalin)
When malformations compress nerves or cause burning, shooting or tingling pain, medicines such as gabapentin or pregabalin may be prescribed. These drugs calm over-active nerve signalling rather than directly affecting the malformations. They are started at low doses and increased slowly to reduce dizziness, drowsiness or mood changes. They are usually part of a broader pain-management plan that also includes physiotherapy and psychological support.

7. Antibiotics for infected lymphatic malformations
Lymphatic malformations in CLOVES can become infected, causing fever, redness and severe pain. When this happens, doctors may prescribe oral or intravenous antibiotics for 2–3 weeks, sometimes followed by longer preventive courses in people with repeated infections. Antibiotic choice depends on likely bacteria and local guidelines; early treatment is important to prevent sepsis and tissue damage.

8. Corticosteroids (short courses in specific complications)
Short courses of corticosteroids may be used in selected situations, such as severe inflammation around malformations or after certain procedures, to reduce swelling and nerve compression. Because long-term steroids weaken bones, increase infection risk and may slow growth in children, they are used carefully and tapered as quickly as is safe.

9. Local anaesthetic and sclerosant drugs (as part of procedures)
During sclerotherapy, doctors inject sclerosant agents (for example ethanol-based or detergent-type solutions) directly into abnormal veins or lymphatic spaces under image guidance. These medicines damage the inner lining of vessels, causing them to collapse and scar. They are powerful and must be used only by skilled interventional radiologists in hospital settings, because they can cause tissue injury or systemic effects if they spread outside the target area.

10. Experimental or off-label targeted agents in studies
Beyond alpelisib, researchers are testing other PI3K, AKT and mTOR pathway inhibitors and combination regimens in PROS. These medicines are usually available only through clinical trials or compassionate-use protocols at specialized centres. They aim to fine-tune pathway blockade to reduce overgrowth with fewer side-effects, but long-term safety data are still limited. Families interested in such options should discuss eligibility and risks with their specialist team and research coordinators.

(Because CLOVES is extremely rare and evidence is limited, most other medicines used in care—such as additional pain relievers, anti-clotting drugs or supportive treatments—are chosen individually for each patient rather than from a standard list of “20 specific drugs.”)

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Dietary molecular supplements

There are no supplements proven to reverse CLOVES syndrome, but some nutrients can support bone, muscle and overall health in people living with chronic disease. Always discuss supplements with your doctor, because doses and interactions matter.

1. Vitamin D
Vitamin D helps the body absorb calcium and maintain strong bones and muscles, which is important for people with skeletal deformities or reduced mobility. Many children and adults have low vitamin D levels, so guidelines often suggest daily supplementation within age-appropriate safe limits, avoiding very high doses that can cause toxicity. Testing levels and individualizing the dose with a doctor is safer than self-prescribing large amounts.

2. Calcium
Adequate calcium intake through food or supplements supports bone strength, especially if steroids or reduced weight-bearing increase osteoporosis risk. Doctors consider total calcium from diet and other supplements before adding extra, because too much calcium combined with certain medicines can increase kidney stone risk.

3. Omega-3 fatty acids (fish-oil–type supplements)
Omega-3 fatty acids such as EPA and DHA have anti-inflammatory effects and may reduce pain intensity in some chronic inflammatory conditions. They might support cardiovascular and joint health in people with limited mobility, but they can also slightly increase bleeding risk, especially when combined with anticoagulants or aspirin. Typical doses in studies range from 1–3 g/day of combined EPA/DHA, always under medical supervision.

4. Multivitamin supplement (age-appropriate)
A simple multivitamin can help cover small gaps in daily intake of vitamins and trace elements, particularly in children with poor appetite due to pain, procedures or medications. The goal is to meet, not greatly exceed, recommended daily intakes, so “mega-dose” products are usually avoided unless a doctor prescribes them for a specific deficiency.

5. Protein-rich supplements (when needed)
Some patients with CLOVES undergo repeated surgeries or have higher energy needs due to chronic disease. Oral nutrition supplements rich in protein can support wound healing and maintain muscle mass. A dietitian can help choose products that match age, kidney function and taste preferences, and can integrate them into normal meals rather than replacing food.

6. Probiotics (for gut support during repeated antibiotics)
Frequent antibiotic courses for infected malformations can upset the gut microbiome and cause diarrhoea. Probiotics containing well-studied strains may help restore healthy gut bacteria, although evidence is not specific to CLOVES. They should be used with caution in severely immunocompromised patients and chosen based on products with clinical data.

7. Magnesium (within safe limits)
Magnesium supports muscle and nerve function and may help with cramps or constipation in some people. It should be used carefully in patients with kidney problems, and the dose must stay inside recommended limits to avoid diarrhoea or heart rhythm issues.

8. Iron (only if deficiency is proven)
Chronic bleeding from vascular malformations or heavy periods can lead to iron-deficiency anaemia. If blood tests confirm low iron, doctors may recommend oral or intravenous iron to restore levels and reduce fatigue. Taking iron without testing can cause stomach upset and, rarely, overload, so it must be guided by lab results.

9. B-complex vitamins (for general energy metabolism)
B-vitamins support energy production and nerve health. A standard-dose B-complex may be used when dietary intake is poor, but mega-doses are generally unnecessary. Some patients with neuropathic pain appreciate knowing that basic vitamin deficiencies have been ruled out or corrected.

10. Individualized supplementation plans
Because every person with CLOVES has different surgeries, medicines and activity levels, supplement plans should be tailored and regularly reviewed. Over-supplementation can be harmful, so doctors and dietitians balance lab results, diet history and medication list to keep nutrition supportive but safe.

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Immune-supporting, regenerative and stem-cell related drugs

Right now, there are no approved “stem cell drugs” that cure or reverse CLOVES syndrome. Research into gene-targeted and cell-based therapies is ongoing, but these treatments remain experimental and are not standard of care. Targeted pathway inhibitors such as alpelisib and sirolimus are the closest we have to “regenerative” approaches, because they directly address the over-active growth pathway driving the disease.

Doctors may also focus on supporting the immune system indirectly, for example by keeping vaccinations up to date, treating infections quickly, optimising nutrition and adjusting immunosuppressive drugs like sirolimus to the lowest effective dose. Families should be cautious about commercial “immune booster” or “stem cell clinic” offers that are not part of regulated clinical trials, as these can be expensive, unproven and risky.

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Surgeries and interventional procedures

1. Debulking surgery
Debulking surgery removes part of the overgrown fatty tissue and abnormal vessels to reduce bulk, improve limb function and relieve pain. It is a major procedure that requires careful planning, because overgrown tissue tends to bleed more and can regrow with time. Debulking is often combined with pre-operative embolization and followed by compression and physiotherapy to maintain the benefit.

2. Surgical resection of focal malformations
When a vascular malformation is well-defined and located in a safer area, surgeons may fully remove it. This can relieve pain, stop recurrent bleeding or protect nearby nerves and organs. Complete resection lowers the risk of recurrence but may not be possible if vital structures are intertwined with the malformation, so decisions are highly individualized.

3. Orthopaedic procedures (limb length and alignment surgery)
Orthopaedic surgeons may perform bone-lengthening or shortening, joint stabilisation or corrective osteotomies (bone cuts) to improve alignment, leg length differences and function. These surgeries can greatly improve walking and reduce pain but require long recovery and rehabilitation. Planning is complex because bone growth may continue asymmetrically during childhood.

4. Spinal and neurosurgical operations
If CLOVES causes spinal canal narrowing, tethered cord or compression of the spinal cord or nerves, neurosurgeons may perform decompression or detethering procedures. These surgeries aim to prevent permanent nerve damage, weakness or bladder and bowel problems. They are carefully timed based on symptoms and imaging, balancing surgical risk against the risk of waiting.

5. Combined sclerotherapy-plus-resection strategies
Large lymphatic malformations associated with overgrowth may benefit from a combined approach in which sclerotherapy is used first to shrink and solidify the lesion, followed by surgical removal of remaining abnormal tissue. This strategy can reduce blood loss and improve contour outcomes. It is usually planned by a vascular anomalies team with interventional radiology and surgery working closely together.

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Prevention: what can and cannot be prevented

1. Primary prevention of CLOVES is not currently possible, because the PIK3CA mutation happens randomly in early development and is not usually inherited.

2. Preventing complications is possible through early diagnosis, regular follow-up and timely imaging to detect dangerous vascular or spinal problems.

3. Skin infection prevention includes daily gentle cleansing, careful drying, quick care of small cuts and prompt medical review of any redness, warmth or fever near malformations.

4. Clot prevention uses lifestyle measures (staying active, hydration, compression garments on long trips) and, in high-risk cases, carefully supervised antiplatelet or anticoagulant therapy.

5. Bone and joint protection is supported by physiotherapy, orthotics, healthy weight, and early management of scoliosis and limb length differences.

6. Respiratory complications can be reduced by monitoring chest overgrowth, managing posture and treating sleep-disordered breathing early when suspected.

7. Anaesthesia-related risks are lowered by using centres familiar with CLOVES and PROS, where anaesthetists plan carefully around vascular anomalies and airway differences.

8. Emotional stress and social isolation can be reduced through mental-health support, school accommodations and rare-disease communities.

9. Nutritional problems are prevented by regular dietitian review, especially around major surgeries or during long treatments like alpelisib or sirolimus.

10. Medication side-effects are minimised by regular lab monitoring, dose adjustments and good communication between the family and the multidisciplinary team.

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When to see a doctor (or go to emergency)

People with CLOVES should have regular planned visits with their vascular anomalies team at least once or twice a year, plus extra visits whenever new symptoms appear. Urgent medical help is needed if there is sudden severe pain, rapidly increasing swelling, new redness and warmth over a malformation, fever, shortness of breath, chest pain, new weakness, loss of bladder or bowel control, seizures or sudden changes in walking. These may signal infection, deep-vein thrombosis, pulmonary embolism or spinal cord compression, all of which can be life-threatening if not treated quickly.

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What to eat and what to avoid

1. Focus on a balanced, anti-inflammatory style diet rich in fruits, vegetables, whole grains, lean protein and healthy fats to support general health and weight control.

2. Include calcium- and vitamin-D-rich foods, such as dairy or fortified plant milks and safe sunlight exposure, to support bones stressed by deformity or reduced mobility.

3. Choose omega-3 sources like oily fish (where culturally appropriate) or doctor-approved supplements to support heart and joint health.

4. Limit ultra-processed foods high in sugar and saturated fat, which can promote weight gain and inflammation and may worsen pain and cardiovascular strain.

5. Stay well hydrated, especially when mobility is limited or during long travel, to support circulation and reduce clot risk.

6. Avoid very high-dose supplements without medical advice, particularly vitamin D, calcium and herbal “blood thinners,” because they can interact with prescribed clotting or targeted drugs.

7. Limit alcohol (for adults) and avoid smoking or vaping, as these can harm blood vessels and overall health, increasing surgical and clotting risks.

8. Watch salt intake if there is heart or kidney involvement, to help control blood pressure and swelling, following your doctor’s specific guidance.

9. Coordinate diet with medicines such as alpelisib and sirolimus, which may require taking doses with food and monitoring blood sugar and lipids.

10. Work with a dietitian for personalized advice, especially for children, those who are underweight or overweight, or anyone with side-effects that reduce appetite.

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FAQs

1. Is Cloves syndrome the same as PROS?
CLOVES syndrome is one specific condition inside the larger PIK3CA-related overgrowth spectrum (PROS). All PROS conditions share PIK3CA mutations, but they affect different body parts and have different patterns of overgrowth and vascular malformations.

2. Is CLOVES inherited?
In most cases, CLOVES is not inherited. The PIK3CA mutation occurs after conception in one or more cells, creating a mosaic pattern. Parents usually do not carry the mutation in their germ cells, so recurrence risk in future pregnancies is considered low, though genetic counselling is recommended.

3. Can CLOVES be cured?
At present there is no cure that removes the PIK3CA mutation from all affected cells. Treatment aims to control overgrowth, vascular problems and symptoms. New targeted drugs like alpelisib and sirolimus can significantly improve lesions and quality of life for many patients but do not fully eliminate the disease.

4. What is the role of alpelisib in CLOVES?
Alpelisib is the first targeted PI3K-alpha inhibitor approved for PROS, which includes CLOVES, in patients aged 2 years and older with severe disease needing systemic therapy. It is taken once daily with food and has shown benefit in reducing lesion volume and pain, but requires close monitoring of blood sugar, lipids and other labs due to potential side-effects.

5. How is sirolimus different from alpelisib?
Sirolimus blocks mTOR, a downstream part of the same growth pathway, while alpelisib directly targets PI3K-alpha. Sirolimus has been used off-label for many years to treat vascular malformations, with evidence of improved symptoms and quality of life, but it is not specifically licensed for CLOVES. Choice between them depends on disease severity, side-effect profiles, access and specialist experience.

6. Will my child definitely need surgery?
Not every child with CLOVES needs surgery. Many can be managed with medicines, sclerotherapy, compression and physiotherapy. Surgery is considered when overgrowth or malformations cause severe pain, major functional limits, organ pressure or high-risk bleeding or clotting. Decisions are made by a multidisciplinary team together with the family.

7. Do lesions always grow worse over time?
Overgrowth in CLOVES often progresses during childhood and adolescence, but the pattern is variable. Some lesions stabilise, while others enlarge or develop new complications. Regular monitoring allows doctors to act early if dangerous changes appear, and targeted therapies may slow or partially reverse growth in some cases.

8. Can pregnancy make CLOVES symptoms worse?
Pregnancy increases blood volume, hormonal changes and pressure on veins, so vascular malformations may worsen, and clot risk may rise. Case reports in PROS patients treated long-term with alpelisib suggest careful management can allow healthy pregnancies, but this requires close coordination between maternal-fetal medicine, haematology and vascular anomalies specialists.

9. Is it safe to exercise with CLOVES?
Most people with CLOVES are encouraged to stay as active as their condition safely allows. Low-impact activities such as swimming, cycling or gentle walking often help circulation, mood and weight control. High-impact sports or heavy contact activities may need to be limited if there is high bleeding or fracture risk. An individual exercise plan from physiotherapists is safest.

10. Are special diets required?
There is no specific “CLOVES diet,” but a healthy, balanced eating pattern that supports a normal weight, bone strength and cardiovascular health is recommended. Extra attention is given during times of rapid growth, surgery or when medicines affect appetite or blood sugar.

11. Can complementary or herbal treatments help?
Some families explore complementary approaches like mindfulness, yoga or acupuncture for pain and stress relief, and these may be helpful when supervised and integrated into the medical plan. Herbal or high-dose supplements that claim to “cure overgrowth” or “clean the blood” should be treated with caution, as they can interact with prescription medicines or increase bleeding. Always discuss these with the medical team.

12. How can families find expert centres?
Because CLOVES is so rare, care is often concentrated in vascular anomalies programmes at major children’s or academic hospitals. Patient organisations and registries maintain lists of centres with experience in PROS and CLOVES and can help families connect with specialists, support groups and research studies.

13. What is the life expectancy in CLOVES?
Life expectancy depends on how severe and where the malformations are, as well as how early complications are recognised and treated. Serious risks include spinal cord compression, massive bleeding, organ dysfunction and blood clots. With modern imaging, multidisciplinary care and targeted therapy, more patients are living longer with better quality of life, but long-term data are still being collected.

14. Can CLOVES be detected before birth?
Sometimes prenatal ultrasound or fetal MRI shows asymmetric overgrowth, large fatty masses or vascular anomalies suggestive of CLOVES, but diagnosis is difficult and often confirmed after birth. In families with a previously affected child, prenatal testing is rarely useful because the mutation is mosaic and usually not inherited.

15. What should families remember most?
CLOVES syndrome is complex and can feel overwhelming, but families are not alone. Early connection with a multidisciplinary vascular anomalies team, attention to infection and clot warning signs, realistic expectations about treatment goals, and ongoing psychosocial and educational support can all make a major difference in long-term outcomes and quality of life.

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.