Вопросы гематологии/онкологии и иммунопатологии в педиатрии. 2019; 18: 78-87
Синдромальная венозная мальформация – диссеминированный венозный ангиоматоз Бина
https://doi.org/10.24287/1726-1708-2019-18-3-78-87Аннотация
Синдром Бина – редко встречающийся диффузный кожно-слизистый ангиоматоз (множественные венозные мальформации кожи и внутренних органов). В основе патогенеза заболевания лежит соматическая мутация в гене ТЕК. Данная мутация вызывает лиганд-независимую активацию рецептора тиразинкиназы и PI3K/AKT-пути, вовлекая специфическим образом в патологический процесс mTOR. Универсально эффективных методов лечения системных форм сосудистых мальформаций нет, однако в последнее время многочисленные сообщения показывают преимущества рапамицина – ингибитора mTOR – в качестве хорошо переносимой и эффективной терапии у пациентов с сосудистыми аномалиями, в частности с диффузным ангиоматозом. В статье представлен клинический случай: пациентка, 5 лет, которая длительное время наблюдалась с диагнозом «железодефицитная анемия», получала терапию препаратами железа – без эффекта. Диагноз «синдром Бина» был установлен через 5 лет после появления первых клинических симптомов на основании совокупности клинических, лабораторных и инструментальных методов обследования. Выявлена природа железодефицитной анемии – хронические повторные кровотечения из множественных участков патологически сформированных сосудов слизистой желудочно-кишечного тракта. Терапия рапамицином, назначенная пациентке, позволила купировать желудочно-кишечные кровотечения, сократить размеры сосудистых образований и предотвратить формирование новых. Родители пациентки дали согласие на использование информации, в том числе фото ребенка, в научных исследованиях и публикациях.
Список литературы
1. Hammill A.M., Wentzel M., Gupta A., Nelson S., Lucky A., Dasgupta R., et al. Sirolimus for the treatment of complicated vascular anomalies in children. Pediatr Blood Cancer 2011; 57: 1018–24.
2. Wassef M., Enjolras O. Superficial vascular malformations: classification and histopathology. Ann Pathol 1999; 19: 253–64.
3. Dompmartin A., Acher A., Thibon P., Tourbach S., Hermans C., Deneys V., et al. Association of localized intravascular coagulopathy with venous malformation. Arch Dermatol 2008; 144: 873–7.
4. Casanova D., Boon L.M., Vikkula M. Les malformation veineuses: aspects cliniques et diagnostic differentiel. Annales de chirurgie et plastique esthetique 2006; 51: 373–87.
5. Vikkula M., Boon L.M., Carraway K.L., Calvert J.T., Diamonti A.J., Goumnerov B., et al. Vascular dysmorphogenesis cau-sed by an activating mutation in the receptor tyrosine kinase TIE2. Cell 1996; 87: 1181–90.
6. Bean W.B. Blue rubber-bleb nevi of the skin and gastrointestinal tract. In: Bean WB. Vascular Spiders and Related Lesions of the Skin. Springfield, IL: Charles C Thomas 1958: 17–185.
7. Martinez C.A., Rodrigues M.R., Sato D.T., Junior P.P., Gama R.F., Mattavelli C.B., et al. Blue rubber bleb nevus syndrome as a cause of lower digestive bleeding. Case Rep Sutg 2014: 683684: 1–4.
8. Deshpande G.A., Samarasam I., George S.V., Chandran S. Blue rubber bleb nevus syndrome: a rare cause of chronic gastrointestinal bleed in adults. Singapore Med J 2014: 55: el175–el176.
9. Brahami N., Aribi M., Sari B.-E., Van Kien P.K., Touitou I., Lefranc G., Barat-Houari M. Lack of TEK Gene Mutation in Patients with Cutaneomucosal Venous Malformations from the North-Western Region of Algeria. Genet Res Int 2013; 2013: 784–9.
10. Boon L.M., Mulliken J.B., Vikkula M., Watkins H., Seidman J., Olsen B.R., Warman M.L. Assignment of a locus for dominantly inherited venous malformations to chromosome 9p. Hum Mol Genet 1994; 3 (9): 1583–7.
11. Soblet J., Kangas J., Natynki M., Mendola A., Helaers R., Uebelhoer M., et al. Boon and Miikka Vikkula (2017). Blue rubber bleb nevus (BRBN) syndrome is caused by somatic TEK (TIE2) mutations. Journal of Investigative Dermatology 2017; 137: 207–16.
12. Blind A.M., Vabres P., Carmignac V., Duffourd Y., Mahé A. Malformations veineuse liées à des mutations du gene TEK: illustration d'un continuum Clinique et génétique à partir d'un cas de syndrome de Bean. Annales de Dermatologie et de Vénérélogie 2017 Dec; 144 (12, Suppl), S243–4.
13. Eterm D., Acar Y., Kotilogu E., Yucelten D., Pehlivanoglu E. Blue rubber bleb nevus syndrome. Pediatrics 2001; 107: 418–20.
14. Jin X.L., Wang Z.H., Xiao X.B., Huang L.S., Zhao X.Y. Blue rubber bleb nevus syndrome. A case report and literature rewiew. World J Gastroenterol 2014; 20: 17254–9.
15. Oranje A.P. Blue rubber bleb nevus syndrome. Pediatr Dermatol 1986; 3: 304–10.
16. Salloum R., Fox C.E., Alvarez-Allende C.R., Hammill A.M., Dasgupta R., Dickie B.H., et al. Response of Blue rubber bleb nevus syndrome to Sirolimus treatment Pediatr Blood Cancer 2016 Nov; 63 (11): 1911–4.
17. Apak H., Celkan T., Ozkan A., Yidiz I., Aydermir E.H., Ozdil S., Kuruoglu S. Blue rubber bleb nevus syndrome associated with coagulopathy: Treatment with interferon. Dermatology 2004; 208: 345–8.
18. Fishman S.J., Burrows P.E., Leichtner A.M., Mulliken J.B. Gastrointestinal manifestations of vascular anomalies in childhood: varied etiologies require multiple therapeutic modalities. J Pediatr Surg 1998; 33: 1163–7.
19. Yuksekkaya H., Ozbek O., Keser M., Toy H. Blue rubber bleb nevus syndrome: successful treatment with sirolimus. Pediatrics 2012; 129 (4): 1080–4.
20. Ünlüsoy Aksu A., Sari S., Eğritas Gürkan Ö., Dalgiç B. Favorable reponse to Sirolimus in a child with Blue Rubber Bleb Nevus Syndrome in the Gastrointestinal tract. J Pediatric Hematology/Oncology 2017; 39 (2): 147–9.
21. Deng Z.H., Xu C.D., Chen S.N. Diagnosis and treatment of blue rubber bleb nevus syndrome in children. World J Pediatr 2008; 4: 70–3.
22. Dobru D., Seuchea N., Dorin M., Careianu V. Blue rubber bleb nevus syndrome: a case report and literature review. Rom J Gastroenterol 2004; 13: 237–40.
23. Fishman S.J., Smithers C.J., Folkman J., Lund D.P., Burrows P.E., Mulliken J.B., Fox V.L. Blue rubber bleb nevus syndrome: Surgical eradication of gastrointestinal bleeding. Ann Surg 2005; 241: 523–8.
24. Warner B., Butt A., Cairns S. Sirolimus is a successful treatment for recurrent iron deficiency anaemia in Blue Rubber Bleb Nevus Syndrome. Journal of Pediatric Gastroenterology and Nutrition 2015; 60 (6): 49–50.
25. Ferrés-Ramis L., Knöpfel N., Salinas-Sans J.A., Martin-Santiago A. Rapamycin in the treatment of Blue Rubber Bleb Nevus Syndrome. Atlas Dermofisiologr 2015; 106: 137–8.
26. Hammill A.M., Wentzel M., Gupta A., Nelson S., Lucky A., Elluru R., et al. Sirolimus for the treatment vascular anomalies in children. Pediatr Blood Cancer 2011; 57: 1018–24.
27. Cardoso H., Dias J.A., Silva M., VilasBas F., Trindade E., Tavares M., Macedo G. Successful treatment with sirolimus of a patient with Blue Rubber Bleb Nevus Syndrome. J. of Gastroenterology and Hepatology 2016; 31 (3): 519.
28. Neuhaus P., Klupp J., Langrehr J.M. mTOR inhibitors: An overview. Liver Transpl 2001; 7: 473–84.
29. Soria J.-C., Vignot S., Massard C., Mir O. Cours de chimiotherapie antitumorale et traitement medical du cancer. 2013: 182–5.
30. Özgönelel B., Martin A. Low-dose sirolimus controls recurrent iron deficiency in a patient with blue rubber bleb nevus syndrome. Pediatric Blood Cancer 2015; 62 (11): 20154–5.
Pediatric Hematology/Oncology and Immunopathology. 2019; 18: 78-87
Syndromе associated with multiple venous malformations (Bean syndrome)
https://doi.org/10.24287/1726-1708-2019-18-3-78-87Abstract
Blue rubber bleb nevus syndrome (BRBNS) also called Bean's syndrome is a rare disorder characterized by mucocutaneous angiomatose multiple cutaneous venous malformations. Pathogenesis of the BRBNS is caused by the somatic mutations in angiopoietin receptor gene TEK. These mutations cause ligand-independent activation of the tyrosine kinase receptor and the PI3K / AKT pathway and involve the mTOR in the pathological process in a specific way. There are no universally effective methods for treating systemic forms of vascular malformations currently. However, recent numerous reports have shown the advantages of rapamycin, an mTOR inhibitor, as a well-tolerated and effective therapy in patients with vascular abnormalities, in particular with diffuse angiomatose. This article presents a clinical case of a 5-years old patient with a diagnosis of iron deficiency anemia, who has been treated for a long time and received iron supplements therapy without achieving any effect. The diagnosis of Bean's syndrome was established after 5 years from the first clinical manifestation and based on clinical, laboratory and instrumental methods. The cause of iron deficiency anemia was established. It was repeated chronic bleedings from multiple sites of the gastrointestinal mucosa vessels. Prescribed rapamycin therapy allowed to contain gastrointestinal bleeding, to reduce the size of vascular lesions and to prevent the formation of new ones. Parents gave their consent to use information about the child in the article.
References
1. Hammill A.M., Wentzel M., Gupta A., Nelson S., Lucky A., Dasgupta R., et al. Sirolimus for the treatment of complicated vascular anomalies in children. Pediatr Blood Cancer 2011; 57: 1018–24.
2. Wassef M., Enjolras O. Superficial vascular malformations: classification and histopathology. Ann Pathol 1999; 19: 253–64.
3. Dompmartin A., Acher A., Thibon P., Tourbach S., Hermans C., Deneys V., et al. Association of localized intravascular coagulopathy with venous malformation. Arch Dermatol 2008; 144: 873–7.
4. Casanova D., Boon L.M., Vikkula M. Les malformation veineuses: aspects cliniques et diagnostic differentiel. Annales de chirurgie et plastique esthetique 2006; 51: 373–87.
5. Vikkula M., Boon L.M., Carraway K.L., Calvert J.T., Diamonti A.J., Goumnerov B., et al. Vascular dysmorphogenesis cau-sed by an activating mutation in the receptor tyrosine kinase TIE2. Cell 1996; 87: 1181–90.
6. Bean W.B. Blue rubber-bleb nevi of the skin and gastrointestinal tract. In: Bean WB. Vascular Spiders and Related Lesions of the Skin. Springfield, IL: Charles C Thomas 1958: 17–185.
7. Martinez C.A., Rodrigues M.R., Sato D.T., Junior P.P., Gama R.F., Mattavelli C.B., et al. Blue rubber bleb nevus syndrome as a cause of lower digestive bleeding. Case Rep Sutg 2014: 683684: 1–4.
8. Deshpande G.A., Samarasam I., George S.V., Chandran S. Blue rubber bleb nevus syndrome: a rare cause of chronic gastrointestinal bleed in adults. Singapore Med J 2014: 55: el175–el176.
9. Brahami N., Aribi M., Sari B.-E., Van Kien P.K., Touitou I., Lefranc G., Barat-Houari M. Lack of TEK Gene Mutation in Patients with Cutaneomucosal Venous Malformations from the North-Western Region of Algeria. Genet Res Int 2013; 2013: 784–9.
10. Boon L.M., Mulliken J.B., Vikkula M., Watkins H., Seidman J., Olsen B.R., Warman M.L. Assignment of a locus for dominantly inherited venous malformations to chromosome 9p. Hum Mol Genet 1994; 3 (9): 1583–7.
11. Soblet J., Kangas J., Natynki M., Mendola A., Helaers R., Uebelhoer M., et al. Boon and Miikka Vikkula (2017). Blue rubber bleb nevus (BRBN) syndrome is caused by somatic TEK (TIE2) mutations. Journal of Investigative Dermatology 2017; 137: 207–16.
12. Blind A.M., Vabres P., Carmignac V., Duffourd Y., Mahé A. Malformations veineuse liées à des mutations du gene TEK: illustration d'un continuum Clinique et génétique à partir d'un cas de syndrome de Bean. Annales de Dermatologie et de Vénérélogie 2017 Dec; 144 (12, Suppl), S243–4.
13. Eterm D., Acar Y., Kotilogu E., Yucelten D., Pehlivanoglu E. Blue rubber bleb nevus syndrome. Pediatrics 2001; 107: 418–20.
14. Jin X.L., Wang Z.H., Xiao X.B., Huang L.S., Zhao X.Y. Blue rubber bleb nevus syndrome. A case report and literature rewiew. World J Gastroenterol 2014; 20: 17254–9.
15. Oranje A.P. Blue rubber bleb nevus syndrome. Pediatr Dermatol 1986; 3: 304–10.
16. Salloum R., Fox C.E., Alvarez-Allende C.R., Hammill A.M., Dasgupta R., Dickie B.H., et al. Response of Blue rubber bleb nevus syndrome to Sirolimus treatment Pediatr Blood Cancer 2016 Nov; 63 (11): 1911–4.
17. Apak H., Celkan T., Ozkan A., Yidiz I., Aydermir E.H., Ozdil S., Kuruoglu S. Blue rubber bleb nevus syndrome associated with coagulopathy: Treatment with interferon. Dermatology 2004; 208: 345–8.
18. Fishman S.J., Burrows P.E., Leichtner A.M., Mulliken J.B. Gastrointestinal manifestations of vascular anomalies in childhood: varied etiologies require multiple therapeutic modalities. J Pediatr Surg 1998; 33: 1163–7.
19. Yuksekkaya H., Ozbek O., Keser M., Toy H. Blue rubber bleb nevus syndrome: successful treatment with sirolimus. Pediatrics 2012; 129 (4): 1080–4.
20. Ünlüsoy Aksu A., Sari S., Eğritas Gürkan Ö., Dalgiç B. Favorable reponse to Sirolimus in a child with Blue Rubber Bleb Nevus Syndrome in the Gastrointestinal tract. J Pediatric Hematology/Oncology 2017; 39 (2): 147–9.
21. Deng Z.H., Xu C.D., Chen S.N. Diagnosis and treatment of blue rubber bleb nevus syndrome in children. World J Pediatr 2008; 4: 70–3.
22. Dobru D., Seuchea N., Dorin M., Careianu V. Blue rubber bleb nevus syndrome: a case report and literature review. Rom J Gastroenterol 2004; 13: 237–40.
23. Fishman S.J., Smithers C.J., Folkman J., Lund D.P., Burrows P.E., Mulliken J.B., Fox V.L. Blue rubber bleb nevus syndrome: Surgical eradication of gastrointestinal bleeding. Ann Surg 2005; 241: 523–8.
24. Warner B., Butt A., Cairns S. Sirolimus is a successful treatment for recurrent iron deficiency anaemia in Blue Rubber Bleb Nevus Syndrome. Journal of Pediatric Gastroenterology and Nutrition 2015; 60 (6): 49–50.
25. Ferrés-Ramis L., Knöpfel N., Salinas-Sans J.A., Martin-Santiago A. Rapamycin in the treatment of Blue Rubber Bleb Nevus Syndrome. Atlas Dermofisiologr 2015; 106: 137–8.
26. Hammill A.M., Wentzel M., Gupta A., Nelson S., Lucky A., Elluru R., et al. Sirolimus for the treatment vascular anomalies in children. Pediatr Blood Cancer 2011; 57: 1018–24.
27. Cardoso H., Dias J.A., Silva M., VilasBas F., Trindade E., Tavares M., Macedo G. Successful treatment with sirolimus of a patient with Blue Rubber Bleb Nevus Syndrome. J. of Gastroenterology and Hepatology 2016; 31 (3): 519.
28. Neuhaus P., Klupp J., Langrehr J.M. mTOR inhibitors: An overview. Liver Transpl 2001; 7: 473–84.
29. Soria J.-C., Vignot S., Massard C., Mir O. Cours de chimiotherapie antitumorale et traitement medical du cancer. 2013: 182–5.
30. Özgönelel B., Martin A. Low-dose sirolimus controls recurrent iron deficiency in a patient with blue rubber bleb nevus syndrome. Pediatric Blood Cancer 2015; 62 (11): 20154–5.
