Capillary Malformation-Arteriovenous Malformation Syndrome
Summary
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.
Diagnosis
Diagnostic criteria for capillary malformation-arteriovenous malformation (CM-AVM) syndrome have been proposed but not systematically evaluated [Orme et al 2013, Weitz et al 2015].
Suggestive Findings
CM-AVM syndrome should be suspected in individuals 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 variant in EPHB4 or RASA1 identified by molecular genetic testing (see Table 1).
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).
Option 1
When the phenotypic and laboratory findings suggest the diagnosis of CM-AVM syndrome, molecular genetic testing approaches can include use of a multigene panel. A multigene panel that includes EPHB4, RASA1, and other genes of interest (see Differential Diagnosis) is most likely to identify the genetic cause of the condition at the most reasonable cost while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests. For this disorder a multigene panel that also includes deletion/duplication analysis is recommended (see Table 1).
For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.
Note: (1) In RASA1-CM-AVM syndrome, ~30% of probands have a de novo pathogenic variant [Revencu et al 2008]; in EPHB4-CM-AVM syndrome, ~20% of affected individuals have a de novo pathogenic variant [Vivanti et al 2018, Wooderchak-Donahue et al 2019]; therefore, testing of parental samples for variants identified in a proband may be helpful for the interpretation of the variant. (2) Somatic mosaicism for a de novo EPHB4 pathogenic variant (identified in ~20% of blood cells) has been reported [Wooderchak-Donahue et al 2019]; therefore, detection of mosaicism should be considered in assay selection and development.
Option 2
When the phenotype is indistinguishable from many other inherited disorders characterized by capillary malformations and/or arteriovenous malformations, comprehensive genomic testing (which does not require the clinician to determine which gene[s] are likely involved) is another option. Exome sequencing is most commonly used; genome sequencing is also possible.
If exome sequencing is not diagnostic – and particularly when evidence supports autosomal dominant inheritance – exome array (when clinically available) may be considered to detect (multi)exon deletions or duplications that cannot be detected by sequence analysis.
For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.
Table 1.
Molecular Genetic Testing Used in Capillary Malformation-Arteriovenous Malformation (CM-AVM) Syndrome
| Gene 1, 2 | Proportion of CM-AVM Syndrome Attributed to Pathogenic Variants in Gene | Proportion of Probands with a Pathogenic Variant 3 Detectable by Method | |
|---|---|---|---|
| Sequence analysis 4 | Gene-targeted deletion/duplication analysis 5 | ||
| EPHB4 | ~10% 6 | 54/54 6 | Unknown 6 |
| RASA1 | ~50% 7 | ~92% 7, 8 | ~8% 7, 8 |
| Unknown 8 | ~40% 6 | NA | |
- 1.
Genes are listed in alphabetic order.
- 2.
See Table A. Genes and Databases for chromosome locus and protein.
- 3.
See Molecular Genetics for information on allelic variants detected in these genes.
- 4.
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.
- 5.
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
- 6.
Amyere et al [2017] reported 54 index patients identified by sequence analysis.
- 7.
Revencu et al [2008], Revencu et al [2013b]
- 8.
Wooderchak-Donahue et al [2018]
Clinical Characteristics
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.
Table 2.
Features of Capillary Malformation-Arteriovenous Malformation
| Feature | % of Persons with Feature by Associated Gene | |
|---|---|---|
| RASA1-CM-AVM 1 | EPHB4-CM-AVM 2 | |
| Capillary malformations | ~97% | 100% |
| Arteriovenous malformations/ arteriovenous fistulas 3 | ~24% includes:
| ~18% includes:
|
| Parkes Weber syndrome | 8% | 8% |
| Bier spots | None reported | 12% |
| Telangiectasias (upper thorax, lips, or arms/legs) | None reported | ~80% 2 |
| Epistaxis | None reported | ~60% 2 |
- 1.
Revencu et al [2013b]
- 2.
An ascertainment bias exists for the two studies included. In the first large study individuals were ascertained for CM-AVM syndrome [Amyere et al 2017], and in the second small study for hereditary hemorrhagic telangiectasia [Wooderchak-Donahue et al 2019]. In this second group, epistaxis and telangiectasia ratio was higher than in the first study (epistaxis: 6/10 individuals; telangiectasia: 8/10 individuals; CM: 8/10 individuals).
- 3.
Not all individuals with CM-AVM syndrome are likely to have had comprehensive imaging studies; therefore, the frequency of AVMs/AVFs is difficult to determine.
Capillary Malformations (CMs)
CMs are multiple round or oval pink lesions often with a blanched halo. CMs can be present at birth and tend to increase in number over time.
Arterial flow with Doppler ultrasound has been reported over the CMs [Kim et al 2015] and is hypothesized to be a manifestation of an underlying AVM. It is unclear if arterial flow abnormalities associated with the CMs can increase or develop over time.
Arteriovenous Malformations / Arteriovenous Fistulas (AVMs/AVFs)
Current data on long-term development of AVMs/AVFs after initial screening are insufficient. Although it has been hypothesized that AVMs/AVFs may develop over time [Orme et al 2013], to date no individuals who had normal imaging screens have subsequently been reported to have developed AVMs/AVFs.
Intracranial AVMs/AVFs can manifest early in life [Revencu et al 2008, Revencu et al 2013b]. Vein of Galen aneurysmal malformation and other intracranial AVMs have led to seizures, hydrocephalus, migraine headaches, and cardiac failure [Eerola et al 2003, Revencu et al 2008, Grillner et al 2016, Amyere et al 2017]. Vivanti et al [2018] reported on a series of 19 children with vein of Galen malformation; 10% had EPHB4 pathogenic variants.
Revencu et al [2008] reported that most of the intracranial lesions were macrofistulas causing symptoms in infancy. However, this finding may be biased given that the identification of the AVMs/AVFs may be secondary to associated symptoms and that asymptomatic individuals may not have had the imaging studies needed to detect the lesions.
Extracranial AVMs and AVFs are typically reported in skin, muscle, and spine.
Although approximately 50% of AVMs/AVFs have been reported to be in the head/neck region [Revencu et al 2013b], the frequency of AVMs/AVFs in this location may be an overestimate because it is likely that imaging is preferentially performed in this region.
Symptomatic intraspinal AVMs resulting in neurologic deficits have been reported; MRI has identified intraspinous lesions requiring endovascular/surgical treatment [Thiex et al 2010].
AVMs/AVFs have not been commonly reported in viscera [Revencu et al 2008], a distinguishing difference from hereditary hemorrhagic telangiectasia.
Parkes Weber Syndrome
Limb overgrowth has been reported in both the upper and lower extremities in individuals with CM-AVM syndrome. The overgrowth is typically noticeable in infancy and can range in severity. Most individuals with limb overgrowth fulfill the findings of Parkes Weber syndrome, defined by Revencu et al [2013b] as the presence of a capillary stain, bony and soft tissue hyperplasia, and multiple arteriolovenular microfistulas throughout an upper or lower extremity [Amyere et al 2017].
Other
Bier spots, white spots on the skin surrounded by a pale halo of erythema, have been described in individuals with EPHB4-CM-AVM syndrome [Amyere et al 2017, Wooderchak-Donahue et al 2019].
Telangiectasia has been reported primarily in individuals with EPHB4-CM-AVM syndrome. The telangiectases were typically located on the lips, trunks, and/or arms/legs [Amyere et al 2017, Wooderchak-Donahue et al 2019].
Epistaxis has been reported in individuals with EPHB4-CM-AVM syndrome [Amyere et al 2017, Wooderchak-Donahue et al 2019].
Cardiac overload/failure is a potential complication in individuals with significant fast-flow lesions.
In particular, one third of individuals with RASA1 Parkes Weber syndrome required cardiac follow up [Revencu et al 2008].
One infant with RASA1-CM-AVM syndrome had an AVF between the left carotid artery and jugular vein that caused cardiac overload requiring treatment [Eerola et al 2003].
One woman with RASA1-CM-AVM syndrome reported worsening of symptoms during pregnancy; she developed pulmonary and peripheral edema with concern for high-output heart failure that resolved after pregnancy [Durrington et al 2013].
Nonimmune hydrops fetalis due to an AVM has been reported in RASA1-CM-AVM syndrome [Overcash et al 2015].
Congenital heart defects have been reported in a few individuals with RASA1- and EPHB4-CM-AVM syndrome; however, this finding may be coincidental [Revencu et al 2008, Martin-Almedina et al 2016].
Lymphatic malformations have been reported in several individuals with EPHB4- and RASA1-CM-AVM syndrome [de Wijn et al 2012, Burrows et al 2013, Macmurdo et al 2016]. Lymphangiography and near-infrared fluorescence lymphatic imaging showed abnormally dilated collecting lymphatics with sluggish flow in the unaffected limb, and tortuous lymphatics of the affected limb with lymphocele-like vesicles in the groin of individuals with RASA1-CM-AVM syndrome [Burrows et al 2013]. Whether these lymphatic abnormalities are progressive is not yet known. An EPHB4 pathogenic variant was identified in a four-generation pedigree with central conducting lymphatic anomaly [Li et al 2018]. Hydrops fetalis was reported in individuals from two families with EPHB4-CM-AVM syndrome [Martin-Almedina et al 2016].
Tumors. Individuals with RASA1-CM-AVM syndrome may be at increased risk for tumor development, but review of the reported cases does not confirm this: Revencu et al [2008] reported several different types of tumors (e.g., optic glioma, lipoma, superficial basal cell carcinoma, angiolipoma, non-small-cell lung cancer, and vestibular schwannoma) in 44 families; however, in their larger series of 138 individuals, the only tumors reported were two common basal cell carcinomas in two individuals from the same family [Revencu et al 2013b]. Whether the rate of tumors is increased compared to the general population is as yet unknown, but it is likely not dramatically increased.
Additional findings observed in a small number of individuals with RASA1-CM-AVM syndrome include seizures, headaches, hydrocephalus, neurogenic bladder, varicosities, and hemangiomas. It is not clear if these findings are primary manifestations of a germline heterozygous RASA1 pathogenic variant, secondary complications of AVMs/AVFs, or unrelated.
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].
Differential Diagnosis
Table 3.
Other Genes of Interest in the Differential Diagnosis of Capillary Malformation-Arteriovenous Malformation (CV-AVM) Syndrome
| Gene(s) | Differential Diagnosis Disorder | MOI | Clinical Features of Differential Diagnosis Disorder | |
|---|---|---|---|---|
| Overlapping w/CV-AVM syndrome | Distinguishing from CV-AVM syndrome | |||
| ACVRL 1 ENG 1 GDF2 1 SMAD4 1 | Hereditary hemorrhagic telangiectasia | AD | Multiple AVMs that lack intervening capillaries & result in direct connections between arteries & veins |
|
| GNAQ | Sturge-Weber syndrome (SWS) (OMIM 185300) | See footnote 2. | Intracranial vascular anomaly 3 | Segmental facial cutaneous vascular malformations (port-wine stains), seizures, & glaucoma 4 |
| PIK3CA | Klippel-Trenaunay-Weber syndrome 5 | See footnote 6. | CMs & hypertrophy of the related bones & soft tissues | Vascular malformations are typically low-flow lesions w/out high-flow AVMs. 7 |
| PTEN | PTEN hamartoma tumor syndromes 8 | AD | Overgrowth & fast-flow lesions |
|
| TEK | Multiple cutaneous and mucosal venous malformations | AD | Cutaneous VMs can be mistaken for CMs. |
|
| GLMN | Hereditary glomuvenous malformations (GVMs) (OMIM 138000) | AD | Cutaneous VMs can be mistaken for CMs. |
|
AD = autosomal dominant; AVM = arteriovenous malformation; CM = capillary malformation; MOI = mode of inheritance; VM = venous malformation
- 1.
The known hereditary hemorrhagic telangiectasia-related genes are involved in the TGF-β/BMP signaling cascade.
- 2.
Somatic mosaic mutation of GNAQ has been reported in individuals with Sturge-Weber syndrome [Shirley et al 2013].
- 3.
Leptomeningeal angiomatosis most often involves the occipital and posterior parietal lobes.
- 4.
No RASA1 pathogenic variants were identified in nine persons with SWS who represented simplex cases (i.e., a single occurrence in a family) [Zhou et al 2011] or in 37 individuals with SWS [Revencu et al 2013b].
- 5.
Also referred to as Klippel-Trenaunay syndrome (KTS)
- 6.
Mosaic variants in PIK3CA have been reported in KTS [Vahidnezhad et al 2016].
- 7.
Diagnostic criteria for KTS have been proposed [Oduber et al 2008]. To date no RASA1 pathogenic variants have been identified in individuals with typical Klippel-Trenaunay syndrome [Revencu et al 2013a].
- 8.
PTEN hamartoma tumor syndromes include Cowden syndrome, Bannayan-Riley-Ruvalcaba syndrome, PTEN-Proteus syndrome, and Proteus-like syndrome.
- 9.
Caux et al [2007], Tan et al [2007]
- 10.
Hereditary GVMs have a cobblestone appearance with a consistency harder than that of venous malformations. Histologically, glomuvenous malformations are distinguishable by the presence of pathognomonic rounded cells (glomus cells) around the distended vein-like channels [Brouillard et al 2002].
Hereditary benign telangiectasia (OMIM 187260). Some of the cutaneous AVMs in the autosomal dominant disorder hereditary benign telangiectasia (HBT) can be of similar size to those seen in CM-AVM syndrome. However, solid organ AVMs are not seen in HBT.
Deletion 5q14.3q15. Individuals with microdeletion of 5q14.3q15 including RASA1 and neighboring genes have been reported [Carr et al 2011, Zweier & Rauch 2012]. Findings included multifocal CMs and severe developmental delay associated with MEF2C haploinsufficiency. In their review of the findings in four other individuals previously reported with deletions of both RASA1 and MEF2C, Carr et al [2011] determined that CMs had not been reported, but the report by Zweier and Rauch [2012] showed images of a child with multiple round capillary malformations of variable sizes. The severe developmental delays are not thought to result from deletion of RASA1.
Management
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
Table 4.
Treatment of Manifestations in Individuals with CM-AVM Syndrome
| Manifestation/Concern | Treatment | Considerations/Other |
|---|---|---|
| CMs & telangiectases | Referral to dermatologist | To evaluate CMs of cosmetic concern & discuss risks & benefits of intervention |
| AVMs/AVFs | Multidisciplinary team incl specialists in interventional radiology, neurosurgery, surgery, cardiology, & dermatology depending on location & symptoms |
|
| Cardiac overload | Referral to cardiologist | |
| Hemihyperplasia &/or leg length discrepancy | Referral to orthopedist | Consider:
|
| Epistaxis (nosebleeds) | Humidification & nasal lubricants; referral to otolaryngologist | If epistaxis, perform complete blood count for eval of anemia. |
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.