Understanding rickets in osteopetrosis via a case: mechanisms and treatment implications
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Meliha Esra Bilici
,
Zeynep Şıklar
Abstract
Objectives
Osteopetrorickets is a rare autosomal recessive disease that affects many systems and is characterized by dense bone mass and paradoxical rickets due to insufficient resorption of calcified cartilage. Its rarity and presentation with nonspecific symptoms may cause delays in diagnosis. Early diagnosis and improvement of rickets accompanying bone marrow transplantation as a curative treatment option before the development of any irreversible complications are essential for prognosis. However, the etiopathogenesis and management of rickets treatment strategies are still controversial.
Case presentation
A 4-month-old female patient, whose loss of vision had been followed for 1.5 months, was admitted to our clinic with the request for a disability report. Clinical and laboratory findings were consistent with osteopetrorickets. Molecular analysis revealed a homozygous variant in the TCIRG1 gene. She was normocalcemic and hypophosphatemic, and the 25-OH vitamin D level was normal, while 1.25-dihydroxyvitamin D levels were quite high. Treatment was started with low-dose calcium replacement and calcitriol. The dose of calcitriol was gradually increased to 300 ng/kg/d, and a significant clinical response was achieved. Bone marrow transplantation was conducted at 8 months postnatally from an HLA-compatible non-related donor; nonetheless, the patient succumbed to respiratory problems on the 71st day following the procedure.
Conclusions
Nonspecific symptoms of osteopetrorickets should be considered for early diagnosis, as a timely intervention in the first months of life can be life-saving. The pathophysiology of rickets remains unclear, but low calcium-phosphorus product and resistance to 1.25-dihydroxyvitamin D appear to play key roles. High-dose calcitriol and cautious calcium supplementation may improve outcomes, though further research is needed to optimize treatment strategies.
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Research ethics: This is a single case report without experimental intervention and does not require Ethical Committee approval.
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Informed consent: Written informed consent was obtained from the patient’s legal guardian for the publication of this case report and any accompanying images, in accordance with institutional policies and the Declaration of Helsinki.
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Author contributions: All authors have accepted responsibility for the entire content of this manuscript and approved its submission.
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Use of Large Language Models, AI and Machine Learning Tools: None declared.
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Conflict of interest: The authors state no conflict of interest.
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Research funding: None declared.
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Data availability: Not applicable.
References
1. Marks, SCJr. Congenital osteopetrotic mutations as probes of the origin, structure, and function of osteoclasts. Clin Orthop Relat Res 1984;189:239–63. https://doi.org/10.1097/00003086-198410000-00026.Suche in Google Scholar
2. Simanovsky, N, Rozovsky, K, Hiller, N, Weintraub, M, Stepensky, P. Extending the spectrum of radiological findings in patients with severe osteopetrosis and different genetic backgrounds. Pediatr Blood Cancer 2016;63:1222–6. https://doi.org/10.1002/pbc.25952.Suche in Google Scholar PubMed
3. Faden, MA, Krakow, D, Ezgu, F, Rimoin, DL, Lachman, RS. The erlenmeyer flask bone deformity in the skeletal dysplasias. Am J Med Genet A 2009;149A:1334–45. https://doi.org/10.1002/ajmg.a.32253.Suche in Google Scholar PubMed PubMed Central
4. Kaplan, FS, August, CS, Fallon, MD, Stelnicki, EJ, Glorieux, FH, Olsen, BR. Osteopetrorickets. The paradox of plenty. Pathophysiology and treatment. Clin Orthop Relat Res 1993;294:64–78. https://doi.org/10.1097/00003086-199309000-00008.Suche in Google Scholar
5. Atay, AA, Kurekci, AE, Azik, FM, Keser, I, Tuncer, O, Akyol, G. High dose calcitriol in osteopetrorickets. J Pediatr Endocrinol Metab 2009;22:1179–83. https://doi.org/10.1515/jpem.2009.22.12.1179.Suche in Google Scholar PubMed
6. Gerritsen, EJ, Vossen, JM, van Loo, IH, Hermans, J, Helfrich, MH, Griscelli, C, et al.. Autosomal recessive osteopetrosis: variability of findings at diagnosis and during the natural course. Pediatrics 1994;93:247–53. https://doi.org/10.1542/peds.93.2.247.Suche in Google Scholar
7. Klintworth, GK. The neurologic manifestations of osteopetrosis (Albers-Schonberg’s disease). Neurology 1963;13:512–9. https://doi.org/10.1212/wnl.13.6.512.Suche in Google Scholar PubMed
8. Lehman, RA, Reeves, JD, Wilson, WB, Wesenberg, RL. Neurological complications of infantile osteopetrosis. Ann Neurol 1977;2:378–84. https://doi.org/10.1002/ana.410020506.Suche in Google Scholar PubMed
9. Steward, CG. Neurological aspects of osteopetrosis. Neuropathol Appl Neurobiol 2003;29:87–97. https://doi.org/10.1046/j.1365-2990.2003.00474.x.Suche in Google Scholar PubMed
10. Wu, CC, Econs, MJ, DiMeglio, LA, Insogna, KL, Levine, MA, Orchard, PJ, et al.. Diagnosis and management of osteopetrosis: consensus guidelines from the osteopetrosis working group. J Clin Endocrinol Metab 2017;102:3111–23. https://doi.org/10.1210/jc.2017-01127.Suche in Google Scholar PubMed
11. Orchard, PJ, Fasth, AL, Le Rademacher, J, Fischer, RT, Cowan, MJ, Wall, DA, et al.. Hematopoietic stem cell transplantation for infantile osteopetrosis. Blood 2015;126:270–6. https://doi.org/10.1182/blood-2015-01-625541.Suche in Google Scholar PubMed PubMed Central
12. Gerritsen, EJA, Vossen, JM, Fasth, A, Heitink-Pollé, KMJ, Fischer, A, Porta, F, et al.. Bone marrow transplantation for autosomal recessive osteopetrosis: a report from the working party on inborn errors of the European bone marrow transplantation group. J Pediatr 1994;125:896–902. https://doi.org/10.1016/s0022-3476-05-82004-9.Suche in Google Scholar
13. Supanchart, C, Wartosch, L, Schlack, C, Kühnisch, J, Felsenberg, D, Fuhrmann, JC, et al.. ClC-7 expression levels critically regulate bone turnover, but not gastric acid secretion. Bone 2014;58:92–102. https://doi.org/10.1016/j.bone.2013.09.022.Suche in Google Scholar PubMed
14. Schinke, T, Schilling, AF, Baranowsky, A, Seitz, S, Marshall, RP, Linn, T, et al.. Impaired gastric acidification negatively affects calcium homeostasis and bone mass. Nat Med 2009;15:674–81. https://doi.org/10.1038/nm.1963.Suche in Google Scholar PubMed
15. Sobacchi, C, Frattini, A, Orchard, P, Villa, A, Vezzoni, P, Helfrich, MH, et al.. The variantal spectrum of human malignant autosomal recessive osteopetrosis. Hum Mol Genet 2001;10:1767–73. https://doi.org/10.1093/hmg/10.17.1767.Suche in Google Scholar PubMed
16. Barvencik, F, Kurth, I, Koehne, T, Schulz, A, Niecke, M, Devernejoul, MC, et al.. CLCN7 and TCIRG1 variants differentially affect bone matrix mineralization in osteopetrotic individuals. J Bone Min Res 2014;29:982–91. https://doi.org/10.1002/jbmr.2100.Suche in Google Scholar PubMed
17. Crockett, JC, Mellis, DJ, Scott, DI, Helfrich, MH. New knowledge on critical osteoclast formation and activation pathways from study of rare genetic diseases of osteoclasts: focus on the RANK/RANKL axis. Osteoporos Int 2011;22:1–20. https://doi.org/10.1007/s00198-010-1272-8.Suche in Google Scholar PubMed
18. Blair, HC, Athanasou, NA. Recent advances in osteoclast biology and pathological bone resorption. Histol Histopathol 2004;19:189–99. https://doi.org/10.14670/HH-19.189.Suche in Google Scholar PubMed
19. Sobacchi, C, Schulz, A, Coxon, FP, Villa, A, Helfrich, MH. Osteopetrosis: genetics, treatment and new insights into osteoclast function. Nat Rev Endocrinol 2013;9:522–36. https://doi.org/10.1038/nrendo.2013.137.Suche in Google Scholar PubMed
20. Villa, A, Guerrini, MM, Cassani, B, Pangrazio, A, Sobacchi, C. Infantile malignant, autosomal recessive osteopetrosis: the rich and the poor. Calcif Tissue Int 2009;84:1–12. https://doi.org/10.1007/s00223-008-9196-4.Suche in Google Scholar PubMed
21. Zamboni, G, Cecchettin, M, Marradi, P, Zordan, G, Rigon, F. Association of osteopetrosis and vitamin D-resistant rickets. Helv Paediatr Acta 1977;32:363–8.Suche in Google Scholar
22. Oliveira, G, Boechat, MI, Amaral, SM, Fonseca, L, Ramos, EA, Ferreira, C. Osteopetrosis and rickets: an intriguing association. Am J Dis Child 1986;140:377–8.Suche in Google Scholar
23. Datta, V, Prajapati, NC, Kamble, M, Pathak, S. Osteopetrorickets. Indian Pediatr 2000;37:98–9.Suche in Google Scholar
24. Kirubakaran, C, Ranjini, K, Scott, JX, Basker, M, Sridhar, G. Osteopetrorickets. J Trop Pediatr 2004;50:185–6. https://doi.org/10.1093/tropej/50.3.185.Suche in Google Scholar PubMed
25. Di Rocco, M, Buoncompagni, A, Loy, A, Gelmetti, C, Gatti, R. Osteopetrorickets: case report. Eur J Pediatr 2000;159:579–81. https://doi.org/10.1007/s004310000485.Suche in Google Scholar PubMed
26. Unachak, K, Visrutaratna, P, Dejkamron, P, Khlumchoo, W, Suphapeetiporn, K. Infantile osteopetrosis in four Thai infants. J Pediatr Endocrinol Metab 2004;17:1455–9. https://doi.org/10.1515/jpem.2004.17.10.1455.Suche in Google Scholar PubMed
27. Patra, S, Pemde, HK, Singh, V, Sagar, R, Sreenivas, V. Infantile osteopetrorickets. Indian J Pediatr 2009;76:1182–3. https://doi.org/10.1007/s12098-009-0276-x.Suche in Google Scholar PubMed
28. Donnelly, LF, Johnson, JF3rd, Benzing, G. Infantile osteopetrosis complicated by rickets. AJR Am J Roentgenol 1995;164:968–70. https://doi.org/10.2214/ajr.164.4.7726058.Suche in Google Scholar PubMed
29. Tfifha, M, Gaha, M, Gamaoun, W, Chemli, J, Mabrouk, S, Hassayoun, S, et al.. Clinical and imaging features of malignant infantile osteopetrosis. Turk J Pediatr 2017;59:452–7. https://doi.org/10.24953/turkjped.2017.04.012.Suche in Google Scholar PubMed
30. Olgaç, A, Tümer, L, Boyunağa, Ö, Kızılkaya, M, Hasanoğlu, A. Diagnostic dilemma: osteopetrosis with superimposed rickets causing neonatal hypocalcemia. J Trop Pediatr 2015;61:146–50. https://doi.org/10.1093/tropej/fmv001.Suche in Google Scholar PubMed
31. Gonen, KA, Yazici, Z, Gokalp, G, Ucar, AK. Infantile osteopetrosis with superimposed rickets. Pediatr Radiol 2013;43:189–95. https://doi.org/10.1007/s00247-012-2511-2.Suche in Google Scholar PubMed
32. Nour, M, Ward, LM. Infantile malignant osteopetrosis. J Pediatr 2013;163:1230–1. https://doi.org/10.1016/j.jpeds.2013.04.031.Suche in Google Scholar PubMed
33. Essabar, L, Meskini, T, Ettair, S, Erreimi, N, Mouane, N. Malignant infantile osteopetrosis: case report with review of the literature. Pan Afr Med J. 2014;17:63. https://doi.org/10.11604/pamj.2014.17.63.3759.Suche in Google Scholar PubMed PubMed Central
34. Demirel, F, Esen, I, Tunc, B, Tavil, B. Scarcity despite wealth: osteopetrorickets. J Pediatr Endocrinol Metab 2010;23:931–4. https://doi.org/10.1515/jpem.2010.149.Suche in Google Scholar PubMed
35. Kulkarni, ML, Matadh, PS. Rickets in osteopetrosis–a paradoxical association. Indian Pediatr 2003;40:561–5.Suche in Google Scholar
36. Freese, J, Greenup, E, Sunil, B, Ashraf, AP. Osteopetrorickets presenting with failure to thrive and hypophosphatemia. J Endocr Soc 2020;4:bvaa044. https://doi.org/10.1210/jendso/bvaa044.Suche in Google Scholar PubMed PubMed Central
37. Katsafiloudi, M, Gombakis, N, Hatzipantelis, E, Tragiannidis, A. Osteopetrorickets in an infant with coexistent congenital cytomegalovirus infection. Balk J Med Genet 2021;23:107–10. https://doi.org/10.2478/bjmg-2020-0019.Suche in Google Scholar PubMed PubMed Central
38. Behr, G, Kuhn, M, Oved, JH, Sulis, ML. Osteopetrorickets: two contradictory patterns–one unifying diagnosis. Skelet Radiol 2024;53:817–20. https://doi.org/10.1007/s00256-023-04443-z.Suche in Google Scholar PubMed PubMed Central
39. Lee, A, Cortez, S, Yang, P, Aum, D, Singh, P, Gooch, C, et al.. Neonatal hydrocephalus: an atypical presentation of malignant infantile osteopetrosis. Childs Nerv Syst 2021;37:3695–703. https://doi.org/10.1007/s00381-021-05345-y.Suche in Google Scholar PubMed
40. Solh, H, Da Cunha, AM, Giri, N, Sahdev, I, Mahoney, DH, Clink, H, et al.. Bone marrow transplantation for infantile malignant osteopetrosis. J Pediatr Hematol Oncol 1995;17:350–5. https://doi.org/10.1097/00043426-199511000-00013.Suche in Google Scholar PubMed
41. Mankin, HJ. Rickets, osteomalacia, and renal osteodystrophy. An update. Orthop Clin North Am. 1990;21:81–96. https://doi.org/10.1016/s0030-5898-20-31567-4.Suche in Google Scholar
42. Safadi, FF, Hermey, DC, Popoff, SN, Seifert, MF. Skeletal resistance to 1.25-dihydroxyvitamin D3 in osteopetrotic rats. Endocrine 1999;11:309–19. https://doi.org/10.1385/endo:11:3:309.10.1385/ENDO:11:3:309Suche in Google Scholar PubMed
43. Kaur, S, Kulkarni, K. Osteopetrorickets: a twin paradox. BMJ Case Rep 2010;2010:bcr06.2009.2012. https://doi.org/10.1136/bcr.06.2009.2012.Suche in Google Scholar PubMed PubMed Central
44. Boyce, RW, Weisbrode, SE, Kindig, O. Ultrastructural development of hyperosteoidosis in 1.25(OH)2D3-treated rats fed high levels of dietary calcium. Bone 1985;6:165–72. https://doi.org/10.1016/8756-3282-85-90049-3.Suche in Google Scholar
45. Suda, T, Takahashi, N, Abe, E. Role of vitamin D in bone resorption. J Cell Biochem 1992;49:53–8. https://doi.org/10.1002/jcb.240490110.Suche in Google Scholar PubMed
46. Key, L, Carnes, D, Cole, S, Hamrick, M, MacDonald, M, Eyre, DR, et al.. Treatment of congenital osteopetrosis with high-dose calcitriol. N Engl J Med 1984;310:409–15. https://doi.org/10.1056/nejm198402163100701.Suche in Google Scholar
© 2025 Walter de Gruyter GmbH, Berlin/Boston
Artikel in diesem Heft
- Frontmatter
- Original Articles
- Spatiotemporal associations between incidence of type 1 diabetes and COVID-19 vaccination rates in children in Germany – a population-based ecological study
- Continuous glucose monitoring evidence of celiac disease in type 1 diabetes
- Impact of race and delayed adoption of diabetes technology on glycemia and partial remission in type 1 diabetes
- Immunogenetic profiling of type 1 diabetes in Jordan: a case-control study on HLA-associated risk and protection
- Annual case counts and clinical characteristics of pediatric and adolescent patients with diabetes in Kenyatta National Hospital, Nairobi, Kenya. A 14 year retrospective study
- Real-world effectiveness of sodium glucose transporter 2 inhibitors among youth with type 2 diabetes
- Investigation of the association between nitric oxide synthase gene variants and NAFLD in adolescents with obesity
- Cardiometabolic outcomes in girls with premature adrenarche: a longitudinal analysis of typical vs. exaggerated presentations
- A disease that is difficult to predict: regional distribution and phenotypic, histopathological and genetic findings in McArdle disease
- Causal analysis of uterine artery pulsatility index-related proteins and the risk of precocious puberty in girls: a Mendelian randomization study
- Case Reports
- Understanding rickets in osteopetrosis via a case: mechanisms and treatment implications
- A case of JAGN1 mutation presenting with atypical diabetes and immunodeficiency
- Compound heterozygous ROBO1 gene variants in a neonate with congenital hypopituitarism, dysmorphic features and midline abnormalities: a case report and review of the literature
- Phenotypic variation among four members in a family with DAX1 deficiency
- MMP13-related metaphyseal dysplasia: a differential diagnosis of rickets
- Congress Abstracts
- JA-PED | Annual Meeting of the German Society for Pediatric and Adolescent Endocrinology and Diabetology (DGPAED e. V.)
Artikel in diesem Heft
- Frontmatter
- Original Articles
- Spatiotemporal associations between incidence of type 1 diabetes and COVID-19 vaccination rates in children in Germany – a population-based ecological study
- Continuous glucose monitoring evidence of celiac disease in type 1 diabetes
- Impact of race and delayed adoption of diabetes technology on glycemia and partial remission in type 1 diabetes
- Immunogenetic profiling of type 1 diabetes in Jordan: a case-control study on HLA-associated risk and protection
- Annual case counts and clinical characteristics of pediatric and adolescent patients with diabetes in Kenyatta National Hospital, Nairobi, Kenya. A 14 year retrospective study
- Real-world effectiveness of sodium glucose transporter 2 inhibitors among youth with type 2 diabetes
- Investigation of the association between nitric oxide synthase gene variants and NAFLD in adolescents with obesity
- Cardiometabolic outcomes in girls with premature adrenarche: a longitudinal analysis of typical vs. exaggerated presentations
- A disease that is difficult to predict: regional distribution and phenotypic, histopathological and genetic findings in McArdle disease
- Causal analysis of uterine artery pulsatility index-related proteins and the risk of precocious puberty in girls: a Mendelian randomization study
- Case Reports
- Understanding rickets in osteopetrosis via a case: mechanisms and treatment implications
- A case of JAGN1 mutation presenting with atypical diabetes and immunodeficiency
- Compound heterozygous ROBO1 gene variants in a neonate with congenital hypopituitarism, dysmorphic features and midline abnormalities: a case report and review of the literature
- Phenotypic variation among four members in a family with DAX1 deficiency
- MMP13-related metaphyseal dysplasia: a differential diagnosis of rickets
- Congress Abstracts
- JA-PED | Annual Meeting of the German Society for Pediatric and Adolescent Endocrinology and Diabetology (DGPAED e. V.)
