On this page
Capillary malformation-AVM syndrome
Also known as Parkes Weber syndrome
CM-AVM syndrome is a rare genetic disorder affecting the vascular system. It typically causes distinctive skin lesions and can lead to more serious, fast-flowing blood vessel malformations in various parts of the body, including the brain and internal organs.
Overview
Capillary malformation-arteriovenous malformation (CM-AVM) syndrome is a rare inherited condition primarily affecting the body's blood vessels. It is characterised by specific types of birthmarks, known as capillary malformations, and more complex vascular anomalies called arteriovenous malformations (AVMs) [PMID:24075133]. Capillary malformations often appear as reddish-purple patches on the skin, present from birth. AVMs are abnormal connections where arteries bypass capillaries and connect directly to veins, leading to high-flow shunting of blood. These AVMs can occur in various locations, including the skin, muscles, bones, brain, spinal cord, and internal organs [PMID:24755913].
Symptoms & clinical features
The main clinical signs of CM-AVM syndrome are capillary malformations, which are typically multiple, round or oval, and reddish-purple. These lesions can be found anywhere on the body and may be warm to the touch. Unlike many other birthmarks, some capillary malformations in CM-AVM syndrome can have a pale halo around their edges. Arteriovenous malformations (AVMs) are the other key feature and can vary significantly in size and location. Skin AVMs may present as visible swellings that are warm and pulsatile. Internal AVMs might not be visible externally but can cause symptoms depending on their location, such as pain, bleeding, or issues with organ function. For instance, brain AVMs can lead to headaches or neurological symptoms, and spinal AVMs may cause back pain or weakness [PMID:17963032].
Video: Genetics 101
Affected organs
CM-AVM syndrome can affect various organs and tissues due to the widespread nature of the vascular anomalies. The skin is commonly affected with capillary malformations and superficial AVMs. Deeper AVMs can occur in muscles, bones, and joints, potentially leading to pain or swelling. More critically, AVMs can develop in the brain and spinal cord, which may result in neurological complications such as seizures, headaches, or even haemorrhage. Internal organs, including the liver, lungs, and gastrointestinal tract, can also be sites for AVM development, potentially impacting their function.
Risks & severity
The severity of CM-AVM syndrome can vary widely among affected individuals, even within the same family. Some people may have only mild skin capillary malformations, while others can develop severe AVMs that pose significant health risks. Brain AVMs, for example, carry a risk of bleeding, which can lead to serious neurological damage or even be life-threatening. AVMs in other locations can also cause complications such as pain, swelling, or organ dysfunction. The condition is present from birth, although symptoms of AVMs may develop or worsen over time. The exact prevalence of CM-AVM syndrome is not well established, but it is considered a rare condition.
Genetic causes
CM-AVM syndrome is caused by pathogenic variants in the RASA1 gene. This gene provides instructions for making a protein called p120-RasGAP. The p120-RasGAP protein plays a critical role in regulating the RAS/MAPK signalling pathway, which is essential for cell growth, division, and differentiation. Specifically, p120-RasGAP acts as a 'brake' on this pathway, helping to switch off signals that promote cell proliferation. When the RASA1 gene has a pathogenic variant, the p120-RasGAP protein may not function correctly, or its amount might be reduced. This can lead to uncontrolled or inappropriate activation of the RAS/MAPK pathway in some cells, contributing to the abnormal development of blood vessels seen in CM-AVM syndrome.
- RASA1 RAS p21 protein activator 1The RASA1 gene encodes a protein crucial for regulating the RAS/MAPK signalling pathway and plays a vital role in the normal development of the vascular system.
Inheritance pattern
CM-AVM syndrome is inherited in an autosomal dominant pattern. This means that a person only needs to inherit one copy of the altered RASA1 gene from one parent to develop the condition. If a parent has CM-AVM syndrome, there is a 50% chance with each pregnancy that their child will also inherit the pathogenic variant and develop the condition. In some cases, the pathogenic variant can occur spontaneously in the affected individual and is not inherited from either parent; this is known as a de novo variant. Family members who do not have the pathogenic variant cannot pass it on to their children.
Each child has a 50% chance of inheriting the pathogenic variant, regardless of sex.
Subtypes & variants
This page covers Capillary malformation-AVM syndrome as a single condition. Several distinct variants and clinical subtypes are recognised in the literature - they share the underlying biology and broad management approach, but differ in severity, age of onset, or causative gene:
- Parkes-Weber syndrome OMIM 608354
A high-flow vascular phenotype within the CM-AVM spectrum, characterised by limb overgrowth in addition to capillary and arteriovenous malformations. Same RASA1 / EPHB4 genetic basis as classical CM-AVM.
Diagnosis & testing
A diagnosis of CM-AVM syndrome is typically suspected based on characteristic clinical features, such as the presence of multiple capillary malformations with or without a pale halo, and the identification of high-flow AVMs. Confirmation of the diagnosis is achieved through genetic testing, which looks for pathogenic variants in the RASA1 gene. Genetic testing can be initiated following a referral to a clinical genetics service, often after a vascular specialist suspects the condition. In the UK, genetic testing for CM-AVM syndrome would fall under the NHS Genomic Medicine Service (GMS) testing directory, likely linked to an R-code for vascular anomalies. Referral to clinical genetics can be made by a GP or other specialist to discuss the appropriateness of genetic testing.
Management & lifestyle
Management of CM-AVM syndrome focuses on monitoring and treating the vascular anomalies to prevent or manage complications. This often involves a multidisciplinary team, including dermatologists, interventional radiologists, neurologists, and geneticists. Surveillance for AVMs, particularly in critical locations like the brain, is crucial and may involve imaging techniques such as MRI or MRA. Treatment options for AVMs depend on their location and size and may include embolisation (blocking the AVM with a substance), surgical removal, or stereotactic radiosurgery for brain AVMs. Symptomatic management for pain or other complications may also be required. Individuals and families affected by CM-AVM syndrome can benefit from genetic counselling to understand the inheritance pattern and implications for family planning, and to access support resources through the NHS Genomic Medicine Service pathway.
UK care pathway
In the UK, individuals suspected of having a genetic condition like CM-AVM syndrome can access care through the NHS Genomic Medicine Service. This typically begins with a referral to a clinical genetics department from a GP or other specialist. Genetic counsellors within these services provide information, support, and facilitate genetic testing as appropriate. Testing for conditions like CM-AVM syndrome is listed within the National Genomic Test Directory (accessible via specific R-codes), which outlines the genetic tests available within the NHS. Genetic counsellors also help families understand inheritance patterns and potential implications for other family members.
Frequently asked questions
What is the difference between a capillary malformation and an arteriovenous malformation?
A capillary malformation is a type of birthmark, typically a flat, reddish-purple patch on the skin, made of widened capillaries. An arteriovenous malformation (AVM) is a more complex anomaly where arteries connect directly to veins, bypassing the normal capillary bed, leading to a high-flow shunting of blood that can be more medically significant.
Can CM-AVM syndrome be passed down to children?
Yes, CM-AVM syndrome is inherited in an autosomal dominant manner. If a parent has the condition, there is a 50% chance with each child that they will also inherit the genetic variant and develop the syndrome.
Are the vascular malformations always visible?
No, while capillary malformations on the skin are often visible from birth, arteriovenous malformations (AVMs) can occur internally in organs like the brain, spinal cord, or liver, and may not be visible externally. Internal AVMs can cause symptoms depending on their location.
What kind of doctors treat CM-AVM syndrome?
Management of CM-AVM syndrome usually involves a team of specialists due to the varied nature of the condition. This team may include dermatologists, interventional radiologists, neurologists, neurosurgeons, and clinical geneticists, among others, to address the specific types and locations of malformations.
Is there a cure for CM-AVM syndrome?
There is currently no cure for CM-AVM syndrome. Treatment focuses on managing symptoms, preventing complications, and addressing specific vascular malformations through various interventions like embolisation, surgery, or medication, depending on their location and severity.
References
- Naganathan S, Tadi P. Klippel-Trenaunay-Weber Syndrome. 2023. PMID: 32644415
- Adam MP, Bick S, Mirzaa GM. Capillary Malformation-Arteriovenous Malformation Syndrome. 1993. PMID: 21348050
- Kumar V, Jorwal P, Biswas A. Parkes Weber syndrome. QJM : monthly journal of the Association of Physicians. 2019. PMID: 31086946
- Capraro PA, Fisher J, Hammond DC. Klippel-Trenaunay syndrome. Plastic and reconstructive surgery. 2002. PMID: 11994613
- Kirkorian AY, Grossberg AL, Püttgen KB. Genetic basis for vascular anomalies. Seminars in cutaneous medicine and surgery. 2016. PMID: 27607321
- Bertino F, Braithwaite KA, Hawkins CM. Congenital Limb Overgrowth Syndromes Associated with Vascular Anomalies. Radiographics : a review publication of the Radiological Society of North America, Inc. 2019. PMID: 30844349
- Calvo-Garcia MA, Kline-Fath BM, Adams DM. Imaging evaluation of fetal vascular anomalies. Pediatric radiology. 2015. PMID: 25492302
- Brouillard P, Vikkula M. Genetic causes of vascular malformations. Human molecular genetics. 2007. PMID: 17670762