The appropriate dermatologic response when considering the capillary malformation-arteriovenous malformation syndrome: Fast flow to referral

By Warren R. Heymann, MD, FAAD
Sept. 18, 2024
Vol. 6, No. 38

I have had the privilege of contributing to Dr. Ronni Wolf’s outstanding AAD symposium devoted to Emergency Dermatology by presenting the lecture “Dermatological Urgent Care: When Banalities Surprise You,” discussing several cutaneous disorders that could easily be dismissed as “nothing to worry about” but should demand attention because of potential profound systemic complications. An excellent example of this concept is the Capillary Malformation-Arteriovenous Malformation (CM-AVM), which is the focus of this commentary.

The following is the abstract by Eerola et al., who first described CM-AVM:

“Capillary malformation” (CM), or “port-wine stain,” is a common cutaneous vascular anomaly that initially appears as a red macular stain that darkens over years. CM also occurs in several combined vascular anomalies that exhibit hypertrophy, such as Sturge-Weber syndrome, Klippel-Trenaunay syndrome, and Parkes Weber syndrome. Occasional familial segregation of CM suggests that there is genetic susceptibility, underscored by the identification of a large locus, CMC1, on chromosome 5q. We used genetic fine mapping with polymorphic markers to reduce the size of the CMC1 locus. A positional candidate gene, RASA1, encoding p120-RasGAP, was screened for mutations in 17 families. Heterozygous inactivating RASA1 mutations were detected in six families manifesting atypical CMs that were multiple, small, round to oval in shape, and pinkish red in color. In addition to CM, either arteriovenous malformation, arteriovenous fistula, or Parkes Weber syndrome was documented in all the families with a mutation. We named this newly identified association caused by RASA1 mutations “CM-AVM,” for capillary malformation-arteriovenous malformation. The phenotypic variability can be explained by the involvement of p120-RasGAP in signaling for various growth factor receptors that control proliferation, migration, and survival of several cell types, including vascular endothelial cells.

In their discussion, the authors speculated that the formation of direct shunts in AVMs and arteriovenous fistulas (AVFs) could also be due to dysregulated signaling of EphB-receptor–mediated pathways, in which p120-RasGAP has a role. (1) As anticipated, this group subsequently found EPHB4 variants in patients with multifocal CMs associated with AVMs who did not display the RASA1 variants (CM-AVM1, OMIM 608354). The phenotype, CM-AVM2 (OMIM 618196), mimics RASA1-related CM-AVM1 and hereditary hemorrhagic telangiectasia. (2)

CM-AVM is an autosomal dominant disorder with a penetrance of almost 100%; de novo cases are common. The prevalence of the CM-AVM syndrome is 1:100,000 — although considered rare, both CM-AVM1 and CM-AVM2 are probably highly underdiagnosed, based on the often mild phenotype and the likelihood that many cases are misdiagnosed as hereditary hemorrhagic telangiectasia (HHT). (3,4)

The pathomechanism(s) of CM-AVM is based on the two-hit hypothesis where a heterozygous loss-of-function germline pathogenic variant constitutes the first hit, followed by a second hit inducing a pathogenic variant in the other allele of the endothelial cells. (4) This causes disorganized vascular development through a lack of suppression of RAS-MEK-ERK and RAS-AKT-mTORC1 pathways. (5) A genetic change has not been defined in approximately 25% of CM-AVM cases — presumably, these cases may be due to mosaicism or yet-to-be-defined variants. (6)

Brix et al eloquently detail the clinical manifestations of CM-AVM. “CM-AVM1 and CM-AVM2 have some similar clinical characteristics. Both conditions present with cutaneous CMs that can be associated with the presence of 1 or more AVMs/AVFs. The CMs are described as macular, possible multifocal, light red, red or violet lesions varying in size typically from 1 to 3 cm in diameter. Larger lesions can occur, and CMs up to 15 cm in diameter have been described. A white halo can be seen around the CMs as a result of micro shunting. [emphasis added by WRH.] The cutaneous CMs can be present at birth and new lesions can evolve over time. The typical locations are face, thorax and extremities. Doppler pulsation can be found even in minor CMs and is explained by an arterial component in the CMs. As a consequence, a higher skin temperature or thrill in the affected area can be observed. Fast-flow malformations, such as AVMs/ AVFs, can be present in different sizes and locations. Cutaneous, subcutaneous, intramuscular, intraosseous, intraspinal and intracerebral locations are described. The presence of AVMs/AVFs can cause hypertrophy of the underlying bone and tissue, resulting in limb over-growth. This phenotype of CM-AVM is named Parkes Weber syndrome (PWS). For CM-AVM2, especially, the presence of telangiectasia and episodes of spontaneous recurrent epistaxis are characteristic symptoms. The telangiectasia can be either discrete or prominent and with or without a white halo, due to vasoconstriction. Bier spots, an unspecific phenomenon with anaemic white-spotted skin, can be observed in some patients.” (4) Valente et al. reported a 6-year-old girl with right-sided unilateral CM-AVM2 accompanied soft tissue and skeletal hypertrophy of the affected limb. (5)

Coccia et al. reported 4 cases of molecularly confirmed CM-AVM syndrome which manifested during the prenatal period. The authors note that signs found on ultrasound such as polyhydramnios, non-immune hydrops fetalis (pleural effusion, pericardial effusion, ascites), and chylothorax mandate a correct interpretation due to the possible fatal consequences of unrecognized encephalic and thoracoabdominal deep vascular malformations in newborns and in family members carrying the same RASA1 variant. (7) Mologousis et al. reported 7 patients with CM-AVM and lymphatic abnormalities. Five patients were diagnosed prenatally: 4 with pleural effusions (including one suspected chylothorax) and 1 with ascites. Chylous pericardial effusion presented in a sixth patient at 2 months. A seventh patient was diagnosed with a left lower extremity lymphatic malformation at 16 months. Six patients underwent genetic testing, and all had a RASA1 variant; a RASA1 variant was novel in 3 patients. (7)

Most cases of CM-AVM are benign, however, about 33% of CM-AVM syndrome patients have fast-flow lesions mainly located in CNS or skin with the potential to cause morbidity, including severe complications such as seizures, hydrocephalus, and migraine headaches, while non-CNS-AVMs can result in pain, ulceration, and cardiac failure. (4,6) CNS involvement occurs in both CM-AVM1 (12.5%) and CM-AVM2 (3%). (9) Therapeutic measures have included surgery, laser, and targeted therapies (sirolimus, trametinib). (10)

CV-AVM is a work in progress. There are no defined criteria to secure the diagnosis, which is based on clinical suspicion and molecular confirmation. There is a need for screening and follow-up guidelines. (4,6) Regardless, dermatologists should recognize characteristic cutaneous vascular lesions with a halo of pallor and consider the diagnosis. I encountered a 20ish-year-old woman last week with several lesions and referred her to the vascular anomalies clinic at the Children’s Hospital of Philadelphia for genetic screening and assessment for AVMs. If such patients come to my clinic, they are visiting yours too.

Point to Remember: The diagnosis of the Capillary Malformation-Arteriovenous Malformation (CM-AVM) syndrome should be recognized by vascular lesions surrounded by pallor. Although the prognosis is excellent for most patients, the risk of associated central nervous system AVMs mandates diagnostic confirmation and appropriate imaging assessment.

Our experts’ viewpoint

Robert Duffy, MD
Division of General Pediatrics, Section of Dermatology. Children’s Hospital of Philadelphia. Perelman School of Medicine, University of Pennsylvania.

Alexandra Borst, MD
Division of Hematology, Associate Professor of Pediatrics, Perelman School of Medicine, University of Pennsylvania

James Treat, MD, FAAD
Professor of Clinical Pediatrics and Dermatology, Perelman School of Medicine, University of Pennsylvania

As Dr. Heymann excellently described, capillary malformation-arteriovenous malformation (CM-AVM) syndrome is an inherited vascular dysplasia with unclear diagnostic criteria and evolving therapeutics. Dermatologic examination can reveal two characteristic subsets of cutaneous lesions: the first are so-called “rhodoid naevus” which are the classically described lesions summarized above as numerous (nine was a previously identified average number), ovoid or round, usually pink, vascular macules and small patches with peripheral pallor. (11-12) The second subset of lesions that can be visualized are described as reddish-brown macules. (12) These lesions can often be mistaken for café-au-lait macules (CALM) but will have an underlying erythema that would not be characteristic of CALM. Dermatoscopy can be particularly helpful in identifying lesions of concern. Gandon et al. described the dermatoscopic features as “predominant linear branched vascular pattern with an underlying homogeneous brown background. On compression, vessels disappeared and revealed an underlying light brown network.” (13)

Although no diagnostic criteria have been universally adopted, one was proposed in 2013 and split clinical findings into definite vs probable CM-AVM. Definite CM-AVM had numerous (1-60) characteristic capillary malformations (CMs) with either arteriovenous-malformations (AVMs), a family history of CMs (with or without AVMs) and/or confirmed RASA1 testing. Probable CM-AVM was defined as either a patient presenting with greater than three characteristic CMs, a patient presenting with one characteristic CM and a personal history of AVM, or a patient presenting with one characteristic CM and a family history of CMs (with or without AVMs). (14) It is important to note that this paper was written prior to the discovery of EPHB4 as an associated genetic cause of CM-AVM2, which is why it was not included in the diagnostic criteria.

As our understanding of this condition improves through increased recognition and publications, more precise criteria will be able to be extrapolated from the data. The advent and widespread implementation of medical genetics have allowed for this entity to be better characterized — we propose that patients should be referred to medical genetics for testing if clinical suspicion exists. Currently, CM-AVM1 (RASA1) and CM-AVM2 (EPHB4) are considered clinically indistinguishable except for the presence of cutaneous telangiectasias on exam in CM-AVM2. (15) As genetic testing becomes more widely accessible, the known phenotypic spectrum in CM-AVM1 and CM-AVM2 will likely be better defined.

Screening and management of CM-AVM (collectively referring to both CM-AVM1 and CM-AVM2) is also under discussion within the vascular malformation community. In patients with probable or definite CM-AVM, brain and spinal MRIs should be performed at the time of diagnosis. (14) Radiologic findings are varied, but can include: spinal arteriovenous lesions, pial arteriovenous fistulae, and other syndromes, including Parkes-Weber syndrome and vein of Galen malformation. (16) There are no consensus guidelines on imaging or management of CM-AVM, but many consider it reasonable to consider re-imaging if neurologic symptoms develop. Our comprehensive vascular anomalies program’s current practice is to re-image every five years, but data is currently being compiled to determine best practice. Genetic counseling should be performed and imaging on other affected family members should be considered as central nervous system (CNS) AVMs can be asymptomatic but present acutely with devastating consequences.

No treatment is needed if the disease is skin-limited. However, CNS AVMs may require surgical or interventional procedures, or at the least, frequent monitoring. Patients with AVMs or lymphatic anomalies caused by RASA1 or EPHB4 have been treated with medical therapy, such as mTOR or MEK inhibitors. (17) As advances in our understanding of the genetics and pathophysiology in CM-AVM continue, the many questions surrounding this new entity will be further clarified.

1. Eerola I, Boon LM, Mulliken JB, Burrows PE, Dompmartin A, Watanabe S, Vanwijck R, Vikkula M. Capillary malformation-arteriovenous malformation, a new clinical and genetic disorder caused by RASA1 mutations. Am J Hum Genet. 2003 Dec;73(6):1240-9. doi: 10.1086/379793. Epub 2003 Nov 24. PMID: 14639529; PMCID: PMC1180390.

2. Amyere M, Revencu N, Helaers R, Pairet E, Baselga E, Cordisco M, Chung W, Dubois J, Lacour JP, Martorell L, Mazereeuw-Hautier J, Pyeritz RE, Amor DJ, Bisdorff A, Blei F, Bombei H, Dompmartin A, Brooks D, Dupont J, González-Enseñat MA, Frieden I, Gérard M, Kvarnung M, Hanson-Kahn AK, Hudgins L, Léauté-Labrèze C, McCuaig C, Metry D, Parent P, Paul C, Petit F, Phan A, Quere I, Salhi A, Turner A, Vabres P, Vicente A, Wargon O, Watanabe S, Weibel L, Wilson A, Willing M, Mulliken JB, Boon LM, Vikkula M. Germline Loss-of-Function Mutations in EPHB4 Cause a Second Form of Capillary Malformation-Arteriovenous Malformation (CM-AVM2) Deregulating RAS-MAPK Signaling. Circulation. 2017 Sep 12;136(11):1037-1048. doi: 10.1161/CIRCULATIONAHA.116.026886. Epub 2017 Jul 7. PMID: 28687708.

3. Alluhaibi R, Alkhayat LN, Aqeeli W. Capillary Malformation-Arteriovenous Malformation Syndrome. Cureus. 2021 Jan 7;13(1):e12562. doi: 10.7759/cureus.12562. PMID: 33437561; PMCID: PMC7793427.

4. Brix ATH, Tørring PM, Bygum A. Capillary Malformation-arteriovenous Malformation Type 2: A Case Report and Review. Acta Derm Venereol. 2022 Mar 8;102:adv00662. doi: 10.2340/actadv.v102.1126. PMID: 35088870; PMCID: PMC9558756.

5. Valente C, Caldeira MB, Duarte B, Batista J, Cordeiro AI. Unilateral segmental presentation and a novel EPHB4 gene variant in capillary malformation-arteriovenous malformation type 2. Pediatr Dermatol. 2023 Dec 13. doi: 10.1111/pde.15493. Epub ahead of print. PMID: 38092051.

6. Haefliger S, Adams S, Nandakumar A, Nguyen L, Wargon O. CM-AVM syndrome - A prospective observational study of unrelated paediatric cases. Australas J Dermatol. 2021 Aug;62(3):347-353. doi: 10.1111/ajd.13651. Epub 2021 Jun 25. PMID: 34170521.

7. Coccia E, Valeri L, Zuntini R, Caraffi SG, Peluso F, Pagliai L, Vezzani A, Pietrangiolillo Z, Leo F, Melli N, Fiorini V, Greco A, Lepri FR, Pisaneschi E, Marozza A, Carli D, Mussa A, Radio FC, Conti B, Iascone M, Gargano G, Novelli A, Tartaglia M, Zuffardi O, Bedeschi MF, Garavelli L. Prenatal Clinical Findings in RASA1-Related Capillary Malformation-Arteriovenous Malformation Syndrome. Genes (Basel). 2023 Feb 22;14(3):549. doi: 10.3390/genes14030549. PMID: 36980822; PMCID: PMC10048332.

8. Mologousis MA, Ostertag-Hill CA, Haimes H, Fishman SJ, Mulliken JB, Liang MG. Spectrum of lymphatic anomalies in patients with RASA1-related CM-AVM. Pediatr Dermatol. 2023 Nov-Dec;40(6):1028-1034. doi: 10.1111/pde.15443. Epub 2023 Sep 28. PMID: 37767822.

9. Boccara O, Mazereeuw J, Martin L, Bessis D, Hubiche T, Chiaverini C, Dompmartin A, Mallet S, Miquel J, Aubert H, Puzenat E, Abasq C, Gusdorf L, Hadj-Rabia S, Maruani A; Groupe de Recherche Clinique de Dermatologie Pédiatrique (GRDP,); Filière Maladies rares Dermatologiques (FIMARAD). Central nervous system screening in capillary malformation-arteriovenous malformation syndrome: An observational study. J Am Acad Dermatol. 2022 Oct;87(4):914-916. doi: 10.1016/j.jaad.2021.12.030. Epub 2021 Dec 24. PMID: 34954287

10. Nicholson CL, Flanagan S, Murati M, Boull C, McGough E, Ameduri R, Weigel B, Maguiness S. Successful management of an arteriovenous malformation with trametinib in a patient with capillary-malformation arteriovenous malformation syndrome and cardiac compromise. Pediatr Dermatol. 2022 Mar;39(2):316-319. doi: 10.1111/pde.14912. Epub 2022 Jan 10. PMID: 35014097.

11. Happle R. Capillary malformations: a classification using specific names for specific skin disorders. J Eur Acad Dermatol Venereol. 2015;29:2295-2305.

12. Larralde M, Abad ME, Luna PC, et al. Capillary malformation-Arteriovenous malformation syndrome: a clinical review of 45 patients. Int J Dermatol. 2013;53:458-461.

13. Gandon C, Bonniaud B, Collet C, et al. A typical vascular and pigmentary dermoscopic pattern of capillary malformations in capillary malformation-ateriovenous malformation syndrome: report of four cases. Ped Dermatol. 2016;33(5):e337-341.

14. Orme CM, Boyden LM, Choate KA, et al. Capillary malformation-arteriovenous malformation syndrome: review of the literature, proposed diagnostic criteria, and recommendations for management. Ped Derm. 2013;30(4):409-415.

15. EPHB4-RASA1-mediated negative regulation of Ras-MAPK signaling in the vasculature: implications in the treatment of EPHB4- and RASA1-related vascular anomalies in humans. Pharmaceuticals (Basel). 2023;16(2):165.

16. Burch EA and Orbach DB. Pediatric central nervous system vascular malformations. Pediatr Radiol. 2015;45(suppl 3):S463-472.

17. Jia H, Chen Y, Yang X, et al. Treatment of challenging extracranial arteriovenous malformations: a single-center experience and literature review. Ann Plast Surg. 2023;90(55 suppl 2):S177-182.

18. Boyden LM, Orme CM, Antaya RJ, Choate KA, King BA. Capillary malformation-arteriovenous malformation syndrome: identification of a family with a novel mutation. J Am Acad Dermatol. 2012;67(6):e287-e289. doi:10.1016/j.jaad.2012.07.004.

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