CLOVES syndrome

CLOVES syndrome which stands for Congenital Lipomatous Overgrowth, Vascular Malformations, Epidermal Nevi and Spinal/Skeletal Anomalies and/or Scoliosis, is a rare condition that is primarily characterized by congenital overgrowth of fatty tissue; malformations of the vascular system (the vessels that carry blood and lymph throughout the body); epidermal nevi; and spinal or skeletal abnormalities ¹. Other signs and symptoms may include disproportionate fat distribution, overgrowth of the extremities (arms and legs), skin abnormalities and kidney problems such as an unusually small or absent kidney ². The severity of CLOVES syndrome and the associated signs and symptoms vary significantly from person to person.

CLOVES syndrome is rare and evident at birth. It affects males and females equally regardless of their race or ethnicity. Many of the patients with CLOVES syndrome are misdiagnosed as having other syndromes such as Klippel-Trenaunay syndrome or Proteus syndrome.

CLOVES syndrome is caused by somatic mutations in the PIK3CA gene ³. Because these mutations do not affect egg or sperm cells, CLOVES syndrome is not passed on from parent to child.

Given its rarity and complexity, patients with CLOVES syndrome should be referred to a specialized center with experience in managing complex overgrowth and vascular anomalies for confirmation of diagnosis, interdisciplinary assessment, delineation of clinical risks and complications, management and coordination of care ⁴. Treatment is based on the signs and symptoms present in each person ².

Treatment for CLOVES syndrome involves addressing each symptom or complication and improving quality of life (palliative care). There is currently no cure. Palliative care aims to relieve symptoms caused by masses and minimize disease progression and disability. Management is very individualized because symptoms can vary in severity and body location for each person. Follow-up with various specialists is recommended every 6 months until the end of puberty, to assess for overgrowth and complications ³.

Medical treatment may include embolization and surgical removal of masses, especially those that are large, deep, or in the spinal region ³. Sclerotherapy may be used in adults to lessen pain and reduce the size of vascular and lymphatic malformations ³.

Orthopedic and neurosurgical checkups with possible surgical intervention are needed to reduce complications from overgrowth. Surveillance of hands, feet, and limb abnormalities is important so surgery can be done promptly to minimize limb disfigurement and loss of function. Because there is increased risk of tumor growth in people with overgrowth syndromes, people with CLOVES syndrome should have surveillance for tumors and have masses assessed ³.

In general, the earlier surveillance and intervention are started, the better the outcome ³.

Is there a cure for CLOVES syndrome?

There is no cure for CLOVES syndrome, but experienced vascular anomaly specialists can manage or prevent symptoms with the right medical and surgical care. Treatment for CLOVES syndrome involves addressing each symptom or complication and improving quality of life (palliative care). Surgery and other medical interventions are the only treatments for CLOVES syndrome overgrowth, vascular anomalies and other related medical issues.

CLOVES syndrome causes

CLOVES syndrome is a nonhereditary disorder caused by a somatic (body cell) mutation in a gene known as PIK3CA. Mutations in this growth regulatory PIK3CA gene result in two sets of cells within the body (mosaic status): those with the mutation and those without the mutation. The mutated cells give rise to the abnormal tissue.

The PIK3CA gene provides instructions for making the p110 alpha (p110α) protein, which is one piece (subunit) of an enzyme called phosphatidylinositol 3-kinase (PI3K). The p110α protein is called the catalytic subunit because it performs the action of PI3K, while the other subunit (produced by a different gene) regulates the enzyme’s activity.

Like other kinases, PI3K adds a cluster of oxygen and phosphorus atoms (a phosphate group) to other proteins through a process called phosphorylation. PI3K phosphorylates certain signaling molecules, which triggers a series of additional reactions that transmit chemical signals within cells. PI3K signaling is important for many cell activities, including cell growth and division (proliferation), movement (migration) of cells, production of new proteins, transport of materials within cells, and cell survival. Studies suggest that PI3K signaling may be involved in the regulation of several hormones and may play a role in the maturation of fat cells (adipocytes).

CLOVES syndrome symptoms

CLOVES syndrome belongs to the spectrum of overgrowth syndromes with complex vascular anomalies caused by mosaic mutations in the PIK3CA gene. The rare CS may affect the soft tissue, blood vessels, bone and internal organs. The manifestations are very variable ranging from mild to severe anomalies. These abnormalities are typically present at birth.

The most common features of CLOVES syndrome are:

1. Fatty overgrowth. Soft fatty masses of variable size are noted at birth and can be located in the back, flanks, axilla, abdomen and buttocks. These masses may affect one or both sides of the body. The skin over the mass is typically covered with a red-pinkish birthmark (capillary malformation or port-wine stain).
2. Vascular anomalies. Dilated veins in the chest, upper and lower extremities may cause clot formation and occasionally serious pulmonary embolism (clot travelling from the vein to the lungs). Lymphatic malformations are abnormal, large spaces filled with lymph. These malformations are frequently noted within the fatty masses or in the abdomen, chest and extremities. A small subgroup of patients may suffer from the more aggressive arteriovenous malformation around the area of the spinal cord.
3. Abnormal extremities (arms and legs) are common. Large wide hands or feet, large fingers or toes, wide space between digits (sandal gap toe) and uneven size of extremities are common.
4. Spinal anomalies include scoliosis (curving of the spine), fatty masses and vessels pushing on the spinal cord and tethered cord (spinal cord fixed by abnormal band).
5. Skin birthmarks include port-wine stains, prominent veins, lymphatic vesicles, moles and epidermal nevus (slightly raised areas of skin with light brownish color).
6. Kidney anomalies. The size of the kidneys could be asymmetric (one is larger) and may show some abnormal features on imaging studies. Wilms tumor has been noted in a small number of young patients with CLOVES syndrome. This requires screening with serial ultrasound examinations during childhood.

Additional findings can occur in CLOVES syndrome including bleeding from the intestine, urinary bladder and asymmetric face and head.

Not all patients with CLOVES syndrome have all these signs, but rather a combination of abnormalities. Some can be subtle and a dedicated physical exam and proper imaging studies are required.

CLOVES syndrome diagnosis

Because symptoms of CLOVES syndrome can be subtle or obvious, it’s critical to seek a diagnosis from an experienced vascular anomalies specialist. CLOVES is still not widely known and so rare that an ultrasound is not a foolproof way to detect it. A clinical exam must be performed after birth. The diagnosis is evident at birth based on physical signs and symptoms. Prenatal diagnosis with imaging tools is feasible.

To diagnose CLOVES syndrome, doctors will usually combine these steps:

• obtain a detailed medical and family history
• perform a thorough physical exam
• order imaging studies such as magnetic resonance imaging (MRI), computed tomography (CT) scans, ultrasound and x-rays

Confirmation of diagnosis can be done with molecular genetic testing for the PIK3CA gene mutation. Imaging studies include plain x-rays (radiography), magnetic resonance imaging (MRI) of the chest, abdomen, pelvis, spine and limbs and ultrasound for vascular anomalies and kidneys.

Children with CLOVES syndrome are often mistakenly diagnosed as having other disorders that cause overgrowth of the blood vessels and abnormalities in certain parts of the body, such as:

• Hemihypertrophy: a condition in which the structures on one side of a child’s body are larger than on the other
• Klippel-Trenaunay syndrome: a rare disease that causes abnormal fatty growths of the leg, dilated veins, lymphatic malformations and port-wine stain birthmarks
• Proteus syndrome: a rare condition that causes progressive deformities of the bone, skin and soft tissue

The main difference between these conditions and CLOVES syndrome is that CLOVES syndrome causes a combination of vascular, skin and limb/torso abnormalities and truncal/spinal abnormalities (like fatty masses, scoliosis or tethered cord).

Early MRI

CLOVES syndrome patients may benefit from an MRI of the chest, abdomen, pelvis and lower extremities performed in the neonatal or early infantile period or at the time of initial presentation. This help define deeper components of the syndrome that may require from intervention in early childhood (e.g. lymphatic and venous malformations, gastrointestinal and genitourinary involvement); as well as characterize overgrowth and extension into the retroperitoneum, peritoneum, superior and posterior mediastinum, pelvis, pleural spaces and paraspinal muscles, tethered spinal cord, neural tube defects).

If the study (referred to as “early MRI”) requires general anesthesia, the scan can be delayed until the risk of anesthesia is reduced (i.e. > 6 months of age). Optimal timing of imaging best balances the risks of anesthesia with the information to be gained.

Genetics

CLOVES syndrome is diagnosed primarily on the basis of clinical and imaging findings. Discovery of the somatic mutation in PIK3CA gene in resected tissues from patients with CLOVES syndrome opens up the possibility of a medical therapy; PI3K and mTOR inhibitors are actively being investigated. Currently there are no commercially available genetic tests for detecting PIK3CA mutations. At the research level, droplet digital polymerase chain reaction (PCR) can reliably detect the most common mutations. A positive test can confirm the mutation, whereas a negative test result cannot exclude the mutation. The presence or absence of the mutation does not define a patient as having CLOVES syndrome.

CLOVES syndrome treatment

The management of CLOVES syndrome can be very challenging and requires an interdisciplinary team of physicians with experience in overgrowth and vascular anomalies. The treatment should address the specific problems in the affected child.

Some of the treatments your child’s care team might recommend include:

• Drug therapy with sirolimus: Also known as rapamycin, this oral medication suppresses the immune system and slows the growth of abnormal lymphatic vessels that cause the vascular anomalies present in children with CLOVES. It can also improve symptoms, including pain.
• Sclerotherapy: This non-surgical procedure can help reduce the size of the vascular anomalies associated with CLOVES, as well as the pain they may cause.
• Embolization: This minimally invasive procedure is used to reduce the size of arteriovenous malformations and other vascular anomalies associated with CLOVES syndrome.
• Debulking surgery: Some children need debulking surgery to remove a portion of the overgrown tissue and blood vessels caused by CLOVES syndrome. Though debulking is a major, invasive operation, it can be life-changing for children who have limited mobility due to limb abnormalities or painfully overgrown veins.
• IVC Filter: A device called an inferior vena cava (IVC) filter can prevent pulmonary embolisms, life-threatening clots that can form and travel through the bloodstream and into the lungs of children with CLOVES. The filter, which is surgically implanted, sits in the inferior vena cava (the main abdominal vein responsible for transporting blood from a child’s lower body) and traps any clots, before they reach the heart and lungs.

Orthopedic procedures are usually necessary for large limb anomalies. CLOVES syndrome patients may benefit from hematology evaluation including basic coagulopathy work up early in life and pre-procedurally. Large veins and lymphatic malformations should be treated with minimally invasive procedures such as sclerotherapy, embolization and laser treatment before undergoing surgical procedures due to the risk of vein thrombosis. Tethered cord is treated surgically.

Medical therapy with sirolimus demonstrated promising results; particularly for patients with lymphatic malformation and pain. The use of sirolimus or other medical therapies is rapidly changing in CLOVES syndrome and other vascular anomalies and should be guided by an experienced hematologist/oncologist.

Nutritional support

CLOVES syndrome patients with poor weight gain or failure to thrive may benefit from nutritional consultation and ongoing support. The presence of both fatty overgrowth in some areas and the appearance of malnourishment are frequent in CLOVES syndrome and not currently well understood. Many patients have improved weight gain in later childhood and some may improve after resection of large lipomatous masses.

Psychosocial support

Comprehensive interdisciplinary management should address the psychological burden of the disease on the child and issues related to adaptation, coping, and distress. Management should aim at alleviating not only the physical issues, but also the psychological burden on the child and the family. Stress factors among caregivers should be identified so proper intervention or support can be provided. Social workers help families with coping with a diagnosis, mental health, parenting and behavioral concerns as well as identifying helpful resources. Psychosocial intervention can also be provided through community-based organizations or support groups.

Lymphatic malformation

Lymphatic malformations in CLOVES syndrome vary in size from small skin vesicles of minor clinical significance to massive, deforming lesions, which are typically associated with fatty overgrowth. Lymphatic malformations may be macrocystic, microcystic or combined. The clinical consequences and treatment of these lesions vary widely. Small, superficial cutaneous vesicles are prone to leakage, bleeding, and increase the risk of infection. Larger lymphatic malformations, typically associated with overgrowth, are most commonly located in the chest and abdominal wall with variable extension into the abdominal and thoracic cavities. The morbidity of these lesions is related to mass effect (resulting in decreased range of motion and deformity) and infection.

Macrocystic lymphatic malformations can be treated with minimally-invasive techniques such as sclerotherapy. Large lymphatic malformations associated with overgrowth may benefit from surgical debulking. A combined approach with sclerotherapy and resection can be beneficial in selected patients.

When lymphatic malformations become infected, prompt evaluation and oral antibiotic treatment are necessary. Some patients may initially require intravenous antibiotics. Patients typically require a long course of at least 14 to 21 days of treatment. For recurrent infections, a prolonged course of prophylactic antibiotics should be considered. Infected lymphatic macrocysts may require drainage and sclerotherapy. Proper hygiene is imperative for cutaneous and mucosal lymphatic vesicles; they can be treated with sclerotherapy (including the use of bleomycin) or CO2 laser photovaporation.

For patients with significant complications from the lymphatic components of their disease, medical therapy with sirolimus has been used with promising early results. The use of sirolimus or other medical therapies is rapidly changing in CLOVES syndrome and other vascular anomalies and should be guided by an experienced hematologist/oncologist.

Venous malformation

Venous malformation also known as phlebectasia or dilatation of veins, in CLOVES syndrome is often seen in the upper and lower extremity and lateral truncal wall. These veins include orthotopic (normally located) or persistent embryonic veins. Involved orthotopic veins include the subclavian, axillary, innominate, intercostal, azygous, hemiazygous, short saphenous and jugular veins, as well as the superior vena cava (SVC) and inferior vena cava (IVC). Embryonic veins include the sciatic and marginal veins in the lower extremity and the lateral chest wall. Other anomalies, such as azygos continuation of the inferior vena cava, or persistent left superior vena cava, may exist. Ectatic veins can be the source of blood clot formation and life-threatening pulmonary embolism (thromboembolism). In addition, patients may develop painful clots (thrombophlebitis).

All patients should undergo preoperative imaging to assess the venous system. If an MRI has not been performed, proper imaging to evaluate the venous anatomy prior to any invasive intervention is strongly recommended.

Ultrasonography may demonstrate certain veins including subclavian, axillary, short saphenous and marginal veins in the lower extremity and the lateral truncal wall. Deeply seated veins (innominate, azygous, hemiazygous and sciatic veins as well as the superior vena cava (SVC) and inferior vena cava (IVC) can be visualized by MRI or CT.

Patients with an extensive venous malformation may have altered blood tests due to stagnant or slowed blood flow and increased activation of the clotting cascade as an indicator of blood clot formation with venous malformations.

• Thrombophlebitis can be treated with limb elevation, non-narcotic analgesics, and anti-inflammatory medications.
• Prior to invasive surgical procedures, CLOVES syndrome patients may benefit from evaluation by an anesthesiologist and multidisciplinary optimization of physical status.
• CLOVES syndrome patients with dilated veins and increased risk of venous thrombosis may benefit from prophylactic anticoagulation during the perioperative period. A hematology consultation and a coagulation profile should be obtained before any procedure. Anticoagulation is often recommended both pre- and post-procedure to minimize the risk of blood clot formation and migration to the lungs. Placement of temporary IVC (or SVC) filters may also be considered.
• Closure of the dilated veins may reduce the risk of thromboembolism, particularly prior to surgical procedures. Experts recommend closing specific dilated veins (lower limb and truncal marginal veins, axillary-subclavian, sciatic and short saphenous veins) early in life using minimally invasive techniques such as embolization and endovenous laser, by an experienced interventional radiologist.

Arteriovenous malformations

A subgroup of CLOVES syndrome patients develops a fast-flow vascular lesions or arteriovenous malformation (AVM). Most of these lesions are located in the paraspinal region and less frequently in the chest wall and extremities. Paraspinal AVM is associated with infiltrative fatty tissue in the posterior mediastinum that may extend into the spinal canal and cord, causing cord compression, venous hypertension and myelopathy.

Patients should be screened for these vascular lesions with an early MRI. If fast-flow anomalies or extension into the spinal canal are found, neurosurgical consultation and a dedicated spinal MRI, with sagittal and axial T2 and pre- and post-contrast T1 weighted sequences covering all potentially involved levels, are warranted. Patients who develop signs of spinal cord dysfunction (extremity weakness, urinary incontinence, constipation) should be promptly evaluated. Treatment may include spinal angiography, embolization and resection.

Depending on the degree of flow through a fast-flow lesion, cardiac function may be compromised. Evaluation by an anesthesiologist prior to a procedure may reveal the need for a cardiologist’s assistance in perioperative management.

Capillary malformation

Capillary malformations (also known as port wine stains) typically occur overlying truncal overgrowth and in the extremities. These stains are of limited clinical significance and usually require no treatment unless desired by the patient for cosmetic reasons.
Lymphatic vesicles often coexist and may require therapy.

Flashlamp-pumped pulsed dye laser (FPDL) therapy can be used to lighten the color of capillary stains.

Large lipomatous masses

Large lipomatous masses are most commonly located in the trunk and chest wall and can be associated with lymphatic and capillary malformations. These masses of variable size, are present at birth, and can be identified prenatally. Overgrowth can be unilateral or bilateral and may also extend into the abdominal wall, flank, gluteal and cervical areas as well as the extremities. Deeper extension may occur into the retroperitoneum, peritoneum, superior and posterior mediastinum, pelvis, pleural spaces and paraspinal muscles.

The clinical behavior of paraspinal-posterior mediastinal infiltrative tissue is distinct from the larger fatty masses. Paraspinal lesions can be hypervascular, aggressive and infiltrate into the epidural space and compromise the spinal cord and adjacent vessels.

Lipomatous overgrowth should be evaluated by a surgeon. Work up generally includes MRI of the affected areas. Surgical debulking of these lesions can improve mobility and quality of life. Removal of very large masses may also prevent growth disturbance of the underlying or nearby musculoskeletal structures (e.g. removal of a large chest wall mass may prevent rib cage deformity and resultant lung compression and restriction). When applicable, resection can include removal of cutaneous lymphatic vesicles, thereby reducing leaking and infection risk as well. Patients often require multiple staged operations. Lipomatous masses can regrow after resection, though this is difficult to predict for an individual patient.

Proper perioperative planning should be undertaken to prevent major complications such as thromboembolism. As mentioned above, initiation of perioperative anticoagulation and closure of veins deemed to be at high risk of initiating thromboemboli may be beneficial prior to a major operative resection. Multidisciplinary preoperative team meetings which include surgeons, anesthesiologists, interventional radiologists, hematologists, nurses and blood bank can be invaluable in preparing a team prior to large resections.

Maxillofacial asymmetry

Soft tissue overgrowth is typically caused by facial infiltrating lipomatosis, which can be associated with maxillofacial bony asymmetry and dental malocclusion. The cheek, lip, and underlying bone can be enlarged and cause psychological distress.

Facial and dental arch asymmetry should be evaluated by a plastic or maxillofacial surgeon early in life. Dental abnormalities are addressed by a dentist. Work up includes an MRI of the head and brain.

Brain asymmetry

Multiple types of brain abnormalities have been described in CLOVES syndrome including hemimegalencephaly, cerebral asymmetry, cerebral white matter lesions, cortical dysplasia/migrational anomalies. These findings can be associated with seizures and developmental delay.

Cerebral abnormalities and neurologic symptoms should be evaluated by a neurologist or neurosurgeon. Work up includes an MRI of the brain.

Epidermal nevus and moles

Epidermal nevi and moles in CLOVES syndrome are of limited clinical significance and may require no intervention beyond dermatologic screening and investigation of suspicious appearing moles.

Chest wall deformity

Chest wall deformity, which is typically associated with large overgrowth, should be evaluated by a pediatric surgeon.

Scoliosis

Scoliosis in CLOVES syndrome tends to be progressive. It can be secondary to paraspinal-truncal soft tissue masses and disordered musculature, vertebral and other anomalies but can also be a separate, primary finding.

Patients with CLOVES syndrome should be screened for scoliosis by early MRI and routinely with physical examinations. Scoliosis should be treated per the usual recommendations by a pediatric orthopedic specialist. It can be difficult to manage with orthotic care due to truncal overgrowth. Surgical treatment may be indicated to prevent further deformity, pulmonary decompensation, and spinal cord injury.

Tethered cord and neural tube defects

There is an increased risk of tethered spinal cord and neural tube defects (e.g. spina bifida and myelomeningocele) in CLOVES syndrome.

All patients with CLOVES syndrome should be evaluated clinically and screened for neural tube defects and tethered cord by spinal ultrasonography in the neonatal period. If early MRI study was performed and reliably characterized the spinal cord then an further ultrasonography is not necessary. If no imaging has been done at the time of first presentation, then a dedicated spinal MRI study is warranted.

Tethered spinal cord and neural tube defects should be managed and followed by a neurosurgeon with early detethering considered (if feasible) to prevent neurologic damage.

Paraspinal hypervascular-lipomatous overgrowth

Paraspinal Hypervascular-Lipomatous Overgrowth is characteristic of CLOVES syndrome. Elongated posterior mediastinal masses are located along the bilateral anterior paravertebral spaces and can mimic neurogenic tumors on cross-sectional imaging. Unlike overgrown tissue elsewhere, paravertebral lesions may be aggressive, and infiltrative with hypervascular, fast-flow malformations which may compromise the spinal cord and associated vessels. The tissue may extend into the spinal canal and cause compression of the thecal sac, spinal cord and nerve roots.

The natural history of these masses is variable. Many lesions remain stable in size and cause no signs or symptoms, while others can cause different types of neurologic injury, including mass effect on the spinal cord and nerve roots and high-flow/arteriovenous malformation, as described above.

Patients should be screened with an early MRI. Extension into the spinal canal should be evaluated and followed by a neurosurgeon. Work up includes a dedicated spinal MRI. The course of the behavior of these lesions should be evaluated with physical examination and annual spinal MRI study. Patients who develop signs of spinal cord dysfunction (extremity weakness, urinary incontinence, constipation) should be promptly evaluated and managed by a neurosurgeon. These masses may recur after partial surgical removal and follow-up is necessary.

Gastrointestinal involvement

Thickening of the anorectum and sigmoid colon is caused by circumferential venous and lymphatic malformation and may cause intestinal bleeding. Bleeding may also be caused by perianal lymphatic vesicles. Patients typically have slow, chronic bleeding leading to anemia. They may also experience episodes of acute, high volume bleeding. The presence of ectatic portomesenteric veins is associated with thrombosis and portal hypertension.

Splenomegaly and splenic lesions, thought to be multifocal lymphatic anomalies, can be present in CLOVES syndrome and typically of little clinical significance and therefore do not commonly require intervention.

Patients should be evaluated by a gastroenterologist and surgeon. Work up may include MRI study and colonoscopy. Anemia due to chronic bleeding may require iron supplementation or blood transfusions. Venous malformation can be treated with sclerotherapy, or surgical resection. For refractory bleeding, partial colectomy, anorectal mucosectomy, and coloanal pull-through may be considered. Ectatic portomesenteric veins, which can be visualized with MRI, CT scan or ultrasonography, can be managed initially with anticoagulation while surgical intervention is contemplated. A massively dilated, incompetent inferior mesenteric vein should be evaluated for ligation at its junction with the splenic vein to prevent siphoning of blood flow from the portal vein and resultant portal thrombosis.

Genitourinary involvement

Unilateral renal hypogenesis or agenesis and compensatory enlargement of the contralateral kidney are frequently present in CLOVES syndrome. Other findings include renal cysts, hydroureteronephrosis, heterogeneous renal parenchyma and renal malposition. There is an increased risk of Wilms tumors in CLOVES syndrome, occurring in ~3% of CLOVES syndrome patients studied. Wilms tumor prognosis is generally excellent, especially when found early.

Enlargement and thickening of the urinary bladder in CLOVES syndrome may assume an elongated configuration with anterosuperior displacement. Venous malformation in the urothelial lining of the bladder and urethra may cause bleeding with urination (hematuria). Some patients experience functional urinary abnormalities or incontinence.

Children with CLOVES syndrome should undergo screening renal ultrasonography every 3 months until the age of 8 years to monitor for the development of Wilms tumor.

• Experts recommended an initial renal ultrasound in the neonatal period which also can be used as a baseline for Wilms tumor screening.
• Unilateral renal hypogenesis or agenesis is usually of little clinical significance.
• Functional abnormalities and hematuria should be evaluated by a urologist. Neurological causes of functional abnormalities should be excluded. Work up may include MRI study and cystoscopy. Venous lesions can be treated with laser coagulation.

Other abdominal findings include inguinal hernias, undescended testicles and ascites. Groin and scrotal masses appearing to be inguinal hernias may in fact be lymphatic malformations extending from the retroperitoneum. Resection can be challenging due to investment within the vital spermatic cord structures. This should be anticipated prior to scheduled herniorrhaphy so the surgeon is prepared to undertake meticulous and lengthy resection rather than a straightforward hernia repair.

Limb abnormalities

Limb abnormalities should be evaluated early in life. When present, these abnormalities should be followed by a team familiar with the relevant components of overgrowth.

Asymmetric girth or length of the upper or lower extremities is a common finding in CLOVES syndrome. Diffuse overgrowth typically affects bones, muscles, nerves and fat. This enlargement may involve specific regions of the hand, foot, forearm, or leg and not necessarily the entire limb. Fat overgrowth in the affected portion of the limb may be markedly large and accounts for most of the enlargement.

Overgrowth and other musculoskeletal malformations may lead to secondary problems, such as early arthritis, contractures, stiff joint and neuromas. Capillary malformations and anomalous veins may also be present.

Developmental dysplasia of the hip and dislocation may exist particularly with large overgrowth of the pelvic and gluteal regions.

Knee deformities include valgus deformity, dysplasia, dislocation and chondromalacia patellae.

Common deformities of the foot include large, wide triangular foot with broad forefoot wide metatarsal spaces, wide sandal gap between first and second toes, lipomatous masses, macrodactyly (large toes), polydactyly (extra toes), syndactyly (fused toes), talipes, and furrowed soles. Lymphatic vesicles may affect the feet, especially the toes. These deformities may make finding appropriate shoe wear difficult.

Common deformities of the hands include broad spadelike asymmetric digits, macrodactyly, polydactyly, syndactyly, ulnar deviation of the digits and a laxity of collateral ligaments. Some digits and thumbs may be minimally enlarged and deviated. Significant deviation of the thumb is frequently seen Capillary malformations of the fingers are common. Fingers affected by macrodactyly may exhibit significant stiffness starting from birth. Fatty overgrowth of the forearm and hand may be seen. Dorsally-located lymphatic malformations of the digits may pose functional problems if large. Premature osteo-arthritis is common in the 3rd and 4th decades of life.

• Leg length discrepancy: Standard follow up with physical exam and motion radiography should be established. Shoe lift and epiphysiodesis of long bones or digits may be considered.
• Debulking of the overgrown adipose and vascular tissues can provide functional and cosmetic benefits. Staged reconstruction is often indicated. Other treatment options include osteotomies, ostectomies, ray resection or amputations of markedly overgrown digits or limb.
• Arthroscopy may be helpful in assessing the joint changes related to peri- and intra-articular vascular malformations. Sclerotherapy may minimize pain related to venous malformations. Hematologic evaluation prior to major orthopedic procedures is important to prevent thromboembolism.
• Debulking of lymphatic malformations of the digits may help with function. Lymphatic malformations and fatty overgrowth of the palm are more difficult to address due to presence of tendons and neurovascular structures.
• Syndactyly and polydactyly treatment should be considered in light of functional requirements. If the syndactyly involves an overgrown, stiff digit, simultaneous amputation will provide ample skin for closure of the webspace.
• Deviation of the thumb can be challenging, possibly requiring osteotomy and/or amputation of the bulk or a border digit depending on the degree of deformity.

CLOVES syndrome prognosis

As CLOVES syndrome is rare disease that affects each child differently and was only defined in 2007, there are many unknowns still.

Your child’s long-term outlook or prognosis will depends on many factors, including:

• Age at diagnosis (the earlier treatment is started, the better)
• Specific symptoms
• Overall health

Many children with CLOVES syndrome do very well when the disease is mild and diagnosed early. Your child’s doctor will give you specific information about a recommended plan of care and long-term outlook.

References

1. https://www.clovessyndrome.org/sites/default/files/CSC_onepager.pdf
2. Martinez-Lopez A, Blasco-Morente G, Perez-Lopez I, Herrera-Garcia JD, Luque-Valenzuela M, Sanchez-Cano D, Lopez-Gutierrez JC, Ruiz-Villaverde R, Tercedor-Sanchez J. CLOVES syndrome: review of a PIK3CA-related overgrowth spectrum (PROS). Clin Genet. July 2016
3. Anderson S, Brooks SS. An Extremely Rare Disorder of Somatic Mosaicism: CLOVES Syndrome. Adv Neonatal Care. October 2016; 16(5):347-359.
4. Clinical Practice Guidelines for CLOVES syndrome. Boston Children’s Hospital. https://www.clovessyndrome.org/sites/default/files/CLOVES_Syndrome_Management_Guidelines_For_Families_6-21-2014-2.pdf