PATIENTS AREA

Overgrowth syndromes are defined as a group of rare genetic syndromes characterized by malformations and tissue proliferation caused by somatic mutations affecting different mTOR genes of which the most well-known is PIK3CA.

Patients with these syndromes may have gain-of-function mutations (PIK3CA, AKT1, AKT2 or AKT3, mTOR, etc.) or loss-of-function mutations (PTEN, TSC1, TSC2, etc.). Either way, these lead to excessive activation of the mTOR pathway, a signaling pathway that plays a major role in controlling cell growth and proliferation. These mutations usually occur during embryonic development, in other words, after fertilization (mosaic), and can affect any type of tissue.

Clinical presentation

The clinical presentation at birth is extremely variable depending not only on when the mutation occurred (e.g. at early or late stage of the embryological development) but also on the type of tissue affected (vessels, muscle, fat, bones, nerve cells, etc.). The excessive activation of the mTOR pathway leads to excessive proliferation (hyperplasia) as well as an increase in the size of cells (hypertrophy) which are both responsible for complex and anarchic malformations that deform the body and limbs. The disease is present since the moment of birth, it can even sometimes be identified during the antenatal period and will progress with age. Malformations are not stable and increase in volume throughout the patients’ life. The rate of growth is extremely variable from one patient to another.

Clinical diagnosis

In addition to complex clinical diagnosis, the identification of the mutated gene can be extremely difficult. The detection of the mutation requires a biopsy of the affected tissue (mosaic) and current sequencing methods, namely Next-Generation Sequencing – NGS since the mosaic rate can be as low as 1%. For this reason, only a few medical centers can provide a precise diagnosis. The broad clinical presentation and the technical problems in identifying the mutation make the diagnosis extremely difficult for physicians.

It is important to recall that in several cases (approximately 20% in our experience), no genetic abnormalities are identified among the genes known to cause overgrowth syndromes.

Clinical complications

These syndromes may include several complications such as functional impairment (e.g. in walking or in the activities of daily living) pain, recurrent superficial infections (erysipelas), phlebitis with or without pulmonary embolism, bleeding, and/or organ dysfunction. These conditions are responsible for substantial morbidity and premature mortality. Currently, there is no specific treatment available for these pathologies and only symptomatic treatments are proposed (analgesics, anticoagulation, radiological embolization or surgery). Most of the time a multidisciplinary therapeutic approach is required. Unfortunately, these patients often undergo numerous mutilating surgical procedures (orthopedic, visceral, maxillofacial, etc.).

Furthermore, overgrowth syndromes are frequently associated with crippling disabilities resulting in deleterious social consequences characterized by a high rate of school drop out for children and desocialization.

Among patients with overgrowth syndromes, there is a group characterized by the presence of gain-of-function mutation of the PIK3CA gene. These patients are classed under the general term PIK3CA-related overgrowth syndrome (PROS) which encompasses a group of syndromes with various phenotypes, including (but not limited to):

  • CLOVES Syndrome(Congenital Lipomatous Overgrowth, Vascular Malformations, and Epidermal Nevi)
  • Macrocephaly-capillary malformation (M-CM)
  • HemiHyperplasia-Multiple Lipomatosis syndrome (HHML)
  • FibroAdipose Overgrowth (FAO)
  • Hemimegalencephaly or Unilateral Megalencephaly (HME)
  • Facial Infiltrating Lipomatosis (FIL)
  • Klippel-Trenaunay Syndrome (KTS)

Importantly, these genetic mutations are commonly found in cancer and the reposition and/or repurpose drugs primarily developed for oncology can be very promising for patients with these rare syndromes. Some of these molecules, when used at low levels, show therapeutic effects that have yet to be confirmed.

From Research to Discovery of Treatment

We recently created the first mouse model of PROS syndrome, identified BYL719 (alpelisib, a PIK3CA inhibitor developed in oncology), and demonstrated its effectiveness in our PROS mouse model. Based on these results, we obtained the authorization of the French National Agency for the Safety of Medicines and Health Products to treat 19 patients with a severe form of the disease. The results were remarkable with an improvement in numerous parameters (bleeding, pain, fatigue, etc.) but also morphological changes with a rapid reduction in the size and volume of tumors. This molecule is well tolerated with little or no side effects observed thus far.

After the release of the scientific paper, we received a certain number of patients with PROS and severe disabilities, to whom we were authorized to give the BYL719 under a compassionate use program.


Hospital Facility

So far, more than 3500 patients across the globe have reached us including 480 French patients. Most of the patients were affected by overgrowth but without a molecular diagnosis. To face this huge demand, we organized our clinical department at Necker-Enfants Malades hospital in order to offer the best services as possible. In a single day, patients have access to all physicians, surgeons, biopsy, DNA storage, and imaging. Patient flow is always very high with new daily requests.

The diagnosis process

〉 During the antenatal period, through your gynecologist

The diagnosis is sometimes recommended during the antenatal period, before the association of segmental hypertrophy and/or extensive lymphatic malformation, and/or presence of limb abnormalities.

Your case report will be presented by your gynecologist to a Multidisciplinary Centre for Prenatal Diagnosis (Centre Pluridisciplinaire de Diagnostic PréNatal - CPDPN), where gynecologists, radiologists, and geneticists will be called upon.

〉 After birth, through your pediatrician or general practitioner

The general practitioner’s role is to ensure that patients can have a precise diagnosis and a follow-up plan from an Expert Center (for example Necker-Enfants Malades hospital). The diagnosis will be given as early as possible after birth, before the presence of segmental hypertrophy associated or not with skin, vascular, and extremity abnormalities.

The pediatrician or general practitioner will contact specialized dermatologists, vascular specialists, and/or clinical geneticists, and you will be informed about the following steps to have a genetic diagnosis. For this purpose, sampling of the affected tissue is necessary to identify the causative mutation, which, in most cases, is not detectable in blood. Tissue sampling is performed by a dermatologist at the expert center and, thanks to the application of an anesthetic cream, is painless. The test results are communicated by the expert center and are available within 4 months.

WARNING: The first mention of the name Cloves Syndrome may lead you to do a web search. Information should be analyzed with great caution because not all sources are reliable. Besides, it may contain images that may offend the sensibilities of visitors. Remember that EVERY CASE IS DIFFERENT, and the clinical presentation differs according to the individual ranging from severe to moderate.


Centers for patient care in France

  • 4 Reference Centers

A reference center brings together a highly specialized hospital team with proven expertise in a rare disease - or a group of rare diseases - which carries out its activities in the fields of care, education, training and research. This medical team, also with paramedical, psychological, medical and social, educational and social skills, organizes patient care in connection with all the relevant health professionals.

  • 54 Competence Centers

    At the regional level, the Competence Centers establish the diagnosis of rare diseases, implement therapy when available and organize patient care in conjunction with reference centers and nearby medico-social structures.
    Find the Competence Center near your home in the interactive directory of Fava-Multi : https://www.favamulti.fr/annuaires/annuaire-detaille-de-la-filiere/

Health Professionals

Follow-up is often coordinated by a geneticist or dermatologist at the expert centers. In the case of children, they are also regularly followed by a pediatrician or a general practitioner. Patients are informed of possible complications and always supported by their expert centers.

Usually, several specialists are needed for the management of the patient, whose solicitation will not be systematic, but depending on the clinical presentation and its evolution: vascular doctors, orthopedic surgeons, plastic surgeons, digestive surgeons, pediatric surgeons, functional re-education physicians, radiologists, interventional radiologists, anesthesiologists, hematologists, hemostasis, molecular biologists, otolaryngologists, stomatologists, gastroenterologists, thoracic surgeons, neurologists, urologists, nephrologists, cardiologists, maxillofacial surgeons, neurosurgeons, cardiovascular surgeons…

If necessary, all the medical care is done along with other health professionals depending on the patient’s impairments: nurses, physiotherapists, occupational therapists, psychologists, orthoprothesists, dentists, orthodontists, podiatrists, dieticians, psychomotors, speech language pathologists…

All these professionals work alongside general practitioners, pediatricians, dermatologists, and/or geneticists for overall patient care, and all the expert center professionals remain available as the main interlocutors.


At School

The school's health professional and social worker are a great support for families. They help to solve medical-social problems. The social worker can provide assistance with administrative procedures, support the relationship with administrative bodies, supervise school integration, offer vocational guidance, and inform of legislation relative to disability if the clinical situation requires it.


Regularity and content of medical follow-up

Usually, 2 to 3* jointly follow-up consultations with dermatologists and genetics are organized per year.

1* annual (or more frequent) clinical examination is recommended: follow-up of vascular, lymphatic, venous malformations, cutaneous manifestations, lipomatous masses, complete orthopedic examination, particularly including the vertebral statics, hypertrophy, thromboembolic risk, and sometimes cardiac.

* The frequency of medical consultations and exams should be adapted according to the clinical presentation as well as its evolution.


Therapeutics and treatment

Currently, no specific treatment for OS with a marketing authorization (MA) is available, but there are PI3K inhibitors available through Temporary Authorisation for Use (ATU) and/or therapeutic trials.

If a patient is eligible to be included in a therapeutic trial, this option is always preferable due to the constant drug safety monitoring, the addition to medical knowledge related to the treatment, and the possibility of being listed for future therapeutics.

Syndrome CLOVES : https://www.facebook.com/Association-Syndrome-Cloves-1202453779845122

CLOVES Syndrome Community : https://clovessyndrome.org/

Klippel-Trenaunay Syndrome : https://k-t.org/


Find information about a rare disease in France

The Orphanet website is the most important European portal for information on rare diseases. https://www.orpha.net/consor/cgi-bin/index.php

Orphanet publishes and updates every year the "Living with a rare disease in France" section which addresses in detail the many aids and devices available. Do not hesitate to consult all the glossary entries as well as the infographic "Living with a rare endocrine disease".

Maladies Rares Info Service : is the reference information and support service on rare diseases. To be listened to, to be informed, to testify, to exchange : https://www.maladiesraresinfo.org / 01 56 53 81 36


Living with a rare disease

Interactive presentation which addresses themes such as "Living with your illness", "living with your disability", "being treated in the city", "being treated in the hospital" is available in French on : http://parcourssantevie.maladiesraresinfo.org

Infographics : Source : https://www.favamulti.fr/wp-content/uploads/2017/06/Vivre-avec-la-maladie-rare-3-01.jpg

Video "What is a rare disease" : Foundation for Rare Diseases : https://youtu.be/3CmJRl0BNQg


Useful Links and Resources

The Rare Disease Platform brings together 6 French and Europeans organizations that are engaged in the fight against rare diseases: AFM Téléthon, Alliance Maladies Rares, Fondation Maladies Rares, Orphanet, Maldies Rares Info Service et Eurordis. https://www.plateforme-maladiesrares.org


The Rare Disease Platform of Necker hospital in
available on : https://www.plateforme-maladiesrares.org

Useful links for rare diseases

  • AnDDI-Rares – Anomalies du développement et déficience intellectuelle de causes rares : website
  • BRAIN-TEAM – Maladies rares à expression motrice ou cognitive du système nerveux central : website
  • CARDIOGEN – Maladies cardiaques héréditaires : website
  • DéfiScience – Maladies rares du développement cérébral et déficience intellectuelle : website
  • FAI²R – Maladies auto-immunes et auto-inflammatoires systémiques rares : website
  • FILFOIE – Maladies hépatiques rares de l’enfant et de l’adulte : website
  • FILNEMUS – Maladies neuromusculaires : website
  • FILSLAN – Scélrose latérale amyotrophique : website
  • FIMARAD – Maladies rares en dermatologie : website
  • FIMATHO – Malformations abdomino-thoraciques : website
  • FIRENDO – Maladies rares endocriniennes : website
  • G2M – Maladies héréditaires du métabolisme : website
  • MARIH – Maladies rares immuno-hématologiques : website
  • MCGRE – Maladies constitutionnelles rares du globule rouge et de l’érythropoïèse : website
  • MHémo – Maladies hémorragiques constitutionnelles : website
  • Muco/CFTR – Muscoviscidose et affections liées à une anomalie de CFTR : website
  • NeuroSphinx – Complications neurologiques et sphinctériennes des malformations pelviennes et médullaires rares : website
  • ORKID – Maladies rénales rares : website
  • OSCAR – Maladies rares de l’os, du calcium et du cartilage : website
  • RespiFIL – Maladies respiratoires rares : website
  • SENSGENE – Maladies rares sensorielles : website
  • TETECOU – Maladies rares de la tête, du cou et des dents website


DG SANTE - DG for Health and Food Safety


European research infrastructure websites

European Commission - DG Research & Innovation - Horizon 2020 - EU Research and Innovation program - European Research Council (ERC)