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| ==Vascular malformations== | | ==Vascular malformations== |
| ===Simple vascular malformations=== | | ===Simple vascular malformations=== |
| ====Venous malformations (VM)====
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| =====Common VM=====
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| * 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.<ref name="pmid26319232">{{cite journal |vauthors=Nätynki M, Kangas J, Miinalainen I, Sormunen R, Pietilä R, Soblet J, Boon LM, Vikkula M, Limaye N, Eklund L |title=Common and specific effects of TIE2 mutations causing venous malformations |journal=Hum. Mol. Genet. |volume=24 |issue=22 |pages=6374–89 |date=November 2015 |pmid=26319232 |pmc=4614705 |doi=10.1093/hmg/ddv349 |url=}}</ref><ref name="pmid27030595">{{cite journal |vauthors=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 |title=Somatic activating mutations in Pik3ca cause sporadic venous malformations in mice and humans |journal=Sci Transl Med |volume=8 |issue=332 |pages=332ra43 |date=March 2016 |pmid=27030595 |pmc=5973268 |doi=10.1126/scitranslmed.aad9982 |url=}}</ref><ref name="pmid26637981">{{cite journal |vauthors=Limaye N, Kangas J, Mendola A, Godfraind C, Schlögel MJ, Helaers R, Eklund L, Boon LM, Vikkula M |title=Somatic Activating PIK3CA Mutations Cause Venous Malformation |journal=Am. J. Hum. Genet. |volume=97 |issue=6 |pages=914–21 |date=December 2015 |pmid=26637981 |pmc=4678782 |doi=10.1016/j.ajhg.2015.11.011 |url=}}</ref>
| |
| * 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.<ref name="pmid26319232">{{cite journal |vauthors=Nätynki M, Kangas J, Miinalainen I, Sormunen R, Pietilä R, Soblet J, Boon LM, Vikkula M, Limaye N, Eklund L |title=Common and specific effects of TIE2 mutations causing venous malformations |journal=Hum. Mol. Genet. |volume=24 |issue=22 |pages=6374–89 |date=November 2015 |pmid=26319232 |pmc=4614705 |doi=10.1093/hmg/ddv349 |url=}}</ref><ref name="pmid27030595">{{cite journal |vauthors=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 |title=Somatic activating mutations in Pik3ca cause sporadic venous malformations in mice and humans |journal=Sci Transl Med |volume=8 |issue=332 |pages=332ra43 |date=March 2016 |pmid=27030595 |pmc=5973268 |doi=10.1126/scitranslmed.aad9982 |url=}}</ref><ref name="pmid26637981">{{cite journal |vauthors=Limaye N, Kangas J, Mendola A, Godfraind C, Schlögel MJ, Helaers R, Eklund L, Boon LM, Vikkula M |title=Somatic Activating PIK3CA Mutations Cause Venous Malformation |journal=Am. J. Hum. Genet. |volume=97 |issue=6 |pages=914–21 |date=December 2015 |pmid=26637981 |pmc=4678782 |doi=10.1016/j.ajhg.2015.11.011 |url=}}</ref>
| |
| * 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.<ref name="pmid27030595">{{cite journal| author=Castillo SD, Tzouanacou E, Zaw-Thin M, Berenjeno IM, Parker VE, Chivite I et al.| title=Somatic activating mutations in Pik3ca cause sporadic venous malformations in mice and humans. | journal=Sci Transl Med | year= 2016 | volume= 8 | issue= 332 | pages= 332ra43 | pmid=27030595 | doi=10.1126/scitranslmed.aad9982 | pmc=5973268 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=27030595 }}</ref>
| |
| =====Familial VM cutaneo-mucosal (VMCM)=====
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| * 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.<ref name="pmid28316284">{{cite journal |vauthors=Brahami N, Subramaniam S, Al-Ddafari MS, Elkaim C, Harmand PO, Sari BE, Lefranc G, Aribi M |title=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 |journal=J Negat Results Biomed |volume=16 |issue=1 |pages=9 |date=March 2017 |pmid=28316284 |pmc=5357811 |doi=10.1186/s12952-017-0072-5 |url=}}</ref>
| |
| * Associated with mutation in TEK/TIE2 receptor tyrosine kinase that plays critical role in development of vessels and cardiovascular system.<ref name="pmid28316284">{{cite journal |vauthors=Brahami N, Subramaniam S, Al-Ddafari MS, Elkaim C, Harmand PO, Sari BE, Lefranc G, Aribi M |title=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 |journal=J Negat Results Biomed |volume=16 |issue=1 |pages=9 |date=March 2017 |pmid=28316284 |pmc=5357811 |doi=10.1186/s12952-017-0072-5 |url=}}</ref><ref name="pmid19888299">{{cite journal |vauthors=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 |title=Hereditary cutaneomucosal venous malformations are caused by TIE2 mutations with widely variable hyper-phosphorylating effects |journal=Eur. J. Hum. Genet. |volume=18 |issue=4 |pages=414–20 |date=April 2010 |pmid=19888299 |pmc=2841708 |doi=10.1038/ejhg.2009.193 |url=}}</ref>
| |
| =====Blue rubber bleb nevus (Bean) syndrome VM=====
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| * 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.<ref name="pmid29515720">{{cite journal |vauthors=El Bakkaly A, Ettayebi F, Oubeja H, Erraji M, Zerhouni H |title=[Bean's syndrome in children: about two cases] |language=French |journal=Pan Afr Med J |volume=28 |issue= |pages=102 |date=2017 |pmid=29515720 |pmc=5837144 |doi=10.11604/pamj.2017.28.102.11109 |url=}}</ref><ref name="pmid27519652">{{cite journal |vauthors=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 |title=Blue Rubber Bleb Nevus (BRBN) Syndrome Is Caused by Somatic TEK (TIE2) Mutations |journal=J. Invest. Dermatol. |volume=137 |issue=1 |pages=207–216 |date=January 2017 |pmid=27519652 |doi=10.1016/j.jid.2016.07.034 |url=}}</ref><ref name="pmid23272612">{{cite journal |vauthors=Akutko K, Krzesiek E, Iwańczak B |title=[Blue rubber bleb naevus syndrome] |language=Polish |journal=Pol. Merkur. Lekarski |volume=33 |issue=196 |pages=226–8 |date=October 2012 |pmid=23272612 |doi= |url=}}</ref>
| |
| * 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.<ref name="pmid24003209">{{cite journal |vauthors=Jeltsch M, Leppänen VM, Saharinen P, Alitalo K |title=Receptor tyrosine kinase-mediated angiogenesis |journal=Cold Spring Harb Perspect Biol |volume=5 |issue=9 |pages= |date=September 2013 |pmid=24003209 |pmc=3753715 |doi=10.1101/cshperspect.a009183 |url=}}</ref><ref name="pmid23272612">{{cite journal |vauthors=Akutko K, Krzesiek E, Iwańczak B |title=[Blue rubber bleb naevus syndrome] |language=Polish |journal=Pol. Merkur. Lekarski |volume=33 |issue=196 |pages=226–8 |date=October 2012 |pmid=23272612 |doi= |url=}}</ref><ref name="pmid29537205">{{cite journal |vauthors=Gawlikowska-Sroka A, Glura B, Mokrzycka M, Ociepa T |title=[Bean Syndrome (blue rubber bleb nevus syndrome)] |language=Polish |journal=Pomeranian J Life Sci |volume=62 |issue=2 |pages=5–7 |date=2016 |pmid=29537205 |doi= |url=}}</ref><ref name="pmid27519652">{{cite journal |vauthors=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 |title=Blue Rubber Bleb Nevus (BRBN) Syndrome Is Caused by Somatic TEK (TIE2) Mutations |journal=J. Invest. Dermatol. |volume=137 |issue=1 |pages=207–216 |date=January 2017 |pmid=27519652 |doi=10.1016/j.jid.2016.07.034 |url=}}</ref>
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| * 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.<ref name="pmid27519652">{{cite journal |vauthors=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 |title=Blue Rubber Bleb Nevus (BRBN) Syndrome Is Caused by Somatic TEK (TIE2) Mutations |journal=J. Invest. Dermatol. |volume=137 |issue=1 |pages=207–216 |date=January 2017 |pmid=27519652 |doi=10.1016/j.jid.2016.07.034 |url=}}</ref><ref name="pmid29515720">{{cite journal |vauthors=El Bakkaly A, Ettayebi F, Oubeja H, Erraji M, Zerhouni H |title=[Bean's syndrome in children: about two cases] |language=French |journal=Pan Afr Med J |volume=28 |issue= |pages=102 |date=2017 |pmid=29515720 |pmc=5837144 |doi=10.11604/pamj.2017.28.102.11109 |url=}}</ref><ref name="pmid24133559">{{cite journal |vauthors=Lindsey SF, Reiders B, Mechaber HF |title=Life-threatening pharyngeal edema after sclerotherapy of oral venous malformations in a patient with blue rubber bleb nevus syndrome |journal=J Dermatol Case Rep |volume=7 |issue=3 |pages=74–6 |date=2013 |pmid=24133559 |pmc=3797012 |doi=10.3315/jdcr.2013.1145 |url=}}</ref>
| |
| =====Glomuvenous malformation (GVM)=====
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| * 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.<ref name="pmid28683898">{{cite journal |vauthors=Wortsman X, Millard F, Aranibar L |title=Color Doppler Ultrasound Study of Glomuvenous Malformations with its Clinical and Histologic Correlations |journal=Actas Dermosifiliogr |volume=109 |issue=3 |pages=e17–e21 |date=April 2018 |pmid=28683898 |doi=10.1016/j.ad.2017.04.013 |url=}}</ref><ref name="pmid28163461">{{cite journal |vauthors=Jha A, Khunger N, Malarvizhi K, Ramesh V, Singh A |title=Familial Disseminated Cutaneous Glomuvenous Malformation: Treatment with Polidocanol Sclerotherapy |journal=J Cutan Aesthet Surg |volume=9 |issue=4 |pages=266–269 |date=2016 |pmid=28163461 |pmc=5227083 |doi=10.4103/0974-2077.197083 |url=}}</ref><ref name="pmid27065433">{{cite journal |vauthors=Whipple KM, Godfrey KJ, Solomon JP, Lin JH, Korn BS, Kikkawa DO |title=Glomuvenous Malformation: A Rare Periorbital Lesion of the Thermoregulatory Apparatus |journal=Ophthalmic Plast Reconstr Surg |volume=33 |issue=2 |pages=e36–e37 |date=2017 |pmid=27065433 |pmc=5118188 |doi=10.1097/IOP.0000000000000695 |url=}}</ref><ref name="pmid25382523">{{cite journal |vauthors=Jha A, Ramesh V, Singh A |title=Disseminated cutaneous glomuvenous malformation |journal=Indian J Dermatol Venereol Leprol |volume=80 |issue=6 |pages=556–8 |date=2014 |pmid=25382523 |doi=10.4103/0378-6323.144200 |url=}}</ref>
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| * 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.<ref name="pmid24345188">{{cite journal |vauthors=Borroni RG, Grassi S, Concardi M, Puccio I, Giordano C, Agozzino M, Caspani C, Grasso M, Diegoli M, Arbustini E |title=Glomuvenous malformations with smooth muscle and eccrine glands: unusual histopathologic features in a familial setting |journal=J. Cutan. Pathol. |volume=41 |issue=3 |pages=308–15 |date=March 2014 |pmid=24345188 |doi=10.1111/cup.12283 |url=}}</ref><ref name="pmid23801931">{{cite journal |vauthors=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 |title=Genotypes and phenotypes of 162 families with a glomulin mutation |journal=Mol Syndromol |volume=4 |issue=4 |pages=157–64 |date=April 2013 |pmid=23801931 |pmc=3666456 |doi=10.1159/000348675 |url=}}</ref><ref name="pmid22405651">{{cite journal |vauthors=Tron AE, Arai T, Duda DM, Kuwabara H, Olszewski JL, Fujiwara Y, Bahamon BN, Signoretti S, Schulman BA, DeCaprio JA |title=The glomuvenous malformation protein Glomulin binds Rbx1 and regulates cullin RING ligase-mediated turnover of Fbw7 |journal=Mol. Cell |volume=46 |issue=1 |pages=67–78 |date=April 2012 |pmid=22405651 |pmc=3336104 |doi=10.1016/j.molcel.2012.02.005 |url=}}</ref><ref name="pmid15689436">{{cite journal |vauthors=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 |title=Four common glomulin mutations cause two thirds of glomuvenous malformations ("familial glomangiomas"): evidence for a founder effect |journal=J. Med. Genet. |volume=42 |issue=2 |pages=e13 |date=February 2005 |pmid=15689436 |pmc=1735996 |doi=10.1136/jmg.2004.024174 |url=}}</ref>
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| * 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.<ref name="pmid28683898">{{cite journal |vauthors=Wortsman X, Millard F, Aranibar L |title=Color Doppler Ultrasound Study of Glomuvenous Malformations with its Clinical and Histologic Correlations |journal=Actas Dermosifiliogr |volume=109 |issue=3 |pages=e17–e21 |date=April 2018 |pmid=28683898 |doi=10.1016/j.ad.2017.04.013 |url=}}</ref><ref name="pmid28163461">{{cite journal |vauthors=Jha A, Khunger N, Malarvizhi K, Ramesh V, Singh A |title=Familial Disseminated Cutaneous Glomuvenous Malformation: Treatment with Polidocanol Sclerotherapy |journal=J Cutan Aesthet Surg |volume=9 |issue=4 |pages=266–269 |date=2016 |pmid=28163461 |pmc=5227083 |doi=10.4103/0974-2077.197083 |url=}}</ref><ref name="pmid27065433">{{cite journal |vauthors=Whipple KM, Godfrey KJ, Solomon JP, Lin JH, Korn BS, Kikkawa DO |title=Glomuvenous Malformation: A Rare Periorbital Lesion of the Thermoregulatory Apparatus |journal=Ophthalmic Plast Reconstr Surg |volume=33 |issue=2 |pages=e36–e37 |date=2017 |pmid=27065433 |pmc=5118188 |doi=10.1097/IOP.0000000000000695 |url=}}</ref><ref name="pmid26177926">{{cite journal |vauthors=Rivers JK, Rivers CA, Li MK, Martinka M |title=Laser Therapy for an Acquired Glomuvenous Malformation (Glomus Tumour): A Nonsurgical Approach |journal=J Cutan Med Surg |volume=20 |issue=1 |pages=80–3 |date=January 2016 |pmid=26177926 |doi=10.1177/1203475415596121 |url=}}</ref><ref name="pmid25933083">{{cite journal |vauthors=Phillips CB, Guerrero C, Theos A |title=Nd:YAG laser offers promising treatment option for familial glomuvenous malformation |journal=Dermatol. Online J. |volume=21 |issue=4 |pages= |date=April 2015 |pmid=25933083 |doi= |url=}}</ref><ref name="pmid24996811">{{cite journal |vauthors=Flors L, Norton PT, Hagspiel KD |title=Glomuvenous malformation: magnetic resonance imaging findings |journal=Pediatr Radiol |volume=45 |issue=2 |pages=286–90 |date=February 2015 |pmid=24996811 |doi=10.1007/s00247-014-3086-x |url=}}</ref><ref name="pmid17511950">{{cite journal |vauthors=Henning JS, Kovich OI, Schaffer JV |title=Glomuvenous malformations |journal=Dermatol. Online J. |volume=13 |issue=1 |pages=17 |date=January 2007 |pmid=17511950 |doi= |url=}}</ref>
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| =====Cerebral cavernous malformation (CCM)=====
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| * 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.<ref name="pmid24481819">{{cite journal |vauthors=Draheim KM, Fisher OS, Boggon TJ, Calderwood DA |title=Cerebral cavernous malformation proteins at a glance |journal=J. Cell. Sci. |volume=127 |issue=Pt 4 |pages=701–7 |date=February 2014 |pmid=24481819 |pmc=3924200 |doi=10.1242/jcs.138388 |url=}}</ref><ref name="pmid30252265">{{cite journal |vauthors=Zyck S, Gould GC |title= |journal= |volume= |issue= |pages= |date= |pmid=30252265 |doi= |url=}}</ref><ref name="pmid25896717">{{cite journal |vauthors=Trapani E, Retta SF |title=Cerebral cavernous malformation (CCM) disease: from monogenic forms to genetic susceptibility factors |journal=J Neurosurg Sci |volume=59 |issue=3 |pages=201–9 |date=September 2015 |pmid=25896717 |doi= |url=}}</ref>
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| * 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.<ref name="pmid24481819">{{cite journal |vauthors=Draheim KM, Fisher OS, Boggon TJ, Calderwood DA |title=Cerebral cavernous malformation proteins at a glance |journal=J. Cell. Sci. |volume=127 |issue=Pt 4 |pages=701–7 |date=February 2014 |pmid=24481819 |pmc=3924200 |doi=10.1242/jcs.138388 |url=}}</ref><ref name="pmid30252265">{{cite journal |vauthors=Zyck S, Gould GC |title= |journal= |volume= |issue= |pages= |date= |pmid=30252265 |doi= |url=}}</ref><ref name="pmid30252535">{{cite journal |vauthors=Wang Y, Li Y, Zou J, Polster SP, Lightle R, Moore T, Dimaano M, He TC, Weber CR, Awad IA, Shen L |title=The cerebral cavernous malformation disease causing gene KRIT1 participates in intestinal epithelial barrier maintenance and regulation |journal=FASEB J. |volume= |issue= |pages=fj201800343R |date=September 2018 |pmid=30252535 |doi=10.1096/fj.201800343R |url=}}</ref><ref name="pmid30161288">{{cite journal |vauthors=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 |title=A single-center study on 140 patients with cerebral cavernous malformations: 28 new pathogenic variants and functional characterization of a PDCD10 large deletion |journal=Hum. Mutat. |volume= |issue= |pages= |date=August 2018 |pmid=30161288 |doi=10.1002/humu.23629 |url=}}</ref>
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| * 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.<ref name="pmid30252265">{{cite journal |vauthors=Zyck S, Gould GC |title= |journal= |volume= |issue= |pages= |date= |pmid=30252265 |doi= |url=}}</ref><ref name="pmid25629087">{{cite journal |vauthors=Mouchtouris N, Chalouhi N, Chitale A, Starke RM, Tjoumakaris SI, Rosenwasser RH, Jabbour PM |title=Management of cerebral cavernous malformations: from diagnosis to treatment |journal=ScientificWorldJournal |volume=2015 |issue= |pages=808314 |date=2015 |pmid=25629087 |pmc=4300037 |doi=10.1155/2015/808314 |url=}}</ref><ref name="pmid26923303">{{cite journal |vauthors=Kim J |title=Introduction to cerebral cavernous malformation: a brief review |journal=BMB Rep |volume=49 |issue=5 |pages=255–62 |date=May 2016 |pmid=26923303 |pmc=5070704 |doi= |url=}}</ref><ref name="pmid15987569">{{cite journal |vauthors=Wurm G, Schnizer M, Fellner FA |title=Cerebral cavernous malformations associated with venous anomalies: surgical considerations |journal=Neurosurgery |volume=57 |issue=1 Suppl |pages=42–58; discussion 42–58 |date=July 2005 |pmid=15987569 |doi= |url=}}</ref><ref name="pmid20809765">{{cite journal |vauthors=Washington CW, McCoy KE, Zipfel GJ |title=Update on the natural history of cavernous malformations and factors predicting aggressive clinical presentation |journal=Neurosurg Focus |volume=29 |issue=3 |pages=E7 |date=September 2010 |pmid=20809765 |doi=10.3171/2010.5.FOCUS10149 |url=}}</ref>
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| =====Familial intraosseous vascular malformation (VMOS)=====
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| * 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.<ref name="pmid27476657">{{cite journal |vauthors=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 |title=Loss-of-Function Mutations in ELMO2 Cause Intraosseous Vascular Malformation by Impeding RAC1 Signaling |journal=Am. J. Hum. Genet. |volume=99 |issue=2 |pages=299–317 |date=August 2016 |pmid=27476657 |pmc=4974086 |doi=10.1016/j.ajhg.2016.06.008 |url=}}</ref><ref name="pmid11932989">{{cite journal |vauthors=Vargel I, Cil BE, Er N, Ruacan S, Akarsu AN, Erk Y |title=Hereditary intraosseous vascular malformation of the craniofacial region: an apparently novel disorder |journal=Am. J. Med. Genet. |volume=109 |issue=1 |pages=22–35 |date=April 2002 |pmid=11932989 |doi= |url=}}</ref><ref name="pmid24701461">{{cite journal |vauthors=Handa H, Naidu GS, Dara BG, Deshpande A, Raghavendra R |title=Diverse imaging characteristics of a mandibular intraosseous vascular lesion |journal=Imaging Sci Dent |volume=44 |issue=1 |pages=67–73 |date=March 2014 |pmid=24701461 |pmc=3972408 |doi=10.5624/isd.2014.44.1.67 |url=}}</ref>
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| * 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.<ref name="pmid27476657">{{cite journal |vauthors=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 |title=Loss-of-Function Mutations in ELMO2 Cause Intraosseous Vascular Malformation by Impeding RAC1 Signaling |journal=Am. J. Hum. Genet. |volume=99 |issue=2 |pages=299–317 |date=August 2016 |pmid=27476657 |pmc=4974086 |doi=10.1016/j.ajhg.2016.06.008 |url=}}</ref><ref name="pmid27539661">{{cite journal |vauthors=Peotter JL, Phillips J, Tong T, Dimeo K, Gonzalez JM, Peters DM |title=Involvement of Tiam1, RhoG and ELMO2/ILK in Rac1-mediated phagocytosis in human trabecular meshwork cells |journal=Exp. Cell Res. |volume=347 |issue=2 |pages=301–11 |date=October 2016 |pmid=27539661 |pmc=5333770 |doi=10.1016/j.yexcr.2016.08.009 |url=}}</ref>
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| * 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.<ref name="pmid27476657">{{cite journal |vauthors=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 |title=Loss-of-Function Mutations in ELMO2 Cause Intraosseous Vascular Malformation by Impeding RAC1 Signaling |journal=Am. J. Hum. Genet. |volume=99 |issue=2 |pages=299–317 |date=August 2016 |pmid=27476657 |pmc=4974086 |doi=10.1016/j.ajhg.2016.06.008 |url=}}</ref><ref name="pmid24701461">{{cite journal |vauthors=Handa H, Naidu GS, Dara BG, Deshpande A, Raghavendra R |title=Diverse imaging characteristics of a mandibular intraosseous vascular lesion |journal=Imaging Sci Dent |volume=44 |issue=1 |pages=67–73 |date=March 2014 |pmid=24701461 |pmc=3972408 |doi=10.5624/isd.2014.44.1.67 |url=}}</ref><ref name="pmid29670739">{{cite journal |vauthors=Cariati P, Marín-Fernández AB, Julia-Martínez MÁ, Pérez-de Perceval-Tara M, Sánchez-López D, Martínez-Lara I |title=Endovascular treatment of an intraosseous arteriovenous malformation of the mandible in a child. A case Report |journal=J Clin Exp Dent |volume=10 |issue=2 |pages=e189–e191 |date=February 2018 |pmid=29670739 |pmc=5899801 |doi=10.4317/jced.54550 |url=}}</ref>
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| =====Verrucous venous malformation=====
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| * 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.<ref name="pmid28761841">{{cite journal |vauthors=Singh J, Sharma P, Tandon S, Sinha S |title=Multiple Verrucous Hemangiomas: A Case Report with New Therapeutic Insight |journal=Indian Dermatol Online J |volume=8 |issue=4 |pages=254–256 |date=2017 |pmid=28761841 |pmc=5518576 |doi=10.4103/idoj.IDOJ_313_16 |url=}}</ref><ref name="pmid30156622">{{cite journal |vauthors=Oppermann K, Boff AL, Bonamigo RR |title=Verrucous hemangioma and histopathological differential diagnosis with angiokeratoma circumscriptum neviforme |journal=An Bras Dermatol |volume=93 |issue=5 |pages=712–715 |date=2018 |pmid=30156622 |pmc=6106676 |doi=10.1590/abd1806-4841.20187259 |url=}}</ref>
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| * Somatic mutation in MAP3K3 mitogen-activated protein kinase kinase kinase 3 are thought to be the cause.<ref name="pmid25728774">{{cite journal |vauthors=Couto JA, Vivero MP, Kozakewich HP, Taghinia AH, Mulliken JB, Warman ML, Greene AK |title=A somatic MAP3K3 mutation is associated with verrucous venous malformation |journal=Am. J. Hum. Genet. |volume=96 |issue=3 |pages=480–6 |date=March 2015 |pmid=25728774 |pmc=4375628 |doi=10.1016/j.ajhg.2015.01.007 |url=}}</ref>
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| * 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.<ref name="pmid28761841">{{cite journal |vauthors=Singh J, Sharma P, Tandon S, Sinha S |title=Multiple Verrucous Hemangiomas: A Case Report with New Therapeutic Insight |journal=Indian Dermatol Online J |volume=8 |issue=4 |pages=254–256 |date=2017 |pmid=28761841 |pmc=5518576 |doi=10.4103/idoj.IDOJ_313_16 |url=}}</ref><ref name="pmid30156622">{{cite journal |vauthors=Oppermann K, Boff AL, Bonamigo RR |title=Verrucous hemangioma and histopathological differential diagnosis with angiokeratoma circumscriptum neviforme |journal=An Bras Dermatol |volume=93 |issue=5 |pages=712–715 |date=2018 |pmid=30156622 |pmc=6106676 |doi=10.1590/abd1806-4841.20187259 |url=}}</ref><ref name="pmid30048660">{{cite journal |vauthors=Zhang G, Chen H, Zhen Z, Chen J, Zhang S, Qin Q, Liu X |title=Sirolimus for treatment of verrucous venous malformation: A retrospective cohort study |journal=J. Am. Acad. Dermatol. |volume= |issue= |pages= |date=July 2018 |pmid=30048660 |doi=10.1016/j.jaad.2018.07.014 |url=}}</ref>
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| ==See also== | | ==See also== |
| * [[Vascular disease]] | | * [[Vascular disease]] |