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

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 expected to begin in February of 2021.

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

 

Genetic testing for CLOVES Syndrome/PROS is more complicated than traditional genetic testing.  Many healthcare providers are still unfamiliar with what mutations to test for and what samples are needed.

Visual of the common genetic mutations for Vascular Anomalies and Vascular Anomaly Syndromes – Arin Greene et al 2018.

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

July 2014 — Clinical Genetic Test available via Washington University  
This test must be ordered by a geneticist/physician. This is somatic variant analysis by next-generation sequencing for Segmental Overgrowth, McCune Albright (SOMA) and related syndromes. The test includes concise, expert interpretations by board-certified clinical genomicists and is covered by most insurance.

https://gps.wustl.edu/wp-content/uploads/2015/11/SOMA_info_sheet_UTD.pdf

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 Anna Buser at [email protected]  or by phone at 301-435-6689.
More information 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


Clinical Signs

 

CLOVES Syndrome is an overgrowth syndrome with complex vascular anomalies. CLOVES stands for Congenital, Lipomatous Overgrowth, Vascular malformations, Epidermal nevi and Scoliosis/Skeletal/Spinal anomalies. The syndrome was described independently by Saap et al. and Alomari [1,2]. The syndrome shows no inheritance among families of affected patients.

CLOVES syndrome is rare and very 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 and extending into gluteal or groin regions. The skin over the mass is covered with a red-pinkish birthmark known as a 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. A person with CLOVES may have large wide hands or feet, large fingers or toes, wide space between digits and uneven size of extremities.
  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, abnormal patella (knee cap), knee and hip joints.

Most people 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 a dedicated physical exam and proper imaging studies.

The diagnosis can be established right after birth, though prenatal diagnosis with modern imaging tools may be feasible [3].

Diagnosis:

Historically CLOVES Syndrome diagnosis has been made by medical exam, observed physical characteristics and clinical information/history. With the discovery of genetic mutation in CLOVES and PROS conditions, tissue testing for PIK3CA can be performed. The diagnosis can be established right after birth, though prenatal diagnosis with modern imaging tools may be feasible.

Criteria:

  • Fatty Truncal Mass
  • Vascular Anomalies
  • Abnormal extremities
  • Skin abnormalities
  • Other abnormalities include small or absent kidney, abnormal, knee and hip joints, and/or scoliosis.

The management of CLOVES syndrome can be very challenging and requires an interdisciplinary team of physicians with experience in overgrowth and vascular anomalies.

References:

Sapp JC, Turner JT, van de Kamp JM, van Dijk FS, Lowry RB, Biesecker LG. 2007. Newly delineated syndrome of congenital lipomatous overgrowth, vascular malformations, and epidermal nevi (CLOVE syndrome) in seven patients. AmJ Med Genet Part A 143A: 2944-2958.

Alomari AI. 2009. 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;18:1-7.

Fernandez-Pineda I, Fajardo M, Chaudry G, Alomari AI. Perinatal clinical and imaging features of CLOVES syndrome. Pediatr Radiol.


Working with Industry

 

CLOVES Syndrome Community seeks the highest level of ethical conduct in engagement with biopharmaceutical companies. The goal of engaging with biopharmaceutical companies is to help enable the development of therapies while maintaining our autonomy.

Guidelines for Interactions Between CLOVES Syndrome Community and Biopharmaceutical Companies

Background

The interactions between CLOVES Syndrome Community (“CSC”) and biopharmaceutical companies are important and complex. Collaborations between these two stakeholders have become more common in recent years as CLOVES Syndrome Community has evolved and biopharmaceutical industry activity has increased, particularly in rare diseases.

The principles outlined in the following guidelines are intended to help CLOVES Syndrome Community navigate critically important interactions with biopharmaceutical companies.

These guidelines were developed with input from an Independent Expert Panel from the rare disease community with expertise in these collaborations from both the industry and patient advocacy organization point of view. More information on the Independent Expert Panel and the process for developing these Guidelines is provided in the article entitled “Principles for interactions with biopharmaceutical companies: the development of guidelines for patient advocacy organizations in the field of rare diseases,” published in The Orphanet Journal of Rare Diseases, 2018.

Introduction

CLOVES Syndrome Community seeks the highest level of ethical conduct in engagement with biopharmaceutical companies. The goal of engaging with biopharmaceutical companies is to help enable the development of therapies while maintaining our autonomy. All interactions between CLOVES Syndrome Community, industry and the disease community should be transparent; should enable trust, accountability and shared learning; and ultimately should work most efficiently and effectively toward advancing meaningful treatments for patients.

There are four main areas of engagement between CLOVES Syndrome Community and biopharmaceutical companies described in the following Guidelines:

  1. Identification and Engagement with Companies
  2. Patient Engagement and Patient Privacy
  3. Financial Contributions
  4. Clinical Trial Communication and Support

Patient Support & Emotional Wellbeing

 

Patient-centered care is key to obtaining positive health outcomes. Studies have shown it is vital to treat the whole patient and not just the disorder. We strongly suggest you refer all families affected by CLOVES to our site. Here they can learn more about CLOVES, join our registry, obtain information on a number of resources, and find support by joining our community.


PIK3CA Related Conditions Research Network

 

CLOVES Syndrome Community is proud to be launching the  PIK3CA Related Conditions Collaborative Research Network, a patient and caregiver led research network that encourages the sharing of ideas among patients, scientists, and physicians.   CLOVES Syndrome Community is one of thirty organizations chosen to participate in the Rare As One Network, which will provide CSC with capacity building tools, resources, funding, training and support, to strengthen our expanding patient community and scientific goals.

Goals

CLOVES Syndrome Community is working to create a patient-led collaborative research network in order to broaden the medical knowledge base, accelerate treatment options and improve quality of life for people with CLOVES and PIK3CA Related Conditions.  

A patient led collaborative research network pulls together a community of stakeholders – including people with specific diseases, their family members, researchers and physicians – to discover and prioritize critical research questions.  The research network relies on the collective voice to identify the most pressing questions and knowledge gaps about a disease. It then recruits the most qualified researchers to help answer these questions and to conduct these studies.  We believe in the power of the collective.   We believe that together, we can make a change in the lives of people with CLOVES and PIK3CA Related Conditions. 
Sign up to learn more about our goals and upcoming projects. 


Publications

 

The publications database will serve as a reference list and educational resource for our existing community as well as young researchers and clinicians as we develop our International PIK3CA Conditions Collaborative Research Network. The database contains information as well as Pubmed links to all published literature on CLOVES and more broadly, on PROS. In this resource, we highlight different article types such as primary research, case series, and reviews, as well as areas of research such as diagnosis, management, and treatment of CLOVES/PROS. New articles will be added each month as they are published to keep our community up to date. 

The publications database is best viewed on a large screen such as a computer or Ipad.

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