NOVA Medical Director, Denise Adams, MD has transferred her practice to Boston Children’s Hospital. Dr. Adams has served as the Medical Director of NOVA since 2005 and has been an advisor to our organization since 1999. Dr. Adams can be reached at firstname.lastname@example.org. Visit our physician directory for more information on physicians.
In the 2011 years that NOVA has worked to assist individuals diagnosed with vascular anomalies there have been incredible advances in the science of vascular tumors and malformations. These scientific discoveries often lead to targeted therapies and treatments for patients. The relief on a parent’s face, when they discover there is finally a treatment for the pain and suffering their child has endured reminds us at NOVA of the important life changing work we have been involved in for over 2 decades now. Some of the latest scientific discoveries are listed here:
Researchers at Memorial Sloan Kettering Cancer Institute have identified the PIK3CA gene in vascular malformations. This gene is a known cancer gene and its isolation in vascular malformations will lead to better treatments and therapies for patients. You can read the entire article on the MSKCI website: https://www.mskcc.org/blog/surprising-discovery-connects-rare-vascular-disease-cancer-gene
Another discovery this year has led us to a better understanding of Port Wine Stains and Sturge Webber Syndrome. Published in The New England Journal of Medicine, these vascular birthmarks have been linked to a single change in a single gene after conception. This genetic anomaly resulting in a PWS is known to affect about one in 300 babies, while Sturge-Weber Syndrome occurs in about one in 20,000 births. Advances in bioinformatics have helped identify when and where the molecular switch gets tipped. Jonathan Pevsner, director of bioinformatics at the Kennedy Krieger Institute in Baltimore, says: “It’s great because we have an immediate biochemical understanding of what’s happening, and that means we can immediately move on to the idea of what to do about it.” You can read the full article at http://zalea.com/article/15336/2016/03/31/the-science-behind-the-port-wine-birthmark?utm_source=Combined+Newsletter+List&utm_campaign=84acffbcf6-Weekly_Newsletter4_04_2016&utm_medium=email&utm_term=0_5615138614-84acffbcf6-367630497
Lymphatic Malformations can be very challenging for the clinician to treat. Interventions include sclerotherapy and surgery are invasive and may result in complications and recurrence of the lesion. A new study published in the Journal of the American Academy of Dermatology 2014 March 20 pii: S0190-9622(14)0119-0 examines sildenafil generic for viagra to treat lymphatic malformations.
Patients were placed on 20 weeks of oral sildenafil, LM were assessed for volum and symptoms. Sever male children and 3 females were observed; ages 13-85 months. There was a therapeutic response of softening and compressiblity in all patients. Adverse events were minimal. A larger randomized controlled study is needed to better verify these results however; it seems sildenafil may reduce lymphatic malformation volume and symptoms in some patients.
J Am Acad Dermatol. 2014 Mar 20. pii: S0190-9622(14)01119-0. doi: 10.1016/j.jaad.2014.02.005. [Epub ahead of print]
An open-label study to evaluate sildenafil for the treatment of lymphatic malformations.
- 1Department of Dermatology, Lucile Packard Children’s Hospital at the Stanford University School of Medicine, Palo Alto.
- 2Department of Radiology, Stanford University School of Medicine, Stanford.
- 3Department of Dermatology, Lucile Packard Children’s Hospital at the Stanford University School of Medicine, Palo Alto. Electronic address: email@example.com.
Just finished reading 6 Abstracts on the use of Propranolol in the management of Infantile Hemangioma. All of the information came from presentations at the 2014 ISSVA meeting in Melbourne, Australia last week. A summary is below. Much of the information is just now being published in the latest Medical Journals so it truly is the latest medical information on the subject.
Propranolol is a widely prescribed medication classified as a beta-blocker used for the treatment of infantile hemangioma. Since 2007 it has been used off-label because there has not been an approved formulation of propranolol, specific for infants and the treatment of infantile hemangioma. Several institutions here in the USA and Europe have taken part in a 2+ year study assessing the safety of propranolol in infants. As a result an oral formulation will be available here in the USA in June 2014 under the brand name Hemangeol. (Pierre Fabre Pharmaceuticals USA will be manufacturing the medication) The studies have not only produced a new brand name of propranolol here in the USA but it has produced data on the safety and efficacy of this medication in the treatment of infantile hemangioma.
Oral Propranolol has a favorable risk profile in the pediatric population studied. In one study of 460 infants the IH improved in 88% of the patients treated with no unexpected safety concerns. This same group reported that patients tolerated the medication with mild or moderate side effects. The only contraindication being noted is bronchial reactivity. (1,2)
Another study examined the impact of propranolol on pediatric growth and human growth hormone levels in infants. No impact was found. (3)
A group from Russia studied the effects of propranolol on the cardiovascular system with and without preexisting heart problems. 154 infants with IH were prescribed propranolol and cardiological evaluation with EKG, ECHO, holter monitoring and blood pressure was observed for more then 9 months. Only a small percentage of adverse events were noted. This group recommends monitoring children at risk for cardiac complications during use of propranolol. A similar study out of Oregon concluded that routine ECG monitoring for patients prior to propranolol use is not necessary and a more purposed driven strategy is a better approach. (4,5)
272 Hemangioma Patients were evaluated for developmental psychomotor skills. No delays or effects on psychomotor development was found. (6)
In my review of this information propranolol appears to be safe to use in most infants and children presenting with infantile hemangioma. Patients should be monitored during treatment and physicians should be awear of the indications for concern. More studies are on going.
1.Christine Leaute-Labreze, Ilona Frieden, Pierre Vabres, Sorilla Prey, Jean-Jacques Voisard, Propranolol in IH: Results from an international randomized placebo controlled study.
2.Sorilla Prey, Christinen Leute-Labreze, Ilona Frieden, Allain Delarue, Jean Jacquez Voisard, Safety of oral propranolol for the treatment of IH: 2 years results of a controlled multicenter trial
3.Rachel Giese, Mario Cleves, Jessica Boswell, James Suen, Gresham Richter, Propranolol for Treatment of IH: Efficacy and Effect on Growth and Development
4. Margarita Timofeeva and Natalia Katlukova, Cardiovascular Complications of Propranolol Treatment for IH
5.Kevin Yarbrough, Alfan Krol, Julianne Mann, Sabra Leitenberger, Carol MacArthur, Is Routine ECG necessary prior to initiation of propranolol for treatment of IH
6. Andre Moyakine, Denise Hermans, Joris Fuijkschot, Carine van der Vleuten, Development Milestone: no negative effects detected upon psychomotor development
As these articles get published we will update the references and citations.
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After 25 years of searching, the Sturge-Weber Foundation (SWF) is thrilled to join patients, physicians, researchers and government agencies in celebrating the identification of the gene mutation responsible for Sturge-Weber syndrome and port-wine birthmarks. The new research was published online today in The New England Journal of Medicine. http://www.sturge-weber.org/
FOR IMMEDIATE RELEASE
Thursday, May 31, 2012
Researchers at Boston Children’s Hospital identify a genetic cause for CLOVES, a rare but debilitating overgrowth and malformation syndrome
Discovery opens doors to targeted therapeutic development and to understanding other, similar disorders
Boston, Mass.—Using advanced technologies for rapidly sequencing and analyzing DNA from clinical and pathologic samples, a multidisciplinary research team consisting of geneticists, pathologists and surgeons at Boston Children’s Hospital has identified the genetic basis for CLOVES syndrome, a rare congenital malformation and overgrowth disorder.
The discovery raises the hope that, for the first time, it will be possible to develop targeted medical treatments capable of delaying, reversing or possibly preventing CLOVES’s debilitating consequences. Importantly, it also demonstrates the potential of advanced DNA sequencing technologies for identifying the underlying molecular roots of malformation disorders that are genetic but not hereditary.
The team—led by Matthew Warman, MD, director of the Orthopedic Research Laboratories at Boston Children’s, and Kyle Kurek, MD, of the hospital’s department of Pathology, and members of the hospital’s Vascular Anomalies Center—reported the discovery today in the online edition of the American Journal of Human Genetics.
Some 90 children worldwide have been diagnosed with CLOVES (which stands for Congenital Lipomatous Overgrowth, Vascular malformations, Epidermal nevis, Spinal/skeletal anomalies/scoliosis) since 2006, when the condition was first characterized by Boston Children’s Ahmad Alomari, MD, and investigators at the National Institutes of Health. Alomari co-directs the Vascular Anomalies Center with Steven Fishman, MD, and John Mulliken, MD; all three are authors on the paper.
The clinical features of CLOVES—in general a combination of fatty growths in the torso, vascular and skin anomalies, overgrowth in or deformities of limbs or extremities and spinal problems such as scoliosis—can vary greatly from child to child. Presently there is no cure for CLOVES, only surgical treatments aimed at alleviating symptoms or managing the syndrome’s progression.
Until now, the exact nature of the genetic defect or defects that cause CLOVES has remained a mystery.
“CLOVES is dynamic, presenting itself in new ways all the time, even within the same patient,” said Fishman, who with Alomari and others in the Vascular Anomalies Center has treated numerous children with CLOVES. “With this discovery we are optimistic that it will now be possible to develop treatments that take less of a shotgun approach and which could prevent the syndrome’s progression.”
The researchers started from the assumption that CLOVES is genetic but not inherited, because the syndrome always appears sporadically and is never passed from affected parents to their children; nor do the parents of affected children show signs of the syndrome.
“We suspected that a mutation in a single gene would be the cause, but in the beginning we weren’t sure if the mutation would affect the gene’s coding sequence or genetic regions that determine how a gene’s expression is regulated.” said Warman. “We also did not know whether the mutation would be the same across patients.”
To identify the disease-causing mutation, Warman, Kurek and their colleagues used massively parallel (also known as next generation) sequencing technologies to read and compare the full exomes (all protein-coding gene sequences) of affected and unaffected tissues from several CLOVES syndrome patients treated in the Vascular Anomalies Center at Boston Children’s.
The team found that between six and 60 percent of cells in each individual’s affected tissues contained mutations in a gene called PIK3CA, a component of a key molecular pathway regulating cell division and growth. Even though the precise mutations differed slightly between the patients, each mutation—a simple replacement of one DNA base for another, altering the structure of the protein PIK3CA encodes—has the effect of activating the pathway in the absence of external signals promoting growth.
The mutations were absent in the unaffected tissues tested.
Based on their findings, Warman and his colleagues determined that CLOVES is the result of a somatic mosaic mutation—a mutation that appears only in a portion of an individual’s cells, rather than being present throughout his or her entire body.
“These are point mutations that likely arise spontaneously in a single cell during embryonic or fetal development, and which are passed on only to cells derived from that original mutant cell,” Warman explained. “The presence of a large percentage of unmutated cells within affected tissues suggests that there is a kind of innocent bystander effect occurring, where unmutated cells respond to abnormal signals produced by cells carrying the mutation and contribute to the syndrome’s malformations and overgrowths.”
Both Fishman and Warman credit the interdisciplinary environment at Boston Children’s with making the team’s breakthrough possible.
“Gene discovery in rare conditions like CLOVES requires a combination of circumstances nearly unique to Children’s: doctors who classified CLOVES as a new condition; tissues from the large number of CLOVES patients referred to the Vascular Anomalies Center because of our experience with unusual vascular and overgrowth conditions; and world-class molecular genetic expertise,” Fishman said. “The methods Drs. Warman and Kurek developed to find these mutations are very exciting and could help many other children with sporadically occurring diseases that are not hereditary but likely genetic.”
“This project represents the perfect marriage of surgery, pathology and genetics,” said Warman. “It was only through the combined efforts of multiple specialists—the surgeons in the Vascular Anomalies Center who had the foresight to save for future genetic studies the tissues resected from their patients, the pathologists who could tease apart affected and unaffected tissues from within the lesions, and the geneticists with the tools to sequence and compare unaffected and affected genomes—that this breakthrough was possible.
“Having now found these driving mutations in CLOVES,” he continued, “we have a good starting point from which to both develop models to understand how mutations in PIK3CA cause malformation and overgrowth and to determine which drugs and other therapies can be used safely and successfully to improve the lives of individuals with CLOVES and other conditions with similar clinical characteristics, such as Klippel-Trenaunay syndrome.”
The study was supported by the National Institute of Arthritis and Musculoskeletal and Skin Diseases, the Manton Center for Orphan Disease Research and the Stuart and Jane Weitzman Family Vascular Anomalies Fund (both at Boston Children’s Hospital), and the Howard Hughes Medical Institute.
Boston Children’s Hospital is home to the world’s largest research enterprise based at a pediatric medical center, where its discoveries have benefited both children and adults since 1869. More than 1,100 scientists, including nine members of the National Academy of Sciences, 11 members of the Institute of Medicine and nine members of the Howard Hughes Medical Institute comprise Boston Children’s research community. Founded as a 20-bed hospital for children, Boston Children’s today is a 395 bed comprehensive center for pediatric and adolescent health care grounded in the values of excellence in patient care and sensitivity to the complex needs and diversity of children and families. Boston Children’s also is the primary pediatric teaching affiliate of Harvard Medical School. For more information about research and clinical innovation at Boston Children’s, visit: http://vectorblog.org.
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We have had a lot of discussion on face-book concerning the genetic/inheritance of hemangioma. It is the generally understood that infantile hemangioma is sporadic, that there is not an inheritance pattern. However there has been some families where it has appeared that there was more of an incidence then the rest of the population. This has cause concern for many parents, wondering if a sibling might also have a significant hemangioma.
First lets go over some basic terminology:
Congenital- simply means you were born with it. This does not necessarily mean that it is inherited for that it was passed down from your parents.
Genetic:- when this term is used it may mean that there is an inheritance pattern but it may also simply mean that a mutation or change in the gene occurred randomly.
Inherited- this is the term that when used is meant that there is a known inherited link in a family. There are many diseases that run in families, that there is a genetic cause that is passed down.
This is an over simplification of things but it will help you keep things straight.
In vascular anomalies we have two main groups. Tumors and Malformations.
The most common benign vascular tumor is the Infantile Hemangioma. It is this lesion that primarily occurs randomly. There is also the Congenital Hemangioma either the RICH or NICH forms. These are less common and while the child is born with a fully formed hemangioma it is not known to be inherited.
There are many types of vascular malformations. Malformations may occur in the veins, arteries, smaller vessels and even the lymphatic vessels.
Scientists have identified Genes and markers associated with malformations and hemangiomas. They have been able to test for the presence of the genes and markers to help distinguish between the types of anomalies.
MOST vascular anomalies are considered non-hereditary. Through the detailed analysis they have discovered inheritance forms of some vascular anomalies. They have identified mutations in genes that have cause familial malformations in RARE cases.
*Tie-2 gene (angiopoietin receptor): in mucocutaneous venous malformations (VMCM0
*Glomulin: in glomuvenous malformations (GVM)
*RASA1: in campllary malformations-arteriovenous malformations (CM-AVM)
The identification of these genes has allowed for more accurate and precise diagnosis, differential diagnosis, evaluation of variability in patients with known mutations and the study of treatments in identified patients. Identification of these genes will allow the clinician to determine the type of vascular anomaly and differentiate between malformation and tumor.
In infantile hemangioma there was an identified gene in one family that appeared in the published work of Doug Marchuk at Duke University. There have also been identified biomarks that have helped researchers understand the pathogenesis of hemangioma and to distinguish between infantile hemangioma/congenital hemangioma and malformations. At this time hemangioma is still primarily considered to be occurring sporadically.
Vikkula, M; Pathogenesis and Genetics of Vascular Anomalies, Ann Chir Plast Esthet, 2006 Aug-oct 51(4-5) .
Nauyen, VA; Kutzner, H; Furhapter, C; tzankov, A; Sepp, N, Infantile hemangioma is porliferation of LYVE-1-Negative blood endothelial cells without lymphatic competence, Modern Pathology, 2006 Feb:192(2):291-8
Mulliken, John, Enjolras, Odile, Congenital Hemangioma and Infantile Hemangioma: missing links. Journal of American Academy of Dermatology, July 2004; (875-881)