Capillary malformation-AVM syndrome 2

Overview

Capillary malformation-AVM syndrome 2 represents a specific inherited vascular disorder in which blood vessels develop abnormally during early growth. The condition typically presents with visible capillary malformations on the skin alongside more complex arteriovenous malformations, where arteries connect directly to veins without the normal capillary network in between. These structural anomalies can affect various body regions and may cause complications depending on their location and size.

The syndrome follows an autosomal dominant inheritance pattern, meaning a pathogenic variant in just one copy of the causative gene is sufficient to cause the condition. Because this is a rare disorder, exact prevalence figures are not well established, though it accounts for a small proportion of inherited vascular malformation syndromes seen in clinical genetics services across the UK.

Recognising this condition matters clinically because arteriovenous malformations can occasionally cause serious complications including bleeding, tissue damage, or effects on organ function. Early identification through genetic testing enables appropriate monitoring and timely intervention when required.

Symptoms & clinical features

The hallmark feature of capillary malformation-AVM syndrome 2 is the presence of multiple small capillary malformations visible on the skin surface. These appear as flat, reddish or pink patches that do not fade with pressure, distinguishing them from ordinary birthmarks. The distribution and number of these skin markings vary considerably between affected individuals, even within the same family.

Arteriovenous malformations represent the more clinically significant aspect of the condition. These abnormal connections between arteries and veins bypass the usual capillary beds, creating areas where blood flows directly from high-pressure arteries into veins. Depending on their location, arteriovenous malformations may remain asymptomatic or cause noticeable problems such as localised warmth, visible pulsations, pain, or tissue swelling. In some cases, larger or strategically positioned malformations can lead to bleeding episodes, particularly if they affect internal organs or the brain. The spectrum of severity ranges from mild skin changes with no functional impact to more complex presentations requiring ongoing specialist oversight.

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Affected organs

The skin represents the most visibly affected organ system, with capillary malformations serving as external markers of the underlying vascular disorder. However, arteriovenous malformations can develop in deeper tissues and organs, including the brain, spinal cord, lungs, liver, and gastrointestinal tract.

When arteriovenous malformations occur in the central nervous system, they carry particular clinical significance because bleeding or altered blood flow patterns may affect neurological function. Lesions in other organs similarly pose risks proportional to their size and location, with potential complications including haemorrhage, localised tissue damage from abnormal blood flow, or in rare instances, effects on heart function if large malformations create significant circulatory shunting.

Multiple body systems

Systemic involvement

Cellular impact

Mechanism at cellular level

Risks & severity

Clinical severity in capillary malformation-AVM syndrome 2 varies markedly. Some individuals experience only cosmetic skin changes with no functional impairment throughout life, whilst others develop arteriovenous malformations requiring medical or surgical management. This variability occurs even between relatives carrying the same pathogenic variant, reflecting the complex interplay between genetic and developmental factors.

The principal medical concern relates to potential complications from arteriovenous malformations, particularly bleeding risk. Intracranial lesions carry the highest stakes, though serious events remain relatively uncommon. Age of symptom onset spans from early childhood through adulthood, with some malformations present from birth and others becoming apparent or symptomatic later. Families often show distinct patterns of severity, though predicting individual clinical course remains challenging.

Genetic causes

Capillary malformation-AVM syndrome 2 results from pathogenic variants in EPHB4, which encodes EPH receptor B4, a transmembrane protein crucial for normal blood vessel development. During embryonic growth and throughout life, EPH receptor B4 participates in coordinating how arteries and veins form proper connections and maintain their distinct identities within the vascular system.

The normal EPHB4 protein functions as a receptor tyrosine kinase, responding to molecular signals that guide vascular patterning. This signalling pathway helps ensure that arteries, capillaries, and veins develop appropriate structures and connections. When pathogenic variants disrupt EPHB4 function, the usual developmental programme goes awry, allowing inappropriate direct connections between arteries and veins and abnormal capillary formation in the skin.

Research suggests that haploinsufficiency represents a key disease mechanism, where having only one functional gene copy proves insufficient for completely normal vascular development. The resulting imbalance in signalling during critical developmental windows produces the characteristic vascular malformations seen in affected individuals.

• EPHB4
  EPH receptor B4

Inheritance pattern

Capillary malformation-AVM syndrome 2 follows an autosomal dominant inheritance pattern. This means that inheriting one pathogenic variant in EPHB4 from either parent is sufficient to cause the condition, as each person carries two copies of every gene (one from each parent). An affected parent has a 50 per cent chance of passing the pathogenic variant to each child, regardless of the child's sex.

However, some cases arise from de novo variants, meaning the genetic change occurred spontaneously in the affected individual rather than being inherited from a parent. When this happens, the parents typically do not carry the variant and have a low recurrence risk for future children, though the affected individual can pass the variant to their own offspring. Family members of someone diagnosed with this syndrome may benefit from discussing genetic testing and implications with a genetic counsellor, particularly when planning families or investigating unexplained vascular symptoms in relatives.

Diagnosis & testing

Diagnosis of capillary malformation-AVM syndrome 2 combines clinical evaluation with genetic testing. Clinicians assess the pattern and characteristics of vascular lesions, often using imaging studies such as MRI or ultrasound to identify and characterise arteriovenous malformations in deeper tissues. The presence of multiple small capillary malformations alongside arteriovenous malformations raises suspicion for an inherited vascular syndrome.

Genetic testing confirms the diagnosis by identifying a pathogenic variant in EPHB4. This testing is typically arranged through NHS clinical genetics services, with referrals coming from dermatologists, paediatricians, neurologists, or other specialists who recognise the clinical pattern. Within the NHS Genomic Medicine Service framework, this condition may be captured under relevant test directories for inherited vascular disorders. Confirming the genetic cause provides diagnostic certainty, informs family planning discussions, enables cascade testing for relatives, and helps distinguish this syndrome from other inherited vascular malformation disorders with different genetic causes and management implications.

Management & lifestyle

Management of capillary malformation-AVM syndrome 2 focuses on monitoring for complications and addressing symptomatic lesions when necessary. The approach is individualised based on the size, location, and behaviour of vascular malformations in each person. Regular clinical review typically involves specialist vascular or neurovascular teams with experience managing complex vascular anomalies.

For arteriovenous malformations causing symptoms or carrying significant bleeding risk, treatment options may include interventional procedures such as embolisation (blocking abnormal vessels) or surgical removal, though decisions require careful multidisciplinary discussion weighing risks against benefits. Skin capillary malformations themselves rarely require treatment beyond cosmetic considerations, though laser therapy represents one option some individuals pursue. Genetic counselling forms an important component of care, helping families understand inheritance patterns and options for predictive testing in relatives. Currently, no specific lifestyle modifications or medical therapies have established evidence for preventing malformation development or progression, though affected individuals should promptly report new neurological symptoms or signs of bleeding.

UK care pathway

Within the NHS, individuals with suspected capillary malformation-AVM syndrome 2 typically enter care pathways through referral to clinical genetics services or specialist vascular anomaly clinics. Following genetic confirmation, ongoing management involves coordination between genetics teams, vascular specialists, and other relevant disciplines depending on malformation locations. The NHS Genomic Medicine Service facilitates access to appropriate genetic testing panels that include EPHB4 analysis for inherited vascular disorders.

Genetic counsellors play a vital role in helping families understand test results, inheritance patterns, and reproductive options. They can arrange predictive testing for at-risk relatives and provide support around the emotional and practical aspects of living with an inherited condition. Access to these services varies by region, but clinical genetics departments across the UK offer comprehensive assessment and long-term support for families affected by rare inherited disorders like this syndrome.

Related conditions

Several other inherited syndromes feature vascular malformations with overlapping clinical presentations. Capillary malformation-AVM syndrome 1, caused by pathogenic variants in RASA1, shares many features including multiple small capillary malformations and arteriovenous malformations, making genetic testing essential for distinguishing between these two related conditions. Hereditary haemorrhagic telangiectasia represents another important differential diagnosis, characterised by arteriovenous malformations particularly affecting lungs, liver, and brain, alongside recurrent nosebleeds and small telangiectases.

Other considerations include cerebral cavernous malformation syndromes, which involve clusters of abnormal capillary-like vessels in the brain, and various sporadic vascular malformations that occur without an inherited basis. Accurate genetic diagnosis helps distinguish these conditions, as each carries distinct natural history, recurrence risks, and surveillance recommendations. Genetic testing through NHS services typically examines multiple genes simultaneously when evaluating inherited vascular disorders, improving diagnostic accuracy and enabling targeted family counselling.

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