porozendoОстеопороз и остеопатииOsteoporosis and Bone Diseases2072-26802311-0716Endocrinology Research Centre10.14341/osteo13178porozendo-13178Research ArticleКЛИНИЧЕСКИЕ СЛУЧАИCASE REPORTSКлинический случай аутосомно-доминантного гипофосфатемического рахита вследствие мутации в гене FGF23 у взрослого: трудности диагностикиA case report of autosomal dominant hypophosphatemic rickets due to a mutation in the FGF23 gene in an adult: diagnostic difficultieshttps://orcid.org/0000-0002-7102-5323СахноваЕ. Е.SakhnovaE. E.

Сахнова Екатерина Евгеньевна.

111539, Москва, ул. Вешняковская, д. 23

Ekaterina E. Sakhnova - MD.

23 Veshnyakovskaya street, 111539 Moscow

katerisaa_29@mail.ruhttps://orcid.org/0000-0001-9119-2447ПржиялковскаяЕ. Г.PrzhiyalkovskayaE. G.

Пржиялковская Елена Георгиевна - к.м.н.

Москва

Elena G. Przhiyalkovskaya - MD, PhD.

Moscow

przhiyalkovskaya.elena@gmail.comhttps://orcid.org/0000-0002-9783-3599МамедоваЕ. О.MamedovaE. O.

Мамедова Елизавета Октаевна - к.м.н.

Москва

Elizaveta O. Mamedova - MD, PhD.

Moscow

lilybet@mail.ruhttps://orcid.org/0000-0003-4915-1267ЧугуновИ. С.ChugunovI. S.

Чугунов Игорь Сергеевич - к.м.н.

Москва

Igor S. Chugunov - MD, PhD.

Moscow

chugunovigor@gmail.comГБУЗ «ГКБ №15 имени О.М. Филатова ДЗМ»РоссияO.M. Filatov City Clinical Hospital №15Russian FederationГНЦ РФ ФБГУ «НМИЦ эндокринологии» Минздрава РоссииРоссияEndocrinology Research CentreRussian Federation2024161020242741724Copyright © Сахнова Е.Е., Пржиялковская Е.Г., Мамедова Е.О., Чугунов И.С., 20252025Сахнова Е.Е., Пржиялковская Е.Г., Мамедова Е.О., Чугунов И.С.Sakhnova E.E., Przhiyalkovskaya E.G., Mamedova E.O., Chugunov I.S.This work is licensed under a Creative Commons Attribution 4.0 License.https://www.osteo-endojournals.ru/jour/article/view/13178

Остеомаляция — это системное заболевание скелета, характеризующееся нарушением минерализации или дефектной минерализацией вновь образованного костного матрикса у взрослых. Наиболее частой причиной является выраженный дефицит витамина D любой этиологии, дефицит кальция и дефицит фосфора (патология почек, мезенхимальные опухоли, секретирующие фактор роста фибробластов 23 (ФРФ23/FGF23), генетические заболевания). Среди генетических заболеваний чаще всего встречается X-сцепленный доминантный гипофосфатемический рахит (ген PHEX, лат. X-linked hypophosphatemic rickets (XLHR), OMIM: 307800), гораздо реже — аутосомно-доминантный гипофосфатемический рахит (ген FGF23, лат. Autosomal dominant hypophosphatemic rickets (ADHR), OMIM: 193100) и аутосомно-рецессивный гипофосфатемический рахит 1 и 2 типа (ген DMP1, ENPP1, FAM20C, лат. Autosomal recessive hypophosphatemic rickets-1 (ARHR1), OMIM: 241520; Autosomal recessive hypophosphatemic rickets-2 (ARHR2), OMIM: 613312). ADHR — крайне редкая наследственная патология, обусловленная мутацией в гене FGF23, для которой характерна манифестация в любом возрасте. В литературе описано около 50 случаев данной патологии. В статье впервые в Российской Федерации представлен клинический случай взрослой пациентки с ADHR. В ходе дифференциальной диагностики такие причины остеомаляции, как выраженный дефицит витамина D, заболевания, связанные с нарушением канальцевой реабсорбции почек, ФРФ23-продуцирующая опухоль, были исключены. Пациентке проведено генетическое исследование, по результатам которого выявлена мутация в гене FGF23, подтвержден диагноз ADHR. Инициирована терапия препаратами фосфора и активными метаболитами витамина D, на фоне которой отмечалось улучшение самочувствия в виде уменьшения болей при ходьбе, увеличения мышечной силы.

Трудности диагностики остеомаляции обусловлены отсутствием рутинного определения уровня фосфора в крови и малой осведомленностью врачей об этом заболевании. В свою очередь генетическое исследование в ряде случаев позволяет подтвердить наследственные формы, что предотвращает неоправданные хирургические вмешательства, обеспечивает своевременное назначение медикаментозной терапии и значимо улучшает качество жизни пациентов.

Osteomalacia is a systemic disease of the skeleton, accompanied by the formation of an unmineralized or poorly mineralized osteoid instead of full-fledged bone tissue. The most common cause is severe vitamin D and calcium deficiency, phosphorus deficiency (kidney pathology, mesenchymal tumors secreting an excess of FGF23, genetic diseases). Among inherited pathologies, X-linked dominant hypophosphatemic rickets (XLHR, gene PHEX, OMIM: 307800) is the most frequent form, while autosomal dominant hypophosphatemic rickets (ADHR, gene FGF23, OMIM: 193100) and autosomal recessive hypophosphatemic rickets 1,2 (ARHR1-2, genes DMP1, ENPP1, FAM20C, OMIM: 241520, OMIM: 613312) are much less common. ADHR is an extremely rare form of genetic rickets caused by mutations in the FGF23 gene. It can manifest at any age. About 50 cases of this disease have been reported in the literature. This article presents the first clinical case of ADHR in an adult in the Russian Federation. Severe vitamin D deficiency, renal tubular disorders and tumor-induced osteomalacia were excluded in differential diagnosis. The patient underwent a genetic test, which revealed a mutation in the FGF23 gene and confirmed the diagnosis of ADHR. Therapy with an active vitamin D analog and phosphate supplement was initiated, after which the patient noticed decreased pain when walking and increased muscle strength.

Difficulties in diagnosing osteomalacia are due to the lack of routine determination of serum phosphate and low awareness of doctors about this disease. In some cases, genetic tests make it possible to confirm hereditary forms, which prevents unnecessary surgical treatment, ensures timely prescription of therapy and significantly improves the quality of patients’ lives.

остеомаляцияаутосомно-доминантный гипофосфатемический рахитФРФ23гипофосфатемияклинический случайosteomalaciaautosomal dominant hypophosphatemic ricketsFGF23hypophosphatemiacase reportРабота выполнена в рамках государственного задания «Новые технологии диагностики и дифференциальной диагностики первичного и вторичного остеопороза на фоне эндокринопатий и орфанных заболеваний скелета» № 124020700097-8.ReferencesFukumoto S, Ozono K, Michigami T, et al. Pathogenesis and diagnostic criteria for rickets and osteomalacia—proposal by an expert panel supported by the Ministry of Health, Labour and Welfare, Japan, the Japanese Society for Bone and Mineral Research, and the Japan Endocrine Society. J Bone Miner Metab. 2015;33(5):467-473. doi: https://doi.org/10.1007/s00774-015-0698-7Fukumoto S, Ozono K, Michigami T, et al. Pathogenesis and diagnostic criteria for rickets and osteomalacia—proposal by an expert panel supported by the Ministry of Health, Labour and Welfare, Japan, the Japanese Society for Bone and Mineral Research, and the Japan Endocrine Society. J Bone Miner Metab. 2015;33(5):467-473. doi: https://doi.org/10.1007/s00774-015-0698-7Vieth R. Weaker bones and white skin as adaptions to improve anthropological “fitness” for northern environments. Osteoporos Int. 2020;31(4):617-624. doi: https://doi.org/10.1007/s00198-019-05167-4Vieth R. Weaker bones and white skin as adaptions to improve anthropological “fitness” for northern environments. Osteoporos Int. 2020;31(4):617-624. doi: https://doi.org/10.1007/s00198-019-05167-4Голоунина О.О., Рунова Г.Е., Фадеев В.В. Остеомаляция в практике эндокринолога: этиология, патогенез, дифференциальная диагностика с остеопорозом // Остеопороз и остеопатии. — 2019. — Т. 22. — №2. — С. 23-31. doi: https://doi.org/10.14341/osteo12117Golounina OO, Runova GE, Fadeyev VV. Osteomalacia in practice of endocrinologist: etiology, pathogenesis, differential diagnosis with osteoporosis. Osteoporos Bone Dis. 2020;22(2):23-31 (In Russ.). doi: https://doi.org/10.14341/osteo12117Biasucci G, Donini V, Cannalire G. Rickets Types and Treatment with Vitamin D and Analogues. Nutrients. 2024;16(3):1-15. doi: https://doi.org/10.3390/nu16030416Biasucci G, Donini V, Cannalire G. Rickets Types and Treatment with Vitamin D and Analogues. Nutrients. 2024;16(3):1-15. doi: https://doi.org/10.3390/nu16030416Гронская С.А., Белая Ж.Е., Мельниченко Г.А. ФРФ23-индуцированная остеомаляция опухолевого генеза // Проблемы эндокринологии. — 2022. — Т. 68. — №5. — С. 56-66. doi: https://doi.org/10.14341/probl13130Gronskaia SA, Belaya ZE, Melnichenko GA. Fgf23 Tumor Induced Osteomalacia. Probl Endokrinol (Mosk). 2022;68(5):56-66 (In Russ.). doi: https://doi.org/10.14341/probl13130Ackah SA, Imel EA. Approach to Hypophosphatemic Rickets. J Clin Endocrinol Metab. 2023;108(1):209-220. doi: https://doi.org/10.1210/clinem/dgac488Ackah SA, Imel EA. Approach to Hypophosphatemic Rickets. J Clin Endocrinol Metab. 2023;108(1):209-220. doi: https://doi.org/10.1210/clinem/dgac488Gifre L, Peris P, Monegal, A. et al. Osteomalacia revisited: A report on 28 cases. Clin Rheumatol. 2011;30(5):639-645. doi: https://doi.org/10.1007/s10067-010-1587-zGifre L, Peris P, Monegal, A. et al. Osteomalacia revisited: A report on 28 cases. Clin Rheumatol. 2011;30(5):639-645. doi: https://doi.org/10.1007/s10067-010-1587-zHeijboer AC, Cavalier E. The Measurement and Interpretation of Fibroblast Growth Factor 23 (FGF23) Concentrations. Calcif Tissue Int. 2023;112(2):258-270. doi: https://doi.org/10.1007/s00223-022-00987-9Heijboer AC, Cavalier E. The Measurement and Interpretation of Fibroblast Growth Factor 23 (FGF23) Concentrations. Calcif Tissue Int. 2023;112(2):258-270. doi: https://doi.org/10.1007/s00223-022-00987-9Florenzano P, Cipriani C, Roszko KL, et al. Review Approach to patients with hypophosphataemia. LANCET Diabetes Endocrinol. 2020;8587(19). doi: https://doi.org/10.1016/S2213-8587(19)30426-7Florenzano P, Cipriani C, Roszko KL, et al. Review Approach to patients with hypophosphataemia. LANCET Diabetes Endocrinol. 2020;8587(19). doi: https://doi.org/10.1016/S2213-8587(19)30426-7Rosenthall L. DEXA bone densitometry measurements in adults with X-linked hypophosphatemia. Clin Nucl Med. 1993;18(7):564-566. doi: https://doi.org/10.1097/00003072-199307000-00004Rosenthall L. DEXA bone densitometry measurements in adults with X-linked hypophosphatemia. Clin Nucl Med. 1993;18(7):564-566. doi: https://doi.org/10.1097/00003072-199307000-00004Von Falck C, Rodt T, Rosenthal H, et al. 68Ga-DOTANOC PET/CT for the detection of a mesenchymal tumor causing oncogenic osteomalacia. Eur J Nucl Med Mol Imaging. 2008;35(5):1034. doi: https://doi.org/10.1007/s00259-008-0755-8Von Falck C, Rodt T, Rosenthal H, et al. 68Ga-DOTANOC PET/CT for the detection of a mesenchymal tumor causing oncogenic osteomalacia. Eur J Nucl Med Mol Imaging. 2008;35(5):1034. doi: https://doi.org/10.1007/s00259-008-0755-8Cianferotti L. Osteomalacia Is Not a Single Disease. Int J Mol Sci. 2022;23(23). doi: https://doi.org/10.3390/ijms232314896Cianferotti L. Osteomalacia Is Not a Single Disease. Int J Mol Sci. 2022;23(23). doi: https://doi.org/10.3390/ijms232314896White KE, Carn G, Lorenz-Depiereux B, et al. Autosomal-dominant hypophosphatemic rickets (ADHR) mutations stabilize FGF-23. Kidney Int. 2001;60(6):2079-2086. doi: https://doi.org/10.1046/j.1523-1755.2001.00064.xWhite KE, Carn G, Lorenz-Depiereux B, et al. Autosomal-dominant hypophosphatemic rickets (ADHR) mutations stabilize FGF-23. Kidney Int. 2001;60(6):2079-2086. doi: https://doi.org/10.1046/j.1523-1755.2001.00064.xHui Q, Jin Z, Li X, et al. FGF family: From drug development to clinical application. Int J Mol Sci. 2018;19(7). doi: https://doi.org/10.3390/ijms19071875Hui Q, Jin Z, Li X, et al. FGF family: From drug development to clinical application. Int J Mol Sci. 2018;19(7). doi: https://doi.org/10.3390/ijms19071875Li X. The FGF metabolic axis. Front Med. 2019;13(5):511-530. doi: https://doi.org/10.1007/s11684-019-0711-yLi X. The FGF metabolic axis. Front Med. 2019;13(5):511-530. doi: https://doi.org/10.1007/s11684-019-0711-yMameli C, Sangiorgio A, Colombo V, et al. Autosomal dominant hypophosphatemic rickets: A case report and review of the literature. Int J Environ Res Public Health. 2021;18(16):4-13. doi: https://doi.org/10.3390/ijerph18168771Mameli C, Sangiorgio A, Colombo V, et al. Autosomal dominant hypophosphatemic rickets: A case report and review of the literature. Int J Environ Res Public Health. 2021;18(16):4-13. doi: https://doi.org/10.3390/ijerph18168771Куликова К.С., Васильев Е.В., Петров В.М., Тюльпаков А.Н. Аутосомно-доминантный гипофосфатемический рахит, обусловленный мутацией в гене FGF23, – первый клинический случай в России // World Journal of Personalized Medicine. — 2018. — Т. 2. — №1. — С 5-9. doi: https://doi.org/10.14341/pm9661Kulikova KS, Vasiliev EV, Petrov VM, Tiulpakov AN. Autosomal dominant hypophosphataemic rickets is associated with mutations in FGF23 gene in child from Russia. World Journal of Personalized Medicine. 2018;2(1):5-9 (In Russ.). doi: https://doi.org/10.14341/pm9661Liu C, Zhao Z, Wang O, et al. Earlier Onset in Autosomal Dominant Hypophosphatemic Rickets of R179 than R176 Mutations in Fibroblast Growth Factor 23: Report of 20 Chinese Cases and Review of the Literature. Calcif Tissue Int. 2019;105(5):476-486. doi: https://doi.org/10.1007/s00223-019-00597-yLiu C, Zhao Z, Wang O, et al. Earlier Onset in Autosomal Dominant Hypophosphatemic Rickets of R179 than R176 Mutations in Fibroblast Growth Factor 23: Report of 20 Chinese Cases and Review of the Literature. Calcif Tissue Int. 2019;105(5):476-486. doi: https://doi.org/10.1007/s00223-019-00597-yГронская С.А., Белая Ж.Е., Рожинская Л.Я., и др.. Клинические проявления, принципы диагностики и лечения ФРФ23-секретирующих опухолей: результаты наблюдения 40 случаев // Проблемы эндокринологии. — 2023. — Т. 69. — №5. — С. 25-38. doi: https://doi.org/https://doi.org/10.14341/probl13221Gronskaia SA, Belaya ZhE, Rozhinskaya LYa, et al. Clinical features, diagnostics and treatment of FGF23 secreting tumors: series of 40 clinical cases. Problems of Endocrinology. 2023;69(5):25-38 (In Russ.). doi: https://doi.org/https://doi.org/10.14341/probl13221Linglart A, Biosse-Duplan M, Briot K, et al. Therapeutic management of hypophosphatemic rickets from infancy to adulthood. Endocr Connect. 2014;3(1):R13-R30. doi: https://doi.org/10.1530/ec-13-0103Linglart A, Biosse-Duplan M, Briot K, et al. Therapeutic management of hypophosphatemic rickets from infancy to adulthood. Endocr Connect. 2014;3(1):R13-R30. doi: https://doi.org/10.1530/ec-13-0103Zittermann A, Berthold HK, Pilz S. The effect of vitamin D on fibroblast growth factor 23: a systematic review and meta-analysis of randomized controlled trials. Eur J Clin Nutr. 2021;75(6):980-987. doi: https://doi.org/10.1038/s41430-020-00725-0Zittermann A, Berthold HK, Pilz S. The effect of vitamin D on fibroblast growth factor 23: a systematic review and meta-analysis of randomized controlled trials. Eur J Clin Nutr. 2021;75(6):980-987. doi: https://doi.org/10.1038/s41430-020-00725-0Tieder M, Blonder J, Strauss S, et al. Hyperoxaluria is not a cause of nephrocalcinosis in phosphate-treated patients with hereditary hypophosphatemic rickets. Nephron. 1993;64(4):526-531. doi: https://doi.org/10.1159/000187395Tieder M, Blonder J, Strauss S, et al. Hyperoxaluria is not a cause of nephrocalcinosis in phosphate-treated patients with hereditary hypophosphatemic rickets. Nephron. 1993;64(4):526-531. doi: https://doi.org/10.1159/000187395Carpenter TO, Mitnick MA, Ellison A, et al. Nocturnal hyperparathyroidism: A frequent feature of X-Linked hypophosphatemia. J Clin Endocrinol Metab. 1994;78(6):2-7. doi: https://doi.org/10.1210/jcem.78.6.8200940Carpenter TO, Mitnick MA, Ellison A, et al. Nocturnal hyperparathyroidism: A frequent feature of X-Linked hypophosphatemia. J Clin Endocrinol Metab. 1994;78(6):2-7. doi: https://doi.org/10.1210/jcem.78.6.8200940Imel EA, Liu Z, Coffman M, et al. Oral Iron Replacement Normalizes Fibroblast Growth Factor 23 in Iron-Deficient Patients With Autosomal Dominant Hypophosphatemic Rickets. J Bone Miner Res. 2020;35(2):231-238. doi: https://doi.org/10.1002/jbmr.3878Imel EA, Liu Z, Coffman M, et al. Oral Iron Replacement Normalizes Fibroblast Growth Factor 23 in Iron-Deficient Patients With Autosomal Dominant Hypophosphatemic Rickets. J Bone Miner Res. 2020;35(2):231-238. doi: https://doi.org/10.1002/jbmr.3878Imel EA, Hui SL, Econs MJ. FGF23 Concentrations Vary With Disease Status in Autosomal Dominant Hypophosphatemic Rickets. 2007;22(4):520-526. doi: https://doi.org/10.1359/JBMR.070107Imel EA, Hui SL, Econs MJ. FGF23 Concentrations Vary With Disease Status in Autosomal Dominant Hypophosphatemic Rickets. 2007;22(4):520-526. doi: https://doi.org/10.1359/JBMR.070107Klein K, Asaad S, Econs M, Rubin JE. Severe FGF23-based hypophosphataemic osteomalacia due to ferric carboxymaltose administration. BMJ Case Rep. 2018;2018. doi: https://doi.org/10.1136/bcr-2017-222851Klein K, Asaad S, Econs M, Rubin JE. Severe FGF23-based hypophosphataemic osteomalacia due to ferric carboxymaltose administration. BMJ Case Rep. 2018;2018. doi: https://doi.org/10.1136/bcr-2017-222851Shimizu Y, Tada Y, Yamauchi M, et al. Hypophosphatemia induced by intravenous administration of saccharated ferric oxide. Another form of FGF23-related hypophosphatemia. Bone. 2009;45(4):814-816. doi: https://doi.org/10.1016/j.bone.2009.06.017Shimizu Y, Tada Y, Yamauchi M, et al. Hypophosphatemia induced by intravenous administration of saccharated ferric oxide. Another form of FGF23-related hypophosphatemia. Bone. 2009;45(4):814-816. doi: https://doi.org/10.1016/j.bone.2009.06.017Carpenter TO, Whyte MP, Imel EA, et al. Burosumab Therapy in Children with X-Linked Hypophosphatemia. N Engl J Med. 2018;378(21):1987-1998. doi: https://doi.org/10.1056/nejmoa1714641Carpenter TO, Whyte MP, Imel EA, et al. Burosumab Therapy in Children with X-Linked Hypophosphatemia. N Engl J Med. 2018;378(21):1987-1998. doi: https://doi.org/10.1056/nejmoa1714641Imel EA, Glorieux FH, Whyte MP, et al. Burosumab versus conventional therapy in children with X-linked hypophosphataemia: a randomised, active-controlled, open-label, phase 3 trial. Lancet. 2019;393(10189):2416-2427. doi: https://doi.org/10.1016/S0140-6736(19)30654-3Imel EA, Glorieux FH, Whyte MP, et al. Burosumab versus conventional therapy in children with X-linked hypophosphataemia: a randomised, active-controlled, open-label, phase 3 trial. Lancet. 2019;393(10189):2416-2427. doi: https://doi.org/10.1016/S0140-6736(19)30654-3

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