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

Other names
Types (patterns) of CLOVES syndrome
Causes and disease mechanisms
Symptoms and signs
Diagnostic tests
Non-pharmacological treatments
Drug treatments
Dietary molecular supplements
Immune, regenerative and stem-cell–related approaches
Surgical and interventional treatments
Prevention and risk-reduction strategies
When to see a doctor urgently
Diet: what to eat and what to avoid
Frequently asked questions

Congenital lipomatous overgrowth-vascular malformation-epidermal nevi-spinal anomaly syndrome is usually called CLOVES syndrome. It is a very rare birth condition where a baby is born with too much fatty tissue in some body parts, abnormal blood and lymph vessels, special skin patches, and problems in the bones or spine.

LOVES syndrome is a very rare birth condition in which a baby is born with too much fatty tissue (lipomatous overgrowth), abnormal blood and lymph vessels (vascular malformations), thick or warty skin patches (epidermal nevi), and bone or spine problems such as scoliosis or spinal deformity [1]. It is part of a group called PIK3CA-related overgrowth spectrum (PROS), caused by a spelling mistake (mutation) in a gene called PIK3CA that makes a growth-control protein; when this pathway is too active, tissues in certain body areas keep growing more than they should [2]. Symptoms can include big soft masses, limb length difference, visible vein or lymph malformations, back and chest wall deformity, and sometimes problems with breathing, walking, or blood clots, and the condition is long-term but usually not inherited because the mutation happens “after conception” in only some cells (mosaicism) [3].

CLOVES syndrome belongs to a family of diseases called PIK3CA-related overgrowth spectrum (PROS). In these diseases, a change (mutation) in a gene called PIK3CA makes some cells grow too much and too fast. This extra growth happens only in some parts of the body, not everywhere, so the body looks uneven or asymmetric.

The word CLOVES is an acronym. “C” means congenital (present at birth). “L” means lipomatous overgrowth (too much fatty tissue). “O” means overgrowth of body parts. “V” means vascular malformations (abnormal blood or lymph vessels). “E” means epidermal nevi (thick, raised skin patches). “S” means spinal or skeletal anomalies, such as curved spine (scoliosis) or a tethered spinal cord.

People with CLOVES syndrome can have mild, moderate, or very severe problems. Some children only have soft fatty lumps and skin marks. Others may have serious spinal, nerve, or blood-vessel complications that need close follow-up and many treatments.

Other names

Doctors and articles may use different names for the same condition. These names all point to CLOVES syndrome:

CLOVES syndrome – the most common short name.
Congenital Lipomatous Overgrowth, Vascular malformations, Epidermal nevi, Scoliosis/Skeletal/Spinal anomalies – the full phrase that spells out “CLOVES”.
Congenital Lipomatous Overgrowth-Vascular malformation-Epidermal nevi-Spinal anomaly syndrome – similar long name with the word “spinal”.
Congenital Lipomatous Overgrowth-Vascular malformation-Epidermal nevi-Skeletal anomaly syndrome – similar long name with the word “skeletal”.
Some older papers used CLOVE syndrome without the final “S”, but this is now less common.

Types (patterns) of CLOVES syndrome

There is no single official “type 1 / type 2” list, but doctors often describe patterns or sub-groups based on which areas are most affected. This helps with planning tests and treatment.

Mild localized CLOVES – small area of fatty overgrowth and a few vascular or skin changes, usually on the trunk or one limb, with little or no spinal involvement.
Truncal-dominant CLOVES – large soft fatty masses on the back, flank, or chest with many abnormal veins and lymph vessels in the same region.
Limb-dominant CLOVES – overgrowth mainly in arms or legs, with large wide hands or feet, big fingers or toes, and visible vein problems.
Vascular-predominant CLOVES – many venous, capillary, or lymphatic malformations, sometimes including arteriovenous malformations (AVMs), with smaller fatty masses.
Spinal-predominant CLOVES – strong involvement of the spine, such as scoliosis, spinal AVMs, or tethered cord, with a higher risk of nerve problems.
Multi-organ severe CLOVES – extensive disease with involvement of trunk, limbs, organs (such as kidneys), and spine, often with serious complications like blood clots or breathing problems.

Causes and disease mechanisms

Somatic PIK3CA mutation
CLOVES syndrome happens because of a change (mutation) in the PIK3CA gene that occurs after conception, in some cells of the body. This is called a somatic mutation, not a mutation in egg or sperm.
Mosaic pattern
The PIK3CA mutation is mosaic, which means only a portion of cells carry the change. Some body parts have mutated cells and overgrow, while other parts develop normally, causing uneven body shape.
Gain-of-function gene change
The mutation is “gain-of-function.” It makes the PIK3CA protein too active. This over-activity pushes cells to grow and divide more than they should.
PI3K-AKT-mTOR pathway activation
PIK3CA is part of the PI3K-AKT-mTOR signaling pathway inside cells. When this pathway is over-active, cells grow, survive, and make new blood vessels more than normal, leading to overgrowth and vascular malformations.
Early embryonic timing
The mutation usually happens very early in the embryo. Because of this early timing, large areas of the body that grow from those first cells become affected, such as whole parts of the trunk or limbs.
Abnormal fat (adipose) growth
Fat cells with the PIK3CA mutation multiply and enlarge, forming big soft lipomatous masses in the trunk, back, or limbs. These masses are benign but can be very large and deforming.
Abnormal blood vessels
The same pathway change affects blood vessel cells, leading to venous, capillary, and sometimes arteriovenous malformations. These vessels may be wide, twisted, or poorly formed and may clot or bleed easily.
Abnormal lymph vessels
Lymphatic vessels can also be malformed and leaky. This can cause soft, spongy swellings, fluid-filled cysts, and recurrent infections or oozing in the affected areas.
Skin overgrowth and epidermal nevi
Skin cells with the mutation form thick, often brown or skin-colored raised streaks or patches called epidermal nevi. These lesions follow “lines” of skin development on the body.
Bone and spine involvement
When bone and spine cells are affected, they may grow unevenly, leading to scoliosis, limb length differences, or spinal canal changes that press on nerves.
No simple inheritance pattern
CLOVES syndrome usually does not run in families. Because the mutation is somatic and mosaic, parents and siblings are usually unaffected, and the risk of having another child with CLOVES is very low.
Random chance event
For most families, the gene change seems to be a random event during early development. There is no strong link to diet, medication, or exposures in pregnancy at this time.
Part of PIK3CA-related overgrowth spectrum
The same PIK3CA pathway can cause other overgrowth disorders, such as some forms of macrodactyly and other PROS conditions. CLOVES is one specific pattern in this larger group.
Abnormal cell survival
Over-active PI3K-AKT signals help cells avoid natural cell death. Cells that should die stay alive and keep building fatty tissue and malformed vessels.
Abnormal angiogenesis (new vessel growth)
The same signals drive growth of new blood vessels, but these vessels are often irregular and become venous or arteriovenous malformations instead of normal networks.
Tissue “ballooning”
The combination of too many cells, too much fat, and abnormal vessels makes some body parts look swollen or “ballooned”, especially limbs or parts of the trunk.
Compression of nearby organs
Large fatty or vascular masses can press on joints, nerves, lungs, or other organs. This compression can cause pain, movement problems, or breathing issues.
Risk of blood clots
Slow blood flow through abnormal veins and AVMs can increase the risk of deep vein thrombosis (DVT) and pulmonary embolism, which are serious complications.
Risk of infection in lymphatic lesions
Lymphatic malformations can get infected and inflamed. This leads to redness, fever, and pain, and often needs prompt antibiotics.
Chronic and lifelong condition
CLOVES syndrome does not go away. The overgrowth and vessel problems are long-term. Treatment focuses on managing symptoms, preventing complications, and improving quality of life.

Symptoms and signs

Soft fatty masses on the trunk
Many children are born with large, soft, fatty lumps on the back, flanks, or abdomen. These masses may grow with the child and can be uneven from one side to the other.
Overgrowth of arms or legs
One or more limbs can be larger, wider, or longer than the other side. The hands and feet may look broad, with big or extra fingers or toes and wide spaces between them.
Visible abnormal veins
Enlarged, twisted, or bulging veins may appear on the chest, abdomen, arms, or legs. These veins can cause pain, heaviness, or swelling and may be linked with blood clots.
Capillary birthmarks and port-wine stains
Some patients have flat red or purple patches on the skin, often called “port-wine stains.” These capillary malformations can cover large body areas.
Lymphatic swellings and cysts
Soft, spongy, or fluid-filled areas may appear in the skin or deeper tissues. They can swell, ooze, or get infected, and they may change size over time.
Epidermal nevi (skin streaks or plaques)
Thick, raised, often brownish or skin-colored lines or patches can run along the trunk or limbs. They are usually present from birth or early infancy and tend to follow the lines of the skin.
Scoliosis (curved spine)
Many children develop a sideways curve of the spine. Over time this can cause uneven shoulders, back pain, and breathing problems in severe cases.
Spinal cord and nerve problems
Some patients have a tethered spinal cord or vascular malformations inside the spinal canal. This can cause leg weakness, numbness, bladder or bowel problems, and sometimes pain.
Joint and bone deformities
Overgrowth and fatty masses can disturb joint alignment. This may lead to limb length difference, joint dislocation, hip problems, and difficulty walking.
Pain and swelling episodes
Children and adults may have episodes of pain, warmth, and swelling in areas with vascular malformations, especially if there is a clot or infection.
Recurrent skin infections
Areas with lymphatic malformations or skin breakdown are prone to repeated infections. There may be redness, fever, and pus or fluid drainage.
Breathing or chest problems
Very large chest wall masses or vascular malformations can press on the lungs or airways. This may cause shortness of breath or frequent chest infections.
Abdominal organ involvement
Some patients have kidney abnormalities, such as a small or missing kidney, or other organ differences. This may not cause symptoms at first but needs monitoring.
Blood clot (thrombotic) events
Painful swollen legs, sudden chest pain, or shortness of breath can signal deep vein thrombosis or pulmonary embolism, serious complications linked to abnormal veins.
Emotional and social impact
Visible differences, repeated hospital visits, and chronic pain can affect mood, schooling, and social life. Families often need psychological and social support.

Diagnostic tests

Doctors choose tests based on each person’s symptoms. Not every patient needs every test. The aim is to confirm CLOVES syndrome, understand which tissues are involved, and plan safe treatment.

Physical examination tests

Full body inspection and comparison
The doctor looks carefully at the whole body for fatty masses, birthmarks, skin streaks, enlarged veins, and any differences between right and left sides. They note where overgrowth and vascular malformations are present. This visual exam gives the first strong clue for CLOVES syndrome.
Limb length and size measurement
The doctor measures length and circumference of arms, legs, hands, and feet with a tape measure. These measurements show how much overgrowth is present and help track changes over time. They also guide decisions about surgery or shoe lifts.
Spine and posture assessment
By observing the back from behind and from the side, the doctor checks for curves, uneven shoulders, or tilted hips. Simple tests like bending forward can make scoliosis more obvious. These findings decide whether spine X-rays or MRI are needed.
Basic neurological exam
The doctor tests muscle strength, reflexes, and sensation in the legs and sometimes the arms. They watch the child stand and move. Any weakness, abnormal reflex, or loss of feeling may signal spinal cord involvement or nerve compression.

Manual / bedside functional tests

Joint range of motion testing
The doctor gently moves joints in the hips, knees, ankles, shoulders, elbows, and fingers. They look for stiffness, contractures, or limits caused by overgrowth or masses. Poor joint movement can explain pain or walking problems.
Gait and balance assessment
The child is asked to walk, turn, and sometimes walk on toes or heels. The doctor watches for limping, uneven steps, or balance problems that might come from limb differences or nerve issues.
Manual muscle strength testing
The doctor asks the child to push or pull against their hands in different directions. This simple test grades muscle power and helps find weakness from spinal cord compression or nerve damage.
Sensory testing (touch and pain)
Light touch, pinprick, and sometimes temperature are checked on the legs, feet, and other areas. Changes in feeling can point to spinal lesions, nerve entrapment, or previous damage from vascular problems.

Lab and pathological tests

Complete blood count and coagulation tests
A blood sample is used to check red and white cells, platelets, and clotting times. This helps find anemia, inflammation, or clotting problems that might appear with large vascular malformations or after surgery.
Kidney and liver function tests
Blood tests look at creatinine, urea, and liver enzymes. Since some patients have kidney abnormalities and many take long-term medicines, these tests help monitor organ health over time.
Inflammatory markers (CRP, ESR)
When an area is painful, warm, or swollen, blood tests such as C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR) help show if there is active inflammation or infection in lymphatic or vascular lesions.
Genetic testing for PIK3CA in blood
Sometimes doctors test the blood for PIK3CA mutations. Because CLOVES is mosaic, the mutation may be at low level or absent in blood, but a positive result supports the diagnosis.
Genetic testing for PIK3CA in affected tissue
A small sample from an overgrown area, such as a fatty mass or skin lesion, can be sent for detailed genetic testing. This is more sensitive than blood and is often the best way to confirm a PIK3CA mutation.
Biopsy of fatty mass
In some cases, a surgeon removes a tiny piece of the fatty overgrowth to look at under a microscope. The pathologist sees benign lipomatous tissue and may also help rule out rare tumors or other diseases.
Biopsy of skin or vascular lesion
When needed, a small skin or vessel sample is examined. It can show epidermal nevus or specific vascular malformation types and can also be used for genetic testing. Doctors balance this against the risk of bleeding or scarring.

Electrodiagnostic tests

Nerve conduction studies (NCS)
Electrodes are placed on the skin, and small electrical pulses check how fast and how well nerves carry signals. These tests can detect nerve damage from spinal compression or long-term limb overgrowth.
Electromyography (EMG)
A tiny needle electrode is placed in selected muscles to study their electrical activity. EMG helps tell whether weakness is coming from nerve problems, muscle problems, or both. This information guides decisions about surgery or rehabilitation.

Imaging tests

X-rays of spine and limbs
Plain X-rays show bone structure, scoliosis, limb length differences, and joint deformities. They are often the first imaging test for skeletal problems and help monitor changes as the child grows.
Ultrasound and Doppler studies
Ultrasound uses sound waves to look at soft tissues and fluid-filled lymphatic spaces. Doppler ultrasound shows blood flow in veins and arteries, helping detect clots, slow flow, or abnormal connections between vessels. It is non-invasive and safe for children.
Magnetic resonance imaging (MRI) with or without MR angiography
MRI gives detailed pictures of soft tissues, spine, brain, and deep vascular malformations without radiation. MR angiography and venography can map abnormal arteries and veins, including AVMs and spinal lesions. MRI is central for diagnosing the full extent of CLOVES syndrome and planning surgery or targeted drug treatment.

Non-pharmacological treatments

Compression garments and bandages
Special elastic stockings, sleeves, or wraps gently squeeze the limb or body part to reduce swelling from abnormal veins and lymph vessels [1]. They improve blood and lymph flow, lower the risk of skin breakdown and clots, and may ease heaviness and pain during daily activities [2]. These garments must be carefully measured and fitted by trained staff; pressure that is too tight or poorly placed can harm the skin or nerves, so regular review is important as the child grows [3].
Physiotherapy and targeted exercise
A physiotherapist designs safe stretching, strengthening, and balance exercises to keep joints flexible and muscles strong around the areas of overgrowth [1]. This helps prevent contractures, improves posture and walking pattern, and reduces back or limb pain by correcting abnormal loading on bones and joints [2]. Gentle, regular movement also supports circulation and lymph flow, but high-impact or contact sports that risk trauma to vascular malformations are usually avoided [3].
Occupational therapy and adaptive equipment
Occupational therapists teach practical ways to do everyday tasks such as dressing, writing, or using a computer when limbs are large or uneven [1]. They may recommend adapted chairs, desks, cutlery, or bathroom aids so the person can stay independent and safe at home and school [2]. By changing the environment rather than only the body, occupational therapy reduces strain, fatigue, and frustration, which can strongly improve quality of life [3].
Custom orthotics and specialist footwear
If one leg is longer, wider, or heavier, custom shoe inserts, insoles, or raised soles can help balance the pelvis and spine [1]. Orthotic braces for ankles, knees, or the trunk can steady weak or misshapen joints, reduce pain, and prevent worsening deformity, especially during growth spurts [2]. Proper support spreads forces more evenly through the skeleton, which may delay or reduce the need for big orthopedic surgeries later [3].
Scoliosis bracing and posture training
When the spine curves because of uneven growth, a specialist may prescribe a firm plastic brace worn around the chest and waist for many hours each day [1]. The brace gently pushes the spine toward a straighter position while bones are still growing and is combined with posture exercises to strengthen back muscles [2]. Although a brace cannot cure the underlying gene problem, it can slow curve progression and protect lung function until definitive surgery is considered if needed [3].
Limb elevation and positioning strategies
Simple daily habits such as raising a swollen limb above heart level while resting can help fluid drain back toward the trunk [1]. Using pillows, wedges, or adjustable beds keeps the limb supported without cutting off circulation, and changing position regularly prevents pressure sores on areas with abnormal fat or vascular malformations [2]. Over time, good positioning reduces aching, skin tension, and risk of ulcers, especially when combined with compression garments [3].
Specialized wound and skin care
Abnormal vessels and stretched skin can break easily and heal slowly, so careful hygiene, gentle cleansing, and regular moisturizing are very important [1]. Nurses and dermatologists may use non-adhesive dressings, barrier creams, and protective padding over fragile areas to prevent rubbing and infection [2]. Prompt attention to any small cut, blister, or ulcer reduces the risk of cellulitis, sepsis, and scarring, which are serious complications in people with complex malformations [3].
Manual lymphatic drainage (by trained therapists)
Some centers use a gentle massage technique called manual lymphatic drainage, done by specially trained therapists, to encourage lymph fluid to move away from congested areas toward healthy lymph channels [1]. This can temporarily reduce limb size and tightness, especially when followed by compression wrapping [2]. Because CLOVES involves structural changes in lymph vessels, results vary, and therapy must be very careful to avoid damaging fragile malformations or causing pain [3].
Pain psychology and coping strategies
Chronic pain from enlarged tissues, nerve compression, or repeated procedures can strongly affect mood and sleep [1]. Psychologists teach relaxation, breathing exercises, graded activity, distraction, and cognitive-behavioral techniques to re-frame pain signals and reduce anxiety or depression linked to the condition [2]. These methods do not replace medicines but change how the brain processes pain, helping many patients need lower drug doses and feel more in control [3].
Educational and school support
Children with obvious physical differences may face bullying, fatigue, or frequent medical visits, which can affect learning [1]. Early communication with teachers, flexible timetables, extra time for exams, and access to elevators or rest areas make it easier to stay in mainstream school where possible [2]. A formal education plan can include allowances for pain flares, hospital stays, and physiotherapy sessions during school hours [3].
Psychosocial and family counselling
Families often feel shock, guilt, fear about surgeries, and stress from constant care needs and financial costs [1]. Social workers and counsellors can help parents understand the diagnosis, navigate disability benefits, and connect with patient groups such as CLOVES syndrome communities for peer support [2]. Emotional support reduces burnout, improves communication with doctors, and helps siblings cope with changes in family life [3].
Genetic counselling and reproductive advice
Although CLOVES usually is not passed on directly to children, families often worry about future pregnancies [1]. Genetic counsellors explain the concept of somatic mosaic PIK3CA mutations, the very low recurrence risk, and available prenatal or pre-implantation options where appropriate [2]. Clear information lowers anxiety and helps parents make informed choices without unrealistic expectations about “curing” the gene change [3].
Lifestyle advice on safe physical activity
Doctors and physiotherapists usually recommend low-impact activities such as swimming, cycling, or gentle walking to maintain heart and lung fitness without heavy stress on malformed bones and vessels [1]. Contact sports, heavy lifting, or extreme stretching are often limited because they can cause bleeding, clots, or joint damage in overgrown areas [2]. A personalized activity plan balances safety with the psychological benefit of being active and included with peers [3].
Weight management and healthy sleep
Extra body weight adds mechanical load to already stressed joints and veins, and poor sleep raises pain perception and fatigue [1]. Dietitians can guide families in building a balanced, nutrient-dense eating pattern with appropriate calories, while sleep specialists help set routines, address breathing issues, and manage pain at night [2]. Together, weight and sleep management improve overall energy and coping ability for daily life and rehabilitation [3].
Thrombosis risk education and travel precautions
Because large venous malformations and limited mobility can increase blood clot risk, teams often teach families early warning signs such as sudden limb swelling or chest pain [1]. During long journeys, simple measures like frequent movement, comfortable non-tight clothing, and sometimes medical compression can reduce stasis in affected limbs [2]. Understanding when to seek urgent care for possible deep-vein thrombosis or pulmonary embolism can be life-saving [3].
Smoking and second-hand smoke avoidance (for older teens/adults)
Tobacco smoke damages blood vessels and impairs wound healing, which is especially dangerous when veins and lymphatics are already abnormal [1]. Avoiding smoking and second-hand smoke helps reduce infection risk, improves oxygen delivery to tissues, and makes surgeries and anesthesia safer [2]. Counselling, nicotine-replacement therapy, and support groups can help older patients stop if needed [3].
Vaccination according to specialist advice
Many patients may later receive immune-suppressing drugs like sirolimus or alpelisib, which increase infection risk [1]. Keeping routine vaccines (including influenza and COVID-19 where recommended) up to date before strong medicines are started helps reduce serious infections [2]. Doctors individualize vaccine timing and type, especially for live vaccines, based on the patient’s drug plan and overall health [3].
Multidisciplinary clinic follow-up
Regular visits with an integrated vascular anomalies or PROS clinic allow early detection of new problems such as worsening scoliosis, organ compression, or clotting issues [1]. Imaging, growth measurements, and functional tests can be coordinated on the same day, avoiding repeated hospital trips [2]. This ongoing review supports timely adjustments in compression, therapy, medicines, or surgical plans as the disease evolves [3].
Peer support and patient organizations
Joining patient groups, in person or online, lets families share experiences, practical tips, and emotional support with others facing the same rare condition [1]. Many organizations also advocate for research, better insurance coverage, and awareness among doctors and schools [2]. Feeling less alone often improves mental health and encourages adherence to long-term treatment plans [3].
Telemedicine and digital monitoring
For families living far from specialist centers, telehealth visits and secure photo or video sharing can help monitor skin lesions, wounds, and brace fit between in-person appointments [1]. Early remote review of new symptoms can guide whether urgent travel or local evaluation is needed, reducing delays [2]. Digital tools cannot replace physical exams but can make lifelong follow-up more practical and less disruptive to daily life [3].

Drug treatments

Important: The medicines below are examples used by specialists for CLOVES or its complications. Most are off-label for this syndrome. Exact drug choice and dose must always be decided by a vascular-anomaly or PROS expert; this information is educational and not a self-treatment guide.

Alpelisib (Vijoice / Piqray) – PI3K-α inhibitor, targeted PROS therapy
Alpelisib is an oral targeted drug that blocks the PI3K-alpha enzyme, directly calming the overactive PIK3CA pathway that drives overgrowth in PROS conditions including CLOVES [1]. The FDA has granted accelerated approval to alpelisib (Vijoice) for adults and children ≥2 years with severe PROS who need systemic therapy; typical starting doses are 50 mg once daily with food in children and 250 mg once daily in adults, adjusted by specialists [2]. Common side-effects include high blood sugar, diarrhea, mouth sores, and skin rash, so blood tests and glucose checks are essential during treatment [3].
Sirolimus (Rapamune) – mTOR inhibitor for vascular malformations
Sirolimus is an oral medicine that blocks mTOR, a key protein downstream of the PI3K pathway, slowing abnormal cell growth and reducing activity in complex venous and lymphatic malformations [1]. Case series and reviews show sirolimus can shrink lesions, reduce pain and bleeding, and improve quality of life in patients with CLOVES and related vascular anomalies, although it is used off-label for this purpose [2]. Dosing is usually weight-based with blood-level monitoring; side-effects include mouth ulcers, high lipids, delayed wound healing, and increased infection risk, so vaccinations, dental hygiene, and careful surgery planning are important [3].
Everolimus (Afinitor / Zortress) – alternative mTOR inhibitor
Everolimus is a close chemical relative of sirolimus that also blocks mTOR and is approved for some cancers and tuberous sclerosis–related tumors [1]. Emerging data suggest that systemic everolimus can help treat certain vascular malformations, especially when sirolimus is not tolerated or not available, though experience in CLOVES is still limited [2]. Typical oral dosing is adjusted by body surface area and blood levels; side-effects resemble sirolimus, including mouth sores, high cholesterol, infections, and delayed wound healing, so similar monitoring is required [3].
Topical sirolimus (creams or gels) for superficial lesions
In some patients, doctors use sirolimus in a cream or gel applied directly to superficial skin malformations or epidermal nevi to reduce thickness, redness, and pain [1]. Because the drug mostly acts locally, systemic blood levels and side-effects are usually lower than with tablets, but regular monitoring is still advised, especially in children with large treated areas [2]. This approach can be useful for visible facial or limb lesions that cause social distress or irritation, though evidence is still growing and products are often prepared by specialist pharmacies [3].
Paracetamol (acetaminophen) – basic pain and fever relief
Paracetamol is commonly used as first-line medicine for mild to moderate pain from soft-tissue overgrowth, procedures, or musculoskeletal strain in CLOVES [1]. It works mainly in the brain to reduce pain signals and fever without thinning the blood, which is an advantage in people who already have bleeding-prone vascular malformations [2]. Doses must respect strict daily limits based on body weight to avoid liver damage, and any long-term or high-dose use requires medical supervision [3].
Non-steroidal anti-inflammatory drugs (NSAIDs) – ibuprofen and others
NSAIDs such as ibuprofen help with inflammatory pain, joint discomfort, and post-procedure soreness by blocking cyclo-oxygenase enzymes that make prostaglandins (pain and swelling chemicals) [1]. They can be effective in short courses, but in patients with vascular malformations, doctors weigh benefits against risks of stomach irritation, kidney strain, and possible increased bleeding tendency [2]. Dose and duration should be kept as low and short as possible, and taken with food unless a specialist advises otherwise [3].
Opioid analgesics (for severe, short-term pain)
For strong acute pain after surgery or invasive procedures, specialists may prescribe opioids such as morphine or oxycodone for a limited time [1]. These drugs act on opioid receptors in the brain and spinal cord to blunt pain perception but can cause drowsiness, constipation, nausea, and, with long use, dependence or tolerance [2]. In children and teens with CLOVES, opioid use is usually carefully time-limited, combined with non-drug methods, and monitored by pain specialists [3].
Low-dose aspirin – antiplatelet to lower clot risk (selected cases)
Some patients with large venous malformations or previous blood clots may receive low-dose aspirin to reduce platelet stickiness and lower the chance of new clots [1]. Aspirin blocks the COX-1 enzyme in platelets, reducing thromboxane A2 and making platelets less able to clump, which can help in slow-flow venous systems [2]. However, it also increases bleeding risk, so the decision is individualized and often combined with compression and lifestyle measures, with careful monitoring for bruising or gastrointestinal side-effects [3].
Low-molecular-weight heparin (e.g., enoxaparin) – anticoagulant for acute thrombosis
When serious clots such as deep-vein thrombosis or pulmonary embolism occur, injectable anticoagulants like enoxaparin can be used to prevent clot extension and new clot formation [1]. These medicines boost the body’s natural antithrombin activity against clotting factors, thinning the blood in a controlled way [2]. Dosing is weight-based and requires monitoring for bleeding, especially around large vascular malformations or recent surgery sites, and is always managed by experienced hematologists [3].
Direct oral anticoagulants (DOACs, e.g., rivaroxaban)
In some older patients, long-term anticoagulation may be switched from injections to tablets such as rivaroxaban or apixaban, which directly inhibit clotting factors (factor Xa) to prevent recurrence of venous thromboembolism [1]. These drugs have predictable dosing and do not require routine lab monitoring in many cases, making them more convenient for long-term use [2]. However, they still carry bleeding risks and must be used cautiously in people with large vascular malformations or upcoming surgeries, under specialist supervision [3].
Gabapentin – neuropathic pain modulator
Overgrowth and spinal anomalies can compress nerves, causing burning, shooting, or tingling pain that does not respond well to simple painkillers [1]. Gabapentin reduces abnormal nerve firing by acting on calcium channels in nerve cells, making it useful for chronic neuropathic pain in some CLOVES patients [2]. It is started at low doses at night and slowly increased; side-effects can include dizziness, sleepiness, and weight gain, so careful titration is needed [3].
Pregabalin – alternative neuropathic pain medicine
Pregabalin works in a similar way to gabapentin but is absorbed more predictably and can be dosed twice daily [1]. It may help people with nerve-related pain or restless, uncomfortable limbs who did not respond well to gabapentin, but it shares side-effects like dizziness, fatigue, and swelling [2]. Because it can also affect mood, regular mental-health check-ins are important during treatment [3].
Tricyclic antidepressants (e.g., amitriptyline) for chronic pain and sleep
Low-dose tricyclic antidepressants can help modulate chronic pain and improve sleep quality by influencing serotonin and noradrenaline in pain pathways, even at doses lower than those used for depression [1]. In CLOVES, they may be considered for persistent mixed nociceptive and neuropathic pain, usually taken at night [2]. Side-effects include dry mouth, constipation, drowsiness, and in some cases heart rhythm changes, so ECG monitoring and careful dose selection are needed [3].
Topical anesthetic patches or gels (e.g., lidocaine)
Lidocaine patches or gels can numb small painful skin areas overlying malformations or scars without affecting the whole body [1]. By blocking sodium channels in nerve endings, they reduce pain signals from that spot, often used in combination with other systemic treatments [2]. Skin irritation, redness, or allergy are possible, so patches are moved around and skin is checked regularly [3].
Antihistamines (e.g., cetirizine) for itch and minor reactions
Skin over vascular malformations or epidermal nevi can itch or react to minor trauma and dressings; oral antihistamines help reduce itching and allergic-type symptoms by blocking histamine receptors [1]. Non-sedating options such as cetirizine are often preferred during the day, while sedating ones might be used at night if sleep is disturbed [2]. Dry mouth and drowsiness are common side-effects, so schooling and concentration are considered when choosing the exact medicine [3].
Topical corticosteroids for inflamed skin lesions (short courses)
When epidermal nevi or surrounding skin become inflamed, red, or eczematous, short courses of topical steroid creams (for example, mild hydrocortisone or stronger options under specialist advice) can calm inflammation [1]. These drugs reduce immune activity in the skin and quickly improve itching and scaling [2]. Over-use can thin the skin and worsen fragility over vascular malformations, so treatment is time-limited and monitored carefully [3].
Broad-spectrum antibiotics for skin and soft-tissue infections
Because abnormal tissues can be poorly perfused, infections such as cellulitis around malformations may spread quickly and become serious [1]. Timely oral or intravenous antibiotics chosen for local resistance patterns are used when there are signs of infection like redness, warmth, pain, fever, or systemic illness [2]. Completing the full course and combining with wound care is essential to prevent recurrence and complications such as sepsis [3].
Proton-pump inhibitors (e.g., omeprazole) for stomach protection
When patients need prolonged NSAIDs, anticoagulants, or steroids, doctors may add a proton-pump inhibitor to reduce stomach acid and help prevent ulcers and bleeding in the digestive tract [1]. These drugs block acid pumps in stomach lining cells, decreasing irritation [2]. Long-term use must be balanced against possible effects on mineral absorption and infection risk, so the lowest effective dose and duration are used [3].
Metformin or other glucose-lowering drugs (with alpelisib)
Alpelisib frequently causes high blood sugar by interfering with insulin signalling, so some patients need metformin or other diabetes medicines while on treatment [1]. Metformin lowers glucose by reducing liver sugar production and improving insulin sensitivity in muscles [2]. Regular monitoring of blood sugar, kidney function, and digestive tolerance helps adjust doses and prevent complications such as lactic acidosis [3].
Emergency medicines during surgery or bleeding episodes
During major operations or acute bleeding from vascular lesions, anesthetists and hematologists may use medicines such as tranexamic acid to stabilize clots, blood products to replace losses, and carefully adjusted anticoagulants to balance bleeding and thrombosis risks [1]. These drugs are only used in hospital under close monitoring with blood tests and imaging [2]. Planning with the vascular-anomaly team before any surgery is essential to keep these powerful medicines as safe as possible [3].

Dietary molecular supplements

Note: Supplements can interact with drugs like sirolimus, everolimus, and anticoagulants. They should only be used after discussion with the specialist team.

Vitamin D3 – supports bone strength and immune function, especially important if mobility is limited and sun exposure is low.
Calcium – works with vitamin D to maintain bone mineral density when spinal or limb deformities alter loading and when children are less active.
Omega-3 fatty acids (fish oil) – may help reduce low-grade inflammation and support heart and vessel health, though they can slightly thin the blood and must be used cautiously with anticoagulants.
Vitamin C – supports collagen formation and wound healing, which is useful after surgeries or frequent dressing changes.
Zinc – a trace element important for skin integrity and immune defence, sometimes supplemented briefly during wound healing under dietetic guidance.
Balanced protein supplements (e.g., whey protein) – can help meet protein needs when appetite is low after procedures, supporting muscle maintenance and tissue repair.
B-complex vitamins – support nerve health and energy metabolism, which may be relevant in patients with chronic fatigue or neuropathic symptoms.
Probiotics – may support gut microbiome balance when repeated antibiotic courses are needed for infections, although evidence is still developing and products vary greatly.
Magnesium – sometimes used under supervision to help with muscle cramps or constipation from opioid painkillers, but doses must respect kidney function.
Multinutrient pediatric or adult formulas – tailored drinks or powders may be prescribed by dietitians for under-weight patients or those with poor oral intake, ensuring adequate vitamins, minerals, and calories.

Each supplement should be individualized, with attention to interactions (for example, high-dose antioxidants can affect wound healing or chemotherapy-like effects of targeted drugs) [1].

Immune, regenerative and stem-cell–related approaches

No approved stem-cell drug specifically for CLOVES
At present, there are no FDA-approved stem-cell medicines or “regenerative drugs” specifically for CLOVES or PROS; the only targeted systemic drug with approval for PROS is alpelisib [1]. Claims of simple stem-cell cures offered outside regulated clinical trials are not evidence-based and can be dangerous, so they should be avoided [2].
Targeted pathway inhibition as “molecular repair support”
Drugs such as alpelisib and sirolimus do not replace tissues, but they slow abnormal growth signalling, allowing the body’s natural repair processes to work in a more balanced way [1]. Over months, this can mean smaller lesions, less pain, and better function, which is why they are often described as disease-modifying therapies rather than simple symptom control [2].
Optimizing immune protection through vaccines and infection control
Because targeted drugs and mTOR inhibitors can weaken immune responses, careful vaccination plans, dental care, skin hygiene, and early treatment of infections are critical “immune-supporting” strategies [1]. These evidence-based steps do far more for long-term health than unproven immune-booster products [2].
Nutritional support to aid tissue repair
Adequate protein, vitamins (especially A, C, D, B-group), and minerals (zinc, iron, selenium) are essential for wound healing, muscle recovery after surgery, and resilience against infections [1]. Working with a dietitian to correct deficiencies is a safe, science-based form of “regenerative support” that avoids risky experimental infusions [2].
Physical rehabilitation as functional regeneration
Physiotherapy and occupational therapy encourage the nervous system and muscles to adapt to structural problems, sometimes letting other muscle groups “take over” functions from weakened areas [1]. This functional regeneration is one of the most effective ways to improve independence and quality of life in CLOVES [2].
Research-only cell-based therapies
A few experimental studies are exploring cell-based or gene-targeted approaches to overgrowth and vascular malformations, but these remain in research settings and are not standard care [1]. Participation in a properly regulated clinical trial, if offered by a major academic center, is the only safe way to access such therapies, and families should discuss risks and unknowns carefully with their team [2].

Surgical and interventional treatments

Debulking surgery for fatty and soft-tissue overgrowth
Surgeons may remove part of very large fatty masses or overgrown soft tissues to reduce weight, improve movement, or relieve pressure on organs [1]. This is called debulking rather than cure because tissues can regrow over time, especially without targeted medical therapy; planning aims to maximize function while minimizing scarring and complications [2].
Orthopedic surgery for bone and spine deformities
Procedures such as spinal fusion for severe scoliosis, limb-length equalization, or correction of joint deformities can improve posture, walking, and pain [1]. These operations are complex because bones, vessels, and nerves may all be abnormal, so they are usually done in specialist centers after detailed imaging and multidisciplinary discussion [2].
Endovascular embolization of vascular malformations
Interventional radiologists can inject agents or place coils through tiny catheters to close off abnormal blood vessels from the inside, reducing bleeding, pain, and clotting risk in targeted areas [1]. These minimally invasive procedures are often repeated over time and may be combined with sirolimus or alpelisib for better long-term control [2].
Sclerotherapy for lymphatic and venous malformations
In sclerotherapy, a medicine is injected directly into abnormal lymph or venous spaces to irritate and shrink them, reducing size and leakage [1]. It is usually done under imaging guidance and anesthesia, with careful dosing to avoid damage to surrounding tissues [2]. Multiple sessions are often needed, and mild pain or swelling after each treatment is common but usually temporary [3].
Laser or surgical treatment of epidermal nevi and skin lesions
Thick, warty, or cosmetically distressing epidermal nevi may be treated with lasers, surgical shaving, or excision, especially if they frequently become inflamed or catch on clothing [1]. Because skin overlies abnormal vessels, careful planning is needed to reduce bleeding and scarring, and some lesions may recur or leave color changes despite treatment [2].

Prevention and risk-reduction strategies

Early diagnosis and referral to a vascular-anomalies/PROS center.
Consistent use of compression and orthotics as prescribed.
Protecting skin from cuts, burns, and pressure, especially on malformations.
Rapid treatment of infections or ulcers to prevent serious spread.
Avoiding unnecessary trauma, heavy contact sports, and unsafe lifting.
Maintaining a healthy body weight and regular gentle exercise.
Following anticoagulation and antiplatelet plans exactly when prescribed.
Preparing carefully for any surgery with the full specialist team involved.
Keeping all follow-up appointments and recommended imaging.
Supporting mental health early to reduce long-term stress and burnout.

These steps cannot prevent CLOVES itself, but they can significantly reduce complications and improve long-term outcomes [1].

When to see a doctor urgently

People living with CLOVES should seek urgent medical care if they notice any of the following red-flag symptoms: sudden swelling, redness, heat, or pain in a limb (possible clot or serious infection); sudden chest pain, shortness of breath, coughing blood (possible pulmonary embolism); rapidly enlarging mass, especially with severe pain or color change; new weakness, numbness, or loss of bladder/bowel control (possible spinal cord compression); high fever with chills; or heavy uncontrolled bleeding from a lesion [1]. Any new severe headache, seizures, or visual changes also need immediate evaluation, as rare brain or spinal vascular problems can occur [2]. For non-urgent worries such as gradual change in size of lesions, brace discomfort, or mood changes, contacting the specialist clinic soon rather than waiting for routine follow-up is wise [3].

Diet: what to eat and what to avoid

Eat plenty of colorful vegetables and fruits to provide antioxidants, vitamins, and fiber that support general health and wound healing.
Choose lean proteins such as fish, poultry, eggs, beans, and lentils to help repair muscles and tissues after procedures.
Include healthy fats from olive oil, nuts, seeds, and oily fish to support heart and vessel health without excessive saturated fat.
Prefer whole grains (brown rice, whole-wheat bread, oats) over refined grains to maintain steady energy and support weight control.
Stay well hydrated with water and unsweetened drinks, which helps circulation and may ease constipation from pain medicines.
Limit very salty foods (chips, instant noodles, processed meats) that can increase fluid retention and swelling in affected limbs.
Avoid sugary drinks and excess sweets, especially if taking alpelisib, because they can worsen high blood sugar and weight gain.
Keep saturated and trans fats low (fatty red meat, deep-fried fast foods) to reduce cardiovascular risk when on mTOR inhibitors that may raise cholesterol.
Be cautious with herbal products or high-dose supplements that are not discussed with the medical team, as they can interact with sirolimus, everolimus, or anticoagulants.
Avoid alcohol and smoking (for adults), which can harm vessels, liver, and healing, especially when powerful systemic drugs are used.

A dietitian familiar with complex chronic illnesses can personalize these general rules to culture, preferences, and growth needs [1].

Frequently asked questions

Can CLOVES syndrome be completely cured?
Right now there is no cure that removes the PIK3CA mutation from all affected cells, so CLOVES is considered a lifelong condition [1]. However, targeted drugs like alpelisib and sirolimus, together with surgery, sclerotherapy, and rehabilitation, can control many symptoms and significantly improve quality of life in many patients [2].
Is CLOVES inherited from parents?
In most cases, CLOVES is not inherited; it results from a new PIK3CA mutation that happens after fertilization in only some cells (mosaicism), so parents and siblings typically do not carry the same change [1]. The chance of parents having another child with CLOVES is usually very low, but genetic counselling can give more precise estimates for each family [2].
What is the difference between CLOVES and other overgrowth syndromes?
CLOVES is one member of the PIK3CA-related overgrowth spectrum, which also includes conditions like Klippel-Trénaunay syndrome and some isolated lymphatic or venous malformations [1]. CLOVES is defined by the combination of congenital lipomatous overgrowth, complex vascular malformations, epidermal nevi, and spinal or skeletal anomalies, while other syndromes have different patterns of tissue involvement [2].
Why are targeted drugs such as alpelisib and sirolimus important?
These medicines focus on the exact signalling pathway that is overactive in PROS (PI3K/AKT/mTOR), so they can slow or partially reverse overgrowth rather than just treating pain or infection [1]. Clinical studies and real-world programs have shown meaningful volume reductions in target lesions and symptom improvements in many patients, which is why they are becoming central to modern management [2].
Are these powerful drugs safe for children?
Both alpelisib and sirolimus have been used in children within carefully monitored clinical trials and expanded-access programs, with dose adjustments based on age, weight, and side-effects [1]. They are not risk-free, so regular blood tests, growth monitoring, and infection precautions are essential, and decisions are made by experienced pediatric teams together with families [2].
Will my child always need surgery?
Not every person with CLOVES needs large operations; some can be managed mainly with targeted drugs, compression, and minor procedures [1]. Surgery is usually considered when there is major functional impairment, severe pain, or risk to organs, and is planned as part of a wider strategy with interventional radiology and medical therapies to reduce recurrence [2].
Can CLOVES affect life expectancy?
Severe cases with big internal malformations, recurrent clots, or organ compression can have serious complications, but many people with milder disease and good specialist care live into adulthood and have meaningful lives [1]. Long-term outcome depends on the exact organs involved, access to multidisciplinary treatment, and how early complications are detected and managed [2].
Is pregnancy safe for someone with CLOVES?
Pregnancy in adults with CLOVES is possible, but it needs very careful planning with high-risk obstetricians, vascular-anomaly specialists, and anesthetists [1]. Blood volume, clot risk, and pressure on malformations all increase in pregnancy, so medicines, compression, and birth plans must be adjusted to keep parent and baby safe [2].
Can normal sports and physical education continue?
Many children can take part in adapted physical education and low-impact sports such as swimming or cycling, which support fitness and social inclusion [1]. Contact sports, heavy lifting, and high-risk activities may need to be limited, but creative adjustments often allow the child to stay active and engaged with friends [2].
Does diet change the disease itself?
Diet alone cannot switch off the PIK3CA mutation, so it cannot cure CLOVES, but a balanced eating pattern helps maintain a healthy weight, supports wound healing, and reduces side-effects of some medicines [1]. Avoiding extreme diets and unproven supplements is important, as they can do more harm than good [2].
Are experimental stem-cell treatments recommended?
At present there is no strong clinical evidence that commercial stem-cell infusions cure or control CLOVES, and such treatments may be unsafe or unethical outside regulated trials [1]. Families are strongly advised to discuss any advertised “regenerative” cures with their specialist team before considering them [2].
How often will imaging scans be needed?
Frequency of MRI or other imaging depends on lesion size, location, symptoms, and treatments used; in growing children, periodic scans help check for progression or response to therapies like alpelisib or sirolimus [1]. Doctors try to balance detailed monitoring with minimizing anesthesia and radiation exposure, choosing MRI when possible [2].
Can children with CLOVES attend regular school?
Most children can attend regular school with reasonable adjustments such as extra time between classes, elevator access, flexible physical education, and allowances for medical appointments [1]. Early collaboration between parents, school staff, and healthcare providers helps prevent misunderstandings and supports academic success [2].
Where can families find trustworthy information and support?
Reputable sources include hospital vascular-anomaly centers, national rare-disease organizations, and patient-led CLOVES or PROS communities linked to major academic centers [1]. These groups often offer educational materials, webinars, and peer support, and may share updates about clinical trials and new therapies [2].
What is the most important thing families can do?
The most important steps are to stay connected with a knowledgeable specialist team, attend regular follow-ups, ask questions, and seek psychological as well as physical support when needed [1]. CLOVES is complex, but with coordinated care, many children and adults can reach their own educational, social, and life goals [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.

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