Last updated:
07/17/2025
Years published: 2025
NORD gratefully acknowledges Michelle Nguyen, MS and Pinar Bayrak-Toydemir, MD, PhD, FACMG, Department of Pathology, University of Utah, ARUP Laboratories, for the preparation of this report.
Capillary malformation-arteriovenous malformation (CM-AVM) syndrome is a rare genetic condition characterized by multiple, small flat red or pink patches on the skin (capillary malformations). Capillary malformations are mostly found on the face and limbs. Affected people may also have tangles of blood vessels called arteriovenous malformations (AVM) and/or arteriovenous fistulas (AFV). AVMs and AFVs arise in the skin, muscle, bone, spine and brain resulting in bleeding, heart failure and/or neurologic symptoms early in life. CM-AVM is an autosomal dominant condition caused by a change (variant) in one copy of the EPHB4 or RASA1 gene. In most people, the disease-causing gene variant is inherited from a parent. The diagnosis is suspected based on signs and symptoms and confirmed with a genetic test. Treatment of capillary malformations is cosmetic and determined by dermatologists. Treatment for AVMs and AVFs may include surgery or a procedure to block blood flow to the affected blood vessel (embolism).1–3
CM-AVM symptoms include any of the following:
CM-AVM syndrome may present with an excessive amount of amniotic fluid (polyhydramnios) that surrounds the developing baby in the womb, or hydrops fetalis, characterized by fluid accumulation in fetal tissues and buildup of lymphatic fluid in the chest cavity during prenatal development which can be rare but serious manifestations (chylothorax).5 Other findings may include pleural effusion, the buildup of fluid in the space between the lungs and chest wall (pleural space) and pericardial effusion, the buildup of fluid around the heart (pericardial sac). As expected, the main features of CM-AVM syndrome, such as skin abnormalities, vascular malformations, heart problems or limb overgrowth can be better recognized after the baby is born.5
In addition, people with CM-AVM may have different symptoms depending on which gene is affected. The main differences include:3
See the “Causes” section for more information on the genes involved in CM-AVM.
CM-AVM is linked to changes (variants) in the RASA1 or EPHB4 gene. Accordingly, CM-AVM can be called CM-AVM1 (CM-AVM due to variants in RASA1 gene) and CM-AVM2 (CM-AVM due to variants in the EPHB4 gene).6 Genes provide instructions for our cells to create proteins that play a variety of different roles in how our bodies grow and function.
The EPHB4 gene is responsible for making a protein (EPH receptor B4) that guides blood vessel development. CM-AVM involves problems with these genes that are important for how blood vessels grow and connect with each other correctly. The RASA1 gene is responsible for making a protein (Ras p21 activator) that controls the RAS/MAPK pathway, which tells cells how to grow, change and multiply.2,3,7
Inheritance of CM-AVM is autosomal dominant with variable expression. Dominant genetic disorders occur when only a single copy of a disease-causing gene variant is necessary to cause the disease. The gene variant can be inherited from either parent or can be the result of a new (de novo) altered gene in the affected person. A parent with an autosomal dominant condition has a 50% chance of having a child with the condition. This is true for each pregnancy and for both males and females. Children who do not inherit the gene variant will not develop or pass on the disease. If someone is diagnosed with an autosomal dominant disease, their parents should also be tested for the gene variant.
Variable expressivity refers to the range of signs and symptoms that can occur in different people with the same genetic condition. 7/10 patients with CM-AVM due to a RASA1 variant have an affected parent. 8/10 patients with CM- AVM due to an EPHB4 variant have an affected parent.2
CM-AVM due to a variant in the RASA1 gene is estimated to affect 1 out of 12,000 people. CM -AVM due to a variant in the EPHB4 gene is estimated to affect 1 out of 20,000 people.2
The diagnosis of CM-AVM is made in patients who have any of the following:
Several evaluations are recommended after the diagnosis of CM-AVM:2
Treatment for CM-AVM includes:3,6
Information on current clinical trials is posted on the Internet at https://clinicaltrials.gov/
All studies receiving U.S. Government funding, and some supported by private industry, are posted on this government web site.
For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:
Tollfree: (800) 411-1222
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Email: [email protected]
Some current clinical trials also are posted on the following page on the NORD website:
https://rarediseases.org/living-with-a-rare-disease/find-clinical-trials/
For information about clinical trials sponsored by private sources, contact:
http://www.centerwatch.com/
For information about clinical trials conducted in Europe, contact:
https://www.clinicaltrialsregister.eu/
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Learn more https://rarediseases.org/patient-assistance-programs/medicalert-assistance-program/Ensuring that patients and caregivers are armed with the tools they need to live their best lives while managing their rare condition is a vital part of NORD’s mission.
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