Capillary Malformation-Arteriovenous Malformation Type 2, A Report of 6 Cases and Main Differential Diagnosis : Journal of Vascular Anomalies

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Clinical study (Prospective, Retrospective, Case Series)

Capillary Malformation-Arteriovenous Malformation Type 2, A Report of 6 Cases and Main Differential Diagnosis

Cordisco, Maria Rosaa,b; El-Feghaly, Jiniaa; Prezzano, James C.a; Lanöel, Agustinab; Torres, Nataliab; Persico, Susanac; Requejo, Flavioc; Sierre, Sergioc; Fiandrino, María Joséd; Luna, Laurae; Maccario, Maria Fernandae; Brouillard, Pascalf; Vikkula, Miikkaf

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Journal of Vascular Anomalies 3(4):p e053, December 2022. | DOI: 10.1097/JOVA.0000000000000053
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Capillary malformation-arteriovenous malformation (CM-AVM) is a rare disorder characterized by multifocal CMs associated with intracranial and extracranial AVMs. In 50% of the cases, CM-AVM is associated with autosomal dominant heterozygous mutations in the Ras p21 protein activator 1 (RASA1) gene, termed CM-AVM1.1 Another subgroup with a closely related phenotype was recently described, with mutations in Ephrin B4 (EPHB4) gene identified in some individuals and was termed CM-AVM2.2,3

CM-AVM2 is characterized by multifocal cutaneous CMs, diffuse telangiectases favoring the lips, perioral area and upper trunk, punctate white anemic macules of various sizes—some with pinpoint central telangiectases—known as Bier spots, and epistaxis.2 Approximately 18% of individuals with CM-AVM2 have fast-flow vascular malformations (FFVMs) including cutaneous, subcutaneous, intramuscular, intraosseous, intraspinal, and intracranial AVMs, and arteriovenous fistulas.2 Parkes Weber syndrome (PKWS) can also be associated with CMAVM2 and is characterized by the presence of diffuse arteriovenous fistulas throughout an extremity underlying extensive CMs with associated limb overgrowth.2

We hereby present a case series of 6 unrelated patients with CM-AVM2 highlighting its distinctive phenotype and its main differential diagnosis, further adding to the limited literature on this condition.

Materials and methods

This is a retrospective review of patients with CM-AVM2. Patients were followed at multiple tertiary care centers in the United States and Argentina; skin examination was performed by pediatric dermatologists. Parental permission for images was obtained in all cases.

Genetic testing was performed at the laboratory of Human Molecular Genetics (Christian de Duve Institute of Cellular Pathology University Catholique de Louvain, Brussels, Belgium) and at Genetic laboratory in Argentina (patient 6).

DNA of patients was screened by Ion Torrent technology with a custom AmpliSeq panel ( covering the coding exons of EPHB4 and 5 bp of flanking introns (= splice sites). Variants were verified by Sanger sequencing (including for cosegregation analyses) and named according to the guidelines established by the Human Genome Variation Society (


We report 6 patients with genetically confirmed CM-AVM2.

Three patients were males (50%) and 3 were females (50%), aged 5 to 10 years at diagnosis, and all born at term.

The reason for referral varied from an enlarging capillary stain with associated soft tissue hypertrophy in patients 1 and 2 (Figures 1 & 2) to a suspected hereditary hemorrhagic telangiectasia (HHT) in patients 3, 4, and 5 due to developing telangiectases over the lips. (Figures 1A, 3D-E, 4D, 5D, 6C)

At presentation, all our patients (100%) had small (0.5–2 cm) multifocal CMs (Figures 1D, 2D, 3B, 4A-C, 5A-B, 6A-B) appearing in early infancy with new lesions developing throughout childhood. Four of 6 patients (75%) had a larger congenital CM (Figures 1A-B, 2A-B, 3A, 5A) ranging between 4 and 23 cm in diameter. The color of the CMs varied from pink, light red, and red-brown to brown. They had either a homogeneous or a heterogeneous pattern, exhibiting at times a central pallor. All congenital CMs and most of the smaller CMs exhibited irregular geographic borders. Some lesions had a surrounding blanched halo seen in 3 of 6 patients (50%).

Figure 1.:
Skin examination of patient 1 showing an AVM of the right face and earlobe. A pink-red large heterogeneous CM with a lighter center and geographic borders (Herald patch), with significant facial asymmetry and lip telangiectases (A, B). Note the mucosal involvement and the right hard palate hypertrophy. C, Multiple smaller CMs on the trunk (D). Bier spots on the trunk, arms, and dorsal hands (E, F). Axial T1-weighted image after gadolinium infusion showing diffuse thickening of cheek maxilla, subcutaneous tissue muscle and bone enhancement. Note skull base and ear lobe involvement (G). Axial T1 weighted fat saturated image showing vascular flow voids with right facial overgrowth of soft tissue and muscle (H). Selective arteriography showing facial AVM without nidus (I). AVM indicates arteriovenous malformation; CM, capillary malformation.
Figure 2.:
Skin examination of patient 2 showing Parkes Weber syndrome on upper right extremity. A large brown CM on the right trunk and right upper extremity (A, B) and left posterior thigh and buttock (C) (Herald patches). Smaller homogeneous CMs on the leg (D). MRA revealing multiple AVFs and overgrowth of the affected right upper extremity (E). AVFs indicates arteriovenous fistulas; CM, capillary malformation, MRA, magnetic resonance angiography.
Figure 3.:
Skin examination of patient 3 showing features of CM-AVM2. CM on the right upper arm (Herald patch) (A), multiple small CMs on the trunk (B), bier spots on the dorsal hands and knees (C, F) as well as numerous telangiectases on the cheeks, vermilion lip, perioral area, and extremities (D, E, F). CM indicates capillary malformation.
Figure 4.:
Skin examination of patient 4 showing multiple features of CM-AVM2. Multiple CMs on the trunk (A) and hands (B, C), as well as multiple telangiectases on the vermilion lips, perioral area, nose, and cheeks (D) and numerous Bier spots on the distal upper extremities (E). CM indicates capillary malformation.
Figure 5.:
Skin examination of patient 5 presenting with multiple features of CM-AVM2. CM on the left arm with a pale central zone (Herald patch) (A) and multiple smaller CMs on the right neck and trunk (A, B). Note the telangiectases on the dorsal hands, vermilion lips, perioral area, nose, and cheeks (C, D). CM indicates capillary malformation.
Figure 6.:
Skin examination of patient 6 showing features of CM-AVM2. Multifocal CMs on the forehead and chest (A, B) with multiple telangiectases on the vermilion lip, perioral area, and dorsal hands (C, D). CM indicates capillary malformation.

All our patients (100%) had multiple to numerous spidery or punctate telangiectases (Figures 1A, 3D-F, 4D, 5C-D, 6C-D) that appeared early during childhood and involved the face, perioral area, vermilion lips, trunk, and, less commonly, the extremities. Of note, cutaneous telangiectases on the lower extremities continued to develop over time in patient 3.

Bier spots are asymptomatic punctate white anemic macules of various sizes, some with pinpoint central telangiectases. All our patients (100%) had Bier spots (Figures 1E-F, 3C/F, 4E) involving the extremities. They were also seen on the trunk in patients 1 and 3 and on the face and neck in patient 5.

Epistaxis was reported in 3 of 6 patients (50%). The first episode occurred between 8 and 11 years of age. Nosebleeds were spontaneous and mild in severity, occurring on a weekly or monthly basis and lasting for a few minutes. Otolaryngologic assessment was normal. At long-term follow-up, no recurrence of epistaxis was reported; it had resolved spontaneously in all 3 patients.

FFVMs were seen in 2 of 6 patients (33%) in our small cohort. The CMs associated with underlying FFVMs were larger in size and were warm to palpation. Patient 1 had an extensive right-sided subcutaneous extracranial facial AVM associated with soft tissue and bone overgrowth, as well as ipsilateral microphthalmy. Imaging showed an AVM involving branches of the right external carotid artery and the right ophthalmic artery. (Figure 1 G-I) The AVM evolved over time requiring arterial embolization of various compartments of the malformation. He has also treated with thalidomide 100 mg for 4 months at 17 years of age, discontinued later by the patient due to lack of improvement.

On the other hand, patient 2 had PKWS of the right upper extremity. (Figure A-B) Imaging revealed diffuse micro-shunting involving the right brachial artery. (Figure 2E) She also had multiple episodes of cardiovascular overload but was lost to follow-up.

In all our index patients, neuroimaging ruled out intracranial anomalies.

Family history was positive in 4 of 6 patients (67%): patients 1, 2, and 3 had a family history of cutaneous CMs, and patient 6 had a family history of a brain AVM.

Genetic testing for RASA1 and EPHB4 was performed in all patients: RASA1 was normal/wild type in all cases, EPHB4 testing showed germline mutations in 5 of 6 patients and a mosaic mutation in 1 of 6 patients (patient 3).

Clinical findings are summarized in Table 1. Clinical photographs are presented in the respective figures.

Table 1. - Clinical Features, Imaging, and Molecular Findings in CM-AVM2
Patient Age (y)/Gender Larger Congenital CM “Herald Patch” Multifocal CMs, Number/Location Telangiectases Bier Spots Epistaxis Imaging Other Findings Family History Genetic Studies
1 5 M R face and R earlobe (>10 cm warm pink heterogeneous irregular patch + lighter center + facial asymmetry + mucosal involvement) >10 Nape of neck, T, Forearms (1–2 cm/irregular borders + peripheral white halo) Perioral area, dorsal hands T, UE, dorsal hands + First episode 11 y, mild, intermittent, 1–2×/mo; resolved spontaneously 1 y later MRI/angiogram: Extracranial AVM R face involving branches of the R external carotid artery and R ophthalmic artery + soft tissue and bone overgrowth + ipsilateral microphthalmy Proptosis, R eye blindness, leukocoria, respiratory andglottic dysfunction, R conductive hearing loss Large solitary CM (father on the trunk/paternal grandfather on the foot) EPHB4+ c.345_347delCTA, p.Y115del
2 8 F RT and RUE (23 cm warm brown irregular patch + thrill) >5 T, E (1–3 cm/irregular borders) LE LE MRA: Multiple AVFs in RUE involving the R brachial artery + soft tissue overgrowth (PKWS) Limb discrepancy (larger RUE), cardiovascular overload, hypoplastic Lt kidney Multiple CMs (mother/maternal grandmother/maternal uncle) EPHB4(+) c.1588 + 5G>C
Posterior Lt thigh and buttock (5 cm red-brown irregular patch) RASA1(–)
3 9 F R arm (4 cm irregular red patch + peripheral white halo) >5 T, E, Palms (<1 cm/ oval and irregular borders + peripheral white halo) Cheeks, vermilion lips, perioral area, nose, T, arms, feet T, distal E + First episode 8 y, mild intermittent, 1–2×/mo, lasting for 3 min; resolved spontaneously 1 y later Brain + spine MRI WNL Large solitary CM (mother on the hand) EPHB4(+) Mosaic c2450G>A
4 10 M >10 T, UE, Feet (<1 cm, red-brown/oval-round) Cheeks, vermilion lips, perioral area, nose Distal UE Brain MRI WNL Unknown EPHB4(+) c.2484 + 1G>T (16%)
5 10 M Lt arm/elbow (5 pink-red irregular patch + central clearing) <10 T, UE (0.5–1 cm/pink-red/irregular borders) Cheeks, vermilion lips, perioral area, nose H&N, hands Brain MRI WNL Unknown EPHB4(+) p.Arg206
6 8 F <10 Forehead, chest, arms, knees (0.5–2 cm/pink-red/oval or irregular borders + peripheral white halo) Forehead, vermilion lips, perioral area, hands Hands + First episode 8 y, mild intermittent, 1×/wk, lasting for few min; resolved spontaneously Brain + spine MRI WNL Cutaneous CMs (–) EPHB4(+) heterozygous c.2114T>C (p.L705P)
Brain AVM (maternal grandmother) RASA1(–)
Abbreviations: —, none/negative AVFs, arteriovenous fistulas; AVM, arteriovenous malformation; CM, capillary malformation; E, extremity; F, female; H&N, head & neck; L, lower; Lt, left; M, male; min, minutes; mo, months; MRA, magnetic resonance angiography; MRI, magnetic resonance imaging; PKWS, Parkes Weber syndrome; R, right; T, trunk; U, upper; wk, weeks; WNL, within normal limits; y, years. LE, Lower Extremity; UE, Upper Extremity; RT, Right Trunk; RUE, Right Upper Extremity


CMAVM2 was first described by Amyere et al2 in 2017 in a group of patients with clinical similarities with CMAVM1 but without associated RASA1 mutation; the group detected pathogenic variants in EPHB4. Including our current cohort, a total of 133 patients with CMAVM2 have been reported so far.4 It is characterized by multifocal diffusely scattered CMs, telangiectases, Bier spots, epistaxis, and FFVMs.

CM-AVM2 exhibits features of 2 unrelated disorders: CM-AVM1 and HHT (Table 2).

Table 2. - Comparison of the Clinical, Radiologic, and Molecular Findings of CM-AVM1, CM-AVM2, and HHT
Findings CM-AVM-1 CM-AVM-2 HHT
Genetic mutation RASA1 EPHB4 ENG
Multifocal CMs + +
Telangiectases –/+ +++ ++
Infancy/childhood Third–fourth decades
Spidery>>punctate Punctate/macular
Diffuse Typically localized
(face [perioral area]trunk, extremities) (face, fingers, mucosa)
Bier spots +/– +++
Epistaxis ++ Intermittent mild episodes with spontaneous resolution +++
Recurrent episodes, with increasing frequency and severity with age
FFVM 31% 18% 15%–78%
CNSFFVM 10% 3% 15%–23%
Visceral FFVM Rare ++*
PKWSandcervico-facialAVMs 7% 7%
Abbreviations: AVM, arteriovenous malformation; CM, capillary malformation; CNS, central nervous system; FFVM, fast-flow vascular malformation; HHT, hereditary hemorrhagic telangiectasia; PKWS, Parkes Weber syndrome.
*Pulmonary 15%–50%, hepatic 32%–78%.

CM-AVM1 was described by Eerola et al1 in 2003; it is characterized by multifocal CMs similar to the CMs seen in CMAVM2 and FFVMs. On the other hand, HHT is characterized by epistaxis, mucocutaneous telangiectases, visceral lesions (gastrointestinal telangiectases, pulmonary, hepatic, cerebral AVMs) and a first-degree relative with HHT, with 4 known implicated genes: ENG, ACVRL1, SMAD4, and GDF2.5–8

CMs are the hallmark of CMAVM 1 and 2; they have not been reported in HHT. All the patients in our cohort presented with multifocal CMs. The larger congenital CM seen in some of our patients was recently termed the “Herald Patch” by Valdivielso-Ramos et al.9 However, this larger stain does not seem to be specific to CMAVM2 and has been described in patients with CMAVM1 as well.10 Of note, brown CMs can be misdiagnosed as café-au-lait spots, particularly in darker Fitzpatrick’s phototypes, and should be considered on the latter’s differential.

Telangiectases are a main feature of CMAVM2 and HHT but were rarely reported in CMAVM1.2,4,9,10 Telangiectases in CMAVM2 can be spidery or punctate; they appear during early childhood and are diffusely distributed.9,11 In contrast, telangiectases in HHT are punctate; they appear in the third/fourth decade of life, are less numerous, and are localized on the face, mucosae, and rarely involve the body.5,6,11

Bier spots are common in CM-AVM2 but can also be seen in CMAVM1.2,4,11 However, to our knowledge, Bier spots were not reported in HHT.

When compared with our cohort of patients, previous studies reported more frequent and more prolonged episodes of epistaxis in CMAVM2.2,11 While epistaxis is not reported in CMAVM1, it is the most common manifestation of HHT; it develops later in life, becomes more frequent and severe with age, and rarely spontaneously resolve.4–6

FFVMs are seen in CMAVM1, CMAVM2, and HHT. There is a lower incidence of AVMs in CM-AVM2 (18%) compared with CM-AVM1 (31%), which might explain their absence in 4 of 6 patients.2 While CNS AVMs are considered a characteristic finding in HHT (23%) and CM-AVM1 (10%), the risk is much lower in CM-AVM2 (3%).2

PKWS can be equally seen in patients with CMAVM1 and CMAVM2.2,12 Germline variants in RASA1 and EPHB4, as well as a somatic variant in RASA1 have been shown to be causative.2,10,13 Recently, a somatic KRAS variant was reported to cause PKWS with or without associated lymphedema. KRAS is a proto-oncogene encoding K-RAS protein, one of the major regulators of cell growth, differentiation and apoptosis in the RAS/MAPK signal transduction pathway.14,15

EPHB4 variants, including mosaic variants, can lead to the general phenotype characterizing patients with CM-AVM2.2–4,9,11 The various mutations in EPHB4 likely explain the variability in the clinical features and associated anomalies as seen in our cohort of patients.

The cutaneous features of CMAVM2 can be subtle and go unnoticed; therefore, it is of utmost importance that providers recognize its cutaneous features and refer patients promptly to the pediatric dermatologist.

Genetic testing for EPHB4 should be performed in all patients presenting with multifocal CMs (in addition to RASA1 testing) and in patients with telangiectases with a negative HHT genetic screen. Genetic counseling should be offered to all families with a confirmed CMAVM2 case.

Imaging should be considered in all patients with extensive CMs to rule out underlying FFVMs. Although the data shows a lower incidence of CNS FFVMs in patients with CMAVM2, close clinical follow-up is still recommended. Brain and spine MRI should be performed in all symptomatic patients with CMAVM2 to screen for CNS AVM.

Our study is limited by its retrospective design and the small cohort of patients.


In conclusion, CMAVM2 should always be considered in the differential diagnosis of CMAVM1 and HHT. The constellation of findings of diffuse multifocal cutaneous CMs, telangiectases favoring the lips, perioral area and upper trunk, Bier spots, epistaxis, or family history of CMs or AVMs, should raise the clinician’s suspicion for CM-AVM2 and prompt further diagnostic studies to screen for FFVM and plan treatment accordingly.


The authors are grateful to the patients and their families for their collaboration and their trust.


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Bier spots; Capillary malformation; CM-AVM2; EPHB4; Telangiectasia

Copyright © 2022 The Authors. Published by Wolters Kluwer Health, Inc. on behalf of The International Society for the Study of Vascular Anomalies.