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)?

Many medical diagnoses start out being described as clinical syndromes. These clinical syndromes are defined by the most common features identified in patients by doctors. Often, the underlying cause of these common features or syndromes is not known yet. However, after the genetic cause or one or more gene mutations are found to cause a clinical syndrome, that clinical syndrome may be named by the gene or genes causing it (in the case of CLOVES syndrome, it is caused by multiple different variations in the gene, PIK3CA). CLOVES syndrome was named after those more common features occurring frequently together: 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 (you have scoliosis or other skeletal abnormalities). We now know that PIK3CA gene mutations not only cause the clinical syndrome, CLOVES, but also other clinical syndromes, including Klippel-Trénaunay syndrome, CLAPO syndrome, FAVA syndrome, Megalencephaly-Capillary malformation (MCAP) syndrome, and isolated Macrodactyly, and others. These syndromes, including CLOVES syndrome may also be referred to as PIK3CA-Related Overgrowth Sequence or Syndrome (PROS). We are still learning about the different types of PIK3CA gene mutations and their correlation with the different findings or complications in CLOVES and the other clinical syndromes. Called genotype-phenotype correlations, these correlations may help doctors understand risk of certain complications in an individual.

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 not found to have a PIK3CA gene mutation, may still have this mutation, but it just wasn’t identified for various reasons, or they may have a different gene mutation in another related 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. The mutation was first described in fatty masses (lipomas) after removal. 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. For example, identical twins are actually not genetically identical. There are hundreds (at least) of genetic differences between identical twins as a result of mistakes copying DNA each time a cell divides. The vast majority of these genetic changes are silent and irrelevant, but occasionally one causes a disease. If a genetic change in PIK3CA occurs in one cell in a 100 cell embryo, this may explain the genetics of CLOVES. One could imagine that this genetic change could occur earlier (1 in 20 cells) in patients with more of their body affected by CLOVES, or later (1 in 400 cells) in patients with milder disease features.

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.
  2. If 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

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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

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