Clinical characteristics.

Capillary malformation-arteriovenous malformation (CM-AVM) syndrome is characterized by the presence of multiple small (1-2 cm in diameter) capillary malformations mostly localized on the face and limbs. Some affected individuals also have associated arteriovenous malformations (AVMs) and/or arteriovenous fistulas (AFVs), fast-flow vascular anomalies that typically arise in the skin, muscle, bone, spine, and brain; life-threatening complications of these lesions can include bleeding, congestive heart failure, and/or neurologic consequences. Symptoms from intracranial AVMs/AVFs appear to occur early in life. Several individuals have Parkes Weber syndrome (multiple micro-AVFs associated with a cutaneous capillary stain and excessive soft-tissue and skeletal growth of an affected limb).

Diagnosis/testing.

The diagnosis of CM-AVM syndrome is established in a proband with suggestive clinical findings and a heterozygous pathogenic variant in EPHB4 or RASA1 identified by molecular genetic testing.

Management.

Treatment of manifestations: For capillary malformations and telangiectases that are of cosmetic concern, referral to a dermatologist. For AVMs and AVFs, the risks and benefits of intervention (embolization vs surgery) must be considered, usually with input from a multidisciplinary team (e.g., specialists in interventional radiology, neurosurgery, surgery, cardiology, and dermatology). For cardiac overload, referral to a cardiologist. For hemihyperplasia and/or leg-length discrepancy, referral to an orthopedist. Lymphangiography to evaluate for lymphatic malformations may be considered; compression stockings for those with evidence of lymphedema; epistaxis treatment includes humidification, nasal lubricants, referral to otolaryngologist, and complete blood count for evaluation of anemia.

Surveillance: Repeat imaging studies if clinical signs/symptoms of AVMs/AVFs become evident.

Evaluation of relatives at risk: Clarification of the genetic status of at-risk relatives is appropriate in order to allow early diagnosis and treatment of AVMs/AVFs to reduce/avoid secondary adverse outcomes.

Genetic counseling.

CM-AVM syndrome is inherited in an autosomal dominant manner. For RASA1-CM-AVM syndrome, about 70% of affected individuals have an affected parent; about 30% have a de novo pathogenic variant. For EPHB4-CM-AVM syndrome, about 80% of affected individuals have an affected parent; about 20% have a de novo pathogenic variant. Each child of an individual with CM-AVM syndrome has a 50% chance of inheriting the pathogenic variant. Prenatal and preimplantation genetic testing are possible if the pathogenic variant has been identified in an affected family member.

Suggestive Findings

CM-AVM syndrome should be suspected in probands who have any of the following:

• Capillary malformations (CMs), the hallmark of CM-AVM syndrome. CMs are generally:
  • Multifocal, atypical pink-to-reddish brown, multiple, small (1-2 cm in diameter), round-to-oval lesions sometimes with a white halo;
  • Composed of dilated capillaries in the papillary dermis [Hershkovitz et al 2008b];
  • Mostly localized on the face and limbs;
  • Seen in combination with arteriovenous malformations (AVMs) or arteriovenous fistulas (AVF), but may be the only finding [Hershkovitz et al 2008a, Revencu et al 2008, Revencu et al 2013b].
• AVMs/AVFs in soft tissue, bone, and brain that may be associated with overgrowth [Eerola et al 2003]
• Parkes Weber syndrome phenotype, a cutaneous capillary malformation associated with underlying multiple micro-AVFs and soft-tissue and skeletal hypertrophy of the affected limb [Mulliken & Young 1988]

Establishing the Diagnosis

The diagnosis of a CM-AVM syndrome is established in a proband with suggestive clinical findings and a heterozygous pathogenic (or likely pathogenic) variant in EPHB4 or RASA1 identified by molecular genetic testing (see Table 1).

Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variants" and "likely pathogenic variants" are synonymous in a clinical setting, meaning that both are considered diagnostic and both can be used for clinical decision making [Richards et al 2015]. Reference to "pathogenic variants" in this section is understood to include any likely pathogenic variants. (2) Identification of a heterozygous EPHB4 or RASA1 variant of uncertain significance does not establish or rule out the diagnosis.

Molecular genetic testing approaches can include a combination of gene-targeted testing (multigene panel) and comprehensive genomic testing (exome sequencing, exome array, genome sequencing) depending on the phenotype.

Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Because the phenotype of CM-AVM syndrome is broad, individuals with the distinctive findings described in Suggestive Findings are likely to be diagnosed using gene-targeted testing (see Option 1), whereas those with a phenotype indistinguishable from many other inherited disorders with capillary malformations and/or AVMs are more likely to be diagnosed using genomic testing (see Option 2).

Clinical Description

The clinical manifestations of RASA1-capillary malformation-arteriovenous malformation (RASA1-CM-AVM) syndrome have been described in many individuals with large cohorts by Eerola et al [2003] (n=39), Revencu et al [2008] (n=101), and Revencu et al [2013b] (n=138), with insights from a number of other case series and case reports [Hershkovitz et al 2008a, Hershkovitz et al 2008b, Thiex et al 2010, Carr et al 2011, Buhl et al 2012, de Wijn et al 2012, Wooderchak-Donahue et al 2012, Burrows et al 2013, Català et al 2013, Durrington et al 2013, Kim et al 2015, Maruani et al 2018, Wooderchak-Donahue et al 2018].

The clinical manifestations of EPHB4 capillary malformation-arteriovenous malformation (EPHB4-CM-AVM) syndrome have been described in two studies by Amyere et al [2017] (n=102), and Wooderchak-Donahue et al [2019] (n=10).

Significant intra- and interfamilial variability in the existence and location of vascular malformations has been described.

Genotype-Phenotype Correlations

Studies to date are insufficient to identify genotype-phenotype correlations.

Penetrance

EPHB4. Penetrance of EPHB4-CM-AVM syndrome was reported to be 93% (102 of 110 individuals) in one study by Amyere et al [2017].

RASA1. Penetrance is 90%-99% for RASA1-CM-AVM syndrome. Revencu et al [2008] determined that 55 of 57 individuals heterozygous for a germline RASA1 pathogenic variant were affected. Revencu et al [2013b] determined that 136 of 138 individuals heterozygous for a germline RASA1 pathogenic variant had multiple CMs.

Nomenclature

Eerola et al [2003] named the phenotype caused by RASA1 pathogenic variants "capillary malformation-arteriovenous malformation" (CM-AVM) syndrome. Later, Amyere et al [2017] named the phenotype caused by RASA1 pathogenic variants "capillary malformation-arteriovenous malformation 1" (CM-AVM1) and the phenotype caused by EPHB4 pathogenic variants "capillary malformation-arteriovenous malformation 2" (CM-AVM2).

Prevalence

Prevalence of CM-AVM syndrome is estimated at 1:100,000 in northern Europeans [Revencu et al 2008]. Another estimate of prevalence using the Exome Aggregation Consortium dataset is around 1:20,000 (RASA1-CM-AVM syndrome) and 1:12,000 (EPHB4-CM-AVM syndrome) [Amyere et al 2017].

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs of an individual diagnosed with capillary malformation-arteriovenous malformation (CM-AVM) syndrome, the following evaluations (if not performed as part of the evaluation that led to the diagnosis) are recommended:

• Medical history and physical examination with a focus on symptoms and findings secondary to arteriovenous malformations/arteriovenous fistulas (AVMs/AVFs)
• Brain imaging – if not already performed – to identify AVMs/AVFs (e.g., vein of Galen aneurysms and other intracranial AVMs) to allow early identification of macrofistulas that can be treated prior to the development of symptoms [Revencu et al 2008]
• Consideration of spine imaging to identify and characterize AVMs/AVFs. Currently no consensus protocols for radiographic evaluation of individuals with CM-AVM syndrome have been developed; therefore, discussion with a radiologist is recommended in order to develop an appropriate plan for imaging based on the patient's age and the capabilities and experience of the imaging facility.
• Consideration of further imaging in individuals with evidence of cardiac overload, to look for causative AVMs/AVFs
• Evaluation for evidence of epistaxis (nosebleeds), and if present, referral to otolaryngologist as appropriate. If epistaxis is present, consider complete blood count for evaluation of anemia.
• Consultation with a clinical geneticist and/or genetic counselor

Treatment of Manifestations

Surveillance

The clinician should have a low threshold to repeat imaging studies if clinical signs/symptoms of AVMs/AVFs become evident over time.

Agents/Circumstances to Avoid

Although no agents/circumstances resulting in complications of CM-AVM syndrome have been reported, a theoretic consideration is avoidance of routine use of anticoagulants unless indicated for treatment of a different medical condition.

Evaluation of Relatives at Risk

Clarification of the genetic status of at-risk relatives is appropriate in order to allow early diagnosis and treatment of AVMs/AVFs to reduce/avoid secondary adverse outcomes. In particular, at-risk infants are candidates for prompt diagnosis given the possible early presentation of neurologic complications from intracranial AVMs/AVFs [Revencu et al 2008].

Evaluations can include:

• Molecular genetic testing if the RASA1 or EPHB4 pathogenic variant in the family is known;
• Physical evaluation of the skin to look for capillary malformations if the pathogenic variant in the family is not known.

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Therapies Under Investigation

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Mode of Inheritance

Capillary malformation-arteriovenous malformation (CM-AVM) syndrome is inherited in an autosomal dominant manner.

Risk to Family Members

Parents of a proband

• About 70% of individuals diagnosed with RASA1-CM-AVM syndrome have an affected parent; about 80% of individuals diagnosed with EPHB4-CM-AVM syndrome have an affected parent.
• A proband with CM-AVM syndrome may have the disorder as the result of a de novo RASA1 or EPHB4 pathogenic variant. In RASA1-CM-AVM syndrome, approximately 30% of probands have a de novo pathogenic variant [Revencu et al 2008]; in EPHB4-CM-AVM syndrome, approximately 20% of affected individuals have a de novo pathogenic variant [Vivanti et al 2018, Wooderchak-Donahue et al 2019]. Note: Somatic mosaicism for a de novo EPHB4 pathogenic variant (identified in ~20% of blood cells) was reported in one affected proband [Wooderchak-Donahue et al 2019].
• Molecular genetic testing is recommended for the parents of a proband with an apparent de novo pathogenic variant.
• If the pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, possible explanations include a de novo pathogenic variant in the proband or germline mosaicism in a parent. Although no instances of parental germline mosaicism have been reported, it remains a possibility.
• The family history of an individual diagnosed with CV-AVM syndrome may appear to be negative because of failure to recognize the disorder in family members, early death of the parent before the onset of symptoms, or late onset of the disease in the affected parent. Therefore, an apparently negative family history cannot be confirmed unless molecular genetic testing has been performed on the parents of the proband.

Sibs of a proband. The risk to the sibs of the proband depends on the genetic status of the proband's parents:

• If a parent of the proband has the RASA1 or EPHB4 pathogenic variant, the risk to the sibs of inheriting the variant is 50%.
• If the pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is estimated to be 1% because of the theoretic possibility of parental germline mosaicism [Rahbari et al 2016].
• If the parents have not been tested for the pathogenic variant but are clinically unaffected, the risk to the sibs of a proband appears to be low. However, the sibs of a proband with clinically unaffected parents are still at increased risk for CV-AVM syndrome because of the possibility of reduced penetrance in a parent.

Offspring of a proband. Each child of an individual with a CV-AVM syndrome has a 50% chance of inheriting the pathogenic variant.

Other family members. The risk to other family members depends on the status of the proband's parents: if a parent has the RASA1 or EPHB4 pathogenic variant, the parent's family members may be at risk.

Related Genetic Counseling Issues

See Management, Evaluation of Relatives at Risk for information on evaluating at-risk relatives for the purpose of early diagnosis and treatment.

Considerations in families with an apparent de novo pathogenic variant. When neither parent of a proband with an autosomal dominant condition has the pathogenic variant identified in the proband or clinical evidence of the disorder, the pathogenic variant is likely de novo. However, non-medical explanations including alternate paternity or maternity (e.g., with assisted reproduction) and undisclosed adoption could also be explored.

Family planning

• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.

DNA banking. Because it is likely that testing methodology and our understanding of genes, pathogenic mechanisms, and diseases will improve in the future, consideration should be given to banking DNA from probands in whom a molecular diagnosis has not been confirmed (i.e., the causative pathogenic mechanism is unknown). For more information, see Huang et al [2022].

Prenatal Testing and Preimplantation Genetic Testing

Once the CV-AVM syndrome causative pathogenic variant has been identified in an affected family member, prenatal and preimplantation genetic testing are possible.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.

Molecular Pathogenesis

The protein RASA1 switches the active GTP-bound Ras to the inactive GDP-bound form. It is a negative regulator of the Ras/MAPK-signaling pathway, which mediates cellular growth, differentiation, and proliferation from various protein kinases on cell surfaces.

Germline heterozygous RASA1 pathogenic variants result in constitutive activation of Ras and resistance to GTPase-activating proteins GAPs.

EPHB4 and its ligand, EphrinB2, are transmembrane proteins, receptor and ligand, respectively. These two proteins act in concert with Notch signaling to control arterial-venous differentiation. EphrinB2-EPHB4 interactions suppress RAS-MAPK-ERK1/2 and P13K-AKT-MTORC1 pathways [Xiao et al 2012, Amyere et al 2017]. EPHB4 is expressed in venous endothelial cells during vascular development [Adams et al 1999] and lack of the protein may lead to disorganized vascular development.

Mechanism of disease causation. Based on the currently identified pathogenic variants in RASA1, haploinsufficiency is a suggested mechanism for the disease. Second hits have been proposed as a mechanism for development of the vascular lesions [Revencu et al 2013b, Macmurdo et al 2016, Lapinski et al 2018].

Loss of function of EPHB4 is a suggested mechanism. EPHB4 pathogenic variants reported include nonsense, frameshift, and splice site variants [Amyere et al 2017, Wooderchak-Donahue et al 2019].

Acknowledgments

We acknowledge Dr Johannes Fredrik Grimmer for his insights.

Revision History

• 12 September 2019 (sw) Comprehensive update posted live
• 6 October 2016 (bp) Comprehensive update posted live
• 19 December 2013 (me) Comprehensive update posted live
• 22 February 2011 (me) Review posted live
• 6 December 2010 (pbt) Original submission

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