Abstract
Objectives
Vitamin D dependent rickets type 1A (VDDR-1A) is a very rare autosomal recessive disorder caused by mutations in the CYP27B1, which encodes vitamin D 1α-hydroxylase. We report the genetics and clinical manifestations of nine patients with VDDR-1A and compare our patients to other cases with the same mutations in the literature.
Methods
The clinical presentations, clinical and laboratory findings and treatment modalities of the patients were evaluated retrospectively.
Results
The mean age of the patients at the time of diagnosis was 39.9 months (range: 4.5–111). At the time of diagnosis, six patients had received stoss vitamin D therapy. Clinical findings related to rickets were obvious in seven patients and unclear in two patients. Except for one case, all patients had laboratory findings of rickets. A novel variant and four previously reported mutations in CYP27B1 were identified. The mean calcitriol and elemental calcium dose were 45.5 ng/kg/day (range: 20–70) and 75.6 mg/kg/day (range: 45–125), respectively.
Conclusions
We found a novel compound heterozygous mutation consisting of a reported duplication [(p.F443Pfs*24 (c.1319_1325 dup CCCACCC)] in exon 8 and a novel deletion [p.D507Efs*34 (c.1521 delC)] in exon 9. Our study suggests that the clinical manifestations and laboratory findings of the patients with VDDR1A are variable even among the patients with the same mutation.
Acknowledgments
We would like to thank the “Intergen Genetic Disorders and Diagnosis Center” for the genetic analysis of our patients.
Research funding: We did not receive any specific grant from any funding agency in the public, commercial or non-profit sector.
Author contributions: Concept and design: Hakan Doneray. Data collection and processing: Ayse Ozden, Hakan Doneray. Analysis and interpretation: Ayse Ozden, Hakan Doneray. Literature research: Hakan Doneray, Ayse Ozden. Writing: Hakan Doneray, Ayse Ozden. All authors have accepted the responsibility for the entire content of this submitted manuscript and approved submission.
Competing interests: The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of this study.
Ethical approval: The funding organization(s) played no role in the study design; in the collection, analysis, and interpretation of data; in the writing of the report; or in the decision to submit the report for publication. The study was approved by the Erzurum Regional Training & Research Hospital Ethics Committee.
References
1. Holick, MF. Vitamin D deficiency. N Engl J Med 2007;357:266–81. https://doi.org/10.1056/nejmra070553.Search in Google Scholar
2. Kim, CJ, Kaplan, LE, Perwad, F, Huang, N, Sharma, A, Choi, Y, et al.. Vitamin D 1alpha-hydroxylase gene mutations in patients with 1alpha-hydroxylase deficiency. J Clin Endocrinol Metab 2007;92:3177–82. https://doi.org/10.1210/jc.2006-2664.Search in Google Scholar PubMed
3. Miller, WL, Portale, AA. Vitamin D biosynthesis and vitamin D 1 alpha-hydroxylase deficiency. Endocr Dev 2003;6:156–74. https://doi.org/10.1159/000072775.Search in Google Scholar PubMed
4. Liu, S, Quarles, LD. How fibroblast growth factor 23 works. J Am Soc Nephrol 2007;18:1637–47. https://doi.org/10.1681/asn.2007010068.Search in Google Scholar
5. Fu, GK, Lin, D, Zhang, MY, Bikle, DD, Shackleton, CH, Miller, WL, et al.. Cloning of human 25-hydroxyvitamin D-1 alpha-hydroxylase and mutations causing vitamin D-dependent rickets type 1. Mol Endocrinol 1997;11:1961–70. https://doi.org/10.1210/mend.11.13.0035.Search in Google Scholar PubMed
6. Feldman, D, Editor in chief. Vitamin D volume 2: health, disease and therapeutics. In: Glorieux, FH, St-Arnaud, R, editors. Vitamin D hydroxylation-deficient rickets, Type 1A: CYP27B1 mutations, 4th ed. Oxford, United Kingdom: Academic Press; 2018:249–62pp.10.1016/B978-0-12-809963-6.00071-7Search in Google Scholar
7. Wang, JT, Lin, CJ, Burridge, SM, Fu, GK, Labuda, M, Portale, AA, et al.. Genetics of vitamin D 1alphahydroxylase deficiency in 17 families. Am J Hum Genet 1998;63:1694–702. https://doi.org/10.1086/302156.Search in Google Scholar PubMed PubMed Central
8. Miller, WL, Portale, AA. Vitamin D 1 alpha-hydroxylase. Trends Endocrinol Metabol 2000;11:315–9. https://doi.org/10.1016/s1043-2760(00)00287-3.Search in Google Scholar PubMed
9. Fraser, D, Kooh, SW, Kind, HP, Holick, MF, Tanaka, Y, DeLuca, HF, et al.. Pathogenesis of hereditary vitamin-D dependent rickets. An inborn error of vitamin D metabolism involving defective conversion of 25-hydroxyvitamin D to 1 alpha,25-dihydroxyvitamin D. N Engl J Med 1973;289:817–22. https://doi.org/10.1056/nejm197310182891601.Search in Google Scholar PubMed
10. Babiker, AM, Al Gadi, I, Al-Jurayyan, NAM, Al Nemri, AMH, Al Haboob, AAN, Al Boukai, AA, et al.. A novel pathogenic mutation of the CYP27B1 gene in a patient with vitamin D-dependent rickets type 1: a case report. BMC Res Notes 2014;7:783. https://doi.org/10.1186/1756-0500-7-783.Search in Google Scholar PubMed PubMed Central
11. Michałus, I, Rusińska, A. Rare, genetically conditioned forms of rickets: differential diagnosis and advances in diagnostics and treatment. Clin Genet 2018;94:103–14. https://doi.org/10.1111/cge.13229.Search in Google Scholar PubMed
12. Untergasser, A, Cutcutache, I, Koressaar, T, Ye, J, Faircloth, BC, Remm, M, et al.. Primer3--new capabilities and interfaces. Nucleic Acids Res 2012;40:e115. https://doi.org/10.1093/nar/gks596.Search in Google Scholar PubMed PubMed Central
13. Richards, S, Aziz, N, Bale, S, Bick, D, Das, S, Gastier-Foster, J, et al.. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med 2015;17:405–24. https://doi.org/10.1038/gim.2015.30.Search in Google Scholar PubMed PubMed Central
14. Kaygusuz, SB, Alavanda, C, Kirkgoz, T, Eltan, M, Abali, ZY, Helvacioglu, D, et al.. Does genotype-phenotype correlation exist in vitamin D-dependent rickets type IA: report of 13 new cases and review of the literature. Calcif Tissue Int 2021. https://doi.org/10.1007/s00223-020-00784-2.Search in Google Scholar PubMed
15. Durmaz, E, Zou, M, Al-Rijjal, RA, Bircan, I, Akçurin, S, Meyer, B, et al.. Clinical and genetic analysis of patients with vitamin D-dependent rickets type 1A. Clin Endocrinol (Oxf) 2012;77:363–9. https://doi.org/10.1111/j.1365-2265.2012.04394.x.Search in Google Scholar PubMed
16. Demir, K, Kattan, WE, Zou, M, Durmaz, E, BinEssa, H, Nalbantoglu, Ö, et al.. Novel CYP27B1 gene mutations in patients with vitamin D-dependent rickets type 1A. PLoS One 2015;10:e0131376. https://doi.org/10.1371/journal.pone.0131376.Search in Google Scholar PubMed PubMed Central
17. Dursun, F, Özgürhan, G, Kırmızıbekmez, H, Keskin, E, Hacıhamdioğlu, B. Genetic and clinical characteristics of patients with vitamin D dependent rickets type 1A. J Clin Res Pediatr Endocrinol 2019;11:34–40. https://doi.org/10.4274/jcrpe.galenos.2018.2018.0121.Search in Google Scholar PubMed PubMed Central
18. Tahir, S, Demirbilek, H, Ozbek, MN, Baran, RT, Tanriverdi, S, Hussain, K, et al.. Genotype and phenotype characteristics in 22 patients with vitamin D-dependent rickets type I. Horm Res Paediatr 2016;85:309–17. https://doi.org/10.1159/000444483.Search in Google Scholar PubMed
19. Cui, N, Xia, W, Su, H, Pang, L, Jiang, Y, Sun, Y, et al.. Novel mutations of CYP27B1 gene lead to reduced activity of 1α-hydroxylase in Chinese patients. Bone 2012;51:563–9. https://doi.org/10.1016/j.bone.2012.05.006.Search in Google Scholar PubMed
20. Axen, E, Postlind, H, Sjoberg, H, Wikvall, K. Liver mitochondrial cytochrome P450 CYP27 and recombinant-expressed human CYP27 catalyze 1 alpha-hydroxylation of 25-hydroxyvitamin D3. Proc Natl Acad Sci USA 1994;91:10014–8. https://doi.org/10.1073/pnas.91.21.10014.Search in Google Scholar PubMed PubMed Central
21. Rowling, MJ, Gliniak, C, Welsh, J, Fleet, JC. High dietary vitamin D prevents hypocalcemia and osteomalacia in CYP27B1 knockout mice. J Nutr 2007;137:2608–15. https://doi.org/10.1093/jn/137.12.2608.Search in Google Scholar PubMed PubMed Central
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