Renal lithiasis and non-parathyroid hormone-dependent hypercalcemia associated with alterations in vitamin d metabolism: a clinical case report
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Abstract
In recent years, it has been discovered that mutations in CYP24A1 (24 alpha-hydroxylase) promote an excess of calcidiol and calcitriol due to a failure in catabolic activity, which manifests as hypercalcemia, renal lithiasis, and nephrocalcinosis. This condition is known as Idiopathic Infantile Hypercalcemia (IIH). Biallelic alterations are severe expressions of the disease and are diagnosed in childhood. Little is known about heterozygous forms. This report presents andult patient illustrating this alteration.
A 27-year-old male was referred for evaluation due to repeated low and inhibited PTH levels. The patient has had bilateral renal lithiasis associated with hypercalciuria since the age of 10, without response to conventional treatment. Persistent lithiasis, chronic kidney disease, and intermittent hypercalcemia were observed. His mother presents with hypercalciuria. The physical examination is normal. Highlights of the studies include hypercalcemia, inhibited PTH, high-normal levels of 25OH vitamin D and 1,25(OH)2 D3, increased creatinine, normal phosphatemia and alkaline phosphatase. The 1,25(OH)₂D₃/PTH ratio is elevated (> 40 pmolL/pmol/L).
Granulomatous and oncological diseases were ruled out by specific studies. The possible mutation of the CYP24A1 gene was considered.
Molecular study of CYP24A1 showed mutations described in IIH: exon 2 variant c.428-430delAAG / alteration p. Glu143del, heterozygous, pathogenic, and exon 8 variant c.999_1006delCAGTCTAA / p. Ser334Valfs*9, heterozygous, possibly pathogenic. It is assumed that the patient presents a monoallelic form of IIH.
It is important to consider the mutations of the enzyme CYP24A1, which catabolizes the metabolites of vitamin D, calcidiol and calcitriol, in the differential diagnosis of non-PTH-dependent hypercalcemia and hypercalciuria.
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Derechos de autor: Actualizaciones en Osteología es la revista oficial de la Asociación Argentina de Osteología y Metabolismo Mineral (AAOMM) que posee los derechos de autor de todo el material publicado en dicha revista.
References
Donovan Walker M, Shane E. Hypercalcemia A Review. JAMA 2022; 328:1624-36. doi:10.1001/jama.2022.18331 //
Schlingmann KP. Vitamin D–dependent Hypercalcemia. Endocrinol Metab Clin N Am 2021;50:729-42 https://doi.org/10.1016/j.ecl.2021.08.005 endo.theclinics.com 0889-8529/21/ª 2021
Schlingmann KP, Kaufmann M, Weber S, et al. Mutations in CYP24A1 and Idiopathic Infantile Hypercalcemia. N Engl J Med 2011;365:410-21; doi: 10.1056/NEJMoa1103864.
Lightwood R. Idiopathic hypercalcaemia with failure to thrive: nephrocalcinosis. Proc R Soc Med 1952; 45:401.
Stapleton T, Macdonald W, Lightwood R. The Pathogenesis of Idiopathic Hypercalcemia in Infancy. Am J Clin Nutrition 1957;5:533-42 doi: 10.1093_ajcn_5.5.533.
Schlingmann KP, Ruminska J, Kaufmann M, et al. Autosomal-Recessive Mutations in SLC34A1 Encoding Sodium-Phosphate Cotransporter 2A Cause Idiopathic Infantile Hypercalcemia. J Am Soc Nephrol 2016;27:604-14. doi: 10.1681/ASN.201410
De Paolis E, Scaglione GL, De Bonis M, Minucci A, Capoluong E. Review: CYP24A1 and SLC34A1 genetic defects associated with idiopathic infantile hypercalcemia: from genotype to phenotype. Clin Chem Lab Med 2019;57(11): 1650-67 https://doi.org/10.1515/cclm-2018-1208
Lemoine S, Figueres L, Bacchetta J, Frey S, Dubourg L. Calcium homeostasis and Hyperparathyroidism: Nephrologic and endocrinologic points of view. Ann Endocrinol (Paris) 2022;83:237-43, doi: 10.1016/j.ando.2022.05.003.
Horowitz M. Non‐Parathyroid Hypercalcemia. En: Bilizekian J (ed). Primer on the Metabolic Bone Diseases and Disorders of Mineral Metabolism. 9th Edition. An Official Publication of the American Society for Bone and Mineral Research. Hoboken, NJ 07030, USA: Wiley; 2019. pp. 639-45.
Kaufmann M, Morse N, Molloy BJ, Cooper DP, Schlingmann KP, Molin A. Improved Screening Test for Idiopathic Infantile Hypercalcemia Confirms Residual Levels of Serum 24,25-(OH)2D3 in Affected Patients. J of Bone and Min Res 2017; 32: 1589-96 DOI: 10.1002/jbmr.3135
Lenherr-Taube N, Young EJ, Furman M, et al. Mild Idiopathic Infantile Hypercalcemia-Part 1: Biochemical and Genetic Findings. J Clin Endoc & Metab 2021;106: 2915-37.
O’Keeffe DT, Tebben J, Kumar R, Singh R, Wu Y, Wermers RA. Clinical and biochemical phenotypes of adults with monoallelic and biallelic CYP24A1 mutations: evidence of gene dose effect. Osteoporosis Int 2016;27(10):3121-5. DOI 10.1007/s00198-016-3615-
Schlingmann KP, Cassar W, Konrad M. Juvenile onset IIH and CYP24A1 mutations. Bone reports.2018;9:42-6. https://doi.org/10.1016/j.bonr.2018.06.005
Jacobs TP, Kaufman M, Jones G, et al. A Lifetime of Hypercalcemia and Hypercalciuria, Finally Explained. J Clin Endoc& Metab 2014;99:708-12 doi: 10.1210/jc.2013-3802.
Cools M, Goemaere S, Baetens B, et al. Calcium and bone homeostasis in heterozygous carriers of CYP24A1 mutations: A cross-sectional study. Bone 2015; 81:89-96. http://dx.doi.org/10.1016/j.bone.2015.06.018.
Gurevich E, Levi S, Borovitz Y, et al. Childhood Hypercalciuric Hypercalcemia With Elevated Vitamin D and Suppressed Parathyroid Hormone: Long-Term Follow Up. Front Pediatr 2021; 9:752312. doi: 10.3389/fped.2021.752312.
Hanna C, Potretzke TA, Cogal AG, et al. High Prevalence of Kidney Cysts in Patients with CYP24A1 Deficiency. Kidney Int Rep 2021; 6:1895-903; https://doi.org/10.1016/j.ekir.2021.04.030.
Halbritter J, Baum M, Hynes AM, et al. Fourteen Monogenic Genes Account for 15% of Nephrolithiasis/Nephrocalcinosis. J Am Soc Nephrol 2015;26:543-51, doi: 10.1681/ASN.2014040388.
Nesterova G, Malicdan MC, Yasuda K, et al. 1,25-(OH)2D-24 Hydroxylase (CYP24A1) Deficiency as a Cause of Nephrolithiasis. Clin J Am Soc Nephrol 2013;8:649-57. doi: 10.2215/CJN.05360512.
Lenherr-Taube N, Furman M, Assor E, et al. Mild Idiopathic Infantile Hypercalcemia—Part 2: A Longitudinal Observational Study. J Clin Endoc & Metab 2021;106: 2938-48 doi:10.1210/clinem/dgab432.
Woods GN, Saitman A, Gao H, Clarke NJ, Fitzgerald RL, Chi Nai-Wen. A Young Woman with Recurrent Gestational Hypercalcemia and Acute Pancreatitis due to CYP24A1 Deficiency. J Bone Miner Res 2016;31:1841-4. doi:10.1002/jbmr.2859
Leung C, Warner J, Harris M, Nourse C. Symptomatic Hypocalcemia Secondary to Rifampicin-induced Hypovitaminosis D. Pediatr Infect Dis J 2016;35:822-3.
Roizen JD, Li D, O’Lear L, et al. CYP3A4 mutation causes vitamin D–dependent rickets type 3. Clin Invest 2018; 128:1913-18. https://doi.org/10.1172/JCI98680.
Hawkes CP, Li D, Hakonarson H, Meyers KE, Thummel KE, Levine MA. CYP3A4 Induction by Rifampin: An Alternative Pathway for Vitamin D Inactivation in Patients with CYP24A1 Mutations. J Clin Endoc & Metab 2017; 102(5):1440-6 doi: 10.1210/jc.2016-4048.
Lenherr-Taube N, Furman M, Assor E, Thummel KE, Levine MA, Sochett E. Rifampin monotherapy for children with idiopathic infantile hypercalcemia. (https://www.sciencedirect.com/science/article/pii/S0960076023000560) J Steroid Biochem Mol Biol. Journal homepage: www.elsevier.com/locate/jsbmb https://doi.org/10.1016/j.jsbmb.2023.106301.
Wang Z, Lin YS, Dickmann LJ, et al. Enhancement of Hepatic 4-Hydroxylation of 25-Hydroxyvitamin D3 Through CYP3A4 Induction In Vitro and In Vivo: Implications for Drug-Induced Osteomalacia. J Bone Min Res 2013;28: 1101-16 DOI: 10.1002/jbmr.1839