porozendoОстеопороз и остеопатииOsteoporosis and Bone Diseases2072-26802311-0716Endocrinology Research Centre10.14341/osteo12920porozendo-12920Research ArticleКлинический случай (или краткое сообщение)Case reportПаратгормон-независимая гиперкальциемия и гиперкальциурия у пациента с нефролитиазом и нефрокальцинозом, обусловленные нарушением метаболизма витамина D вследствие дефекта гена CYP24A1Parathyroid hormone-independent hypercalcemia and hypercalciuria of a patient with nephrolithiasis and nephrocalcinosis and impaired vitamin D metabolism due to a defect in the CYP24A1 genehttps://orcid.org/0000-0001-7041-0732РожинскаяЛ. Я.RozhinskayaL. Ya.

Рожинская Людмила Яковлевна, д.м.н., профессор. eLibrary SPIN: 5691-7775

117036, Москва, ул. Дм. Ульянова, д. 11

Liudmila Ya. Rozhinskaya, MD, PhD, Professor. eLibrary SPIN: 5691-7775

11 Dm. Ulyanova street, 117036 Moscow

lrozhinskaya@gmail.comhttps://orcid.org/0000-0002-2948-5019ПушкареваА. С.PushkarevaA. S.

Пушкарева Анастасия Станиславовна, ординатор

Москва

Anastasiia S. Pushkareva, resident

Moscow

npushkareva96@mail.ruhttps://orcid.org/0000-0002-9783-3599МамедоваЕ. О.MamedovaE. O.

Мамедова Елизавета Октаевна, к.м.н. eLibrary SPIN 3904-6017

Москва

Elizaveta O. Mamedova, MD, Phd. eLibrary SPIN 3904-6017

Moscow

Lilybet@mail.ruhttps://orcid.org/0000-0001-6377-9056БогдановВ. П.BogdanovV. P.

Богданов Виктор Павлович. eLibrary SPIN: 9956-8495

Москва

Victor P. Bogdanov. eLibrary SPIN: 9956-8495

Moscow

siberman@yandex.ruhttps://orcid.org/0000-0001-5949-5317ЗахароваВ. В.ZakharovaV. V.

Захарова Виктория Витальевна. eLibrary SPIN 1491-2770

Москва

Victoria V. Zakharova. eLibrary SPIN 1491-2770

Moscow

neskvikk@mail.ruhttps://orcid.org/0000-0001-9002-1662ИоутсиВ. А.IoutsiV. A.

Иоутси Виталий Алексеевич, к.х.н. Researcher ID: C-3158-2014. eLibrary SPIN: 9734-0997

Москва

Vitaly A. Ioutsi, PhD. Researcher ID: C-3158-2014. eLibrary SPIN: 9734-0997

Moscow

vitalik_org@mail.ruhttps://orcid.org/0000-0002-6674-6441БелаяЖ. Е.BelayaZh. E.

Белая Жанна Евгеньевна, д.м.н., профессор. eLibrary SPIN: 4746-7173

Москва

Zhanna E. Belaya, MD, PhD, Professor. eLibrary SPIN: 4746-7173

Moscow

jannabelaya@gmail.comhttps://orcid.org/0000-0002-5634-7877МельниченкоГ. А.MelnichenkoG. A.

Мельниченко Галина Афанасьевна, академик РАН, д.м.н., профессор. eLibrary SPIN 8615-0038

Москва

Galina A. Melnichenko MD, PhD, Professor. eLibrary SPIN 8615-0038

Moscow

teofrast2000@mail.ruФГБУ «Национальный медицинский исследовательский центр эндокринологии» Минздрава РоссииРоссияEndocrinology Research CentreRussian Federation2021240820212412633Copyright © Рожинская Л.Я., Пушкарева А.С., Мамедова Е.О., Богданов В.П., Захарова В.В., Иоутси В.А., Белая Ж.Е., Мельниченко Г.А., 20212021Рожинская Л.Я., Пушкарева А.С., Мамедова Е.О., Богданов В.П., Захарова В.В., Иоутси В.А., Белая Ж.Е., Мельниченко Г.А.Rozhinskaya L.Y., Pushkareva A.S., Mamedova E.O., Bogdanov V.P., Zakharova V.V., Ioutsi V.A., Belaya Z.E., Melnichenko G.A.This work is licensed under a Creative Commons Attribution 4.0 License.https://www.osteo-endojournals.ru/jour/article/view/12920

Гиперкальциемия, связанная с нарушением метаболизма витамина D, — редкое аутосомно-рецессивное заболевание. Причина данной патологии заключается в нарушении инактивации активных метаболитов витамина D в результате мутаций в гене CYP24A1, что приводит к увеличению абсорбции кальция и развитию гиперкальциемии, гиперкальциурии, нефрокальциноза и нефролитиаза. Фенотип заболевания варьирует от тяжелых форм, диагностируемых в раннем младенчестве (тяжелая гиперкальциемия, связанная с обезвоживанием, рвотой, нефрокальцинозом и иногда смертью), до более легких форм, часто диагностируемых в зрелом возрасте и проявляющихся рецидивирующим нефролитиазом и нефрокальцинозом. Дифференциальную диагностику проводят с наиболее частыми причинами гиперкальциемии: первичным гиперпаратиреозом и злокачественными новообразованиями. С целью диагностики используется определение метаболитов витамина D и генетическое исследование. В качестве лечения при мягких формах рекомендуют ограничение молочных продуктов, соблюдение питьевого режима, отказ от приема препаратов витамина D и кальция, использование солнцезащитных кремов. В статье представлен клинический случай паратгормон-независимой гиперкальциемии вследствие мутации гена CYP24A1 у пациента 20 лет, страдающего с 16 лет нефролитиазом и нефрокальцинозом с подтвержденным нарушением метаболизма витамина D.

Hypercalcemia associated with impaired vitamin D metabolism is a rare autosomal recessive disorder. The mechanism of this pathology is the impairment of inactivation of active metabolites of vitamin D because of mutations in the CYP24A1 gene, which leads to an increase of calcium absorption and the development of hypercalcemia, hypercalciuria, nephrocalcinosis and nephrolithiasis. The phenotype of the disease ranges from severe forms which are diagnosed in early infancy (severe hypercalcemia associated with dehydration, vomiting, nephrocalcinosis, and sometimes death) to milder forms, that often are diagnosed in adulthood and manifested with recurrent nephrolithiasis and nephrocalcinosis. Differential diagnosis is carried out with the most common causes of hypercalcemia: primary hyperparathyroidism and malignant neoplasms. To diagnose, the determination of vitamin D metabolites and genetic research are used. As a treatment for mild forms, it is recommended to limit dairy products, to keep a drinking regimen, to refuse taking vitamin D and calcium preparations, and use of sunscreens. The article presents a clinical case of parathyroid hormone-independent hypercalcemia due to mutation of the CYP24A1 gene of a 20-year-old patient suffering from nephrolithiasis and nephrocalcinosis since the age of 16 with a confirmed violation of vitamin D metabolism.

гиперкальциемиягиперкальциуриянефролитиазнефрокальцинозпаратгормонвитамин Dмутацияhypercalcemiahypercalciurianephrolithiasisnephrocalcinosisparathyroid hormonevitamin DmutationReferencesCappellani D, Brancatella A, Kaufmann M, et al. Hereditary Hypercalcemia Caused by a Homozygous Pathogenic Variant in the CYP24A1 Gene: A Case Report and Review of the Literature. Case Rep Endocrinol. 2019;2019:1-7. https://doi.org/10.1155/2019/4982621Cappellani D, Brancatella A, Kaufmann M, et al. Hereditary Hypercalcemia Caused by a Homozygous Pathogenic Variant in the CYP24A1 Gene: A Case Report and Review of the Literature. Case Rep Endocrinol. 2019;2019:1-7. https://doi.org/10.1155/2019/4982621Marcocci C, Cetani F. Primary Hyperparathyroidism. N Engl J Med. 2011;365(25):2389-2397. https://doi.org/10.1056/NEJMcp1106636Marcocci C, Cetani F. Primary Hyperparathyroidism. N Engl J Med. 2011;365(25):2389-2397. https://doi.org/10.1056/NEJMcp1106636Fisken RA, Heath DA, Bold AM. Hypercalcaemia — A Hospital Survey. QJM An Int J Med. 1980;49:405-418. https://doi.org/10.1093/oxfordjournals.qjmed.a067631Fisken RA, Heath DA, Bold AM. Hypercalcaemia — A Hospital Survey. QJM An Int J Med. 1980;49:405-418. https://doi.org/10.1093/oxfordjournals.qjmed.a067631Jacobs TP, Kaufman M., Jones G, et al. A Lifetime of Hypercalcemia and Hypercalciuria, Finally Explained. Clinical Endocrinology and Metabolism. 2014;99(3):708-712. https://doi.org/10.1210/jc.2013-3802Jacobs TP, Kaufman M., Jones G, et al. A Lifetime of Hypercalcemia and Hypercalciuria, Finally Explained. Clinical Endocrinology and Metabolism. 2014;99(3):708-712. https://doi.org/10.1210/jc.2013-3802Schlingmann KP, Kaufmann M, Weber S, et al. Mutations in CYP24A1 and idiopathic infantile hypercalcemia. The New England Journal of Medicine. 2011;365(5):410-421. https://doi.org/10.1056/nejmoa1103864Schlingmann KP, Kaufmann M, Weber S, et al. Mutations in CYP24A1 and idiopathic infantile hypercalcemia. The New England Journal of Medicine. 2011;365(5):410-421. https://doi.org/10.1056/nejmoa1103864Lightwood R, Stapleton T. Idiopathic hypercalcaemia in infants. Lancet. 1953;265:255-256.Lightwood R, Stapleton T. Idiopathic hypercalcaemia in infants. Lancet. 1953;265:255-256.Nguyen M, Boutignon H, Mallet E, et al. Infantile Hypercalcemia and Hypercalciuria: New Insights into a Vitamin D-Dependent Mechanism and Response to Ketoconazole Treatment. J Pediatr. 2010;157(2):296-302. https://doi.org/10.1016/j.jpeds.2010.02.025Nguyen M, Boutignon H, Mallet E, et al. Infantile Hypercalcemia and Hypercalciuria: New Insights into a Vitamin D-Dependent Mechanism and Response to Ketoconazole Treatment. J Pediatr. 2010;157(2):296-302. https://doi.org/10.1016/j.jpeds.2010.02.025O’Keeffe DT, Tebben PJ, Kumar R, et al. Clinical and biochemical phenotypes of adults with monoallelic and biallelic CYP24A1 mutations: evidence of gene dose effect. Osteoporos Int. 2016;27(10):3121-3125. https://doi.org/10.1007/s00198-016-3615-6O’Keeffe DT, Tebben PJ, Kumar R, et al. Clinical and biochemical phenotypes of adults with monoallelic and biallelic CYP24A1 mutations: evidence of gene dose effect. Osteoporos Int. 2016;27(10):3121-3125. https://doi.org/10.1007/s00198-016-3615-6Pronicka E, Ciara E, Halat P, et al. Biallelic mutations in CYP24A1 or SLC34A1 as a cause of infantile idiopathic hypercalcemia (IIH) with vitamin D hypersensitivity: molecular study of 11 historical IIH cases. J Appl Genet. 2017;58(3):349-353. https://doi.org/10.1007/s13353-017-0397-2Pronicka E, Ciara E, Halat P, et al. Biallelic mutations in CYP24A1 or SLC34A1 as a cause of infantile idiopathic hypercalcemia (IIH) with vitamin D hypersensitivity: molecular study of 11 historical IIH cases. J Appl Genet. 2017;58(3):349-353. https://doi.org/10.1007/s13353-017-0397-2Endres DB. Investigation of hypercalcemia. Clin Biochem. 2012;45(12):954-963. https://doi.org/10.1016/j.clinbiochem.2012.04.025Endres DB. Investigation of hypercalcemia. Clin Biochem. 2012;45(12):954-963. https://doi.org/10.1016/j.clinbiochem.2012.04.025Stewart AF. Hypercalcemia Associated with Cancer. N Engl J Med. 2005;352(4):373-379. https://doi.org/10.1056/NEJMcp042806Stewart AF. Hypercalcemia Associated with Cancer. N Engl J Med. 2005;352(4):373-379. https://doi.org/10.1056/NEJMcp042806Семенова А.И. Гиперкальциемия и синдром распада опухоли // Практическая онкология. — 2006. — Т. 7. — No2. — С. 101-107.Semenova A.I., Hypercalcemia and Tumor Disintegration Syndrome. Practical Oncology. 2006;7(2):101-107. (In Russ.)Jacobs TP, Bilezikian JP. Rare Causes of Hypercalcemia. J Clin Endocrinol Metab. 2005;90(11):6316-6322. https://doi.org/10.1210/jc.2005-0675Jacobs TP, Bilezikian JP. Rare Causes of Hypercalcemia. J Clin Endocrinol Metab. 2005;90(11):6316-6322. https://doi.org/10.1210/jc.2005-0675Kallas M, Green F, Hewison M, et al. Rare Causes of Calcitriol-Mediated Hypercalcemia: A Case Report and Literature Review. J Clin Endocrinol Metab. 2010;95(7):3111-3117. https://doi.org/10.1210/jc.2009-2673Kallas M, Green F, Hewison M, et al. Rare Causes of Calcitriol-Mediated Hypercalcemia: A Case Report and Literature Review. J Clin Endocrinol Metab. 2010;95(7):3111-3117. https://doi.org/10.1210/jc.2009-2673Carpenter TO. CYP24A1 loss of function: Clinical phenotype of monoallelic and biallelic mutations. J Steroid Biochem Mol Biol. 2017;173:337-340. https://doi.org/10.1016/j.jsbmb.2017.01.006Carpenter TO. CYP24A1 loss of function: Clinical phenotype of monoallelic and biallelic mutations. J Steroid Biochem Mol Biol. 2017;173:337-340. https://doi.org/10.1016/j.jsbmb.2017.01.006Hahn CN, Baker E, Laslo P, et al. Localization of the human vitamin D 24-hydroxylase gene (CYP24) to chromosome 20q13.2— >q13.3. Cytogenetics and Cell Genetics. 1993;62(4):192-193. https://doi.org/10.1159/00013347Hahn CN, Baker E, Laslo P, et al. Localization of the human vitamin D 24-hydroxylase gene (CYP24) to chromosome 20q13.2— >q13.3. Cytogenetics and Cell Genetics. 1993;62(4):192-193. https://doi.org/10.1159/00013347Jiráčková J, Hyšpler R, Alkanderi S, et al. Novel CYP24A1 Mutation in a Young Male Patient with Nephrolithiasis: Case Report. Kidney Blood Press Res. 2019;44(4):870-877. https://doi.org/10.1159/000500922Jiráčková J, Hyšpler R, Alkanderi S, et al. Novel CYP24A1 Mutation in a Young Male Patient with Nephrolithiasis: Case Report. Kidney Blood Press Res. 2019;44(4):870-877. https://doi.org/10.1159/000500922DeLuca HF. Vitamin D: the vitamin and the hormone. Federation Proceedings. 1974;33(11):2221-2219.DeLuca HF. Vitamin D: the vitamin and the hormone. Federation Proceedings. 1974;33(11):2221-2219.Nesterova G, Malicdan MC, Yasuda K, et al. 1,25-(OH) 2 D-24 Hydroxylase (CYP24A1) Deficiency as a Cause of Nephrolithiasis. Clin J Am Soc Nephrol. 2013;8(4):649-657. https://doi.org/10.2215/CJN.05360512Nesterova G, Malicdan MC, Yasuda K, et al. 1,25-(OH) 2 D-24 Hydroxylase (CYP24A1) Deficiency as a Cause of Nephrolithiasis. Clin J Am Soc Nephrol. 2013;8(4):649-657. https://doi.org/10.2215/CJN.05360512Dinour D, Beckerman P, Ganon L, et al. Loss-of-Function Mutations of CYP24A1, the Vitamin D 24-Hydroxylase Gene, Cause Long-standing Hypercalciuric Nephrolithiasis and Nephrocalcinosis. J Urol. 2013;190(2):552-557. https://doi.org/10.1016/j.juro.2013.02.3188Dinour D, Beckerman P, Ganon L, et al. Loss-of-Function Mutations of CYP24A1, the Vitamin D 24-Hydroxylase Gene, Cause Long-standing Hypercalciuric Nephrolithiasis and Nephrocalcinosis. J Urol. 2013;190(2):552-557. https://doi.org/10.1016/j.juro.2013.02.3188Sayers J, Hynes A, Rice S, et al. Searching for CYP24A1 mutations in cohorts of patients with calcium nephrolithiasis. OA Nephrol. 2013;1(1). https://doi.org/10.13172/2053-0293-1-1-525Sayers J, Hynes A, Rice S, et al. Searching for CYP24A1 mutations in cohorts of patients with calcium nephrolithiasis. OA Nephrol. 2013;1(1). https://doi.org/10.13172/2053-0293-1-1-525Тихонович Ю.В., Колодкина А.А., Куликова К.С., и др. Идиопатическая гиперкальциемия детей грудного возраста. Описание клинических случаев, обзор литературы // Проблемы эндокринологии. — 2017. — Т. 63. — No1. — С. 51-57. https://doi.org/10.14341/probl201763151Tikhonovich YuV, Kolodkina AA, Kulikova KS, et al. Idiopathic infantile hypercalcemia. Description of clinical cases and review. Problems of Endocrinology. 2017;63(1):51-57. (In Russ.) https://doi.org/10.14341/probl201763151Ferraro PM, Minucci A, Primiano A, et al. A novel CYP24A1 genotype associated to a clinical picture of hypercalcemia, nephrolithiasis and low bone mass. Urolithiasis. 2017;45(3):291-294. https://doi.org/10.1007/s00240-016-0923-4Ferraro PM, Minucci A, Primiano A, et al. A novel CYP24A1 genotype associated to a clinical picture of hypercalcemia, nephrolithiasis and low bone mass. Urolithiasis. 2017;45(3):291-294. https://doi.org/10.1007/s00240-016-0923-4Ahmad S, Kuraganti G, Steenkamp D. Hypercalcemic crisis: a clinical review. The Americal Jоurnal of medicine. 2015;128(3):239-234. https://doi.org/10.1016/j.amjmed.2014.09.030Ahmad S, Kuraganti G, Steenkamp D. Hypercalcemic crisis: a clinical review. The Americal Jоurnal of medicine. 2015;128(3):239-234. https://doi.org/10.1016/j.amjmed.2014.09.030Ralston SH, Alzaid AA, Gardner MD, et al. Treatment of cancer associated hypercalcaemia with combined aminohydroxypropylidene diphosphonate and calcitonin. British medical Journal. 1986;292(6535):1549-1550. https://doi.org/10.1136/bmj.292.6535.1549Ralston SH, Alzaid AA, Gardner MD, et al. Treatment of cancer associated hypercalcaemia with combined aminohydroxypropylidene diphosphonate and calcitonin. British medical Journal. 1986;292(6535):1549-1550. https://doi.org/10.1136/bmj.292.6535.1549Thiebaud D, Jacquet AF, Burckhardt P. Fast and effective treatment of malignant hypercalcemia. Combination of suppositories of calcitonin and a single infusion of 3-amino 1hydroxypropylidene-1-bisphosphonate. Archives of Internal Medicine. 1990;150(10):2125-2128. https://doi.org/10.1001/archinte.1990.00390210095021Thiebaud D, Jacquet AF, Burckhardt P. Fast and effective treatment of malignant hypercalcemia. Combination of suppositories of calcitonin and a single infusion of 3-amino 1hydroxypropylidene-1-bisphosphonate. Archives of Internal Medicine. 1990;150(10):2125-2128. https://doi.org/10.1001/archinte.1990.00390210095021Colussi G, Ganon L, Penco S, et al. Chronic hypercalcaemia from inactivating mutations of vitamin D 24-hydroxylase (CYP24A1): implications for mineral metabolism changes in chronic renal failure. Nephrol Dial Transplant. 2014;29(3):636-643. https://doi.org/10.1093/ndt/gft460Colussi G, Ganon L, Penco S, et al. Chronic hypercalcaemia from inactivating mutations of vitamin D 24-hydroxylase (CYP24A1): implications for mineral metabolism changes in chronic renal failure. Nephrol Dial Transplant. 2014;29(3):636-643. https://doi.org/10.1093/ndt/gft460St-Arnaud R. CYP24A1-deficient mice as a tool to uncover a biological activity for vitamin D metabolites hydroxylated at position 24. J Steroid Biochem Mol Biol. 2010;121(1-2):254-256. https://doi.org/10.1016/j.jsbmb.2010.02.002St-Arnaud R. CYP24A1-deficient mice as a tool to uncover a biological activity for vitamin D metabolites hydroxylated at position 24. J Steroid Biochem Mol Biol. 2010;121(1-2):254-256. https://doi.org/10.1016/j.jsbmb.2010.02.002Tebben PJ, Milliner DS, Horst RL, et al. Hypercalcemia, Hypercalciuria, and Elevated Calcitriol Concentrations with Autosomal Dominant Transmission Due to CYP24A1 Mutations: Effects of Ketoconazole Therapy. J Clin Endocrinol Metab. 2012;97(3):E423-E427. https://doi.org/10.1210/jc.2011-1935Tebben PJ, Milliner DS, Horst RL, et al. Hypercalcemia, Hypercalciuria, and Elevated Calcitriol Concentrations with Autosomal Dominant Transmission Due to CYP24A1 Mutations: Effects of Ketoconazole Therapy. J Clin Endocrinol Metab. 2012;97(3):E423-E427. https://doi.org/10.1210/jc.2011-1935Nguyen M, Boutignon H, Mallet E, et al. Infantile Hypercalcemia and Hypercalciuria: New Insights into a Vitamin D-Dependent Mechanism and Response to Ketoconazole Treatment. J Pediatr. 2010;157(2):296-302. https://doi.org/10.1016/j.jpeds.2010.02.025Nguyen M, Boutignon H, Mallet E, et al. Infantile Hypercalcemia and Hypercalciuria: New Insights into a Vitamin D-Dependent Mechanism and Response to Ketoconazole Treatment. J Pediatr. 2010;157(2):296-302. https://doi.org/10.1016/j.jpeds.2010.02.025Sayers J, Hynes AM, Srivastava S, et al. Successful treatment of hypercalcaemia associated with a CYP24A1 mutation with fluconazole: Fig. 1. Clin Kidney J. 2015;8(4):453-455. https://doi.org/10.1093/ckj/sfv028Sayers J, Hynes AM, Srivastava S, et al. Successful treatment of hypercalcaemia associated with a CYP24A1 mutation with fluconazole: Fig. 1. Clin Kidney J. 2015;8(4):453-455. https://doi.org/10.1093/ckj/sfv028Hawkes CP, Li D, Hakonarson H, Meyers KE, et al. CYP3A4 Induction by Rifampin: An Alternative Pathway for Vitamin D Inactivation in Patients With CYP24A1 Mutations. J Clin Endocrinol Metab. 2017;102(5):1440-1446. https://doi.org/10.1210/jc.2016-4048Hawkes CP, Li D, Hakonarson H, Meyers KE, et al. CYP3A4 Induction by Rifampin: An Alternative Pathway for Vitamin D Inactivation in Patients With CYP24A1 Mutations. J Clin Endocrinol Metab. 2017;102(5):1440-1446. https://doi.org/10.1210/jc.2016-4048Jones G, Kottler ML, Schlingmann KP. Genetic Diseases of Vitamin D Metabolizing Enzymes. Endocrinol Metab Clin North Am. 2017;46(4):1095-1117. https://doi.org/10.1016/j.ecl.2017.07.011Jones G, Kottler ML, Schlingmann KP. Genetic Diseases of Vitamin D Metabolizing Enzymes. Endocrinol Metab Clin North Am. 2017;46(4):1095-1117. https://doi.org/10.1016/j.ecl.2017.07.011

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