Vascular anomalies

Abstract

Vascular malformations are localized errors of vascular development affecting roughly 0.3% of the population (Mulliken & Young, 1988). They are often identified on the skin as ‘birthmarks’ of various sizes and shapes. They usually slowly grow with the growth of the child. The cutaneous malformations may also be signs of lesions in other localizations, such as the liver, intestine and the brain. They consist of tortuous vascular channels of various types, with continuous endothelium surrounded by various numbers of mural support cells. Most of these lesions occur sporadically, without family history, yet sometimes, as an inherited disorder or as part of a syndrome (Brouillard and Vikkula, Hum Mol Genet, 2007). Genetic studies of families have led to the identification of a number of genes that can cause vascular malformations. The first discovery was the identification of the TIE2/TEK gene, which encodes an endothelial receptor tyrosine kinase, responsible for hereditary mucocutaneous venous malformations (Vikkula, Cell, 1996). Thereafter, it was unravelled that loss-of-function mutations in the VEGFR3 gene, encoding the vascular endothelial growth factor 3 receptor, is responsible for congenital hereditary lymphedema (Karkkainen et al., Nat Genet, 1999; Irrthum et al., Am J Hum Genet, 2000). Mutations in three genes (CCM1, CCM2 and CCM3) have been shown to cause cerebral cavernous malformations (Laberge-le-Couteulx et al., Nat Genet, 1999; Liquori et al., Am J Hum Genet, 2003; Denier et al., Am J Hum Genet, 2004), and we linked mutations in the CCM1 gene to cutaneous capillary-venous malformations associated with cerebral cavernous malformations (Eerola et al., Hum Mol Genet, 2000). More recent work has led to the identification of mutations in glomulin to be responsible for hereditary glomuvenous malformations (‘glomangiomas’) (Brouillard et al., Am J Hum Genet, 2002), SOX18 mutations to cause lymphedema-hypotrichosis-telangiectasia syndrome (Irrthum et al., Am J Hum Genet, 2003) and RASA1 mutations to cause a newly recognized disorder, which associates atypical hereditary capillary malformations with arterio-venous anomalies (CM-AVM) (Eerola et al., Am J Hum Genet, 2003; Revencu et al., submitted). As the function of the genes identified using reverse genetics is often unknown, in vivo models are crucial for further dissection of the molecular pathways involved in these disorders. Such models will enable direct evaluation of the developmental functions and significance of the genes in vasculogenesis and angiogenesis. In addition, murine models could serve for screening of novel therapeutic and hopefully curative modalities. Mulliken JB, Young AE. Vascular birthmarks: hemangiomas and malformations. Philadelphia, PA: WB Saunders, 1988. This book on vascular anomalies is the only comprehensive work dedicated to these lesions and gives the current classification, as well as all the main information on the clinical aspects, pathophysiology and treatment of vascular anomalies. Brouillard P, Vikkula M. Genetic causes of vascular malformations (review). Hum Mol Genet, in press. This review summarizes all the most important discoveries on the genetic and pathophysiological causes of vascular anomalies, and discusses these findings in the context of existing murine models directly relevant to the disorders. Vikkula M, Boon LM, Carraway KLI, Calvert JT, Diamonti AJ, Goumnerov B, Pasyk KA, Marchuk DA, Warman ML, Cantley LC, Mulliken JB, Olsen BR. Vascular dysmorphogenesis caused by an activating mutation in the receptor tyrosine kinase TIE2. Cell 1996: 87: 1181–1190. This is the first study implicating mutations in the endothelial-specific tyrosine kinase receptor, the angiopoietin receptor TIE2/TEK, in hereditary mucocutaneous venous malformations (VMCM). It demonstrates that the amino acid substitutions in the receptor cause hyperphosphorylation of the receptor and thus pinpoints it as a target for novel therapies. The study also demonstrates that these lesions are due to a relative lack of mural smooth muscle cells in the lesions. Karkkainen MJ, Ferrell RE, Lawrence EC, Kimak MA, Levinson KL, McTigue MA, Alitalo K, Finegold DN. Missense mutations interfere with VEGFR-3 signalling in primary lymphoedema. Nat Genet 1999: 25: 153–159. Irrthum A, Karkkainen MJ, Devriendt K, Alitalo K, Vikkula M. Congenital hereditary lymphedema caused by a mutation that inactivates VEGFR3 tyrosine kinase. Am J Hum Genet 2000: 67: 295–301. These two studies are the first demonstrations of mutations in the receptor tyrosine kinase receptor VEGFR3 (vascular growth factor receptor three) causing primary congenital lymphedema. Laberge-le Couteulx S, Jung HH, Labauge P, Houtteville J-P, Lescoat C, Cecillon M, Marechal E, Joutel A, Bach J-F, Tournier-Lasserve E. Truncatin mutations in CCM1, encoding KRIT1, cause hereditary cavernous angiomas. Nat Genet 1999: 23: 189–193. This is the first description of mutations in the CCM1 gene causing cerebral cavernous malformations. The work that followed this discovery has led to the identification of two other genes. Liquori CL, Berg MJ, Siegel AM, Huang E, Zawistowski JS, Stoffer T, Verlaan D, Balogun F, Hughes L, Leedom TP, Plummer NW, Cannella M, Maglione V, Squitieri F, Johnson EW, Rouleau GA, Ptacek L, Marchuk DA. Mutations in a gene encoding a novel protein containing a phosphotyrosine-binding domain cause type 2 cerebral cavernous malformations. Am J Hum Genet 2003: 73: 1459–1464. Denier C, Goutagny S, Labauge P, Krivosic V, Arnoult M, Cousin A, Benabid AL, Comoy J, Frerebeau P, Gilbert B, Houtteville JP, Jan M, Lapierre F, Loiseau H, Menei P, Mercier P, Moreau JJ, Nivelon-Chevallier A, Parker F, Redondo AM, Scarabin JM, Tremoulet M, Zerah M, Maciazek J, Tournier-Lasserve E. Mutations within the MGC4607 gene cause cerebral cavernous malformations. Am J Hum Genet 2004: 74: 326–337. These two references are the first demonstrations implicating mutations in CCM2 (malcavernin or MGC4607) in cerebral cavernous malformation type 2. This protein seems to be implicated in intracellular signalling. Bergametti F, Denier C, Labauge P, Arnoult M, Boetto S, Clanet M, Coubes P, Echenne B, Ibrahim R, Irthum B, Jacquet G, Lonjon M, Moreau JJ, Neau JP, Parker F, Tremoulet M, Tournier-Lasserve E. Mutations within the programmed cell death 10 gene cause cerebral cavernous malformations. Am J Hum Genet 2005: 76: 42–51. This is the first demonstration implicating mutations in CCM3 (programmed cell death 10) in cerebral cavernous malformation type 3. Together with CCM1 and CCM2 this protein seems to be implicated in intracellular signalling. Eerola I, Plate KH, Spiegel R, Boon LM, Mulliken JB, Vikkula M. KRIT1 is mutated in hyperkeratotic cutaneous capillary-venous malformation associated with cerebral capillary malformation. Hum Mol Genet 2000: 9: 1351–1355. This is the first demonstration of mutations in the CCM1 gene causing cutaneous hyperkeratotic capillary-venous malformations (HCCVM) associated with cerebral cavernous malformations. Although these lesions seem to be fairly uncommon, they can be the sign of more severe intracerebral lesions. The cutaneous lesions have a variable expressivity. 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: 866–874. This is the first study implicating mutations in glomulin in glomuvenous malformations. In addition, it provides evidence for paradominant inheritance of this vascular anomaly, by showing a somatic second hit mutation in a tissue sample. Irrthum A, Devriendt K, Chitayat D, Matthijs G, Glade C, Steijlen PM, Fryns J-P, Van Steensen MAM, Vikkula M. Mutations in the transcription factor SOX18 underlie recessive and dominant forms of hypotrichosis-lymphedema-telangiectasia. Am J Hum Genet 2003: 72: 1470–1478. This is the first study implicating mutations in the transcription factor SOX18 in a syndrome that associates cutaneous telangiectasias with hypotrichosis and lymphoedema. It demonstrates that the targets of this transcription factor have an important role in the development of the hair and cutaneous capillaries, as well as the function of lymphatics, thereby pinpointing them as targets for development of future therapeutic approaches. Eerola I, Boon LM, Mulliken JB, Burrows PE, Vanwijck R, Vikkula M. Capillary malformation-arteriovenous malformation, a heretofore undescribed clinical and genetic entity, is caused by RASA1 mutations. Am J Hum Genet 2003: 73: 1240–1249. Boon LM, Mulliken JB, Vikkula M. RASA 1: variable phenotype with capillary and arteriovenous malformations. Curr Opin Genet Dev 2005: 15: 265–269. This is the first study implicating mutations in the RAS-GTPase, p120RasGap, in a newly recognized disorder, which associates atypical capillary malformations with fast-flow lesions. These studies name this newly identified association as capillary malformation-arteriovenous malformation (CM-AVM). Revencu N, Boon LM, Mulliken JB, Enjolras O, Cordisco MR, Chitayat D, Burrows PE, Clapuyt Ph, Hammer F, Dubois J, Baselga E, Brancati F, Carder R, Ceballos Quintal JM, Dallapiccola B, Fischer G, Frieden IJ, Garzon M, Harper J, Johnson Patel J, Labrèze C, Martorell L, Paltie HJ, Pohl A, Prendiville J, Quere I, Siegel DH, Valente EM, van Hagen A, van Hest L, Vaux K, Vicente A, Weibel L, Vikkula M. Parkes Weber syndrome, vein of Galen aneurysmal malformation, and other fast-flow vascular anomalies and specific neural tumors associated with RASA1 mutations. (submitted 2007). This is a comprehensive description of the variability of the clinical phenotype caused by mutations in the RASA1 gene. It also demonstrates the differences between the fast-flow malformations associated with RASA1 compared to those associated with PTEN mutations or hereditary haemorrhagic telangiectasia. Moreover, it shows predisposition to certain specific tumors in this disorder. Thanks to the help of Chanel, Galderma International, Laboratoires Bailleul, Laboratoires Pierre Fabre, Laboratoires Serobiologiques, La Roche Posay Laboratoire Pharmaceutique, Leo Pharma, L.V.M.H.