Venous malformation

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Hannan Javed, M.D.[2]

Overview

Venous Malformations (VM)

Common VM
  • Localized defects characterized by dilated venous channels. Microscopically they consist of thin endothelial cells lined by fewer, disorganized smooth muscle cells and extracellular matrix. Patient may present with deforming lesions, bleeding, thrombosis, significant acute or chronic pain, and pressure symptoms. Located on skin and mucosa for majority of the times, lesions often are present at birth.[1][2][3]
  • Sporadic mutations in the TEK gene, that encodes the tyrosine kinase receptor TIE2 that functions to regulate cellular growth and proliferation are found in half of the patients with sporadic venous malformations.[1][2][3]
  • Diagnosis is clinical. Current treatment options include sclerotherapy and surgery, alone or in combination but inaccessible lesions and high recurrence rate remains a problem. mTOR inhibitor rapamycin has been used in some studies with success.[2]
Familial VM cutaneo-mucosal (VMCM)
  • Venous malformations that appear both on skin and mucous membranes. Present at birth, they may not be apparent early in life and can appear after trauma and during pregnancy and puberty because of rapid growth. Patient may present with sequela of these malformations such as cosmetic deformation, pain, bleeding.[4]
  • Associated with mutation in TEK/TIE2 receptor tyrosine kinase that plays critical role in development of vessels and cardiovascular system.[4][5]
Blue rubber bleb nevus (Bean) syndrome VM
  • Also called Bean's syndrome and diffuse angiomatosis, venous malformations in this disorder involve the skin, oral cavity and internal organs, most typically the gastrointestinal tract. Cutaneous malformations are bluish in color, generally smaller than 1-2 cm, often hyperkeratotic, compressible and often found at palms and soles. Anomalies on the skin are usually asymptomatic but GI malformations can cause hemorrhage that can lead to anemia, most frequent presentation in patient population. Other manifestation can include GI infarction, telescoping or twisting of GI tract leading to intussusception and volvulus.[6][7][8]
  • Thought to be caused by somatic double (cis) muatations in TEK gene although autosomal-dominant inheritance has also been described in some cases. The gene that encodes TIE2, receptor tyrosine kinase involved in cell-signaling.[9][8][10][7]
  • The documentation of gastrointestinal lesions by endoscopy, colonoscopy, CT scan or MRI is considered pathognomonic. Sclerotherapy and surgery such as enterotomy remain the mainstay of treatment along with symptomatic management such as long term iron supplementation and/or blood transfusions.[7][6][11]
Glomuvenous malformation (GVM)
  • Defined by presence of glomus cells in in smooth muscle layer of the vessels, these mesynchymal vascular anomaly arises from glomus bodies, arteriovenous anastomosis that help regulate temperature via shunting of blood through its unique neuromyoarterial structure. Classically found in digits, they can occur anywhere but widespread lesions are not common. Clinical presentation varies from asymptomatic bluish to reddish plaques and nodules that are often partially compressible and are tender to painful disfiguring lesions.[12][13][14][15]
  • Mutations in glomulin (GLMN) gene that leads to defective GLMN protein is thought to be the cause. GMLN protein binds Rbx1 and inhibits its E3 ubiquitin ligase activity. If GMLN is defective then it leads to increased activity of Rbx1 causing decreased levels of Fbw7 and thus increased levels of Cyclin E and c-Myc because Fbw7 facilitates the ubiquitination and degradation Cyclin E and c-Myc.Mutations are inherited in autosomal-dominant pattern with incomplete pattern and variable expression although sporadic cases have been reported.[16][17][18][19]
  • Imaging such as MRI and CT scan and ultrasound can localize and define the extent of disease but definitive diagnosis requires biopsy following by histopathological studies demonstrating proliferation of glomus cells and venous malformations. Current treatment modalities include surgical excision and sclerotherapy although recurrence is common. Recently electron beam radiation and Nd:YAG laser have been used with success.[12][13][14][20][21][22][23]
Cerebral cavernous malformation (CCM)
  • Characterized by clusters of malformed endothelial channels forming densely arranged sinusoids that possess little to no intervening brain tissues. Because they lack smooth muscles and connective tissue and are malformed, they are prone to leakage causing micro-hemorrhages and thrombosis leading to hemosiderin deposits and gliosis around them. They can remain asymptomatic throughout life making them incidental finding but can cause symptoms associated with hemorrhage and pressure effects such as headaches, seizures, stroke, and focal neurologic deficits.[24][25][26]
  • Mutations in CCM1 Krev interaction trapped protein 1 (KRIT1), CCM2 Malcavernin, and CCM3 Programmed cell death protein 10 (PDCD10) are thought to be the cause of familial cases that tend to be inherited in autosomal-dominant pattern with incomplete penetrance, and variable expression. These proteins interact with cytoskeleton and endothelial tight junctions during vascular development in neural tissues to help maintain endothelial barrier function. they can occur due to sporadic mutations, usually presenting as single cavernous malformation while familial cases typically present as multiple cavernous malformations.[24][25][27][28]
  • Magnetic resonance (MR) imaging techniques are diagnostic modality of choice. Current treatment options depend on clinical history and location of the malformations. Surgery is usually preferred for symptomatic lesions in easily accessible locations and by some, for refractory epilepsy. If asymptomatic, observation is recommended but in case of single accessible asymptomatic malformation, surgical resection can be done. Surgery is also not recommended for malformations located in brain-stem due to significant mortality and morbidity associated with surgery while some recommend surgery after a second symptomatic bleed. Guidelines for symptomatic lesions located deep vary. Radiosurgery can be an alternative modality for single, symptomatic lesion if risks associated with surgery are unacceptable.[25][29][30][31][32]
Familial intraosseous vascular malformation (VMOS)
  • Described as enlargement and expansion of malformed blood vessels that is severe and progressive, typically in skull, face, and vertebral column. Another typical finding is mid-line abnormalities such as diastasis recti, supraumbilical raphe, and hiatus hernia. Clinical presentation can vary but increasing intracranial pressure and hemorrhage after any surgical procedure such as extraction of tooth are of major concern. Other common findings include pain, enlarging tissues such as expanding jaw, bluish mass/swelling, loose tooth, spontaneous bleeding, and ulceration.[33][34][35]
  • Mutations in ELMO2 gene encoding engulfment and cell motility protein 2 (ELMO2) are thought to be the cause of these malformations. This protein s involved cell-signaling cascade through its attachment to cell membrane. Majority of the cases are sporadic but recently some familial cases with autosomal-recessive inheritance have been described.[33][36]
  • CT angiography and magnetic resonance techniques are the preferred diagnostic modalities and may show widening of neurovascular canal on CTA, hyperintense signal on MRI. Honeycomb and sunburst radiographic appearances have been described as well. Management options include embolization, sclerotherapy, and surgical extirpation.[33][35][37]
Verrucous venous malformation
  • Formerly verrucous hemangioma, this rare congenital malformation is characterized by dilated blood vessels reaching out from papillary layer of dermis into subcutaneous tissue. Earlier presentation is bluish lesion that develops warty surface later on. Painful enlarging mass is the typical complain in symptomatic patients.[38][39]
  • Somatic mutation in MAP3K3 mitogen-activated protein kinase kinase kinase 3 are thought to be the cause.[40]
  • MRI is the diagnostic modality of choice but histopathological confirmation is gold standard for accurate diagnosis because of its close resemblance with angiokeratoma. Superficial ablation, surgical excision are treatment choices. Recently sirolimus has been used in some studies.[38][39][41]

References

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  1. ↑ 1.0 1.1 Nätynki M, Kangas J, Miinalainen I, Sormunen R, Pietilä R, Soblet J, Boon LM, Vikkula M, Limaye N, Eklund L (November 2015). "Common and specific effects of TIE2 mutations causing venous malformations". Hum. Mol. Genet. 24 (22): 6374–89. doi:10.1093/hmg/ddv349. PMC 4614705. PMID 26319232.
  2. ↑ 2.0 2.1 2.2 Castillo SD, Tzouanacou E, Zaw-Thin M, Berenjeno IM, Parker VE, Chivite I, Milà-Guasch M, Pearce W, Solomon I, Angulo-Urarte A, Figueiredo AM, Dewhurst RE, Knox RG, Clark GR, Scudamore CL, Badar A, Kalber TL, Foster J, Stuckey DJ, David AL, Phillips WA, Lythgoe MF, Wilson V, Semple RK, Sebire NJ, Kinsler VA, Graupera M, Vanhaesebroeck B (March 2016). "Somatic activating mutations in Pik3ca cause sporadic venous malformations in mice and humans". Sci Transl Med. 8 (332): 332ra43. doi:10.1126/scitranslmed.aad9982. PMC 5973268. PMID 27030595.
  3. ↑ 3.0 3.1 Limaye N, Kangas J, Mendola A, Godfraind C, Schlögel MJ, Helaers R, Eklund L, Boon LM, Vikkula M (December 2015). "Somatic Activating PIK3CA Mutations Cause Venous Malformation". Am. J. Hum. Genet. 97 (6): 914–21. doi:10.1016/j.ajhg.2015.11.011. PMC 4678782. PMID 26637981.
  4. ↑ 4.0 4.1 Brahami N, Subramaniam S, Al-Ddafari MS, Elkaim C, Harmand PO, Sari BE, Lefranc G, Aribi M (March 2017). "Facial cutaneo-mucosal venous malformations can develop independently of mutation of TEK gene but may be associated with excessive expression of Src and p-Src". J Negat Results Biomed. 16 (1): 9. doi:10.1186/s12952-017-0072-5. PMC 5357811. PMID 28316284.
  5. ↑ Wouters V, Limaye N, Uebelhoer M, Irrthum A, Boon LM, Mulliken JB, Enjolras O, Baselga E, Berg J, Dompmartin A, Ivarsson SA, Kangesu L, Lacassie Y, Murphy J, Teebi AS, Penington A, Rieu P, Vikkula M (April 2010). "Hereditary cutaneomucosal venous malformations are caused by TIE2 mutations with widely variable hyper-phosphorylating effects". Eur. J. Hum. Genet. 18 (4): 414–20. doi:10.1038/ejhg.2009.193. PMC 2841708. PMID 19888299.
  6. ↑ 6.0 6.1 El Bakkaly A, Ettayebi F, Oubeja H, Erraji M, Zerhouni H (2017). "[Bean's syndrome in children: about two cases]". Pan Afr Med J (in French). 28: 102. doi:10.11604/pamj.2017.28.102.11109. PMC 5837144. PMID 29515720.
  7. ↑ 7.0 7.1 7.2 Soblet J, Kangas J, Nätynki M, Mendola A, Helaers R, Uebelhoer M, Kaakinen M, Cordisco M, Dompmartin A, Enjolras O, Holden S, Irvine AD, Kangesu L, Léauté-Labrèze C, Lanoel A, Lokmic Z, Maas S, McAleer MA, Penington A, Rieu P, Syed S, van der Vleuten C, Watson R, Fishman SJ, Mulliken JB, Eklund L, Limaye N, Boon LM, Vikkula M (January 2017). "Blue Rubber Bleb Nevus (BRBN) Syndrome Is Caused by Somatic TEK (TIE2) Mutations". J. Invest. Dermatol. 137 (1): 207–216. doi:10.1016/j.jid.2016.07.034. PMID 27519652.
  8. ↑ 8.0 8.1 Akutko K, Krzesiek E, Iwańczak B (October 2012). "[Blue rubber bleb naevus syndrome]". Pol. Merkur. Lekarski (in Polish). 33 (196): 226–8. PMID 23272612.
  9. ↑ Jeltsch M, Leppänen VM, Saharinen P, Alitalo K (September 2013). "Receptor tyrosine kinase-mediated angiogenesis". Cold Spring Harb Perspect Biol. 5 (9). doi:10.1101/cshperspect.a009183. PMC 3753715. PMID 24003209.
  10. ↑ Gawlikowska-Sroka A, Glura B, Mokrzycka M, Ociepa T (2016). "[Bean Syndrome (blue rubber bleb nevus syndrome)]". Pomeranian J Life Sci (in Polish). 62 (2): 5–7. PMID 29537205.
  11. ↑ Lindsey SF, Reiders B, Mechaber HF (2013). "Life-threatening pharyngeal edema after sclerotherapy of oral venous malformations in a patient with blue rubber bleb nevus syndrome". J Dermatol Case Rep. 7 (3): 74–6. doi:10.3315/jdcr.2013.1145. PMC 3797012. PMID 24133559.
  12. ↑ 12.0 12.1 Wortsman X, Millard F, Aranibar L (April 2018). "Color Doppler Ultrasound Study of Glomuvenous Malformations with its Clinical and Histologic Correlations". Actas Dermosifiliogr. 109 (3): e17–e21. doi:10.1016/j.ad.2017.04.013. PMID 28683898.
  13. ↑ 13.0 13.1 Jha A, Khunger N, Malarvizhi K, Ramesh V, Singh A (2016). "Familial Disseminated Cutaneous Glomuvenous Malformation: Treatment with Polidocanol Sclerotherapy". J Cutan Aesthet Surg. 9 (4): 266–269. doi:10.4103/0974-2077.197083. PMC 5227083. PMID 28163461.
  14. ↑ 14.0 14.1 Whipple KM, Godfrey KJ, Solomon JP, Lin JH, Korn BS, Kikkawa DO (2017). "Glomuvenous Malformation: A Rare Periorbital Lesion of the Thermoregulatory Apparatus". Ophthalmic Plast Reconstr Surg. 33 (2): e36–e37. doi:10.1097/IOP.0000000000000695. PMC 5118188. PMID 27065433.
  15. ↑ Jha A, Ramesh V, Singh A (2014). "Disseminated cutaneous glomuvenous malformation". Indian J Dermatol Venereol Leprol. 80 (6): 556–8. doi:10.4103/0378-6323.144200. PMID 25382523.
  16. ↑ Borroni RG, Grassi S, Concardi M, Puccio I, Giordano C, Agozzino M, Caspani C, Grasso M, Diegoli M, Arbustini E (March 2014). "Glomuvenous malformations with smooth muscle and eccrine glands: unusual histopathologic features in a familial setting". J. Cutan. Pathol. 41 (3): 308–15. doi:10.1111/cup.12283. PMID 24345188.
  17. ↑ Brouillard P, Boon LM, Revencu N, Berg J, Dompmartin A, Dubois J, Garzon M, Holden S, Kangesu L, Labrèze C, Lynch SA, McKeown C, Meskauskas R, Quere I, Syed S, Vabres P, Wassef M, Mulliken JB, Vikkula M (April 2013). "Genotypes and phenotypes of 162 families with a glomulin mutation". Mol Syndromol. 4 (4): 157–64. doi:10.1159/000348675. PMC 3666456. PMID 23801931.
  18. ↑ Tron AE, Arai T, Duda DM, Kuwabara H, Olszewski JL, Fujiwara Y, Bahamon BN, Signoretti S, Schulman BA, DeCaprio JA (April 2012). "The glomuvenous malformation protein Glomulin binds Rbx1 and regulates cullin RING ligase-mediated turnover of Fbw7". Mol. Cell. 46 (1): 67–78. doi:10.1016/j.molcel.2012.02.005. PMC 3336104. PMID 22405651.
  19. ↑ Brouillard P, Ghassibé M, Penington A, Boon LM, Dompmartin A, Temple IK, Cordisco M, Adams D, Piette F, Harper JI, Syed S, Boralevi F, Taïeb A, Danda S, Baselga E, Enjolras O, Mulliken JB, Vikkula M (February 2005). "Four common glomulin mutations cause two thirds of glomuvenous malformations ("familial glomangiomas"): evidence for a founder effect". J. Med. Genet. 42 (2): e13. doi:10.1136/jmg.2004.024174. PMC 1735996. PMID 15689436.
  20. ↑ Rivers JK, Rivers CA, Li MK, Martinka M (January 2016). "Laser Therapy for an Acquired Glomuvenous Malformation (Glomus Tumour): A Nonsurgical Approach". J Cutan Med Surg. 20 (1): 80–3. doi:10.1177/1203475415596121. PMID 26177926.
  21. ↑ Phillips CB, Guerrero C, Theos A (April 2015). "Nd:YAG laser offers promising treatment option for familial glomuvenous malformation". Dermatol. Online J. 21 (4). PMID 25933083.
  22. ↑ Flors L, Norton PT, Hagspiel KD (February 2015). "Glomuvenous malformation: magnetic resonance imaging findings". Pediatr Radiol. 45 (2): 286–90. doi:10.1007/s00247-014-3086-x. PMID 24996811.
  23. ↑ Henning JS, Kovich OI, Schaffer JV (January 2007). "Glomuvenous malformations". Dermatol. Online J. 13 (1): 17. PMID 17511950.
  24. ↑ 24.0 24.1 Draheim KM, Fisher OS, Boggon TJ, Calderwood DA (February 2014). "Cerebral cavernous malformation proteins at a glance". J. Cell. Sci. 127 (Pt 4): 701–7. doi:10.1242/jcs.138388. PMC 3924200. PMID 24481819.
  25. ↑ 25.0 25.1 25.2 Zyck S, Gould GC. PMID 30252265. Missing or empty |title= (help)
  26. ↑ Trapani E, Retta SF (September 2015). "Cerebral cavernous malformation (CCM) disease: from monogenic forms to genetic susceptibility factors". J Neurosurg Sci. 59 (3): 201–9. PMID 25896717.
  27. ↑ Wang Y, Li Y, Zou J, Polster SP, Lightle R, Moore T, Dimaano M, He TC, Weber CR, Awad IA, Shen L (September 2018). "The cerebral cavernous malformation disease causing gene KRIT1 participates in intestinal epithelial barrier maintenance and regulation". FASEB J.: fj201800343R. doi:10.1096/fj.201800343R. PMID 30252535.
  28. ↑ Nardella G, Visci G, Guarnieri V, Castellana S, Biagini T, Bisceglia L, Palumbo O, Trivisano M, Vaira C, Scerrati M, Debrasi D, D'Angelo V, Carella M, Merla G, Mazza T, Castori M, D'Agruma L, Fusco C (August 2018). "A single-center study on 140 patients with cerebral cavernous malformations: 28 new pathogenic variants and functional characterization of a PDCD10 large deletion". Hum. Mutat. doi:10.1002/humu.23629. PMID 30161288.
  29. ↑ Mouchtouris N, Chalouhi N, Chitale A, Starke RM, Tjoumakaris SI, Rosenwasser RH, Jabbour PM (2015). "Management of cerebral cavernous malformations: from diagnosis to treatment". ScientificWorldJournal. 2015: 808314. doi:10.1155/2015/808314. PMC 4300037. PMID 25629087.
  30. ↑ Kim J (May 2016). "Introduction to cerebral cavernous malformation: a brief review". BMB Rep. 49 (5): 255–62. PMC 5070704. PMID 26923303.
  31. ↑ Wurm G, Schnizer M, Fellner FA (July 2005). "Cerebral cavernous malformations associated with venous anomalies: surgical considerations". Neurosurgery. 57 (1 Suppl): 42–58, discussion 42–58. PMID 15987569.
  32. ↑ Washington CW, McCoy KE, Zipfel GJ (September 2010). "Update on the natural history of cavernous malformations and factors predicting aggressive clinical presentation". Neurosurg Focus. 29 (3): E7. doi:10.3171/2010.5.FOCUS10149. PMID 20809765.
  33. ↑ 33.0 33.1 33.2 Cetinkaya A, Xiong JR, Vargel İ, Kösemehmetoğlu K, Canter Hİ, Gerdan ÖF, Longo N, Alzahrani A, Camps MP, Taskiran EZ, Laupheimer S, Botto LD, Paramalingam E, Gormez Z, Uz E, Yuksel B, Ruacan Ş, Sağıroğlu MŞ, Takahashi T, Reversade B, Akarsu NA (August 2016). "Loss-of-Function Mutations in ELMO2 Cause Intraosseous Vascular Malformation by Impeding RAC1 Signaling". Am. J. Hum. Genet. 99 (2): 299–317. doi:10.1016/j.ajhg.2016.06.008. PMC 4974086. PMID 27476657.
  34. ↑ Vargel I, Cil BE, Er N, Ruacan S, Akarsu AN, Erk Y (April 2002). "Hereditary intraosseous vascular malformation of the craniofacial region: an apparently novel disorder". Am. J. Med. Genet. 109 (1): 22–35. PMID 11932989.
  35. ↑ 35.0 35.1 Handa H, Naidu GS, Dara BG, Deshpande A, Raghavendra R (March 2014). "Diverse imaging characteristics of a mandibular intraosseous vascular lesion". Imaging Sci Dent. 44 (1): 67–73. doi:10.5624/isd.2014.44.1.67. PMC 3972408. PMID 24701461.
  36. ↑ Peotter JL, Phillips J, Tong T, Dimeo K, Gonzalez JM, Peters DM (October 2016). "Involvement of Tiam1, RhoG and ELMO2/ILK in Rac1-mediated phagocytosis in human trabecular meshwork cells". Exp. Cell Res. 347 (2): 301–11. doi:10.1016/j.yexcr.2016.08.009. PMC 5333770. PMID 27539661.
  37. ↑ Cariati P, Marín-Fernández AB, Julia-Martínez MÁ, Pérez-de Perceval-Tara M, Sánchez-López D, Martínez-Lara I (February 2018). "Endovascular treatment of an intraosseous arteriovenous malformation of the mandible in a child. A case Report". J Clin Exp Dent. 10 (2): e189–e191. doi:10.4317/jced.54550. PMC 5899801. PMID 29670739.
  38. ↑ 38.0 38.1 Singh J, Sharma P, Tandon S, Sinha S (2017). "Multiple Verrucous Hemangiomas: A Case Report with New Therapeutic Insight". Indian Dermatol Online J. 8 (4): 254–256. doi:10.4103/idoj.IDOJ_313_16. PMC 5518576. PMID 28761841.
  39. ↑ 39.0 39.1 Oppermann K, Boff AL, Bonamigo RR (2018). "Verrucous hemangioma and histopathological differential diagnosis with angiokeratoma circumscriptum neviforme". An Bras Dermatol. 93 (5): 712–715. doi:10.1590/abd1806-4841.20187259. PMC 6106676. PMID 30156622.
  40. ↑ Couto JA, Vivero MP, Kozakewich HP, Taghinia AH, Mulliken JB, Warman ML, Greene AK (March 2015). "A somatic MAP3K3 mutation is associated with verrucous venous malformation". Am. J. Hum. Genet. 96 (3): 480–6. doi:10.1016/j.ajhg.2015.01.007. PMC 4375628. PMID 25728774.
  41. ↑ Zhang G, Chen H, Zhen Z, Chen J, Zhang S, Qin Q, Liu X (July 2018). "Sirolimus for treatment of verrucous venous malformation: A retrospective cohort study". J. Am. Acad. Dermatol. doi:10.1016/j.jaad.2018.07.014. PMID 30048660.
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