CLOVES Syndrome

Congenital Lipomatous Overgrowth, Vascular Malformations, Epidermal Nevis, Spinal/Skeletal Anomalies/Scoliosis (CLOVES) syndrome is a very rare congenital (present at birth) disorder characterized by a combination of vascular (involving the blood vessels), skin, spinal, and bone or joint abnormalities.

Fewer than 200 cases of CLOVES syndrome have been identified worldwide to date. CLOVES is thought to be caused by mutations in a gene called PIK3CA. The long-term picture for a child with CLOVES depends on age and how serious the symptoms are. The sooner the disease is detected and the proper course of treatment is started, the better the general outlook.

The symptoms of CLOVES can vary a great deal from child to child and can range from mild to severe. They are always present at birth but might not be noticeable right away, depending on how extensive they are.

Generally, in order to be diagnosed with CLOVES syndrome, a child will have one or more of the following:

• Soft, fatty masses on their torso or trunk (usually on their back, flank, or abdomen)
• Vascular (blood vessel) malformations — most often, a port wine birthmark, lymphatic malformation, arteriovenous malformation, or enlarged veins or a combination of these
• Limb abnormalities (typically, wide feet or toes and large or extra fingers or toes)
• Spinal problems (in many cases, scoliosis or tethered spinal cord). The presence of these abnormalities often indicates that a child is more likely to have CLOVES syndrome instead of a similar disorder.
• Skin abnormalities (most often, raised, wart-like bumps called epidermal nevi)

Less common symptoms can include:

• Problems with knee or hip joints
• Kidneys that are unusually small or uneven in size

Research by Matthew Warman, MD, director of Boston Children’s Orthopedic Research Laboratories, and pathologist Kyle Kurek, MD, has revealed that CLOVES is caused by mutations in a gene called PIK3CA. These mutations arise spontaneously in the womb, while a baby is developing. Thus far, there are no known risk factors that would make these mutations more or less likely to occur.

Because symptoms of CLOVES syndrome can be subtle or obvious, it’s critical to seek a diagnosis from an experienced vascular anomalies specialist.

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

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.

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 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 is that CLOVES causes a combination of vascular, skin, and limb/torso abnormalities and truncal/spinal abnormalities (like fatty masses, scoliosis, or tethered cord).

There is no cure for CLOVES syndrome, but experienced vascular anomaly specialists can manage or prevent symptoms with the right medical and surgical care.

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.

CLOVES is a rare disease that affects each child differently. Your child's long-term outlook will depends on many factors, including:

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

Many children with CLOVES 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.

CLOVES was first described as a unique condition in 2009 by a clinical and research team led by Ahmad Alomari, MD, co-director of the Vascular Anomalies Center at Boston Children's. Our experience in treating numerous patients with CLOVES syndrome gives us the depth of knowledge about what symptoms to look for and how to plan treatment accordingly.

Our team takes an interdisciplinary approach to care with every child we see. That means that clinicians from many different specialties, all with expertise in treating CLOVES, will see your child as a team. This kind of approach is critical with CLOVES, as it can affect many different parts of a child's body.

The VAC has generated an extensive case database on vascular anomalies, including CLOVES. Using this database, VAC clinicians conduct research that may lead to the development of new, more effective therapies and perhaps ultimately result in ways to prevent CLOVES and other vascular anomalies. As our database grows, it will help shine more light on CLOVES and other vascular anomalies.