perinatologyРоссийский вестник перинатологии и педиатрииRossiyskiy Vestnik Perinatologii i Pediatrii (Russian Bulletin of Perinatology and Pediatrics)1027-40652500-2228Ltd. “The National Academy of Pediatric Science and Innovation”10.21508/1027-4065-2024-69-6-97-106perinatology-2097Research ArticleВ ПОМОЩЬ ПРАКТИЧЕСКОМУ ВРАЧУFOR THE PRACTITIONERКлинические фенотипы гипофосфатазии вследствие мутаций гена ALPL, эффективность заместительной ферментной терапии препаратом Асфотаза альфа у детейClinical phenotypes of hypophosphatasia due to ALPL gene mutations and the effectiveness of enzyme replacement therapy with asphotase alpha in childrenhttps://orcid.org/0000-0002-9415-4785СавенковаН. Д.SavenkovaN. D.

Савенкова Надежда Дмитриевна — д.м.н., проф., зав. кафедрой факультетской педиатрии, заслуженный врач РФ

194100 Санкт-Петербург, ул. Литовская, д. 2

Saint Petersburg

ЛевиашвилиЖ. Г.LeviashviliZh. G.

Левиашвили Жанна Гавриловна — д.м.н., доц. кафедры факультетской педиатрии

194100 Санкт-Петербург, ул. Литовская, д. 2

Saint Petersburg

ФГБОУ ВО «Санкт-Петербургский государственный педиатрический медицинский университет» Минздрава РоссииРоссияSaint Petersburg State Pediatric Medical UniversityRussian Federation20240301202569697106Copyright © Ltd. “The National Academy of Pediatric Science and Innovation”, 20242024Ltd. “The National Academy of Pediatric Science and Innovation”Ltd. “The National Academy of Pediatric Science and Innovation”https://www.ped-perinatology.ru/jour/about/submissions#copyrightNoticehttps://www.ped-perinatology.ru/jour/article/view/2097

Представлены современные сведения о клинических формах гипофосфатазии. В каталоге OMIM приведено 5 форм гипофосфатазии: перинатальная (летальная), инфантильная, детского возраста, взрослых, одонтогипофосфатазия. На портале ORPHA представлены 6 подтипов расстройств: гипофосфатазия взрослых, гипофосфатазия детского возраста, инфантильная, перинатальная (летальная), пренатальная (доброкачественная). M.E. Nunes (2023) выделяет 7 форм гипофосфатазии. По данным международных исследований установлены патогенез, вариабельность фенотипической манифестации и тяжести гипофосфатазии, глобальный консорциум содержит сведения о 446 вариантах мутаций гена ALPL и 797 генотипов у педиатрических и взрослых пациентов. Даны обновленные диагностические критерии гипофосфатазии у детей и взрослых с низким уровнем активности щелочной фосфатазы в крови. Опытом 10-летнего применения в 40 станах доказаны безопасность и эффективность заместительной ферментной терапии препаратом Асфотаза альфа у детей с гипофосфатазией перинатальной, инфантильной, детского возраста и одонтогипофосфатазией. В Российской Федерации детям с гипофосфатазией заместительная ферментная терапия препаратом Асфотаза альфа с 2021 г. проводится за счет средств Фонда «Круг добра», учрежденного Министерством здравоохранения.

The article provides current information on the clinical forms of hypophosphatasia. The OMIM catalog lists 5 forms of hypophosphatasia: perinatal (lethal), infantile, childhood, adult, and odontohypophosphatasia. The ORPHA portal identifies 6 subtypes of the disorder, including adult, childhood, infantile, perinatal (lethal), and prenatal (benign) hypophosphatasia. M.E. Nunes (2023) identifies 7 forms of hypophosphatasia. International studies have established the pathogenesis, phenotypic variability, and severity of hypophosphatasia. A global consortium provides information on 446 mutation variants of the ALPL gene and 797 genotypes in pediatric and adult patients. The review presents updated diagnostic criteria for hypophosphatasia in children and adults with low alkaline phosphatase activity in the blood. Ten years of experience in 40 countries have proven the safety and efficacy of enzyme replacement therapy with Asfotase Alfa in children with perinatal, infantile, childhood hypophosphatasia, and odontohypophosphatasia. In the Russian Federation, enzyme replacement therapy with Asfotase Alfa for children with hypophosphatasia has been funded by the Circle of Kindness Foundation, established by the Ministry of Health, since 2021.

детигипофосфатазиямутации гена ALPLфенотипызаместительная ферментная терапиявзрослыеchildrenhypophosphatasiaALPL gene mutationsphenotypesenzyme replacement therapyadultsReferencesOMIM. https://www.omim.org/search?index=entry&start=1&limit=10&sort=score+desc%2C+prefix_sort+desc&-search=hypophosphatasia / Ссылка активна 12.09. 2024OMIM. https://www.omim.org/search?index=entry&start=1&limit=10&sort=score+desc%2C+prefix_sort+desc&-search=hypophosphatasia / Ссылка активна 12.09. 2024Hypophosphatasie ©Orphanet 2023 https://www.orpha.net/consor/cgi-bin/Disease_Search.php?lng=EN&data_id=162&Disease_Disease_Search_diseaseGroup=436&Disease_Disease_Search_diseaseType=ORPHA&Disease(s)/group%20of%20diseases=Hypophosphatasia&title=Hypophosphatasia&search=Disease_Search_Simple / Ссылка активна на 12.09.2024.Hypophosphatasie ©Orphanet 2023 https://www.orpha.net/consor/cgi-bin/Disease_Search.php?lng=EN&data_id=162&Disease_Disease_Search_diseaseGroup=436&Disease_Disease_Search_diseaseType=ORPHA&Disease(s)/group%20of%20diseases=Hypophosphatasia&title=Hypophosphatasia&search=Disease_Search_Simple / Ссылка активна на 12.09.2024.Клинические рекомендации: Гипофосфатазия. 2023 https://cr.minzdrav.gov.ru/recomend/770_1 / Ссылка активна на 12.09.2024.Клинические рекомендации: Гипофосфатазия. 2023 https://cr.minzdrav.gov.ru/recomend/770_1 / Ссылка активна на 12.09.2024.Whyte M.P., Zhang F., Wenkert D., McAlister W.H., Mack K.E., Benigno M.C. et al. Hypophosphatasia: validation and expansion of the clinical nosology for children from 25 years’ experience with 173 pediatric patients. Bone 2015; 75: 229–239. DOI: 10.1016/j.bone.2015.02.022.Whyte M.P., Zhang F., Wenkert D., McAlister W.H., Mack K.E., Benigno M.C. et al. Hypophosphatasia: validation and expansion of the clinical nosology for children from 25 years’ experience with 173 pediatric patients. Bone 2015; 75: 229–239. DOI: 10.1016/j.bone.2015.02.022.Nunes M.E. Hypophosphatasia. 2007 Nov 20 [updated 2023 Mar 30]. In: GeneReviews® [Internet]. Editors Adam M.P., Feldman J., Mirzaa G.M., Pagon R.A., Wallace S.E., Bean L.J.H., Gripp K.W., Amemiya A. Seattle (WA): University of Washington, Seattle; 1993–2024. PMID:20301329Nunes M.E. Hypophosphatasia. 2007 Nov 20 [updated 2023 Mar 30. In: GeneReviews® [Internet. Editors Adam M.P., Feldman J., Mirzaa G.M., Pagon R.A., Wallace S.E., Bean L.J.H., Gripp K.W., Amemiya A. Seattle (WA): University of Washington, Seattle; 1993–2024. PMID:20301329Whyte M.P., Leung E., Wilcox W.R., Liese J., Argente J., Martos-Moreno G.Á., at al. Study 011–10 Investigators. Natural History of Perinatal and Infantile Hypophosphatasia: A Retrospective Study. J Pediatr 2019; 209: 116–124.e4. DOI: 10.1016/j.jpeds.2019.01.049Whyte M.P., Leung E., Wilcox W.R., Liese J., Argente J., Martos-Moreno G.Á., at al. Study 011–10 Investigators. Natural History of Perinatal and Infantile Hypophosphatasia: A Retrospective Study. J Pediatr 2019; 209: 116–124.e4. DOI: 10.1016/j.jpeds.2019.01.049Bacchetta J. Renal impairment in hypophosphatasia. Arch Pediatr 2017; 24: 5S93–5S95. DOI: 10.1016/S0929–693X(18)30023-Х.Bacchetta J. Renal impairment in hypophosphatasia. Arch Pediatr 2017; 24: 5S93–5S95. DOI: 10.1016/S0929–693X(18)30023-Х.Reis F.S., Lazaretti-Castro M. Hypophosphatasia: from birth to adulthood. Arch Endocrinol Metab 2023; 67(5): e000626. DOI: 10.20945/2359–3997000000626.Reis F.S., Lazaretti-Castro M. Hypophosphatasia: from birth to adulthood. Arch Endocrinol Metab 2023; 67(5): e000626. DOI: 10.20945/2359–3997000000626.Fenn J.S., Lorde N., Ward J.M., Borovickova I. Hypophosphatasia. J Clin Pathol 2021; 74(10): 635–640. DOI: 10.1136/jclinpath-2021–207426Fenn J.S., Lorde N., Ward J.M., Borovickova I. Hypophosphatasia. J Clin Pathol 2021; 74(10): 635–640. DOI: 10.1136/jclinpath-2021–207426Pierpont E.I., Simmons J.H., Spurlock K.J., Shanley R., Sarafoglou K.M. Impact of pediatric hypophosphatasia on behavioral health and quality of life. Orphanet J Rare Dis 2021; 16(1): 80. DOI: 10.1186/s13023–021–01722–7Pierpont E.I., Simmons J.H., Spurlock K.J., Shanley R., Sarafoglou K.M. Impact of pediatric hypophosphatasia on behavioral health and quality of life. Orphanet J Rare Dis 2021; 16(1): 80. DOI: 10.1186/s13023–021–01722–7HPP gene variant registration portal. https://alplmutationdatabase.JKU.at / Ссылка активна 12.09.2024HPP gene variant registration portal. https://alplmutationdatabase.JKU.at / Ссылка активна 12.09.2024Khan A.A., Brandi M.L., Rush E.T., Ali D.S., Al-Alwani H., Almonaei K. et al. Hypophosphatasia diagnosis: current state of the art and proposed diagnostic criteria for children and adults. Erratum in: Osteoporos Int 2024; 35(5): 933–934. DOI: 10.1007/s00198–024–07048-xKhan A.A., Brandi M.L., Rush E.T., Ali D.S., Al-Alwani H., Almonaei K. et al. Hypophosphatasia diagnosis: current state of the art and proposed diagnostic criteria for children and adults. Erratum in: Osteoporos Int 2024; 35(5): 933–934. DOI: 10.1007/s00198–024–07048-xRush E., Brandi M.L., Khan A., Ali D.S., Al-Alwani H., Almonaei K. et al. Proposed diagnostic criteria for the diagnosis of hypophosphatasia in children and adolescents: results from the HPP International Working Group. Osteoporos Int 2024;35(1):1–10. DOI: 10.1007/s00198–023–06843–2Rush E., Brandi M.L., Khan A., Ali D.S., Al-Alwani H., Almonaei K. et al. Proposed diagnostic criteria for the diagnosis of hypophosphatasia in children and adolescents: results from the HPP International Working Group. Osteoporos Int 2024;35(1):1–10. DOI: 10.1007/s00198–023–06843–2Montero-Lopez R., Farman M.R., Högler F., Saraff V., Högler W. Challenges in Hypophosphatasia: Suspicion, Diagnosis, Genetics, Management, and Follow-Up. Horm Res Paediatr 2024; 5. DOI: 10.1159/000540692Montero-Lopez R., Farman M.R., Högler F., Saraff V., Högler W. Challenges in Hypophosphatasia: Suspicion, Diagnosis, Genetics, Management, and Follow-Up. Horm Res Paediatr 2024; 5. DOI: 10.1159/000540692Whyte M.P., McAlister W.H., Mack K.E., Mumm S., Madson K.L. Pediatric hypophosphatasia: avoid diagnosis missteps. J Bone Miner Res 2024; 39(6): 655–660. DOI: 10.1093/jbm098Whyte M.P., McAlister W.H., Mack K.E., Mumm S., Madson K.L. Pediatric hypophosphatasia: avoid diagnosis missteps. J Bone Miner Res 2024; 39(6): 655–660. DOI: 10.1093/jbm098Farman M.R., Rehder C., Malli T., Rockm an-Greenberg C., Dahir K., Martos-Moreno G.Á. et al. The Global ALPL gene variant classification project: Dedicated to deciphering variants. Bone 2024; 178: 116947. DOI: 10.1016/j.bone.2023.116947Farman M.R., Rehder C., Malli T., Rockm an-Greenberg C., Dahir K., Martos-Moreno G.Á. et al. The Global ALPL gene variant classification project: Dedicated to deciphering variants. Bone 2024; 178: 116947. DOI: 10.1016/j.bone.2023.116947Högler W., Langman C., Gomes da Silva H., Fang S., Linglart A., Ozono K. et al. Diagnostic delay is common among patients with hypophosphatasia: initial findings from a longitudinal, prospective, global registry. BMC Musculoskelet Disord 2019; 20: 80. DOI: 10.1186/s12891–019242Högler W., Langman C., Gomes da Silva H., Fang S., Linglart A., Ozono K. et al. Diagnostic delay is common among patients with hypophosphatasia: initial findings from a longitudinal, prospective, global registry. BMC Musculoskelet Disord 2019; 20: 80. DOI: 10.1186/s12891–019242Vogt M., Girschick H., Schweitzer T., Benoit C., Holl-Wieden A., Seefried L. et al. Pediatric hypophosphatasia: lessons learned from a retrospective single-center chart review of 50 children. Orphanet J Rare Dis 2020; 15(1): 212. DOI: 10.1186/s13023–020–01500-xVogt M., Girschick H., Schweitzer T., Benoit C., Holl-Wieden A., Seefried L. et al. Pediatric hypophosphatasia: lessons learned from a retrospective single-center chart review of 50 children. Orphanet J Rare Dis 2020; 15(1): 212. DOI: 10.1186/s13023–020–01500-xLiu M., Liu M., Liang X., Wu D., Li W., Su C. et al. Clinical and genetic characteristics of hypophosphatasia in Chinese children. Orphanet J Rare Dis 2021; 16(1): 159. DOI: 10.1186/s13023–021–01798–1Liu M., Liu M., Liang X., Wu D., Li W., Su C. et al. Clinical and genetic characteristics of hypophosphatasia in Chinese children. Orphanet J Rare Dis 2021; 16(1): 159. DOI: 10.1186/s13023–021–01798–1Glotov O.S., Savostyanov K.V., Nagornova T.S., Chernov A.N., Fedyakov M.A., Raspopova A.N. et al. Clinical and Genetic Characteristics of Pediatric Patients with hypohosphatasia in the Russian Population. Int J Mol Sci 2022; 23(21): 12976. DOI: 10.3390/ijms232112976Glotov O.S., Savostyanov K.V., Nagornova T.S., Chernov A.N., Fedyakov M.A., Raspopova A.N. et al. Clinical and Genetic Characteristics of Pediatric Patients with hypohosphatasia in the Russian Population. Int J Mol Sci 2022; 23(21): 12976. DOI: 10.3390/ijms232112976Su N., Zhu M., Cheng X., Xu K., Kocijan R., Zhang H. Six ALPL gene variants in five children with hypophosphatasia. Ann Transl Med 2021; 9(10): 888. DOI: 10.21037/atm-21–2096Su N., Zhu M., Cheng X., Xu K., Kocijan R., Zhang H. Six ALPL gene variants in five children with hypophosphatasia. Ann Transl Med 2021; 9(10): 888. DOI: 10.21037/atm-21–2096Tilden D.R., Sheehan J.H., Newman J.H., Meiler J., Capra J.A., Ramirez A. et al. Phenotypic Profiling in Subjects Heterozygous for 1 of 2 Rare Variants in the Hypophosphatasia Gene (ALPL). J Endocr Soc 2020; 4(8): bvaa084. DOI: 10.1210/jendso/bvaa084Tilden D.R., Sheehan J.H., Newman J.H., Meiler J., Capra J.A., Ramirez A. et al. Phenotypic Profiling in Subjects Heterozygous for 1 of 2 Rare Variants in the Hypophosphatasia Gene (ALPL). J Endocr Soc 2020; 4(8): bvaa084. DOI: 10.1210/jendso/bvaa084Martins L., Lessa L.G.F., Ali T.M., Lazar M., Kim C.A., Kantovitz K. et al. Childhood Hypophosphatasia Associated with a Novel Biallelic ALPL Variant at the TNSALP Dimer Interface. Int J Mol Sci 2022; 24(1): 282. DOI: 10.3390/ijms24010282Martins L., Lessa L.G.F., Ali T.M., Lazar M., Kim C.A., Kantovitz K. et al. Childhood Hypophosphatasia Associated with a Novel Biallelic ALPL Variant at the TNSALP Dimer Interface. Int J Mol Sci 2022; 24(1): 282. DOI: 10.3390/ijms24010282Савенкова Н.Д., Левиашвили Ж.Г., Барсукова В.Н. Клинические фенотипы и варианты мутаций гена ALPL у детей с гипофосфатазией, заместительная ферментная терапия препаратом Асфотаза альфа: данные литературы и клинического наблюдения. Нефрология 2023; 27(4): 11–21.Savenkova N.D., Leviashvili Zh.G., Barsukova V.N. Clinical phenotypes and variants of mutations of the ALPL gene in children with hypophosphatasia, enzyme replacement therapy with Asfotase alfa: literature and clinical case data. Nefrologiya (Saint-Petersburg). 2023; 27(4): 11–21. (in Russ.) DOI: 10.36485/1561–6274–2023–27–4–11–21Sugiyama Yu., Watanabe T., Tajika M., Matsuhashi T., Shimura M., Fushimi T. et al. Japanese single-center experience in the study of the efficacy and safety of asphotase alpha in hypophosphatasia in children. Orphanet J Rare Dis 2022; 17(1): 78. DOI: 10.1186/s13023–022–02230-ySugiyama Yu., Watanabe T., Tajika M., Matsuhashi T., Shimura M., Fushimi T. et al. Japanese single-center experience in the study of the efficacy and safety of asphotase alpha in hypophosphatasia in children. Orphanet J Rare Dis 2022; 17(1): 78. DOI: 10.1186/s13023–022–02230-yWhyte M.P., Simmons J.H., Moseley S., Fujita K.P., Bishop N., Salman N.J. et al. Asfotase alfa for infants and young children with hypophosphatasia: 7-year outcomes of a single-arm, open-label, phase 2 extension trial. Lancet Diab Endocrinol 2019; 7(2): 93–105. DOI: 10.1016/S2213–8587(18)30307–3Whyte M.P., Simmons J.H., Moseley S., Fujita K.P., Bishop N., Salman N.J. et al. Asfotase alfa for infants and young children with hypophosphatasia: 7-year outcomes of a single-arm, open-label, phase 2 extension trial. Lancet Diab Endocrinol 2019; 7(2): 93–105. DOI: 10.1016/S2213–8587(18)30307–3Гуркина Е.Ю., Воинова В.Ю., Кузенкова Л.М., Соснина И.Б., Витебская А.В., Костик М.М. и др. Гипофосфатазия. Обзор клинических случаев, опубликованных в РФ. РМЖ 2021; 2: 42–48.Gurkina E.Yu., Voinova V.Yu., Kuzenkova L.M., Sosnina I.B., Vitebsk A.V., Kostik M.M. et al. Hypophosphatasia. Review of clinical cases published in the Russian Federation. RMZh 2021; 2: 42–48. (in Russ.)Bowden S.A., Adler B.H. Asfotase alfa treatment for 1 year in a 16-year-old male with severe childhood hypophosphatasia. Osteoporos Int 2018; 29(2): 511–515. DOI: 10.1007/s00198–017–4267-xBowden S.A., Adler B.H. Asfotase alfa treatment for 1 year in a 16-year-old male with severe childhood hypophosphatasia. Osteoporos Int 2018; 29(2): 511–515. DOI: 10.1007/s00198–017–4267-xSchroth R.J., Long C., Lee V.H.K., Alai-Towfigh H., Rockman-Greenberg C. Dental outcomes for children receiving asfotase alfa for hypophosphatasia. Bone 2021; 152: 116089. DOI: 10.1016/j.bone.2021.116089Schroth R.J., Long C., Lee V.H.K., Alai-Towfigh H., Rockman-Greenberg C. Dental outcomes for children receiving asfotase alfa for hypophosphatasia. Bone 2021; 152: 116089. DOI: 10.1016/j.bone.2021.116089Kishnani P.S., Rockman -Greenberg C., Rauch F., Bhatti M.T., Moseley S., Denker A.E. et al. Fife-year efficacy and safety of asfotase alfa therapy for adults and adolescents with hypophosphatasia. Bone 2019; 131: 149–162. DOI: 10.1016/j.bone.2019.12.011Kishnani P.S., Rockman -Greenberg C., Rauch F., Bhatti M.T., Moseley S., Denker A.E. et al. Fife-year efficacy and safety of asfotase alfa therapy for adults and adolescents with hypophosphatasia. Bone 2019; 131: 149–162. DOI: 10.1016/j.bone.2019.12.011Левиашвили Ж.Г., Савенкова Н.Д. Клинический фенотип, диагностика, стратегия терапии гипофосфатазии вследствие мутаций гена ALPL у педиатрических и взрослых пациентов. Нефрология 2021; 25(6): 16–26.Leviashvili Z.G., Savenkova N.D. Clinical phenotype, diagnostics, strategy of hypophosphatasia therapy due to ALPL gene mutations in pediatric and adult patients. Nefrologiya (Saint-Petersburg) 2021; 25(6): 16–26. (in Russ.) DOI: 10.36485/1561–6274–2021–25–6–16–26Schindeler A., Ludwig K., Munns C.F. Enzyme replacement therapy for hypophosphatasia — The current paradigm. Clin Endocrinol (Oxf) 2024; 14. DOI: 10.1111/cen.15063Schindeler A., Ludwig K., Munns C.F. Enzyme replacement therapy for hypophosphatasia — The current paradigm. Clin Endocrinol (Oxf) 2024; 14. DOI: 10.1111/cen.15063Shirinezhad A., Esmaeili S., Azarboo A., Tavakoli Y., Hoveidaei A.H., Zareshahi N. et al. Efficacy and safety of asfotase alfa in patients with hypophosphatasia: A systematic review. Bone 2024; 188: 117219. DOI: 10.1016/j.bone.2024.117219Shirinezhad A., Esmaeili S., Azarboo A., Tavakoli Y., Hoveidaei A.H., Zareshahi N. et al. Efficacy and safety of asfotase alfa in patients with hypophosphatasia: A systematic review. Bone 2024; 188: 117219. DOI: 10.1016/j.bone.2024.117219Alsarraf F., Ali D.S., Almonaei K., Al-Alwani H., Khan A.A., Brandi M.L. Hypophosphatasia: presentation and response to asfotase alfa. Osteoporos Int 2024; 35(4): 717–725. DOI: 10.1007/s00198–023–06943-zAlsarraf F., Ali D.S., Almonaei K., Al-Alwani H., Khan A.A., Brandi M.L. Hypophosphatasia: presentation and response to asfotase alfa. Osteoporos Int 2024; 35(4): 717–725. DOI: 10.1007/s00198–023–06943-zDahir K.M., Ing S.W., Deal C., Messali A., Bates T., Rush E.T. Improvement in quality of life after asfotase alfa treatment in adults with pediatric-onset hypophosphatasia: data from 5 patient-reported outcome measures. JBMR Plus 2024; 8(8): ziae062. DOI: 10.1093/jbmrpl/ziae062Dahir K.M., Ing S.W., Deal C., Messali A., Bates T., Rush E.T. Improvement in quality of life after asfotase alfa treatment in adults with pediatric-onset hypophosphatasia: data from 5 patient-reported outcome measures. JBMR Plus 2024; 8(8): ziae062. DOI: 10.1093/jbmrpl/ziae062Инструкция по медицинскому применению лекарственного препарата «АстраЗенека» в России.Instructions for medical use of the medicinal product «AstraZeneca» in Russia. (in Russ.) https://astrazeneca.ru/content/dam/az-ru/downloads/preparations / Ссылка ак- тивна на 12.09.2024.

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