- Email: [email protected]
Arteriovenous Malformation
10 Capillary Malformation/ Arteriovenous Malformation Nicole Revencu,1 Laurence M. Boon,2,3 Miikka Vikkula3,4 1Center
for Human Genetics, Cliniques universitaires St-Luc and Université catholique de Louvain, Brussels, Belgium, 2Center for Vascular Anomalies, Division of Plastic Surgery, Cliniques universitaires St-Luc, Université catholique de Louvain, Brussels, Belgium, 3Human Molecular Genetics, de Duve Institute, Université catholique de Louvain, Brussels, Belgium, 4Walloon Excellence in Lifesciences and Biotechnology (WELBIO), Université catholique de Louvain, Brussels, Belgium
10.1 INTRODUCTION
10.2 CAPILLARY MALFORMATION
Vascular anomalies are a heterogeneous group of disorders divided into tumors and malformations based on clinical, radiological, and immunohistochemical studies. Vascular malformations are localized defects of vascular morphogenesis. They are usually present at birth, even if not always visible, and based on the type of the affected vessel they are classified into capillary, venous, arterial, and lymphatic malformations. More than one vessel type is involved in combined vascular malformations, such as capillary–venous malformation, capillary–lymphatico–venous malformation, etc. Vascular malformations occur in most of the cases sporadically, but familial forms exist. The latter have facilitated genetic studies and the identification of several genes involved in vascular morphogenesis. Since 2012, next-generation sequencing approaches have enabled identification of somatic mutations in a rapidly increasing number of sporadic vascular malformations. Elucidation of the pathophysiology of most vascular malformations opens the era of targeted therapies, and several clinical trials are ongoing. This chapter reviews sporadic and familial capillary malformations (CMs) and arteriovenous malformations (AVMs).
CM (“port-wine stain”) (Fig. 10.1A) is, with an incidence of 3/1000, the most frequent vascular malformation [1]. Histologically, CM is formed of dilated capillary-like channels, the number of which increases with age. It is usually an isolated, sporadic, solitary flat lesion, present at birth, and grows proportionately with the child and persists throughout life. CM is a slow-flow, homogenous lesion of variable size, with geographic borders, located mainly on the skin, sometimes on the mucosa, appearing as a red macula that darkens and often thickens with age. It is located on the head, neck, trunk, or limbs, and the underlying tissues (skin, fat, muscle, and bone) can be hypertrophic. At least 75% of CMs are caused by a somatic activating recurrent mutation in the GNAQ gene: p.Arg183Gln [2,3]. Another somatic mutation, concerning the same amino acid, p.Arg183Gly, was identified in a single patient [2]. CMs are asymptomatic, but can generate important psychosocial distress. Often, they do not require treatment. When necessary for unsightly reasons, laser, mainly pulsed dye, is the first-line treatment. Laser treatment reduces the coloration in 75% of patients without modifying skin texture. It requires many sessions and
Emery and Rimoin’s Principles and Practice of Medical Genetics and Genomics. https://doi.org/10.1016/B978-0-12-812532-8.00010-0 Copyright © 2020 Elsevier Inc. All rights reserved.
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Figure 10.1 Capillary and arteriovenous malformations. (A) sporadic CM; (B) small, multifocal CMs in a patient with RASA1 mutation; (C) Bier spots in a patient with EPHB4 mutation; (D) large CM in a patient with RASA1 mutation: (E) lip and perioral telangiectasias in a patient with EPHB4 mutation; (F) small CM with halo in a patient with EPHB4 mutation; (G) intracranial AVM in a fetus with RASA1 mutation; (H) intraspinal AVM (arrow) in a patient with RASA1 mutation; (I and J) Parkes Weber syndrome in a patient with RASA1 and EPHB4 mutation, respectively; (K) AVM in a patient with RASA1 mutation. AVM, arteriovenous malformation; CM, capillary malformation. ((E) Courtesy of Prof A. Dompmartin, G, H, J, K: MRI imaging courtesy of Prof Ph. Clapuyt.)
necessitates general anesthesia in children and in adults with large CMs. When laser is ineffective, surgery is an option, and it can also be used to reduce tissue hyperplasia. CMs have to be differentiated from common naevus flammeus, present in up to 50% of newborns and located on the back of the neck or medial part of the forehead, eyelids, or upper lip. CM located on a limb has to be differentiated from Klippel–Trenaunay syndrome (capillary–lymphatico–venous malformation with limb hypertrophy, Online Mendelian Inheritance in Man (OMIM) 149000) and Parkes Weber syndrome (PKWS) (CM, arteriovenous microfistulas, and hypertrophy, OMIM 608355, see Section 10.4). Sometimes, a capillary blush can be observed on top of an AVM and can be misinterpreted as a CM.
10.3 STURGE–WEBER SYNDROME A particular attention has to be paid to CM located on the territory of the first branch of the trigeminal nerve (V1), which in 10% of cases is part of Sturge–Weber syndrome (OMIM 185300). Sturge–Weber syndrome is a sporadic, severe neurocutaneous disorder, with an estimated incidence at 1/50,000. Males and females are equally affected. It usually manifests as a unilateral CM present at birth and located on the forehead and the upper eyelid (V1), with ipsilateral leptomeningeal capillary–venous anomaly and ocular involvement. The CM can be bilateral and/or more extensive, covering the territory of the maxillary (V2) and mandibular (V3) branches of the trigeminal nerve, and sometimes the trunk and limbs. In rare cases, CM is absent. A recent study suggests that CM development follows the embryological vasculature and not the trigeminal nerve
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distribution and that only patients with CM involving part of the forehead are at risk of having Sturge–Weber syndrome [4]. Sturge–Weber syndrome is caused by the same somatic GNAQ activating mutation as isolated CM: p.Arg183Gln [3]. This could be explained by an earlier occurrence of the mutation during development in Sturge–Weber syndrome than in CM. Thus, genetic testing does not help in differential diagnosis between the two conditions. Seventy-five percent of children with intracranial vascular anomaly develop seizures, most often before the age of 2 years, with a risk of contralateral neurologic deficit and learning difficulties. Gyral calcifications can be observed. The major ocular complication is glaucoma, occurring in >50% of patients. This requires regular ophthalmologic follow-up throughout life, especially in infants. Epilepsy and glaucoma necessitate urgent management. It is still questioned if prophylactic anticonvulsant treatment is recommended or not. In patients with intractable seizures, surgery (lobectomy) can be required. Pulsed-dye laser can be used to treat the facial CM.
10.3.1 Arteriovenous Malformations AVM is a fast-flow vascular lesion, either localized, affecting the brain, skin, muscles, bone, or viscera, or regional, as in PKWS. Most AVMs occur sporadically as isolated lesions. They can also be part of inherited conditions, such as CM–AVM (see Section 10.4), hereditary hemorrhagic telangiectasia (see Chapter 3), or PTEN hamartoma tumor syndrome. Males and females are equally affected. The prevalence of AVM is about 1–2 in 10.000, with intracranial AVMs being more frequent than extracranial lesions. In AVMs, the normal capillary bed is replaced by a bundle of abnormal vessels, called “nidus,” via which the blood is shunted at increased speed and high pressure from artery to vein. A direct connection between an artery and a vein is called an arteriovenous fistula (AVF), and they are often post-traumatic. Activating somatic mutations in several genes in the RAS-MAPK-ERK pathway have been identified in sporadic AVMs: KRAS mutations in intracranial AVMs and KRAS, BRAF, and MAP2K1 mutations in extracranial AVMs [5–7]. The evolution of AVMs is variable and unpredictable from asymptomatic to life-threating. They are the most dangerous and difficult-to-treat vascular malformations and are associated with high morbidity and mortality.
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They can by quiescent for a long period of time and expand rapidly, usually at puberty, during pregnancy, after a traumatism or an incomplete treatment. Symptoms depend on the age of the patient and the localization, size, and angioarchitecture of the malformation. AVMs that are symptomatic prenatally or early in life usually develop congestive cardiac failure. At birth, an AVM affecting the skin can present as a red macula, mimicking a CM, but they are warm and show arteriovenous shunting by Doppler ultrasound investigation. In more advanced stages, heaviness, pain, pulsation, thrill, trophic changes, and bleeding occurs. Pulmonary AVMs are associated with right-to-left shunting, clubbing, cyanosis, polycythemia, increased risk of cerebral abscess, and embolic stroke. Brain AVMs are associated with headaches, epilepsy, hemorrhages, focal neurological deficit, or epilepsy. Radiological investigations are used to confirm the diagnosis, often already suspected on a clinical basis, to characterize the type of the lesion and its impact, to decide the best therapeutic options, and for the follow-up of the patient. Doppler ultrasound, magnetic resonance imaging, and magnetic resonance angiography are the major techniques used. Pulmonary AVMs are best investigated by contrast-enhanced computerized tomography. Ultrasound is used to evaluate effect on cardiac function of AVMs with large shunt. Pretreatment characterization of AVMs is performed by conventional angiography. The patients’ management is performed in tertiary referral centers, by multidisciplinary teams, and requires an individualized approach based on the characteristics of the AVM.
10.4 CAPILLARY MALFORMATION— ARTERIOVENOUS MALFORMATION Most CMs and AVMs are sporadic and isolated vascular malformations. They can also be associated in a condition called capillary malformation–arteriovenous malformation (CM-AVM; OMIM 608354). This is an autosomal dominant disorder, characterized by multifocal CMs and fast-flow vascular malformations: AVM, AVFs, and PKWS (Fig. 10.1B–J). The disorder was first described in 2003 [8]. The penetrance is high (>90%) and expressivity is variable even within the same family. The prevalence of CM-AVM is not yet known, but could be similar to that of hereditary hemorrhagic telangiectasia. CM-AVM is strongly underdiagnosed [9].
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Two genes have been identified: RASA1 (OMIM 139150) and EPHB4 (OMIM 600011), and they explain at least 75%–80% of the patients [8,9]. The phenotype has been described in detail in several large series of patients with RASA1 mutations [8,10,11]. Mutations in EPHB4 have been identified in more than 50 families [9]. The phenotypes associated with these two genes, CM-AVM1 and CM-AVM2, respectively, are similar, but there are also some differences and an overlap with hereditary hemorrhagic telangiectasia (see Chapter 3). Most of the affected individuals have CMs, but in contrast with classical CM, they are usually multifocal, infracentimetric, pink, red or brownish, randomly distributed, and frequently surrounded by a pale halo (Fig. 10.1B and F). Large CMs are also observed (Fig. 10.1D). Most of the lesions are present at birth, but new lesions can appear during childhood or adolescence [9–11]. Large areas of white spots with a red dot in the middle, so-called Bier spots, have been reported on limbs (Fig. 10.1C). Patients with CM-AVM2, but not with CM-AVM1, can have telangiectasias on upper thorax and lips, or periorally (Fig. 10.1E). Those lesions are similar to what is observed in hereditary hemorrhagic telangiectasia. Recurrent epistaxis was also reported in some patients with CM-AVM2 [9]. About 30% of the individuals with CM-AVM1 and 18% of individuals with CM-AVM2 have fast-flow vascular malformations located either in the extra- or intra-central nervous system [9–11]. In contrast with hereditary hemorrhagic telangiectasia, no lung or liver AVMs/AVFs have been observed. The fast-flow vascular malformations located in the extra-central nervous system are AVM/AVFs on the head and neck region or extremities, involving cutis, subcutis, and often muscles and bones, or PKWS (OMIM 608355) (Fig. 10.1I–K). The latter is characterized by a capillary blush on an extremity, multiple arteriovenous microfistulas, and soft tissue and bony hypertrophy (Fig. 10.1J). Overall, patients with CM-AVM1 and CM-AVM2 have equal frequency of fast-flow lesions in the face/neck (7%) and PKWS (7%). In contrast, intra-central nervous system lesions are less frequent in CM-AVM2 than in CM-AVM1 (3% and 10%, respectively). Intra-central nervous system lesions include pial AVM/AVF, vein-ofGalen aneurysmal malformation, and intraspinal fastflow lesion [8–12] (Fig. 10.1G–H). Recently, RASA1 and EPHB4 have been tested in a series of 43 children with at least one cerebral or spinal pial AVF fistula. A germline
RASA1 mutation was identified in 14 of them (32%), but none in EPHB4 [13]. In contrast, mutations in EPHB4 were identified in 10% of patients with vein-of-Galen aneurysmal malformation in another study [14]. Most of the RASA1 mutations are nonsense, splicing mutations, or out-of-frame deletions/duplications, leading to premature termination codons and suggesting loss of function. This is further supported by the observation of large genomic RASA1 rearrangements in the context of the 5q14.3 microdeletion syndrome [15]. These patients present with severe intellectual disability, absent speech, hypotonia, stereotypic movements, epilepsy, cerebral malformations, and mild facial dysmorphism due to MEF2C haploinsufficiency [15–17]. When RASA1 is included in the microdeletion, multifocal CMs are an important clue for the diagnosis. More than half of the EPHB4 mutations are premature stop codon, frame-shift, or splice-site alterations again suggesting loss of function. Moreover, in vitro functional studies on EPHB4 missense mutations demonstrated their rapid degradation and is thus in agreement with the proposed loss of function mechanism [9]. The pathophysiology of CM-AVM is unknown, but the number of lesions and their localized nature could indicate that a somatic second hit is required for lesions to develop, as previously reported in other multifocal vascular malformations [18–23]. This mechanism has already been confirmed for RASA1 [10,24]. CM-AVM was first described in 2003. Thus, the natural history is not yet known for developing guidelines for clinical management. Meanwhile, patients should be examined once a year by a clinician aware of the phenotype and its complications. CMs are harmless, and most of them are small and well tolerated. In contrast to sporadic CMs, CMs of CM-AVM do not respond well to pulsed dye laser. In fact, they can have increased flow. Intra-central nervous system fast-flow lesions in CM-AVM patients seem to manifest early in life, before birth or in the first years. These lesions, as well as extracranial fast-flow lesions, require a multidisciplinary approach. The management is similar to the management of sporadic lesions. Patients with PKWS should be treated conservatively; epiphysiodesis for leg length discrepancy should be avoided when possible as it can aggravate the fast-flow vascular malformation [25]. RASA1 encodes p120RASGAP, a cytoplasmic protein that acts as a negative regulator of the RAS-signaling pathway. P120RASGAP is a GTPase-activating protein
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(GAP) of RAS p21. It accelerates the intrinsic GTPase activity of RAS p21, switching it from active GTP-bound form to inactive GDP-bound form, and is involved in cell proliferation and differentiation. EPHB4 is a transmembrane tyrosine kinase receptor preferentially expressed in the venous endothelial cells. Its ligand, ephrinB2, is a transmembrane protein located on the arterial endothelial cells [26,27]. The EPHB4 receptor and its ligand play an important role in heart morphogenesis and angiogenesis. At the arterial–venous boundary, the ephrinB2-EPHB4 forward signaling is involved in cellular repulsion, migration, and adhesion, separating arterial from venous endothelial cells. In mice, the complete or only endothelial cell loss of Rasa1 or complete loss of EphB4 is lethal at midgestation with abnormal angiogenesis [28–30]. In zebrafish, inhibition of RASA1 or EPHB4 has similar effects, especially with arteriovenous endothelial cell connection disturbances [31]. RASA1 is an endothelial downstream effector of EPHB4 and EPHB4/RASA1 deficiency overactivates mTORC1 [31]. These in vitro and in vivo discoveries on EPHB4/RASA1 signaling pathway are now mirrored by human pathology, as mutations in either RASA1 or EPHB4 cause similar phenotypes.
ACKNOWLEDGMENTS The authors’ studies are partially funded by the Concerted Research Actions (A.R.C.) – Convention No 16/21–073 of the Belgian French Community Ministry; the F.R.S.-FNRS (Fonds de la Recherche Scientifique) (T.0026.14 and T.0146.16); and la Communauté française de Wallonie-Bruxelles and Lotterie nationale, Belgium.
REFERENCES [1] Jacobs AH, Walton RG. The incidence of birthmarks in the neonate. Pediatrics 1976;58:218–22. [2] Frigerio A, Wright K, Wooderchak-Donahue W, Tan OT, Margraf R, Stevenson DA, Grimmer JF, Bayrak-Toydemir P. Genetic variants associated with port-wine stains. PLoS One 2015;10:e0133158. [3] Shirley MD, Tang H, Gallione CJ, Baugher JD, Frelin LP, Cohen B, et al. Sturge-Weber syndrome and portwine stains caused by somatic mutation in GNAQ. N Engl J Med 2013;368:1971–9.
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[4] Waelchli R, Aylett SE, Robinson K, Chong WK, Martinez AE, Kinsler VA. New vascular classification of port-wine stains: improving prediction of Sturge-Weber risk. Br J Dermatol 2014;171:861–7. [5] Al-Olabi L, Polubothu S, Dowsett K, Andrews KA, Stadnik P, Joseph AP, et al. Mosaic RAS/MAPK variants cause sporadic vascular malformations which respond to targeted therapy. J Clin Invest 2018;128:1496–508. [6] Couto JA, Huang AY, Konczyk DJ, Goss JA, Fishman SJ, Mulliken JB, Warman ML, Greene AK. Somatic MAP2K1 mutations are associated with extracranial arteriovenous malformation. Am J Hum Genet 2017;100:546–54. [7] Nikolaev SI, Fish JE, Radovanovic I. Somatic activating KRAS mutations in arteriovenous malformations of the brain. N Engl J Med 2018;378:1561–2. [8] 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;73:1240–9. [9] Amyere M, Revencu N, Helaers R, Pairet E, Baselga E, Cordisco M, et al. Germline loss-of-function mutations in EPHB4 cause a second form of capillary malformation-arteriovenous malformation (CM-AVM2) deregulating RAS-MAPK signaling. Circulation 2017;136:1037–48. [10] Revencu N, Boon LM, Mendola A, Cordisco MR, Dubois J, Clapuyt P, et al. RASA1 mutations and associated phenotypes in 68 families with capillary malformation-arteriovenous malformation. Hum Mutat 2013;34:1632–41. [11] Revencu N, Boon LM, Mulliken JB, Enjolras O, Cordisco MR, Burrows PE, et al. Parkes Weber syndrome, vein of Galen aneurysmal malformation, and other fast-flow vascular anomalies are caused by RASA1 mutations. Hum Mutat 2008;29:959–65. [12] Thiex R, Mulliken JB, Revencu N, Boon LM, Burrows PE, Cordisco M, et al. A novel association between RASA1 mutations and spinal arteriovenous anomalies. AJNR Am J Neuroradiol 2010;31:775–9. [13] Saliou G, Eyries M, Iacobucci M, Knebel JF, Waill MC, Coulet F, et al. Clinical and genetic findings in children with central nervous system arteriovenous fistulas. Ann Neurol 2017;82:972–80. [14] Vivanti A, Ozanne A, Grondin C, Saliou G, Quevarec L, Maurey H, et al. Loss of function mutations in EPHB4 are responsible for vein of Galen aneurysmal malformation. Brain 2018;141:979–88. [15] Engels H, Wohlleber E, Zink A, Hoyer J, Ludwig KU, Brockschmidt FF, et al. A novel microdeletion syndrome involving 5q14.3-q15: clinical and molecular cytogenetic characterization of three patients. Eur J Hum Genet 2009;17:1592–9.
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[16] Carr CW, Zimmerman HH, Martin CL, Vikkula M, Byrd AC, Abdul-Rahman OA. 5q14.3 neurocutaneous syndrome: a novel continguous gene syndrome caused by simultaneous deletion of RASA1 and MEF2C. Am J Med Genet 2011;155A:1640–5. [17] Le Meur N, Holder-Espinasse M, Jaillard S, Goldenberg A, Joriot S, Amati-Bonneau P, et al. MEF2C haploinsufficiency caused by either microdeletion of the 5q14.3 region or mutation is responsible for severe mental retardation with stereotypic movements, epilepsy and/or cerebral malformations. J Med Genet 2010;47:22–9. [18] Akers AL, Johnson E, Steinberg GK, Zabramski JM, Marchuk DA. Biallelic somatic and germline mutations in cerebral cavernous malformations (CCMs): evidence for a two-hit mechanism of CCM pathogenesis. Hum Mol Genet 2009;18:919–30. [19] Amyere M, Aerts V, Brouillard P, McIntyre BA, Duhoux FP, Wassef M, et al. Somatic uniparental isodisomy explains multifocality of glomuvenous malformations. Am J Hum Genet 2013;92:188–96. [20] Brouillard P, Boon LM, Mulliken JB, Enjolras O, Ghassibe M, Warman ML, Tan OT, Olsen BR, Vikkula M. Mutations in a novel factor, glomulin, are responsible for glomuvenous malformations (“glomangiomas”). Am J Hum Genet 2002;70:866–74. [21] Gault J, Shenkar R, Recksiek P, Awad IA. Biallelic somatic and germ line CCM1 truncating mutations in a cerebral cavernous malformation lesion. Stroke 2005;36:872–4. [22] Limaye N, Wouters V, Uebelhoer M, Tuominen M, Wirkkala R, Mulliken JB, et al. Somatic mutations in angiopoietin receptor gene TEK cause solitary and multiple sporadic venous malformations. Nat Genet 2009;41:118–24. [23] Soblet J, Kangas J, Natynki M, Mendola A, Helaers R, Uebelhoer M, et al. Blue Rubber Bleb Nevus (BRBN) syndrome is caused by somatic TEK (TIE2) mutations. J Invest Dermatol 2017;137:207–16.
[24] Lapinski PE, Doosti A, Salato V, North P, Burrows PE, King PD. Somatic second hit mutation of RASA1 in vascular endothelial cells in capillary malformation-arteriovenous malformation. Eur J Med Genet 2018;61:11–6. [25] Enjolras O, Chapot R, Merland JJ. Vascular anomalies and the growth of limbs: a review. J Pediatr Orthop B 2004;13:349–57. [26] Adams RH, Wilkinson GA, Weiss C, Diella F, Gale NW, Deutsch U, et al. Roles of ephrinB ligands and EphB receptors in cardiovascular development: demarcation of arterial/venous domains, vascular morphogenesis, and sprouting angiogenesis. Genes Dev 1999;13:295–306. [27] Bai J, Wang YJ, Liu L, Zhao YL. Ephrin B2 and EphB4 selectively mark arterial and venous vessels in cerebral arteriovenous malformation. J Int Med Res 2014;42:405–15. [28] Gerety SS, Wang HU, Chen ZF, Anderson DJ. Symmetrical mutant phenotypes of the receptor EphB4 and its specific transmembrane ligand ephrin-B2 in cardiovascular development. Mol Cell 1999;4:403–14. [29] Henkemeyer M, Rossi DJ, Holmyard DP, Puri MC, Mbamalu G, Harpal K, et al. Vascular system defects and neuronal apoptosis in mice lacking ras GTPaseactivating protein. Nature 1995;377:695–701. [30] Lapinski PE, Kwon S, Lubeck BA, Wilkinson JE, Srinivasan RS, Sevick-Muraca E, King PD. RASA1 maintains the lymphatic vasculature in a quiescent functional state in mice. J Clin Invest 2012;122:733–47. [31] Kawasaki J, Aegerter S, Fevurly RD, Mammoto A, Mammoto T, Sahin M, Mably JD, Fishman SJ, Chan J. RASA1 functions in EPHB4 signaling pathway to suppress endothelial mTORC1 activity. J Clin Invest 2014;124:2774–84.
for Human Genetics, Cliniques universitaires St-Luc and Université catholique de Louvain, Brussels, Belgium, 2Center for Vascular Anomalies, Division of Plastic Surgery, Cliniques universitaires St-Luc, Université catholique de Louvain, Brussels, Belgium, 3Human Molecular Genetics, de Duve Institute, Université catholique de Louvain, Brussels, Belgium, 4Walloon Excellence in Lifesciences and Biotechnology (WELBIO), Université catholique de Louvain, Brussels, Belgium
10.1 INTRODUCTION
10.2 CAPILLARY MALFORMATION
Vascular anomalies are a heterogeneous group of disorders divided into tumors and malformations based on clinical, radiological, and immunohistochemical studies. Vascular malformations are localized defects of vascular morphogenesis. They are usually present at birth, even if not always visible, and based on the type of the affected vessel they are classified into capillary, venous, arterial, and lymphatic malformations. More than one vessel type is involved in combined vascular malformations, such as capillary–venous malformation, capillary–lymphatico–venous malformation, etc. Vascular malformations occur in most of the cases sporadically, but familial forms exist. The latter have facilitated genetic studies and the identification of several genes involved in vascular morphogenesis. Since 2012, next-generation sequencing approaches have enabled identification of somatic mutations in a rapidly increasing number of sporadic vascular malformations. Elucidation of the pathophysiology of most vascular malformations opens the era of targeted therapies, and several clinical trials are ongoing. This chapter reviews sporadic and familial capillary malformations (CMs) and arteriovenous malformations (AVMs).
CM (“port-wine stain”) (Fig. 10.1A) is, with an incidence of 3/1000, the most frequent vascular malformation [1]. Histologically, CM is formed of dilated capillary-like channels, the number of which increases with age. It is usually an isolated, sporadic, solitary flat lesion, present at birth, and grows proportionately with the child and persists throughout life. CM is a slow-flow, homogenous lesion of variable size, with geographic borders, located mainly on the skin, sometimes on the mucosa, appearing as a red macula that darkens and often thickens with age. It is located on the head, neck, trunk, or limbs, and the underlying tissues (skin, fat, muscle, and bone) can be hypertrophic. At least 75% of CMs are caused by a somatic activating recurrent mutation in the GNAQ gene: p.Arg183Gln [2,3]. Another somatic mutation, concerning the same amino acid, p.Arg183Gly, was identified in a single patient [2]. CMs are asymptomatic, but can generate important psychosocial distress. Often, they do not require treatment. When necessary for unsightly reasons, laser, mainly pulsed dye, is the first-line treatment. Laser treatment reduces the coloration in 75% of patients without modifying skin texture. It requires many sessions and
Emery and Rimoin’s Principles and Practice of Medical Genetics and Genomics. https://doi.org/10.1016/B978-0-12-812532-8.00010-0 Copyright © 2020 Elsevier Inc. All rights reserved.
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Figure 10.1 Capillary and arteriovenous malformations. (A) sporadic CM; (B) small, multifocal CMs in a patient with RASA1 mutation; (C) Bier spots in a patient with EPHB4 mutation; (D) large CM in a patient with RASA1 mutation: (E) lip and perioral telangiectasias in a patient with EPHB4 mutation; (F) small CM with halo in a patient with EPHB4 mutation; (G) intracranial AVM in a fetus with RASA1 mutation; (H) intraspinal AVM (arrow) in a patient with RASA1 mutation; (I and J) Parkes Weber syndrome in a patient with RASA1 and EPHB4 mutation, respectively; (K) AVM in a patient with RASA1 mutation. AVM, arteriovenous malformation; CM, capillary malformation. ((E) Courtesy of Prof A. Dompmartin, G, H, J, K: MRI imaging courtesy of Prof Ph. Clapuyt.)
necessitates general anesthesia in children and in adults with large CMs. When laser is ineffective, surgery is an option, and it can also be used to reduce tissue hyperplasia. CMs have to be differentiated from common naevus flammeus, present in up to 50% of newborns and located on the back of the neck or medial part of the forehead, eyelids, or upper lip. CM located on a limb has to be differentiated from Klippel–Trenaunay syndrome (capillary–lymphatico–venous malformation with limb hypertrophy, Online Mendelian Inheritance in Man (OMIM) 149000) and Parkes Weber syndrome (PKWS) (CM, arteriovenous microfistulas, and hypertrophy, OMIM 608355, see Section 10.4). Sometimes, a capillary blush can be observed on top of an AVM and can be misinterpreted as a CM.
10.3 STURGE–WEBER SYNDROME A particular attention has to be paid to CM located on the territory of the first branch of the trigeminal nerve (V1), which in 10% of cases is part of Sturge–Weber syndrome (OMIM 185300). Sturge–Weber syndrome is a sporadic, severe neurocutaneous disorder, with an estimated incidence at 1/50,000. Males and females are equally affected. It usually manifests as a unilateral CM present at birth and located on the forehead and the upper eyelid (V1), with ipsilateral leptomeningeal capillary–venous anomaly and ocular involvement. The CM can be bilateral and/or more extensive, covering the territory of the maxillary (V2) and mandibular (V3) branches of the trigeminal nerve, and sometimes the trunk and limbs. In rare cases, CM is absent. A recent study suggests that CM development follows the embryological vasculature and not the trigeminal nerve
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distribution and that only patients with CM involving part of the forehead are at risk of having Sturge–Weber syndrome [4]. Sturge–Weber syndrome is caused by the same somatic GNAQ activating mutation as isolated CM: p.Arg183Gln [3]. This could be explained by an earlier occurrence of the mutation during development in Sturge–Weber syndrome than in CM. Thus, genetic testing does not help in differential diagnosis between the two conditions. Seventy-five percent of children with intracranial vascular anomaly develop seizures, most often before the age of 2 years, with a risk of contralateral neurologic deficit and learning difficulties. Gyral calcifications can be observed. The major ocular complication is glaucoma, occurring in >50% of patients. This requires regular ophthalmologic follow-up throughout life, especially in infants. Epilepsy and glaucoma necessitate urgent management. It is still questioned if prophylactic anticonvulsant treatment is recommended or not. In patients with intractable seizures, surgery (lobectomy) can be required. Pulsed-dye laser can be used to treat the facial CM.
10.3.1 Arteriovenous Malformations AVM is a fast-flow vascular lesion, either localized, affecting the brain, skin, muscles, bone, or viscera, or regional, as in PKWS. Most AVMs occur sporadically as isolated lesions. They can also be part of inherited conditions, such as CM–AVM (see Section 10.4), hereditary hemorrhagic telangiectasia (see Chapter 3), or PTEN hamartoma tumor syndrome. Males and females are equally affected. The prevalence of AVM is about 1–2 in 10.000, with intracranial AVMs being more frequent than extracranial lesions. In AVMs, the normal capillary bed is replaced by a bundle of abnormal vessels, called “nidus,” via which the blood is shunted at increased speed and high pressure from artery to vein. A direct connection between an artery and a vein is called an arteriovenous fistula (AVF), and they are often post-traumatic. Activating somatic mutations in several genes in the RAS-MAPK-ERK pathway have been identified in sporadic AVMs: KRAS mutations in intracranial AVMs and KRAS, BRAF, and MAP2K1 mutations in extracranial AVMs [5–7]. The evolution of AVMs is variable and unpredictable from asymptomatic to life-threating. They are the most dangerous and difficult-to-treat vascular malformations and are associated with high morbidity and mortality.
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They can by quiescent for a long period of time and expand rapidly, usually at puberty, during pregnancy, after a traumatism or an incomplete treatment. Symptoms depend on the age of the patient and the localization, size, and angioarchitecture of the malformation. AVMs that are symptomatic prenatally or early in life usually develop congestive cardiac failure. At birth, an AVM affecting the skin can present as a red macula, mimicking a CM, but they are warm and show arteriovenous shunting by Doppler ultrasound investigation. In more advanced stages, heaviness, pain, pulsation, thrill, trophic changes, and bleeding occurs. Pulmonary AVMs are associated with right-to-left shunting, clubbing, cyanosis, polycythemia, increased risk of cerebral abscess, and embolic stroke. Brain AVMs are associated with headaches, epilepsy, hemorrhages, focal neurological deficit, or epilepsy. Radiological investigations are used to confirm the diagnosis, often already suspected on a clinical basis, to characterize the type of the lesion and its impact, to decide the best therapeutic options, and for the follow-up of the patient. Doppler ultrasound, magnetic resonance imaging, and magnetic resonance angiography are the major techniques used. Pulmonary AVMs are best investigated by contrast-enhanced computerized tomography. Ultrasound is used to evaluate effect on cardiac function of AVMs with large shunt. Pretreatment characterization of AVMs is performed by conventional angiography. The patients’ management is performed in tertiary referral centers, by multidisciplinary teams, and requires an individualized approach based on the characteristics of the AVM.
10.4 CAPILLARY MALFORMATION— ARTERIOVENOUS MALFORMATION Most CMs and AVMs are sporadic and isolated vascular malformations. They can also be associated in a condition called capillary malformation–arteriovenous malformation (CM-AVM; OMIM 608354). This is an autosomal dominant disorder, characterized by multifocal CMs and fast-flow vascular malformations: AVM, AVFs, and PKWS (Fig. 10.1B–J). The disorder was first described in 2003 [8]. The penetrance is high (>90%) and expressivity is variable even within the same family. The prevalence of CM-AVM is not yet known, but could be similar to that of hereditary hemorrhagic telangiectasia. CM-AVM is strongly underdiagnosed [9].
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Two genes have been identified: RASA1 (OMIM 139150) and EPHB4 (OMIM 600011), and they explain at least 75%–80% of the patients [8,9]. The phenotype has been described in detail in several large series of patients with RASA1 mutations [8,10,11]. Mutations in EPHB4 have been identified in more than 50 families [9]. The phenotypes associated with these two genes, CM-AVM1 and CM-AVM2, respectively, are similar, but there are also some differences and an overlap with hereditary hemorrhagic telangiectasia (see Chapter 3). Most of the affected individuals have CMs, but in contrast with classical CM, they are usually multifocal, infracentimetric, pink, red or brownish, randomly distributed, and frequently surrounded by a pale halo (Fig. 10.1B and F). Large CMs are also observed (Fig. 10.1D). Most of the lesions are present at birth, but new lesions can appear during childhood or adolescence [9–11]. Large areas of white spots with a red dot in the middle, so-called Bier spots, have been reported on limbs (Fig. 10.1C). Patients with CM-AVM2, but not with CM-AVM1, can have telangiectasias on upper thorax and lips, or periorally (Fig. 10.1E). Those lesions are similar to what is observed in hereditary hemorrhagic telangiectasia. Recurrent epistaxis was also reported in some patients with CM-AVM2 [9]. About 30% of the individuals with CM-AVM1 and 18% of individuals with CM-AVM2 have fast-flow vascular malformations located either in the extra- or intra-central nervous system [9–11]. In contrast with hereditary hemorrhagic telangiectasia, no lung or liver AVMs/AVFs have been observed. The fast-flow vascular malformations located in the extra-central nervous system are AVM/AVFs on the head and neck region or extremities, involving cutis, subcutis, and often muscles and bones, or PKWS (OMIM 608355) (Fig. 10.1I–K). The latter is characterized by a capillary blush on an extremity, multiple arteriovenous microfistulas, and soft tissue and bony hypertrophy (Fig. 10.1J). Overall, patients with CM-AVM1 and CM-AVM2 have equal frequency of fast-flow lesions in the face/neck (7%) and PKWS (7%). In contrast, intra-central nervous system lesions are less frequent in CM-AVM2 than in CM-AVM1 (3% and 10%, respectively). Intra-central nervous system lesions include pial AVM/AVF, vein-ofGalen aneurysmal malformation, and intraspinal fastflow lesion [8–12] (Fig. 10.1G–H). Recently, RASA1 and EPHB4 have been tested in a series of 43 children with at least one cerebral or spinal pial AVF fistula. A germline
RASA1 mutation was identified in 14 of them (32%), but none in EPHB4 [13]. In contrast, mutations in EPHB4 were identified in 10% of patients with vein-of-Galen aneurysmal malformation in another study [14]. Most of the RASA1 mutations are nonsense, splicing mutations, or out-of-frame deletions/duplications, leading to premature termination codons and suggesting loss of function. This is further supported by the observation of large genomic RASA1 rearrangements in the context of the 5q14.3 microdeletion syndrome [15]. These patients present with severe intellectual disability, absent speech, hypotonia, stereotypic movements, epilepsy, cerebral malformations, and mild facial dysmorphism due to MEF2C haploinsufficiency [15–17]. When RASA1 is included in the microdeletion, multifocal CMs are an important clue for the diagnosis. More than half of the EPHB4 mutations are premature stop codon, frame-shift, or splice-site alterations again suggesting loss of function. Moreover, in vitro functional studies on EPHB4 missense mutations demonstrated their rapid degradation and is thus in agreement with the proposed loss of function mechanism [9]. The pathophysiology of CM-AVM is unknown, but the number of lesions and their localized nature could indicate that a somatic second hit is required for lesions to develop, as previously reported in other multifocal vascular malformations [18–23]. This mechanism has already been confirmed for RASA1 [10,24]. CM-AVM was first described in 2003. Thus, the natural history is not yet known for developing guidelines for clinical management. Meanwhile, patients should be examined once a year by a clinician aware of the phenotype and its complications. CMs are harmless, and most of them are small and well tolerated. In contrast to sporadic CMs, CMs of CM-AVM do not respond well to pulsed dye laser. In fact, they can have increased flow. Intra-central nervous system fast-flow lesions in CM-AVM patients seem to manifest early in life, before birth or in the first years. These lesions, as well as extracranial fast-flow lesions, require a multidisciplinary approach. The management is similar to the management of sporadic lesions. Patients with PKWS should be treated conservatively; epiphysiodesis for leg length discrepancy should be avoided when possible as it can aggravate the fast-flow vascular malformation [25]. RASA1 encodes p120RASGAP, a cytoplasmic protein that acts as a negative regulator of the RAS-signaling pathway. P120RASGAP is a GTPase-activating protein
CHAPTER 10
Capillary Malformation/Arteriovenous Malformation
(GAP) of RAS p21. It accelerates the intrinsic GTPase activity of RAS p21, switching it from active GTP-bound form to inactive GDP-bound form, and is involved in cell proliferation and differentiation. EPHB4 is a transmembrane tyrosine kinase receptor preferentially expressed in the venous endothelial cells. Its ligand, ephrinB2, is a transmembrane protein located on the arterial endothelial cells [26,27]. The EPHB4 receptor and its ligand play an important role in heart morphogenesis and angiogenesis. At the arterial–venous boundary, the ephrinB2-EPHB4 forward signaling is involved in cellular repulsion, migration, and adhesion, separating arterial from venous endothelial cells. In mice, the complete or only endothelial cell loss of Rasa1 or complete loss of EphB4 is lethal at midgestation with abnormal angiogenesis [28–30]. In zebrafish, inhibition of RASA1 or EPHB4 has similar effects, especially with arteriovenous endothelial cell connection disturbances [31]. RASA1 is an endothelial downstream effector of EPHB4 and EPHB4/RASA1 deficiency overactivates mTORC1 [31]. These in vitro and in vivo discoveries on EPHB4/RASA1 signaling pathway are now mirrored by human pathology, as mutations in either RASA1 or EPHB4 cause similar phenotypes.
ACKNOWLEDGMENTS The authors’ studies are partially funded by the Concerted Research Actions (A.R.C.) – Convention No 16/21–073 of the Belgian French Community Ministry; the F.R.S.-FNRS (Fonds de la Recherche Scientifique) (T.0026.14 and T.0146.16); and la Communauté française de Wallonie-Bruxelles and Lotterie nationale, Belgium.
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