Семейный случай врожденного дискератоза. Клиническое наблюдение.

Лучкин А.В., Михайлова Е.А., Фидарова З.Т., Троицкая В.В., Гальцева И.В., Ковригина А.М., Глинкина С.А., Двирнык В.Н., Райкина Е.В., Павлова А.В., Демина И.А., Паровичникова Е.Н. Семейный случай врожденного дискератоза. Клиническое наблюдение. Терапевтический архив. 2021; 93 (7): 818–825. DOI: 10.26442/00403660.2021.07.200955

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Luchkin AV, Mikhailova EA, Fidarova ZT, Troitskaya VV, Galtseva IV, Kovrigina AM, Glinkina SA, Dvirnyk VN, Raykina EV, Pavlova AV, Demina IA, Parovichnikova EN. A case report of familial dyskeratosis congenital. Case report. Terapevticheskii Arkhiv (Ter. Arkh.). 2021; 93 (7): 818–825. DOI: 10.26442/00403660.2021.07.200955

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Аннотация

Врожденный дискератоз (ВД) – наследственный синдром недостаточности костномозгового кроветворения, развивающийся вследствие нарушения биологии теломер и сочетающийся с предрасположенностью к опухолевым заболеваниям. Классическими клиническими признаками болезни («кожно-слизистая триада») являются ретикулярная пигментация кожи, дистрофические изменения ногтевых пластин, лейкоплакия слизистой оболочки полости рта. Цель – описать алгоритм диагностики, особенностей клинического течения и выбора терапии семейного случая ВД. Представлено клиническое наблюдение диагностики и лечения членов семьи с впервые выявленным ВД. Данное наблюдение демонстрирует важность всех этапов обследования: от сбора анамнеза и клинической картины до применения высокотехнологичных современных диагностических методов (flow-FISH, NGS). Подчеркивается, что при выявлении ВД у больного показано обследование членов семьи на наличие бессимптомного течения болезни. Высокая частота органной токсичности и развития вторичных неоплазий диктует необходимость индивидуального подхода к лечению каждого больного с этим заболеванием (раннее начало приема андрогенов, своевременное рассмотрение возможности выполнения трансплантации аллогенных гемопоэтических стволовых клеток).
Знание патогенеза, клинической картины, принципов диагностики и терапии этой нозологии актуальны как для врачей педиатрической практики, так и для гематологов.

Ключевые слова: врожденный дискератоз, теломеры, недостаточность костно-мозгового кроветворения, flow-FISH, вторичные неоплазии, андрогены

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Dyskeratosis congenita (DC) is a hereditary syndrome of bone marrow failure, which develops because of telomeres’ defects and combines with cancer predisposition. Its classical clinical features are skin pigmentation, nail dystrophy, oral leukoplakia (“skin-mucosa triad”). The goal is to describe the algorithm of diagnosis, clinical specificities of DC and specific treatment for cases of DC in one family. The present report includes descriptions of diagnosis and treatment of family members diagnosed for the first time as having a DC. The report shows an importance of all diagnostic stages: from a medical history and clinical picture to an application of modern high-tech diagnostic methods (flow-FISH, NGS). The report underlines an importance of diagnosis of all family members for excluding an asymptomatic form after a case of DC has been already detected in that family. A high frequency of a toxicity and secondary neoplasia makes it necessary to realize an individual approach at treatment of each patient with DC (the earliest start of androgen treatment, prompt decision of implementation of allogenic hematopoietic stem cell transplantation). The knowledge of pathogenesis, clinical features and principles of diagnosis and therapy of this disease is relevant to pediatricians and hematologists.

Keywords: dyskeratosis congenita, telomeres, bone marrow failure, flow-FISH, secondary neoplasia, androgens

Список литературы

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17. Alter BP, Baerlocher GM, Savage SA, et al. Very short telomere length by flow fluorescence in situ hybridization identifies patients with dyskeratosis congenita. Blood. 2007;110(5):1439-47. DOI:10.1182/blood-2007-02-075598
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23. Sousa SR, Mota PC, Melo N, et al. Heterozygous TERT gene mutation associated with familial idiopathic pulmonary fibrosis. Respir Med Case Rep. 2019;26:118-22. DOI:10.1016/j.rmcr.2018.12.005
24. Hartmann D, Srivastava U, Thaler M, et al. Telomerase gene mutations are associated with cirrhosis formation. Hepatology. 2011;53(5):1608‑17. DOI:10.1002/hep.24217
25. Alter BP, Giri N, Savage SA, Rosenberg PS. Cancer in dyskeratosis congenita. Blood. 2009;113(26):6549-57. DOI:10.1182/blood-2008-12-192880
26. Calado RT, Yewdell WT, Wilkerson KL, et al. Sex hormones, acting on the TERT gene, increase telomerase activity in human primary hematopoietic cells. Blood. 2009;114(11):2236-43. DOI:10.1182/blood-2008-09-178871
27. Townsley DM, Dumitriu B, Liu D, et al. Danazol treatment for telomere diseases. New Engl J Med. 2016;374(20):1922-31. DOI:10.1056/NEJMoa1515319
28. Khincha PP, Wentzensen IM, Giri N, et al. Response to androgen therapy in patients with dyskeratosis congenita. Br J Haematol. 2014;165(3):349‑57. DOI:10.1111/bjh.12748
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DOI:10.24110/0031-403X-2017-95-5-97-103
33. Fioredda F, Iacobelli S, Korthof ET, et al. Outcome of haematopoietic stem cell transplantation in dyskeratosis congenita. Br J Haematol. 2018;183(1):110-8. DOI:10.1111/bjh.15495
34. Dokal I. Dyskeratosis congenital. Hematology Am Soc Hematol Educ Program. 2011;1:480-6. DOI:10.1182/asheducation-2011.1.480

________________________________________________

1. Karpova NS, Abdulkadyrov KM, Selivanov EA, Balashova VA. The modern conception of the proper role of telomeres and telomerase in pathogenesis of hematologic and oncology diseases. Russian biomedical journal. 2012;13(1):38-57 (in Russian)
2. Hashmi SK, Allen C, Klaassen R, et al. Comparative analysis of Shwachman-Diamond syndrome to other inherited bone marrow failure syndromes and genotype–phenotype correlation. Clinical genetics. 2011;79(5):448-58. DOI:10.1111/j.1399-0004.2010.01468.x
3. Alter BP, Giri N, Savage SA, Rosenberg PS. Cancer in the National Cancer Institute inherited bone marrow failure syndrome cohort after fifteen years of follow-up. Haematologica. 2018;103(1):30. DOI:10.3324/haematol.2017.178111
4. Dokal I. Dyskeratosis congenita in all its forms. Br J Haematol. 2000;110(4):768-79. DOI:10.1046/j.1365-2141.2000.02109.x
5. Ershov NM, Ovsyannikova GS, Khachatryan LA, et al. Congenital dyskeratosis: analysis of clinical cases. Pediatriya. Zhurnal im. GN Speranskogo. 2014;93(6):90-5 (in Russian)].
6. Emelianova TA, Khmelevskaya IG, Minenkova TA, et al. Congenital dysceratosis: clinical observation. Kursk Scientific and Practical Bulletin “Man and His Health”. 2018;(2):44-8 (in Russian) DOI:10.21626/vestnik/2018-2/07
7. Nechaevsky VI, Zinina EE, Popova NB. Congenital dyskeratosis: a clinical case. Ugra health care: experience and innovations. 2018;4 (in Russian)
8. Savage SA, Alter BP. Dyskeratosis congenital. Hematol Oncol Clin North Am. 2009;23(2):215-31. DOI:10.1016/j.hoc.2009.01.003
9. Armanios MY, Chen JJL, Cogan JD, et al. Telomerase mutations in families with idiopathic pulmonary fibrosis. New Engl J Med. 2007;356(13):1317-26. DOI:10.1056/NEJMoa066157
10. Nishio N, Kojima S. Recent progress in dyskeratosis congenital. Int J Hematol. 2010;92(3):419-24. DOI:10.1007/s12185-010-0695-5
11. Kim HJ, Kim KJ, Lee KH, et al. Interstitial lung disease in a patient with dyskeratosis congenita. Tuberc Respir Dis. 2013;74(2):70. DOI:10.4046/trd.2013.74.2.70
12. Dvorak LA, Vassallo R, Kirmani S, et al. Pulmonary fibrosis in dyskeratosis congenita: report of 2 cases. Hum Pathol. 2015;46(1):147‑52. DOI:10.1016/j.humpath.2014.10.003
13. Parry EM, Alder JK, Qi X, et al. Syndrome complex of bone marrow failure and pulmonary fibrosis predicts germline defects in telomerase. Blood. 2011;117(21):5607-11. DOI:10.1182/blood-2010-11-322149
14. Glousker G, Touzot F, Revy P, et al. Unraveling the pathogenesis of Hoyeraal–Hreidarsson syndrome, a complex telomere biology disorder. Br J Haematol. 2015;170(4):457-71. DOI:10.1111/bjh.13442
15. Karremann M, Neumaier-Probst E, Schlichtenbrede F, et al. Revesz syndrome revisited. Orphanet J Rare Dis. 2020;15(1):1-13. DOI:10.1186/s13023-020-01553-y
16. Duprey PA, Steger JW. An unusual case of dyskeratosis congenita with intracranial calcifications. J Am Acad Dermatol. 1988;19(4):760-2. DOI:10.1016/s0190-9622(88)80357-8
17. Alter BP, Baerlocher GM, Savage SA, et al. Very short telomere length by flow fluorescence in situ hybridization identifies patients with dyskeratosis congenita. Blood. 2007;110(5):1439-47. DOI:10.1182/blood-2007-02-075598
18. Gutierrez-Rodrigues F, Santana-Lemos BA, Scheucher PS, et al. Direct comparison of flow-FISH and qPCR as diagnostic tests for telomere length measurement in humans. PloS one. 2014;9(11):e113747. DOI:10.1371/journal.pone.0113747
19. Demina IA, Semchenkova AA, Kagirova ZR, Popov AM. Flow cytometric measurement of absolute telomere length. Pediatric Hematology/Oncology and Immunopathology. 2019;17(4):68‑74 (in Russian) DOI:10.24287/1726-1708-0-0-0-1-7
20. Bessler M, Du HY, Gu B, Mason PJ. Dysfunctional telomeres and dyskeratosis congenita. Haematologica. 2007;92(8):1009-12. DOI:10.3324/haematol.11221
21. Yamaguchi H, Baerlocher, GM, Lansdorp, et al. Mutations of the human telomerase RNA gene (TERC) in aplastic anemia and myelodysplastic syndrome. Blood. 2003;102(3):916-8. DOI:10.1182/blood-2003-01-0335
22. Yamaguchi H, Calado RT, Ly H, et al. Mutations in TERT, the gene for telomerase reverse transcriptase, in aplastic anemia. New Engl J Med. 2005;352(14):1413-24. DOI:10.1056/NEJMoa042980
23. Sousa SR, Mota PC, Melo N, et al. Heterozygous TERT gene mutation associated with familial idiopathic pulmonary fibrosis. Respir Med Case Rep. 2019;26:118-22. DOI:10.1016/j.rmcr.2018.12.005
24. Hartmann D, Srivastava U, Thaler M, et al. Telomerase gene mutations are associated with cirrhosis formation. Hepatology. 2011;53(5):1608‑17. DOI:10.1002/hep.24217
25. Alter BP, Giri N, Savage SA, Rosenberg PS. Cancer in dyskeratosis congenita. Blood. 2009;113(26):6549-57. DOI:10.1182/blood-2008-12-192880
26. Calado RT, Yewdell WT, Wilkerson KL, et al. Sex hormones, acting on the TERT gene, increase telomerase activity in human primary hematopoietic cells. Blood. 2009;114(11):2236-43. DOI:10.1182/blood-2008-09-178871
27. Townsley DM, Dumitriu B, Liu D, et al. Danazol treatment for telomere diseases. New Engl J Med. 2016;374(20):1922-31. DOI:10.1056/NEJMoa1515319
28. Khincha PP, Wentzensen IM, Giri N, et al. Response to androgen therapy in patients with dyskeratosis congenita. Br J Haematol. 2014;165(3):349‑57. DOI:10.1111/bjh.12748
29. Al-Rahawan MM, Giri N, Alter BP. Intensive immunosuppression therapy for aplastic anemia associated with dyskeratosis congenital. Int J Hematol. 2006;83(3);275. DOI:10.1532/ijh97.06030
30. García MSF, Teruya-Feldstein J. The diagnosis and treatment of dyskeratosis congenita: a review. J Blood Med. 2014;5:157. DOI:10.2147/JBM.S47437
31. Trautmann K, Jakob C, von Grunhagen U, et al. Eltrombopag fails to improve severe thrombocytopenia in late-stage dyskeratosis congenita and diamond-blackfan-anaemia. Thromb Haemost. 2012;108(08):397-8. DOI:10.1160/TH12-02-0121
32. Demina IA, Ovsyannikova GS, Kalinina II, et al. Telomere length value for individualization of aplastic anemia therapy. Pediatriya named after GN Speransky.2017;96(5):97-103 (in Russian) DOI:10.24110/0031-403X-2017-95-5-97-103
33. Fioredda F, Iacobelli S, Korthof ET, et al. Outcome of haematopoietic stem cell transplantation in dyskeratosis congenita. Br J Haematol. 2018;183(1):110-8. DOI:10.1111/bjh.15495
34. Dokal I. Dyskeratosis congenital. Hematology Am Soc Hematol Educ Program. 2011;1:480-6. DOI:10.1182/asheducation-2011.1.480

Авторы

А.В. Лучкин*1, Е.А. Михайлова1, З.Т. Фидарова1, В.В. Троицкая1, И.В. Гальцева1, А.М. Ковригина1, С.А. Глинкина1, В.Н. Двирнык1, Е.В. Райкина2, А.В. Павлова2, И.А. Демина2, Е.Н. Паровичникова1

1 ФГБУ «Национальный медицинский исследовательский центр гематологии» Минздрава России, Москва, Россия;
2 ФГБУ «Национальный медицинский исследовательский центр детской гематологии, онкологии и иммунологии им. Дмитрия Рогачева» Минздрава России, Москва, Россия
*a_luchkin@rambler.ru

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Anton V. Luchkin*1, Elena A. Mikhailova1, Zalina T. Fidarova1, Vera V. Troitskaya1, Irina V. Galtseva1, Alla M. Kovrigina1, Svetlana A. Glinkina1, Valentina N. Dvirnyk1, Elena V. Raykina2, Anna V. Pavlova2, Irina A. Demina2, Elena N. Parovichnikova1

1 National Research Center for Hematology, Moscow, Russia;
2 Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology, Moscow, Russia
*a_luchkin@rambler.ru

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