vspВопросы современной педиатрииCurrent Pediatrics1682-55271682-5535Издательство «ПедиатрЪ»10.15690/vsp.v18i5.2057vsp-2239Research ArticleВ ПОМОЩЬ ВРАЧУA DOCTOR’S AIDГенетические и клинико-лабораторные особенности синдрома Швахмана-Даймонда в России: проспективное исследованиеGenetic and Clinical Features of Shwachman-Diamond Syndrome in Russian Population: Prospective Studyhttps://orcid.org/0000-0003-0295-4820ИпатоваМ. Г.IpatovaMaria G.

Ипатова Мария Георгиевна - кандидат медицинских наук, руководитель гепатобилиарного центра ДГКБ № 13 им. Н.Ф. Филатова, доцент кафедры госпитальной педиатрии им. акад. В.А. Таболина педиатрического факультета РНИМУ им. Н.И. Пирогова.

117997, Москва, ул. Островитянова, д. 1, тел.: +7 (499) 766-73-20

Moscow

mariachka1@mail.ruhttps://orcid.org/0000-0002-8208-2075ДеордиеваЕ. А.DeordievaEkaterina A.

Москва

Moscow

ШвецО. А.ShvetsOksana A.

Москва

Moscow

МухинаА. А.MukhinaAnna A.

Москва

Moscow

МоисееваА. А.MoiseevaAnna A.

Москва

Moscow

РодинаЮ. А.RodinaYulya A.

Москва

Moscow

https://orcid.org/0000-0002-9567-6761ШумиловП. В.ShumilovPetr V.

Москва

Moscow

https://orcid.org/0000-0002-3974-5662ПавловаА. В.PavlovaAnna V.

Москва

Moscow

https://orcid.org/0000-0002-7634-2053РайкинаЕ. В.RaikinaElena V.

Москва

Moscow

https://orcid.org/0000-0002-5388-8133АсановА. Ю.AsanovAliy Yu.

Moscow

https://orcid.org/0000-0002-1863-3768ЛитвиноваМ. М.LitvinovaMaria M.

Moscow

https://orcid.org/0000-0002-3113-4939ЩербинаА. Ю.ShcherbinaAnna Y.

Москва

Moscow

Российский национальный исследовательский медицинский университет им. Н.И. Пирогова; Детская городская клиническая больница № 13 им. Н.Ф. ФилатоваРоссияPirogov Russian National Research Medical University; Filatov Children's City Hospital № 13Russian FederationНациональный медицинский исследовательский центр детской гематологии, онкологии и иммунологии им. Дмитрия РогачёваРоссияDmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and ImmunologyRussian FederationРоссийский национальный исследовательский медицинский университет им. Н.И. ПироговаРоссияPirogov Russian National Research Medical UniversityRussian FederationПервый Московский государственный медицинский университет им. И.М. Сеченова (Сеченовский Университет)РоссияSechenov First Moscow State Medical University (Sechenov University)Russian FederationПервый Московский государственный медицинский университет им. И.М. Сеченова (Сеченовский Университет); Московский клинический научный центр им. А.С. ЛогиноваРоссияSechenov First Moscow State Medical University (Sechenov University); Sechenov First Moscow State Medical University (Sechenov University)Russian Federation201905012020185393400Copyright © Ипатова М.Г., Деордиева Е.А., Швец О.А., Мухина А.А., Моисеева А.А., Родина Ю.А., Шумилов П.В., Павлова А.В., Райкина Е.В., Асанов А.Ю., Литвинова М.М., Щербина А.Ю., 20202020Ипатова М.Г., Деордиева Е.А., Швец О.А., Мухина А.А., Моисеева А.А., Родина Ю.А., Шумилов П.В., Павлова А.В., Райкина Е.В., Асанов А.Ю., Литвинова М.М., Щербина А.Ю.Ipatova M.G., Deordieva E.A., Shvets O.A., Mukhina A.A., Moiseeva A.A., Rodina Y.A., Shumilov P.V., Pavlova A.V., Raikina E.V., Asanov A.Y., Litvinova M.M., Shcherbina A.Y.Данная работа распространяется под лицензией Creative Commons Attribution 4.0.This work is licensed under a Creative Commons Attribution 4.0 License.https://vsp.spr-journal.ru/jour/article/view/2239Обоснование

Обоснование. Синдром Швахмана-Даймонда (СШД) — редкое генетическое заболевание с аутосомно-рецессив-ным типом наследования, в основе которого лежат патогенные варианты в гене SBDS. Спектр вариантов гена SBDS у больных с СШД и особенности течения болезни в российской популяции ранее не изучались.

Цель исследования — описать варианты гена SBDS и клинико-лабораторные нарушения у детей с СШД.

Методы

Методы. В проспективном исследовании при первичной госпитализации экзокринную функцию поджелудочной железы оценивали по активности амилазы и липазы в крови, наличию стеатореи и содержанию эластазы в кале. Гематологические нарушения определяли в клиническом анализе крови. Костные аномалии диагностировали путем рентгенологического исследования. Задержку роста устанавливали при помощи антропометрических параметров с последующим применением перцентильных кривых. Молекулярно-генетическое исследование проводилось методом секвенирования нового поколения и прямого секвенирования по Сенгеру.

Результаты

Результаты. Патогенные варианты гена SBDS (всего 8) обнаружены у 25 (89%) из 28 детей с СШД. Чаще всего (у 23 пациентов; 82%) обнаруживали вариант с.258+2T>C, из них в 18 случаях в компаунд-гетерозиготном состоянии с вариантом c.183_184delTAinsCT. У 2 больных выявлен вариант a653G>A (p.Arg218Gln), по одному случаю — варианты c.258+1G>A, a107delT, с.356G>A, c.297_300delAAGA, с.338C>T. У всех детей с СШД отмечена задержка роста, у 11 (39%) — костные аномалии. В крови у 24 (86%) детей отмечалась нейтропения, реже — анемия и тромбоцитопения. Снижение активности эластазы 1 (< 200 мкг/г) в кале обнаружено у 26 (92%) пациентов. У 21 (75%) ребенка отмечен синдром цитолиза.

Заключение

Заключение. Патогенные варианты гена SBDS обнаружены у большинства российских детей с СШД, чаще всего варианты с. 258+2T>C и c.183_184delTAinsCT. Клинические симптомы синдрома Швахмана-Даймонда проявляются с первых дней жизни в виде задержки физического развития, стеатореи и гематологических нарушений.

Background

Background. Shwachman-Diamond syndrome (SDS) is the rare genetic autosomal recessive disorder with pathogenic variants in SBDS gene. The spectrum of SBDS gene variants in patients with SDS and features of disease course have not been studied before in Russian population.

Objective

Objective. The aim of the study was to describe all the variants of SBDS gene and clinical and laboratory abnormalities in children with SDS. Methods. In this prospective study exocrine pancreatic function was estimated by amylase and lipase activity in blood, steatorrhea presence and stool elastase levels during the initial hospitalization. Haematological disorders were analysed by complete blood count. Bone abnormalities were diagnosed via X-ray imaging. Growth delay was established due to anthropometry indicators and percentile curves. Molecular genetic testing was performed with using next generation sequencing and Senger sequencing.

Results

Results. Pathogenic variants in SBDS gene (8 in general) were revealed in 25 (89%) out of 28 children with SDS. The most common variant (in 23 patients, 82%) was с.258+2T>C, and in 18 cases it was in compound heterozygous state with c.183_184delTAinsCT. Two patients had с.653G>A (p.Arg218Gln) variant and for one patient for every of the following variants: c.258+1G>A, c.107delT, с.356G>A, c.297_300delAAGA, c.338C>T. All children with SDS had growth delay, in 11 (39%) cases we revealed bone abnormalities. In blood samples of 24 (86%) children we revealed neutropenia and less frequently anemia and thrombocytopenia. The stool elastase I decreased activity (< 200 pg/g) was revealed in 26 (92%) patients. 21 (75%) children had cytolysis syndrome.

Conclusion

Conclusion. Pathogenic variants of SBDS gene were revealed in majority of Russian children with SDS. The most frequent are c.258+2T>C and c.183_184delTAinsCT variants. Clinical signs of Shwachman-Diamond syndrome manifest since birth with growth delay, steatorrhea and haematological disorders.

детисиндром Швахмана-Даймондаген SBDSсимптомылабораторные признакистеатореясиндром цитолизаэластаза кала 1childrenShwachman-Diamond syndromeSBDS genesymptomslaboratory signssteatorrheacytolysis syndromestool elastase IНе указанNot specifiedReferencesShwachman H, Diamond LK, Oski FA, Khaw KT. The syndrome of pancreatic insufficiency and bone marrow dysfunction. J Pediatr. 1964;65:645-663. doi: 10.1016/s0022-3476(64)80150-5.Shwachman H, Diamond LK, Oski FA, Khaw KT. The syndrome of pancreatic insufficiency and bone marrow dysfunction. J Pediatr. 1964;65:645-663. doi: 10.1016/s0022-3476(64)80150-5.Goobie S, Popovic M, Morrison J, et al. Shwachman-Diamond syndrome with exocrine pancreatic dysfunction and bone marrow failure maps to the centromeric region of chromosome 7. Am J Hum Genet. 2001;68(4):1048-1054. doi: 10.1086/319505.Goobie S, Popovic M, Morrison J, et al. Shwachman-Diamond syndrome with exocrine pancreatic dysfunction and bone marrow failure maps to the centromeric region of chromosome 7. Am J Hum Genet. 2001;68(4):1048-1054. doi: 10.1086/319505.Boocock GR, Morrison JA, Popovic M, et al. Mutations in SBDS are associated with Shwachman-Diamond syndrome. Nat Genet. 2003;33(1):97-101. doi: 10.1038/ng1062.Boocock GR, Morrison JA, Popovic M, et al. Mutations in SBDS are associated with Shwachman-Diamond syndrome. Nat Genet. 2003;33(1):97-101. doi: 10.1038/ng1062.Woloszynek JR, Rothbaum RJ, Rawls AS, et al. Mutations of the SBDS gene are present in most patients with Shwachman-Diamond syndrome. Blood. 2004;104(12):3588-3590. doi: 10.1182/blood-2004-04-1516.Woloszynek JR, Rothbaum RJ, Rawls AS, et al. Mutations of the SBDS gene are present in most patients with Shwachman-Diamond syndrome. Blood. 2004;104(12):3588-3590. doi: 10.1182/blood-2004-04-1516.Donadieu J, Fenneteau O, Beaupain B, et al.; Associated investigators of the French Severe Chronic Neutropenia Registry. Classification of and risk factors for hematologic complications in a French national cohort of 102 patients with Shwachman-Diamond syndrome. Haematologica. 2012;97(9):1312-9131. doi: 10.3324/haematol.2011.057489.Donadieu J, Fenneteau O, Beaupain B, et al.; Associated investigators of the French Severe Chronic Neutropenia Registry. Classification of and risk factors for hematologic complications in a French national cohort of 102 patients with Shwachman-Diamond syndrome. Haematologica. 2012;97(9):1312-9131. doi: 10.3324/haematol.2011.057489.Nicolis E, Bonizzato A, Assael BM, Cipolli M. Identification of novel mutations in patients with Shwachman-Diamond syndrome. Hum Mutat. 2005;25(4):410. doi: 10.1002/humu.9324.Nicolis E, Bonizzato A, Assael BM, Cipolli M. Identification of novel mutations in patients with Shwachman-Diamond syndrome. Hum Mutat. 2005;25(4):410. doi: 10.1002/humu.9324.Nakashima E, Mabuchi A, Makita Y, et al. Novel SBDS mutations caused by gene conversion in Japanese patients with Shwachman-Diamond syndrome. Hum Genet. 2004;114(4):345-348. doi: 10.1007/s00439-004-1081-2.Nakashima E, Mabuchi A, Makita Y, et al. Novel SBDS mutations caused by gene conversion in Japanese patients with Shwachman-Diamond syndrome. Hum Genet. 2004;114(4):345-348. doi: 10.1007/s00439-004-1081-2.Burroughs L, Woolfrey A, Shimamura A. Shwachman-Diamond syndrome: a review of the clinical presentation, molecular pathogenesis, diagnosis, and treatment. Hematol Oncol Clin North Am. 2009;23(2):233-248. doi: 10.1016/j.hoc.2009.01.007.Burroughs L, Woolfrey A, Shimamura A. Shwachman-Diamond syndrome: a review of the clinical presentation, molecular pathogenesis, diagnosis, and treatment. Hematol Oncol Clin North Am. 2009;23(2):233-248. doi: 10.1016/j.hoc.2009.01.007.Dror Y, Donadieu J, Koglmeier J, et al. Draft consensus guidelines for diagnosis and treatment of Shwachman-Diamond syndrome. Ann N YAcad Sci. 2011;1242:40-55. doi: 10.1111/j.1749-6632.2011.06349.x.Dror Y, Donadieu J, Koglmeier J, et al. Draft consensus guidelines for diagnosis and treatment of Shwachman-Diamond syndrome. Ann N YAcad Sci. 2011;1242:40-55. doi: 10.1111/j.1749-6632.2011.06349.x.Austin KM, Leary RJ, Shimamura A. The Shwachman-Diamond SBDS protein localizes to the nucleolus. Blood. 2005;106(4): 1253-1258. doi: 10.1182/blood-2005-02-0807.Austin KM, Leary RJ, Shimamura A. The Shwachman-Diamond SBDS protein localizes to the nucleolus. Blood. 2005;106(4): 1253-1258. doi: 10.1182/blood-2005-02-0807.Lesesve JF, Dugue F, Gregoire MJ, et al. Shwachman-Diamond syndrome with late-onset neutropenia and fatal acute myeloid leukaemia without maturation: a case report. Eur J Haematol. 2003; 71(5):393-395. doi: 10.1034/j.1600-0609.2003.00146.x.Lesesve JF, Dugue F, Gregoire MJ, et al. Shwachman-Diamond syndrome with late-onset neutropenia and fatal acute myeloid leukaemia without maturation: a case report. Eur J Haematol. 2003; 71(5):393-395. doi: 10.1034/j.1600-0609.2003.00146.x.Dror Y, Durie P Ginzberg H, et al. Clonal evolution in marrows of patients with Shwachman-Diamond syndrome: a prospective 5-year follow-up study. Exp Hematol. 2002;30(7):659-669. doi: 10.1016/s0301-472x(02)00815-9.Dror Y, Durie P Ginzberg H, et al. Clonal evolution in marrows of patients with Shwachman-Diamond syndrome: a prospective 5-year follow-up study. Exp Hematol. 2002;30(7):659-669. doi: 10.1016/s0301-472x(02)00815-9.Makitie O, Ellis L, Durie PR, et al. Skeletal phenotype in patients with Shwachman-Diamond syndrome and mutations in SBDS. Clin Genet. 2004;65(2):101-112. doi: 10.1111/j.0009-9163.2004.00198.x.Makitie O, Ellis L, Durie PR, et al. Skeletal phenotype in patients with Shwachman-Diamond syndrome and mutations in SBDS. Clin Genet. 2004;65(2):101-112. doi: 10.1111/j.0009-9163.2004.00198.x.Aggett PJ, Cavanagh NP Matthew DJ, et al. Shwachman's syndrome. A review of 21 cases. Arch Dis Child. 1980;55(5):331-347. doi: 10.1136/adc.55.5.331Aggett PJ, Cavanagh NP Matthew DJ, et al. Shwachman's syndrome. A review of 21 cases. Arch Dis Child. 1980;55(5):331-347. doi: 10.1136/adc.55.5.331Ипатова М.Г., Шумилов П.В., Блох С.П., и др. Особенности экзокринной и эндокринной функций поджелудочной железы у детей с синдромом Швахмана-Даймонда // Педиатрия. Журн. им. Г.Н. Сперанского. — 2017. — Т. 96. — № 6. — С. 48-52. doi: 10.24110/0031-403X-2017-96-6-48-52.Ipatova MG, Shumilov PV, Blokh SP et al. Peculiarities of pancreas exocrine and endocrine functions in children with Shwachman-Diamond syndrome. Zhurnal imeni G.N. Speranskogo. Pediatria. 2017;96(6):48-52. (In Russ). doi: 10.24110/0031-403X-2017-96-6-48-52.Kuijpers TW, Nannenberg E, Alders M, et al. Congenital aplastic anemia caused by mutations in the SBDS gene: a rare presentation of Shwachman-Diamond syndrome. Pediatrics. 2004;114(3): e387-391. doi: 10.1542/peds.2003-0651-F.Kuijpers TW, Nannenberg E, Alders M, et al. Congenital aplastic anemia caused by mutations in the SBDS gene: a rare presentation of Shwachman-Diamond syndrome. Pediatrics. 2004;114(3): e387-391. doi: 10.1542/peds.2003-0651-F.Barrios N, Kirkpatrick D, Regueira O, et al. Bone marrow transplant in Shwachman Diamond syndrome. Br J Haematol. 1991; 79(2):337-338. doi: 10.1111/j.1365-2141.1991.tb04545.xBarrios N, Kirkpatrick D, Regueira O, et al. Bone marrow transplant in Shwachman Diamond syndrome. Br J Haematol. 1991; 79(2):337-338. doi: 10.1111/j.1365-2141.1991.tb04545.xSmith OP, Hann IM, Chessells JM, et al. Haematological abnormalities in Shwachman-Diamond syndrome. Br J Haematol. 1996;94(2):279-284. doi: 10.1046/j.1365-2141.1996.d01-1788.xSmith OP, Hann IM, Chessells JM, et al. Haematological abnormalities in Shwachman-Diamond syndrome. Br J Haematol. 1996;94(2):279-284. doi: 10.1046/j.1365-2141.1996.d01-1788.xDror Y, Squire J, Durie P Freedman MH. Malignant myeloid transformation with isochromosome 7q in Shwachman-Diamond syndrome. Leukemia. 1998;12(10):1591-1595. doi: 10.1038/sj.leu.2401147Dror Y, Squire J, Durie P Freedman MH. Malignant myeloid transformation with isochromosome 7q in Shwachman-Diamond syndrome. Leukemia. 1998;12(10):1591-1595. doi: 10.1038/sj.leu.2401147Passmore SJ, Hann IM, Stiller CA, et al. Pediatric myelodysplasia: a study of 68 children and a new prognostic scoring system. Blood. 1995;85(7):1742-1750. doi: 10.1182/blood.v85.7.1742.blood-journal8571742Passmore SJ, Hann IM, Stiller CA, et al. Pediatric myelodysplasia: a study of 68 children and a new prognostic scoring system. Blood. 1995;85(7):1742-1750. doi: 10.1182/blood.v85.7.1742.blood-journal8571742Ипатова М.Г., Куцев С.И., Шумилов П.В., и др. Краткие клинические рекомендации по ведению больных с синдромом Швахмана-Даймонда // Педиатрия. Журн. им. Г.Н. Сперанского. — 2016. — Т. 95. — № 6. — С. 181-186.Ipatova MG, Kutsev SI, Shumilov PV, et al. Brief recommendations for management of patients with Shwachman-Diamond syndrome. Zhurnal imeni G.N. Speranskogo. Pediatria. 2016;95(6):181-186. (In Russ).Kuijpers TW, Alders M, Tool AT, et al. Hematologic abnormalities in Shwachman Diamond syndrome: lack of genotype-phenotype relationship. Blood. 2005;106(1):356-361. doi: 10.1182/blood-2004-11-4371.Kuijpers TW, Alders M, Tool AT, et al. Hematologic abnormalities in Shwachman Diamond syndrome: lack of genotype-phenotype relationship. Blood. 2005;106(1):356-361. doi: 10.1182/blood-2004-11-4371.Finch AJ, Hilcenko C, Basse N, et al. Uncoupling of GTP hydrolysis from eIF6 release on the ribosome causes Shwachman-Diamond syndrome. Genes Dev. 2011;25(9):917-929. doi: 10.1101/gad.623011.Finch AJ, Hilcenko C, Basse N, et al. Uncoupling of GTP hydrolysis from eIF6 release on the ribosome causes Shwachman-Diamond syndrome. Genes Dev. 2011;25(9):917-929. doi: 10.1101/gad.623011.

The authors declare that there are no conflicts of interest present.