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About Cloves

Patients & Families

Newly Diagnosed

 

Welcome! You are probably visiting this page because you or someone you know was recently diagnosed with CLOVES Syndrome or PIK3CA Related Overgrowth Spectrum (PROS). We would like to welcome you to our community and share with you all of the resources we have to offer.

Our online support group:

We feel that it is important to connect with others who understand what you are going through and can offer support during difficult times. We encourage you to get involved by meeting other families online.

If you would like CLOVES Syndrome Community to mail you a welcome packet, please email us at [email protected]

Welcome,
Kristen Davis, CLOVES Syndrome Community

Contact Us:

CLOVES Syndrome Community
PO Box 406 West Kennebunk, ME 04094

Toll free (833)-4CLOVES
(833)425-6837

[email protected]


Screening Guidelines

 

Clinical Practice Guidelines for CLOVES Syndrome – Vascular Anomalies Center, Boston Children’s Hospital

Imaging Guidelines for Vascular Anomalies developed by Children’s Hospital Boston – Guidelines for imaging with MRI, ultrasound, CT and angiogram when indicated.

Recommended Kidney Screening for children with CLOVES – Recommended screening guidelines for children with CLOVES, developed February 2012

The Vascular Anomalies Center team at Children’s Hospital Boston recently became aware of three cases of Wilms Tumor in young patients with CLOVES syndrome. While Wilms tumor has been associated with some overgrowth related disorders, such as Beckwith-Wiedemann Syndrome, it is a new finding in patients with CLOVES syndrome.

Our recommendation for Wilms tumor screening is serial ultrasounds performed every three months up to age 8 years after which there is not thought to be any increased risk of developing Wilms tumor. We have also chosen to notify families and physicians of CLOVES syndrome patients between the ages of 8 and 12 years so that they may decide whether to obtain a single ultrasound to rule out late development of Wilms tumor.

Questions may be addressed to your child’s pediatrician or to the Vascular Anomalies Center, Children’s Hospital Boston, at 617-355-5226.  

There are recent publications about Wilms Tumor in young patients with CLOVES syndrome. While Wilms tumor has been associated with some overgrowth related disorders, such as Beckwith-Wiedemann Syndrome, it is a new finding in patients with CLOVES syndrome.


Treatments & Trials

 

Unfortunately, there is no cure for CLOVES. Surgery and other types of medical interventions are the primary treatments for CLOVES overgrowth, vascular anomalies and other related medical issues. However there are many current opportunities for you to participate in research.

Please read below about research opportunities and new targeted treatment medications to treat CLOVES/PROS. 


Now Recruiting: VACOM Study – Share your experience seeking medical care for Vascular Anomalies

This study is open to adult patients and caregivers over the age of 18, who live in the United States. Participants will receive $40 for their time. If you are interested, please complete this form. Contact Dr. Bryan Sisk with any questions at [email protected]

Study Assessing the Efficacy, Safety and PK of Alpelisib (BYL719) in Pediatric and Adult Patients With PIK3CA-related Overgrowth Spectrum

This is a prospective Phase II multi-center study with an upfront 16-week, randomized, double-blind, placebo-controlled period, and extension periods, to assess the efficacy, safety and pharmacokinetics of alpelisib in pediatric and adult participants with PIK3CA-related overgrowth spectrum (PROS). Enrollment is currently open in Norway and Spain.

Identification of Biomarkers for Patients with Vascular Anomalies 

Purpose: To identify biomarkers in patients diagnosed with a vascular anomaly*. 

Who is eligible: Any participant with a diagnosed vascular anomaly* that are currently not on treatment for the condition and are having labs (blood) drawn as standard of care.

*Vascular anomalies included: Generalized Lymphatic Anomaly (GLA), Gorham-Stout Disease (GSD), Kaposiform Hemangioendothelioma (KHE), Kaposiform Lymphangiomatosis (KLA), Klippel Trenaunay Syndrome (KT), Congenital Lipomatous Overgrowth, Vascular Malformations, and Epidermal Nevi Syndrome (CLOVES) 

FOR MORE INFORMATION CALL OR EMAIL Megan Metcalf at 513-803-2606 [email protected]

Kahle Lab AVM Research

The genetics of AVMs are poorly understood, and many theories currently exist with regards to their development, including the hypothesis that their development begins early in gestation. Kahle Lab is actively recruiting patients with brain or spinal cord AVMs and their families. Participants must have a formal diagnosis based on imaging.   This study is currently open to people in the United States.

If you are interested in participating, please email [email protected] with the following information:

  1. Mailing Address or Addresses where the swabs and paperwork will be sent
  2. Active contact telephone number
  3. Full Names and Ages of participants at each address that will provide DNA samples in your household
  4. Previously referred to genetics? If so, findings? 

First in Human Trial of Topical VT30 in Patients with Venous/Lymphatic Malformations associated with PIK3CA or TEK gene mutations – Venthera    

8/28/20 – VT30-101 is a 2-part first-in-human trial of topically administered VT30 to subjects with cutaneous venous malformations, lymphatic malformations, or mixed venolymphatic malformations associated with PIK3CA or TEK mutations.

Part 1 is a 4-week treatment, open-label, 4-sequence, escalating repeat-application cohort study, with intra-subject and inter-cohort dose escalation.

Part 2 is a 12-week treatment, randomized, placebo-controlled, double-blind, safety and exploratory efficacy study. Part 2 will be initiated only after the successful completion of Part 1 with results that demonstrate the general safety and tolerability of topically applied VT30. Up to 12 subjects who complete Part 1 may be enrolled into Part 2 of the study.

The primary objective is to evaluate the safety and tolerability of VT30. The study will also determine the dose and regimen of VT30 to be carried into Part 2 of the protocol. Other aims include documenting plasma drug levels of VT30 and VT10 and, on an exploratory basis, examining pharmacologic target engagement and change in potential efficacy readouts.

Compassionate Use Access of PIQRAY (formerly BYL719/alpelisib) [7-9-19]
The Novartis Managed Access Program (MAP) for PIQRAY use in PROS is available to patients in the US where PIQRAY is available for commercial use (as well as other countries where not approved).

The FDA approved PIQRAY for HR+/HER2- advanced breast cancer, and thus PROS patients may seek access to the medication through MAP.

Patients should contact their treating physicians who can, if clinically appropriate, make a request to Novartis for access to treatment using this link on the Novartis website https://www.novartis.com/our-focus/healthcare-professionals/managed-access-programs

New Research Opportunity: MOSAIC – ARQULE [6-5-19]
ArQule is currently conducting the MOSAIC (Miransertib in Overgrowth Syndromes in Adults and Children) clinical trial for patients who have been diagnosed with either Proteus syndrome (PS), which involves a mutation in the AKT gene, or those who have been diagnosed with one of a number of distinct overgrowth disorders characterized by a mutation in the PIK3CA gene, referred to as PIK3CA-related overgrowth spectrum (PROS). There are currently no approved medicinal treatments for PS and PROS, leaving patients with minimal treatment options.  ArQule was purchased by Merck in January of 2020.  

The MOSAIC trial aims to determine whether miransertib, a drug which inhibits the biological pathway that both AKT and PIK3CA mutations affect, can effectively treat patients who are diagnosed with overgrowth syndromes associated with these mutations.

Based on the mechanism of action of miransertib, trial participants must have a mutation in either the AKT1 or PIK3CA gene to be eligible to participate in the MOSAIC trial. Learn more about how miransertib works below.

New Research Opportunity: BYL719/NOVARTIS [6-13-18]
A medical first: CLOVES Syndrome and overgrowth syndromes:remarkable improvement in the health of 19 pediatric and adult patients using a new therapeutic strategy called Alpelisib BYL719. Dr. Guillaume Canaud at the Necker-Enfants Malades Hospital – AP-HP, the Paris Descartes University, Inserm (INEM Institute Necker Enfants Malades – Centre for Molecular Medicine) and his team recently demonstrated the efficacy of a novel medication, a specific inhibitor called BYL719, in a cohort of 19 patients treated at the Necker-Enfants Malades Hospital – AP-HP and suffering from CLOVES Syndrome (Congenital Lipomatous Overgrowth, Vascular Malformation, Epidermal Naevi) or similar disorders.

Opportunity for CLOVES Research (ongoing)

April 23, 2013 – Research Opportunity with National Institutes of Health (NIH)


Genetics

 

CLOVES syndrome is different than most other genetic conditions in that it is not inherited.  The gene changes that cause CLOVES syndrome in a person are not found in that person’s parents, siblings, or children. CLOVES syndrome is caused by changes (“mutations”) in a gene called PIK3CA and these changes are only present in some of a person’s cells.  Just like people with CLOVES syndrome have some affected parts of their bodies and some unaffected parts of their bodies (for example, differences in just one leg but not the other, or skin changes in some places and not others), the PIK3CA mutations that cause CLOVES syndrome in a person are not present in all of that person’s cells. Scientists use different words to describe this, including “mosaicism,” and “segmental.” No matter what term is used, the important thing to know about CLOVES syndrome is that where and how you look for a causative mutation really matters. This graphic describes the genetics of CLOVES syndrome.

Genetic testing can be very helpful for people with CLOVES syndrome. Having a genetic test can help families and doctors understand treatment options that are already available.  Treatments that are currently being tested or may become available in the future may also rely on a person’s genetic test results. Many healthcare providers are still unfamiliar with what mutations to test for and what samples are needed. Approximately half of the families involved in the CLOVES syndrome community have told us they had difficulty with genetic testing. The most common challenges are insurance coverage and getting the right kind of genetic test.

Genetic testing for CLOVES syndrome/PROS is more complicated than other kinds of genetic testing. It is important to be sure that the right sample is sent for testing and to understand how different genetic testing laboratories perform the test.  You can read more about this in our FAQThis site also has a good explanation of genetic testing.

What sample will be used for testing?

Almost all traditional genetic testing is done using blood or saliva samples.  These are NOT the best samples to use for genetic testing for CLOVES syndrome.  PIK3CA mutations that cause CLOVES syndrome just can’t be detected as well (or at all) in DNA that comes from these types of samples. No genetic test is perfect, but if a mutation is there, choosing a sample that comes from a part of the body that is clearly “affected” (showing signs of CLOVES syndrome) has the highest chance of finding it. For most people, this means having a skin biopsy done.  Another option is to use tissue that might be available from a surgery that would ordinarily be thrown away. Having a skin biopsy (or sending surgical samples for genetic testing) takes more work for families and clinicians, and many parents don’t like the idea of having their child have a biopsy. Because genetic testing can be expensive and difficult to arrange, it’s often worth it to make sure that the best possible sample is used.

What laboratory will do the test?

Not all genetic testing laboratories (and there are LOTS of genetic testing labs!) test for CLOVES syndrome.  Most offer CLOVES syndrome genetic testing as part of a “panel.” Many different genes that may cause similar conditions are tested at the same time. In some cases, the lab will only test specific mutations within the PIK3CA gene. Sometimes a person’s insurance will cover genetic testing at some laboratories and not others. It’s important for you and your doctor to understand the specific test that will be done. Exome sequencing, a very comprehensive and increasingly common test, especially for people with rare conditions, may not be the best test for people with CLOVES syndrome. It is very expensive and is often only done using a blood sample. Many families tell us that they had exome sequencing as their first diagnostic test.   While CLOVES Syndrome Community does not endorse any of the following laboratories, they each offer tests that, when performed on the right DNA source or tissue sample, have a higher chance of finding a PIK3CA gene change compared to others.

University of Pennsylvania

Washington University

Boston Children’s Hospital

When considering genetic testing, here are some “green lights” and “red flags” that can help you and your doctor decide on the best test for you/your child:

Test Green lights – signs of a more appropriate test for CLOVES syndromeRed flags – signs of a less appropriate test for CLOVES syndrome
Sample typefresh tissue, frozen tissue, DNA extracted from tissueblood, saliva, DNA extracted from blood or saliva
Name of test“Somatic overgrowth panel” includes “CLOVES syndrome” or “mosaic overgrowth” in name of testName of test seems to test for something else, e.g., “polydactyly panel”
Coverage“deep sequencing” “ultra deep sequencing” “100x” “250x”“20x coverage”
Detection language“limit is 1%” “limit is 5%”“variants present at <20% may not be reliably detected”

How will the test be done?

There are lots of different ways genetic tests can be done.  Finding the responsible mutation in a person with CLOVES syndrome is more of a “needle in a haystack” situation than many genetic tests because even in the “perfect” sample, the percentage of DNA with the mutation is lower than with other genetic conditions. Genetic tests designed to find the low-frequency mosaic mutations common in CLOVES syndrome are the best ones for people with CLOVES syndrome to get.  It can be important to understand what the test’s lowest frequency is. Can the test find a mutation that may only be present in 1% of the DNA from the sample? 5%? 25%? Also, some genetic tests just look for specific mutations in specific genes, while others read through (“sequence”) whole genes. Having this information in advance can help families and providers pick the best test for the situation.

What will the results mean?

 A “positive” result means that the test found a gene change or mutation in a gene that is known to be associated with CLOVES syndrome.  Most people with CLOVES syndrome who get positive test results will have changes in the PIK3CA gene. A “negative” result can be complicated in a condition like CLOVES syndrome for a couple of reasons:

1) No genetic test is 100% perfect

2) A mutation may be present but not at a high enough level for the test to find. The lab may label any mutations found in less than 5% of the DNA in the sample as “negative.”

3) A mutation may not be present because the sample came from blood or saliva.  This is common in CLOVES syndrome and why we suggest that DNA from biopsies is the best sample to send for genetic testing

4) A “true negative:” we do not know 100% of the genes that cause CLOVES syndrome so even a perfect test from a perfect sample will not give a positive result in a person whose mutation in a gene that has not been discovered yet.

Additional Resources for Genetics:

Visual created by the National Institutes of Health to help explain PIK3ca mutations and overgrowth. [March 20, 2017] 

NIH Ongoing Research for PIK3CA mutations:
The National Institutes of Health does research testing of patients with all kinds of overgrowth. If you’d like to learn more, contact them at [email protected] or by phone at 301-435-6689. More information can be found here https://www.ncbi.nlm.nih.gov/gtr/tests/5534/

CLOVES Genetic Mutation Discovery (5/31/12)
Researchers at Boston Children’s Hospital identify a genetic cause for CLOVES


Medical Providers

 

Below is a partial list of multidisciplinary Vascular Anomalies Centers that may provide treatment, monitoring, and oversight for CLOVES/PROS. Providers on this list should not be construed as recommendations by CLOVES Syndrome Community. 

UNITED STATES

CANADA

VASCERN Provider Listing

EUROPE

FRANCE

UNITED KINGDOM

Email us at [email protected] to add a provider suggestion


FAQ

 

Frequently Asked Questions – Compiled from doctors, families and people with CLOVES

Updated 11/23/2020 – Reviewed by CLOVES Syndrome Community Scientific and Medical Advisory Board

What is CLOVES syndrome?
CLOVES Syndrome is a segmental overgrowth condition with variable multisystem findings, including complex vascular anomalies. CLOVES stands for Congenital, Lipomatous Overgrowth, Vascular malformations, Epidermal nevi and Scoliosis/Skeletal/Spinal anomalies. The syndrome was described independently by Sapp and coauthors [2007] and Alomari [2009].  The syndrome shows no inheritance among families of affected patients.

CLOVES syndrome is characterized by asymmetric overgrowth that is variable, ranging from mild to severe. The common features in most patients allow for proper diagnosis and distinction from other syndromes. The most consistent features of the syndrome are:

  1. Fatty Truncal Mass: Typically, a soft fatty mass of variable size is noted at birth. The mass can be seen in one or both sides of the back and abdominal wall with extending into gluteal or groin regions. The skin over the mass is covered with a red-pinkish birthmark (port-wine stain or capillary malformation). The fatty mass may extend into the chest, abdomen or into the spinal canal (around the spinal cord).
  2. Vascular Anomalies: In addition to the skin birthmark, patients with CLOVES syndrome have abnormal lymphatic and venous channels. In addition, a group of patients suffer from a more aggressive vascular anomaly (Arteriovenous malformation – AVM) around the area of the spinal cord.
  3. Abnormal extremities (arms and legs) and scoliosis (curving of the spine) are common. Patient may have large wide hands or feet, large fingers or toes, wide space between digits and uneven size of extremities. With significant overgrowth in one part of the body, there can be undergrowth (with decreased body fat) in other parts of the body.
  4. Skin abnormalities include birthmarks, prominent veins, lymphatic vesicles, moles and epidermal nevus (light brownish slightly raised skin in the upper chest, neck or face).
  5. Other abnormalities include small or absent kidney, other kidney or urinary tract anomalies, abnormal patella (kneecap), knee and hip joints.

Most patients with CLOVES syndrome do not have all these signs, but rather a combination of abnormalities; though some can be subtle or deeply seated and requires dedicated physical exam and proper imaging studies.

What is PIK3CA-Related Overgrowth Spectrum (PROS) and how does CLOVES syndrome fit into this disorder?

PIK3CA-Related Overgrowth Spectrum, also known as PROS, is an “umbrella” term used to describe a spectrum of overlapping, yet distinct conditions caused by somatic or mosaic (meaning in some of the body cells), pathogenic  (meaning disease-causing) gene variants (or mutations) in the gene, PIK3CA, and includes CLOVES syndrome, Klippel-Trénaunay syndrome, Fibroadipose hyperplasia or overgrowth, Fibro-apidpose vascular anomaly (FAVA) Facial Infiltrating lipomatosis, CLAPO (Capillary malformation of the lower lip, lymphatic malformation of the face and neck, asymmetry and partial/generalized overgrowth), Megalencephaly-Capillary malformation. (MCAP) syndrome, isolated Hemimegalencephaly and focal cortical malformations, Macrodactyly, and Muscular hemihypetrophy, among other entities.

Is there a cure for CLOVES?

While there is no cure for CLOVES syndrome at present, there are potential drug treatments which may be available under compassionate use and as part of a clinical trial. The medical community has defined characteristics of this disease that need to be monitored throughout an individual’s life, such as the care of vascular anomalies, assessment of anomalous veins and risk for blood clots, tissue overgrowth and its effect on function, skeletal and orthopedic issues and other complications of CLOVES syndrome.

The overarching goal is to create a better quality of life for these patients.

Surgery, Interventional radiology and other medical interventions are the only present available treatments for CLOVES overgrowth, vascular anomalies and other related medical issues. Boston Children’s Hospital started doing research into CLOVES syndrome via genome sequencing in March of 2011. This sequencing led to the PIK3CA genetic mutation discovery of CLOVES in May of 2012. Other medical and research groups have identified the causative PIK3CA gene variant for CLOVES syndrome and related/overlapping disorders.

My child just got diagnosed with CLOVES Syndrome. A lot of what I have read is really scary. What can I expect for him in his lifetime?

As CLOVES syndrome is relatively rare and was only defined in 2007, there are still many unknowns about the possible associated medical complications and natural history.

A new diagnosis of a rare syndrome like CLOVES syndrome can be a challenging time that may cause anxiety and stress for patients and families. We believe that connecting to others is an important component of a new diagnosis and may help to put some of the uncertainty and concern into perspective. You can connect with other families in our secret, non-searchable Facebook group by “friending” our Welcome Account. 

In addition, there are multiple collaborating medial and research centers, that have a robust initiative to collect information from people currently diagnosed with CLOVES syndrome, in order to learn more about what the future holds for our loved ones. The best way to collect information about CLOVES syndrome is to understand what complications these patients have over a lifetime.   One of the ways that we can collect information is through natural history studies.   One such study is called the Lymphatic Anomalies Registry. In addition, the CLOVES Syndrome Community maintains a Contact Registry. The CSC Registry will be used to inform individuals with CLOVES Syndrome and their guardians about:

  • discoveries about CLOVES Syndrome that may impact care decisions
  • opportunities to participate in research
  • opportunities to contribute data

 We encourage new members to sign up for our contact registry.

Treatments and Trials:

Are there any medicines to treat CLOVES?

There is growing experience using sirolimus to manage some symptoms and complications of CLOVES syndrome and PROS [Adams et al., 2016; Hammer et al. 2018; Maruani et al., 2018; Parker et al., 2019]. Sirolimus has been most effective in the complications of vascular anomalies such as controlling infections, leaking from lymphatic vesicles, bleeding and enlarging vascular masses. The decision to recommend sirolimus is based on an individual’s complications and should be considered with your physician.

There are a few companies developing drugs for the treatment of CLOVES and PROS. Uncontrolled single and multiple case reports using Alpelisib (a PI3K inhibitor) have shown some reduction in size of vascular abnormalities and improvement in quality of life [Venot et al., 2018; Lopez Gutierrez et al., 2019]. Other drug therapies, including an AKT1 (a downstream gene to PIK3CA) inhibitor called Miransertib, are being studied in clinical trials. An up-to-date resource of privately and publicly funded clinical studies, including developing drug therapies conducted around the world is available on ClinicalTrials.gov. In addition, we are happy to share contact information of experienced physicians with you, if you need it.

My child’s doctors don’t know much about CLOVES syndrome – what should I do?

The medical management of CLOVES can be challenging, and we recommend that you consult a Multidisciplinary Vascular Anomalies Center that has expertise with both overgrowth and complex vascular anomalies. We can help you in finding a facility near you and/or a multidisciplinary practice to collaborate with you and your child’s local physicians.

If you want to share some information about CLOVES syndrome with your doctors, you can refer them to some of the references noted at the end of this FAQ document. In addition, one resource, which is useful (but not recently updated) and can be shared with your doctors, includes the comprehensive screening guidelines for CLOVES.

Veins and Clotting:

I’ve heard about a risk of blood clots related to CLOVES – what do I need to know?

Blood clots are more likely to occur in patients with CLOVES syndrome and PROS. While this has occurred at any age, most events happen after age 10 years and the risk is higher around procedures. The main predictor of blood clot risk seems to be enlarged draining veins that occur in many patients with CLOVES syndrome and accompanying abnormal blood tests (like D-dimer, fibrinogen and platelets) [Reis et al., 2018; Keppler-Noreuil, et al., 2019]. Before any major surgery, evaluation of enlarged veins to consider closing them and consultation with a hematologist for anticoagulation recommendations is recommended. 

My child’s doctors are suggesting that my child have a large vein removed. I don’t understand why.

Many people with CLOVES are born with a large vein or veins. The concern about large veins and CLOVES is that the blood becomes stagnant (slow moving) and when the blood is not flowing effectively, there is an increased risk of a clot or multiple clots (also called a deep vein thrombosis, or DVT). The decision to remove or close a large vein should be directed by an expert in this procedure, and by weighing risks and benefits of removal. Options for treatment are by surgery, radiofrequency ablation (laser from inside the vein) or the vein may need be carefully monitored or observed. Removing a vein that has ineffective blood flow, does not negatively impact blood flow in that area.

Wilms Tumor:

I also have concerns about the risk of Wilms tumor in CLOVES syndrome. 

There have been eight cases of Wilms tumor identified in patients with CLOVES syndrome. This is a rare complication of CLOVES syndrome. One study by Gripp and co-authors [2016]. estimated the risk of Wilms tumor and nephroblastomatosis (pre-Wilms tumor abnormality in the kidney) to be ~1.6% (based on four patients identified from a cohort of 258 people) and may warrant tumor screening. A more recent study by Peterman and co-authors [2017] identified from a total of 122 patients with CLOVES syndrome (mean age 7.7 years, range 0-53 years), four patients who developed WT; all were diagnosed by 2 years of age. They described an incidence of Wilms tumor of 3.3%, which was significantly greater than the incidence of Wilms tumor in the general population (1/10,000) (P < 0.001). They recommended that given the benefits of early detection and treatment, children with CLOVES syndrome should be considered for quarterly abdominal ultrasonography until age 7 years. Screening may be most beneficial for patients under 3 years of age.

This is similar to Wilms tumor screening in other overgrowth disorders. Wilms tumor is a very treatable kidney cancer. Screening with ultrasound is recommended because treatment is easier and chance of cure is very high when Wilms tumor is caught early. It is not clear why patients with CLOVES syndrome are more likely to develop this tumor.

I just found out through my child’s quarterly ultrasound screening, that my child has cysts on her kidneys. What do we do next?

What we know is that there are a few abnormal kidney findings in people with CLOVES including difference in sizes, cysts, unusual architecture and Wilms tumors. New or changing kidney abnormalities should be reviewed by a Multi-disciplinary Vascular Anomalies Center with expertise in CLOVES syndrome, to help determine their significance.

Neurologic and spinal complications:

The fatty (or lipomatous) overgrowth into the adjacent (paraspinal) and internal spinal spaces is associated with increased risk for compression of the cord, the sac surrounding the cord (called the thecal sac) and nerve roots. Some individuals have spinal abnormalities caused by spinal and paraspinal vascular AVMs (considered to be fast-flow vascular lesions). Additional possible complications, like tethered cord, neural tube defects, and spasticity can occur.

Some individuals with CLOVES syndrome can have variable degrees of intellectual disability associated with larger head size (macrocephaly) and brain malformations, and seizures. Chiari malformation can occur, which may require surgical intervention.

Is tethered cord something you are born with or can it develop later in life?

Tethered cord means that the spinal cord has some kind of attachment that prevents the spinal cord from moving freely within the spinal canal. This attachment is usually some type of tissue that children have from birth, like a fatty filum (strand of fat), lipoma (bigger collection of adipose – fat – tissue) or dermal sinus tract (strand of tissue from outside the spinal canal to the spinal cord). However, sometimes tethering can occur later in life, especially after surgery (when scar tissue can stick the spinal cord to the lining of the spinal canal) or after a bad infection, like meningitis (when the inflammation of the infection can lead to scar tissue). It is important to understand that there is a difference between radiographic tethering (which means that the MRI or other imaging studies show some kind of connection, but which may NOT have symptoms and may NOT need surgery) and clinical tethering (which means that one sees a site of tethering on imaging AND there are symptoms that can be directly related to the things that are seen on the imaging). If there is an attachment that is thought to be tugging on the spinal cord, then sometimes symptoms can develop – depending on where the tethering occurs – that can lead to problems with spinal cord function (like weakness, sensory changes, scoliosis (bend in the back) or pain). The diagnosis of tethered cord can be difficult and it is important to talk with physicians who see these conditions routinely in order to put together the best plan of treatment for your child.

What are the reasons for not surgically treating tethered cord?

As mentioned above, there may be situations in which one can see some kind of tethering (attachment from scar tissue or birth-related structures) on imaging studies (like MRI), but which are not causing any symptoms. In some cases, it may be that the risk of doing surgery to disconnect the tethering site may be greater than the risk of leaving things alone. On the other hand, there are sometimes situations when the child has no symptoms, but the imaging shows a problem that will very likely become worse with time, in which case the risk of surgery – even with no symptoms – may be justified. If a patient is fully grown and has not developed symptoms, the chances of future problems from tethering become very small. The decision to operate or to monitor a tethered cord is often very dependent on individual MRI findings, symptoms and co-existing medical conditions, so it is important to talk to your doctor to learn about the pros and cons of different management plans.

Why do some people with CLOVES have scoliosis?

Progressive scoliosis can occur and range from mild to severe. Asymmetric growth of one side of the body with growth being faster than the other side may be one possible cause. Also, overgrowth of one or more bones in the spine, called vertebral bodies, may cause scoliosis. Scoliosis is important to follow over time in CLOVES patients, especially before pubertal growth, so that any possible interventions to straighten the spine be employed during growth and before surgical rod placement is necessary.

Lumps and bumps:

My child just got a new lump on their body. What am I supposed to do?

New lumps and bumps can cause concern in CLOVES. Gradually enlarging lumps that feel like fatty tissue may be just that – lipomas. Rapidly expanding bumps may be infected (red, painful, fever) or newly blood-filled (purple, painful) lymphatic cysts or clotted venous malformations (painful, bruise-colored, hard).  Physician evaluation is recommended for slow-growing hard lesions, lesions unlike others you’ve seen before in CLOVES, or for any lesions causing concern or needing medication (pain med, antibiotic) to speed recovery.

Surgery:
My child’s doctor is recommending we remove her toes? How do I make the decision to amputate toes or alter her feet?

The decision to surgical alter a child’s foot is often a challenge for parents, to make. Often the recommendation to remove toes or change the shape of feet is made if:

  1. the surgery will improve function (i.e. – walking, running) or
  2. the surgery is restorative (helps child to fit into shoes, increase symmetry between feet). 

Many of our families and children have been through this process and are willing to discuss their experiences.

Does surgery or liposuction work better for removing a lipoma?

Surgical removal or debulking are procedures that have been used, but may carry a risk of complications and disfigurations, and may require repeat procedures. As noted in the previous question, it would be imperative to review the risks and benefits of surgical intervention. The use of liposuction in CLOVES syndrome is not well-established and again it is important to review the risks and benefits of this intervention. Because fatty overgrowth (including lipomas) may have accompanying vascular abnormalities and/or be more vascular, this may raise concern about increased risk of bleeding or infection.

Growth:

What about undergrowth or growth dysregulation?

Undergrowth or sometimes termed regional lipohypoplasia occurs in some individuals with PROS or CLOVES syndrome. In one study, the risk of having regional lipohypoplasia is increased with concomitant or co-occurring increased somatic overgrowth or hemihypertrophy. Several studies have found prevalence of regional undergrowth or lipohypoplasia to occur in ~30% of individuals with CLOVES or PROS.

Life expectancy:

What is the life expectancy of someone with CLOVES syndrome?

Multiple centers studying CLOVES syndrome and PROS are learning more about the natural history and life expectancy of these disorders. However, the life expectancy of CLOVES syndrome and PROS are expected to be normal. It is important to review all the possible medical complications that may occur in each INDIVIDUAL diagnosed with CLOVES syndrome to provide a more accurate determination of prognosis.

Genetics:

Can you explain what is meant by “clinical syndrome” (e.g. CLOVES syndrome, and others), and how that is related to describing a syndrome by its genetic cause (e.g. PIK3CA gene mutation, and PROS)?

The word “syndrome” just means “a set of characteristics that seem to group together.” Many medical diagnoses start out being described as clinical syndromes – they were defined by the most common features found in patients by doctors. Until very recently, the underlying genetic cause (or causes) of most syndromes was unknown. Advances in genetic testing now allow doctors to pair syndrome names with one or more gene names.  This process can cause confusion. CLOVES syndrome is a good example of a syndrome that was initially described because of a set of features – in fact, it’s name comes from those features:

Congenital (you have symptoms when you are first born)

Lipomatous (has to do with fat)

Overgrowth (some parts of your body are larger),

Vascular (veins, arteries, capillaries and lymphatics are involved),

Epidermal Nevi (a type of birth mark on the skin), and

Skeletal or Spinal differences (you have scoliosis or other skeletal abnormalities).

Years after CLOVES syndrome was “named,” scientists found that most people with CLOVES syndrome had changes in one gene called PIK3CA.

It turns out that one gene can cause multiple different conditions. We now know that PIK3CA gene mutations also cause other clinical syndromes, including Klippel-Trénaunay syndrome, CLAPO syndrome, FAVA syndrome, Megalencephaly-Capillary malformation (MCAP) syndrome, and isolated Macrodactyly, and others. Taken as a group, these syndromes, including CLOVES syndrome, may also be referred to as PIK3CA-Related Overgrowth Sequence or Syndrome (PROS).

While a mutation in PIK3CA may confirm or be consistent with the diagnosis of CLOVES, it is not required to make this diagnosis. Some CLOVES syndrome patients don’t have a positive PIK3CA genetic test result.  These individuals may still have a mutation that wasn’t identified for various reasons, or they may have mutation in completely different gene.

Why doesn’t a blood test show PIK3CA mutation?

The short answer: the mutation isn’t in every cell of a patient with CLOVES, but only in involved tissues. When blood or a cheek swab is sent for genetic testing, this only analyzes the DNA in the cells from the blood or cheek lining. There is work underway using super-sensitive technology to try to identify the mutation from a blood test, which may be possible for some patients. If the blood test is negative, testing the affected tissue would then be needed.

The PIK3CA mutations in CLOVES are somatic mutations. This means that CLOVES is not inherited and likely cannot be passed to future children. The mutation only exists in some tissues, generally the abnormal tissues in patients with CLOVES.

Click here to see an image description of a somatic mutation in CLOVES. 

No one knows why these genetic changes happen in CLOVES. We do know that nothing that a person does or does not do during or before pregnancy causes the CLOVES syndrome gene changes to happen.  It is very likely that these gene changes happen very early in embryonic development. Scientists are learning more about how PIK3CA gene changes seem to affect different people with CLOVES syndrome differently. 

My child is diagnosed with CLOVES. Why did her tissue biopsy come back negative for PIK3CA?

Since people with CLOVES still have mostly normal, healthy cells, if we want to diagnose CLOVES we have to look for cells which are most likely to have the CLOVES mutation. The best way to do that is to take a biopsy of affected tissue and search there. However, even in affected tissue the percentage of cells with the CLOVES mutation may still be low. Also, now most physicians only look for PIK3CA mutations in patients with CLOVES. A minority of patients with the clinical syndrome of CLOVES will have mutations in other, often related genes.

Some guidance on how to test for genetic changes in CLOVES

  1. Test affected tissue after biopsy or removal for known mutations. This can be done in a clinical genetics laboratory or in the research setting, then confirmed clinically. If you join a research study, be sure to ask if you will learn clinically confirmed results (or if there is a way for you to have research results confirmed clinically).
  2. If clinical PIK3CA testing is negative, consider research testing of affected tissue. This may be more sensitive and may look for other mutations. Sometimes this involves looking harder at the PIK3CA and related genes. This can also include whole exome or whole genome sequencing where all genes are studied.
  3. If no biopsy or resection has occurred, consider blood (or even urine) testing in a research lab. If negative, testing of affected tissues will still be needed.

REFERENCES:

Adams DM, Trenor CC, Hammill AM, et al. Efficacy and Safety of Sirolimus in the Treatment of Complicated Vascular Anomalies. PEDIATRICS. 2016;137(2):e20153257-e20153257. doi:10.1542/peds.2015-3257

Alomari AI. Characterization of a distinct syndrome that associates complex truncal overgrowth, vascular, and acral anomalies: a descriptive study of 18 cases of CLOVES syndrome: Clin Dysmorphol. 2009;18(1):1-7. doi:10.1097/MCD.0b013e328317a716

Gripp KW, Baker L, Kandula V, et al. Nephroblastomatosis or Wilms tumor in a fourth patient with a somatic PIK3CA mutation. Am J Med Genet A. 2016;170(10):2559-2569. doi:10.1002/ajmg.a.37758

Hammer J, Seront E, Duez S, et al. Sirolimus is efficacious in treatment for extensive and/or complex slow-flow vascular malformations: a monocentric prospective phase II study. Orphanet J Rare Dis. 2018;13(1):191. doi:10.1186/s13023-018-0934-z

Keppler-Noreuil KM, Sapp JC, Lindhurst MJ, Parker VE, Blumhorst C, Darling T, Tosi LL, Huson SM, Whitehouse RW, Jakkula E, Grant I, Balasubramanian M, Chandler KE, Fraser JL, Gucev Z, Crow YJ, Brennan LM, Clark R, Sellars EA, Pena LD, Krishnamurty V, Shuen A, Braverman N, Cunningham ML, Sutton VR, Tasic V, Graham JM Jr, Geer J Jr, Henderson A, Semple RK, Biesecker LG. Clinical delineation and natural history of PIK3CA-Related Overgrowth Spectrum. Am J Med Genet A. 2014 Jul;164A(7):1713-33. doi: 10.1002/ajmg.a.36552. Epub 2014 Apr 29.

Keppler‐Noreuil KM, Lozier J, Oden N, et al. Thrombosis risk factors in PIK3CA‐related overgrowth spectrum and Proteus syndrome. Am J Med Genet C Semin Med Genet. 2019;181(4):571-581. doi:10.1002/ajmg.c.31735

Keppler-Noreuil KM, Rios JJ, Parker VER, et al. PIK3CA -related overgrowth spectrum (PROS): Diagnostic and testing eligibility criteria, differential diagnosis, and evaluation. Am J Med Genet A. 2015;167(2):287-295. doi:10.1002/ajmg.a.36836

Keppler-Noreuil KM. PIK3CA-Related Overgrowth Spectrum. In: Overgrowth Syndromes: A Clinical Guide. Oxford University Press; 2019. https://oxfordmedicine.com/view/10.1093/med/9780190944896.001.0001/med-9780190944896

Maruani A, Boccara O, Groupe de Recherche de la Societé Française de Dermatologie Pédiatrique, et al. Treatment of voluminous and complicated superficial slow-flow vascular malformations with sirolimus (PERFORMUS): protocol for a multicenter phase 2 trial with a randomized observational-phase design. Trials. 2018;19(1):340. doi:10.1186/s13063-018-2725-1

Parker VER, Keppler-Noreuil KM, Faivre L, et al. Safety and efficacy of low-dose sirolimus in the PIK3CA-related overgrowth spectrum. Genet Med. 2019;21(5):1189-1198. doi:10.1038/s41436-018-0297-9

Peterman CM, Fevurly RD, Alomari AI, Trenor CC 3rd, Adams DM, Vadeboncoeur S, Liang MG, Greene AK, Mulliken JB, Fishman SJ. Sonographic screening for Wilms tumor in children with CLOVES syndrome. Pediatr Blood Cancer. 2017 Dec;64(12). doi: 10.1002/pbc.26684. Epub 2017 Jun 19.PMID: 28627003

Reis J, Alomari AI, Trenor CC, et al. Pulmonary thromboembolic events in patients with congenital lipomatous overgrowth, vascular malfomrations, epidermal nevi, and spinal/skeletal abnormalities and Klippel-Trenaunay syndrome. J Vasc Surg Venous Lymphat Disord. 2018;6(4):511-516. Doi: 10.1016/j.jvsv.2018.01.015

Sapp JC, Turner JT, Kamp JM van de, Dijk FS van, Lowry RB, Biesecker LG. Newly delineated syndrome of congenital lipomatous overgrowth, vascular malformations, and epidermal nevi (CLOVE syndrome) in seven patients. Am J Med Genet A. 2007;143A(24):2944-2958. doi:10.1002/ajmg.a.32023

Venot Q, Blanc T, Rabia SH, et al. Targeted therapy in patients with PIK3CA-related overgrowth syndrome. Nature. 2018;558(7711):540-546. doi:10.1038/s41586-018-0217-9

Yu Y, Savage RE, Eathiraj S, et al. Targeting AKT1-E17K and the PI3K/AKT Pathway with an Allosteric AKT Inhibitor, ARQ 092. Cheng JQ, ed. PLOS ONE. 2015;10(10):e0140479. doi:10.1371/journal.pone.0140479

Study of ARQ 092 in Subjects With PIK3CA-related Overgrowth Spectrum and Proteus Syndrome (MOSAIC). Clinicaltrials.gov identifier: NCT03094832. Published July 16, 2020. Accessed June 26, 2020. https://clinicaltrials.gov/ct2/show/NCT03094832

Expanded Access to Provide ARQ 092 for the Treatment of Overgrowth Diseases and/or Vascular Anomalies.  ClinicalTrials.gov Identifier: NCT03317366. Published October 23, 2017. Accessed June 26, 2020. https://clinicaltrials.gov/ct2/show/NCT03317366

Novartis Pharmaceuticals. Managed Access Program (MAP) to Provide Alpelisib (BYL719) for Patients With PIK3CA-Related Overgrowth Spectrum (PROS). clinicaltrials.gov; 2020. Accessed July 1, 2020. https://clinicaltrials.gov/ct2/show/NCT04085653

Novartis Pharmaceuticals. Retrospective Chart Review Study of Patients With PIK3CA-Related Overgrowth Spectrum (PROS) Who Have Received Alpelisib as Part of a Compassionate Use Program (EPIK-P1). clinicaltrials.gov; 2020. Accessed July 9, 2020. https://clinicaltrials.gov/ct2/show/NCT04285723


Contact Registry

 

The CLOVES Syndrome Community Contact Registry will be used to inform individuals with CLOVES Syndrome and their guardians about:

  • discoveries about CLOVES Syndrome and PROS that may impact care decisions
  • opportunities to participate in research
  • opportunities to contribute data

Details about the registry:

  • It’s easy to join!
  • There is no cost to you: the costs are supported by CLOVES Syndrome Community
  • Your information will be transmitted via a secure server and stored in a database.
  • Participation is voluntary
  • You can choose to withdraw from the registry at any point.

How is information stored?

Once you have entered and submitted this information online, the data will be stored in a secure database. No personal identifying information will be given to anyone without your expressed approval.

The information stored in the contact registry will not be shared with anyone outside of CLOVES Syndrome Community. Registrants will be provided with contact information about relevant research and survey efforts.

We may use aggregate data from the contact registry to publish statistics about the incidence of CLOVES Syndrome. For example, we may use contact registry data to say how many people have CLOVES, what their age ranges are and how they are distributed geographically.

Who can join the registry?

Anyone with a diagnosis of CLOVES Syndrome or a PROS condition can be part of the registry.

Other details:

The CLOVES Contact Registry is not the same as our newsletter mailing list. You must opt-in to our Contact Registry by completing the form below.

We will not use this list for marketing or fundraising.

If our policy about acceptable use of our contact registry ever changes, you will be notified. You may opt-out of the contact registry at any time by emailing us at [email protected]

Many thanks to the M-CM Network for allowing us to use their contact registry design as a template for our contact registry.


Research Simplified

 

Want to learn more about CLOVES and PROS research, but you don’t have a PhD? Introducing Research Simplified. Research Simplified is an initiative started by KIF1A Associated Neurological Disorder (KAND) to help patients and families understand complex topics in published papers.    

CLOVES Syndrome Community has identified this as an unmet need for our community, so we are beginning this initiative as well.   We are reaching out to the authors of published papers to assess their interest in helping us with this project.  The summaries will be published here on our website. 

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