Capillary Malformation-arteriovenous Malformation Type 2: A Case Report and Review
DOI:
https://doi.org/10.2340/actadv.v102.1126Keywords:
CM-AVM2, EPHB4, arteriovenous malformation, capillary malformation-arteriovenous malformation syndromeAbstract
Capillary malformation-arteriovenous malformation syndrome is a rare genodermatosis with cutaneous capillary malformations and a risk of associated fast-flow malformations. We describe here a four-generation family with a novel heterozygous pathogenic variant in the EPHB4 gene (NM_004444.5 (EPHB4): c.2224G>C, p.(Ala742Pro)). A review of the literature retrieved 127 patients with capillary malformation-arteriovenous malformation syndrome and confirmed variants in EPHB4. Multiple capillary malformations were present in 114 (89.76%) patients, and 12 (9.44%) patients had a solitary capillary malformation. Arteriovenous malformations/fistulas were present in 23 (18.1%) patients, and were located within the central nervous system in 5 (3.9%) patients. Not all papers included description of epistaxis. Telangiectasias were reported in 28 (22%) patients, and Bier spots were described in 20 (15.7%) patients. The clinical characteristics of capillary malformation-arteriovenous malformation syndrome are diverse and often discrete, which can make it difficult to distinguish capillary malformation-arteriovenous malformation syndrome from hereditary haemorrhagic telangiectasia.
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Eerola I, Boon LM, Mulliken JB, Burrows PE, Dompmartin A, Watanabe, S et al. Capillary malformation-arteriovenous malformation, a new clinical and genetic disorder caused by RASA1 mutations. Am J Hum Genet 2003; 73: 1240-1249.
https://doi.org/10.1086/379793
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: 1037-1048.
https://doi.org/10.1161/CIRCULATIONAHA.116.026886
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: 1632-1641.
https://doi.org/10.1002/humu.22431
Orme CM, Boyden LM, Choate KA, Antaya RJ, King BA. Capillary malformation-arteriovenous malformation syndrome: review of the literature, proposed diagnostic criteria, and recommendations for management. Pediatr Dermatol 2013; 30: 409-415.
https://doi.org/10.1111/pde.12112
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: 959-965.
https://doi.org/10.1002/humu.20746
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: 11-16.
https://doi.org/10.1016/j.ejmg.2017.10.004
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: 188-196.
https://doi.org/10.1016/j.ajhg.2012.12.017
Valdivielso-Ramos M, Martin-Santiago A, Azaña JM Hernández-Nuñez A, Vera A, Perez B, et al. Capillary malformation-arteriovenous malformation syndrome: a multicentre study. Clin Exp Dermatol 2021; 46: 300-305.
https://doi.org/10.1111/ced.14428
Maruani A, Durieux-Verde M, Mazereeuw-Hautier J, Boccara O, Martin L, Chiaverini C, et al. Search for RASA1 variants in capillary malformations of the legs in 113 children: results from the French National Paediatric Cohort CONAPE. Acta Derm Venereol 2018; 98: 251-255.
https://doi.org/10.2340/00015555-2835
Cen Q, Sun Y, Zeng X, Liu Y, Liu F, Chen H, et al. Unilateral and segmental distribution of facial erythema: is it a real port-wine stain? Hereditas 2020; 157: 27.
https://doi.org/10.1186/s41065-020-00143-z
Wooderchak-Donahue WL, Akay G, Whitehead K, Briggs E, Stenvenson DA, O'Fallon B, et al. Phenotype of CM-AVM2 caused by variants in EPHB4: how much overlap with hereditary hemorrhagic telangiectasia (HHT)? Genet Med 2019; 21: 2007-2014.
https://doi.org/10.1038/s41436-019-0443-z
Yedidi RS, Raffi J, Sugarman J. Broadly distributed vascular macules in a pediatric patient. Cutis 2020; 105: E7-E9.
Gourier G, Audebert-Bellanger S, Vourc'h P, Fraitag S, L'Hérondelle K, Labouche A, et al. Multiple capillary malformations of progressive onset: Capillary malformation-arteriovenous malformation syndrome (CM-AVM). Ann Dermatol Venereol 2018; 145: 486-491.
https://doi.org/10.1016/j.annder.2018.04.010
Kim C, Ko CJ, Baker KE, Antaya RJ. Histopathologic and ultrasound characteristics of cutaneous capillary malformations in a patient with capillary malformation-arteriovenous malformation syndrome. Pediatr Dermatol 2015; 32: 128-131.
https://doi.org/10.1111/pde.12188
Rodríguez Bandera AI, Feito Rodríguez M, Chiloeches Fernández C, Stewart N, Valdivielso-Ramos M. Role of colour-Doppler high-frequency ultrasonography in capillary malformation-arteriovenous malformation syndrome: a case series. Australas J Dermatol 2020; 61: 349-352.
https://doi.org/10.1111/ajd.13311
Kluger N, Bessis D. Bier's spots. J Eur Acad Dermatol Venereol 2019; 33: e78-e79.
https://doi.org/10.1111/jdv.15222
El Hajjam M, Mekki A, Palmyre A, Eyries M, Soubrier F, Bourgault Villada I, et al. RASA1 phenotype overlaps with hereditary haemorrhagic telangiectasia: two case reports. J Med Genet 2021; 58: 645-647.
https://doi.org/10.1136/jmedgenet-2019-106792
Yu J, Streicher JL, Medne L, Krantz ID, Yan AC. EPHB4 Mutation implicated in capillary malformation-arteriovenous malformation syndrome: a case report. Pediatr Dermatol 2017; 34: e227-e230.
https://doi.org/10.1111/pde.13208
Rimmer J, Lund VJ. Hereditary haemorrhagic telangiectasia. Rhinology 2015; 53: 195-203.
https://doi.org/10.4193/Rhino14.274
Molho-Pessach V, Agha Z, Libster D, Lere I, Burger A, Jaber S, et al. Evidence for clinical and genetic heterogeneity in hereditary benign telangiectasia. J Am Acad Dermatol 2007; 57: 814-818.
https://doi.org/10.1016/j.jaad.2007.06.024
Ujiie H, Kodama K, Akiyama M, Shimizu H. Hereditary benign telangiectasia: two families with punctate telangiectasias surrounded by anemic halos. Arch Dermatol 2010; 146: 98-99.
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