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Pediatrics
Diagnosis
Musculoskeletal
Constitutional Disorders of Bone
Osteopetrosis
Osteopetrosis
A. Carlson Merrow, Jr., MD, FAAP
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KEY FACTS

  • Terminology

    • Imaging

      • Top Differential Diagnoses

        • Pathology

          TERMINOLOGY

          • Definitions

            • Heterogeneous group of genetic disorders characterized by ↑ bone density due to impaired bone resorption by dysfunctional osteoclasts
              • Osteopetrosis, autosomal recessive (ARO)
                • > 50% due to mutations of TCIRG1 → infantile malignant osteopetrosis (IMO)
                  • Severe anemia, hepatosplenomegaly, recurrent infections, fractures, macrocephaly, progressive blindness > deafness, ± hydrocephalus, coxa vara
                • Other forms of ARO range from mild to severe
                  • Variable degrees of growth restriction, hypocalcemia, hematologic & visual impairment, other CNS symptoms
                  • CA2 mutation → renal tubular acidosis, cerebral Ca²⁺
                  • CLCN7 recessive mutations in 17% of ARO
              • Osteopetrosis, autosomal dominant type 1 (ADO1)
                • Not true osteopetrosis
                  • LRP5 mutation → enhanced osteoblast activity → high bone mass
                • Universal osteosclerosis but marked at cranial vault while spine is almost unaffected
                • Low fracture rate
              • Osteopetrosis, autosomal dominant type 2 (ADO2)
                • Albers-Schönberg disease, osteoclast rich
                • Most common form of osteopetrosis
                • CLCN7 mutation in most → ↓ of chloride channel 7
                  • Variable penetrance & expressivity; 20-40% are asymptomatic
                • Osteosclerosis predominantly involves spine, pelvis, & skull base; mandibular osteomyelitis
              • Osteopetrosis, X-linked recessive (very rare)
                • IKBKG mutation → osteopetrosis, lymphedema, anhidrotic ectodermal dysplasia, immunodeficiency (OL-EDA-ID)

          IMAGING

          • General Features

            • CT Findings

              • MR Findings

                • Ultrasonographic Findings

                  • Nuclear Medicine Findings

                    DIFFERENTIAL DIAGNOSIS

                      PATHOLOGY

                      • General Features

                        • Microscopic Features

                          CLINICAL ISSUES

                          • Presentation

                            • Demographics

                              • Natural History & Prognosis

                                • Treatment

                                  Selected References

                                  1. Shapiro G et al: Skeletal changes following hematopoietic stem cell transplantation in osteopetrosis. J Bone Miner Res.35(9):1645-51, 2020
                                  2. Chawla A et al: Fractures in patients with osteopetrosis, insights from a single institution. Int Orthop. 43(6):1297-302, 2019
                                  3. Stepensky P et al: Stem cell transplantation for osteopetrosis in patients beyond the age of 5 years. Blood Adv. 3(6):862-8, 2019
                                  4. Vomero A et al: Malignant Infantile osteopetrosis. Rev Chil Pediatr. 90(4):443-7, 2019
                                  5. Ahmadpour A et al: Cervical spine fractures in osteopetrosis: a case report and review of the literature. J Biomed Res. 32(1):68-76, 2018
                                  6. Carvalho PHA et al: Maxillary osteomyelitis associated with osteopetrosis: systematic review. J Craniomaxillofac Surg. 46(11):1905-10, 2018
                                  7. Palagano E et al: Genetics of osteopetrosis. Curr Osteoporos Rep. 16(1):13-25, 2018
                                  8. Boulet C et al: Sclerosing bone dysplasias: genetic, clinical, and radiology update of hereditary and non-heriditary disorders. Br J Radiol. 20150349, 2016
                                  9. Simanovsky N et al: Extending the spectrum of radiological findings in patients with severe osteopetrosis and different genetic backgrounds. Pediatr Blood Cancer. 63(7):1222-6, 2016
                                  10. Hashemi Taheri AP et al: Radiologic resolution of malignant infantile osteopetrosis skeletal changes following hematopoietic stem cell transplantation. Pediatr Blood Cancer. 62(9):1645-9, 2015
                                  11. Kirkland JD et al: Osteopetrosis - classic imaging findings in the spine. J Clin Diagn Res. 9(8):TJ01-2, 2015
                                  12. Orchard PJ et al: Hematopoietic stem cell transplantation for infantile osteopetrosis. Blood. 126(2):270-6, 2015
                                  13. Saigal A et al: Recurrent osteomyelitis of the mandible in osteopetrosis: a common complication of an uncommon disease. BMJ Case Rep. 2015, 2015
                                  14. Zheng LC et al: 99Tcm-MDP imaging of osteopetrosis: case report. Medicine (Baltimore). 94(22):e929, 2015
                                  15. Aggarwal S: Skeletal dysplasias with increased bone density: evolution of molecular pathogenesis in the last century. Gene. 528(1):41-5, 2013
                                  16. Bollerslev J et al: Autosomal dominant osteopetrosis revisited: lessons from recent studies. Eur J Endocrinol. 169(2):R39-57, 2013
                                  17. Gonen KA et al: Infantile osteopetrosis with superimposed rickets. Pediatr Radiol. 43(2):189-95, 2013
                                  18. Sobacchi C et al: Osteopetrosis: genetics, treatment and new insights into osteoclast function. Nat Rev Endocrinol. 9(9):522-36, 2013
                                  19. Driessen GJ et al: Long-term outcome of haematopoietic stem cell transplantation in autosomal recessive osteopetrosis: an EBMT report. Bone Marrow Transplant. 32(7):657-63, 2003
                                  20. Steward CG: Neurological aspects of osteopetrosis. Neuropathol Appl Neurobiol. 29(2):87-97, 2003
                                  21. Whyte MP et al: Bisphosphonate-induced osteopetrosis. N Engl J Med. 349(5):457-63, 2003
                                  22. Cleiren E et al: Albers-Schönberg disease (autosomal dominant osteopetrosis, type II) results from mutations in the ClCN7 chloride channel gene. Hum Mol Genet. 10(25):2861-7, 2001
                                  23. Gerritsen EJ et al: Autosomal recessive osteopetrosis: variability of findings at diagnosis and during the natural course. Pediatrics. 93(2):247-53, 1994
                                  24. Elster AD et al: Autosomal recessive osteopetrosis: bone marrow imaging. Radiology. 182(2):507-14, 1992
                                  Related Anatomy
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                                  Related Differential Diagnoses
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                                  References
                                  Tables

                                  Tables

                                  KEY FACTS

                                  • Terminology

                                    • Imaging

                                      • Top Differential Diagnoses

                                        • Pathology

                                          TERMINOLOGY

                                          • Definitions

                                            • Heterogeneous group of genetic disorders characterized by ↑ bone density due to impaired bone resorption by dysfunctional osteoclasts
                                              • Osteopetrosis, autosomal recessive (ARO)
                                                • > 50% due to mutations of TCIRG1 → infantile malignant osteopetrosis (IMO)
                                                  • Severe anemia, hepatosplenomegaly, recurrent infections, fractures, macrocephaly, progressive blindness > deafness, ± hydrocephalus, coxa vara
                                                • Other forms of ARO range from mild to severe
                                                  • Variable degrees of growth restriction, hypocalcemia, hematologic & visual impairment, other CNS symptoms
                                                  • CA2 mutation → renal tubular acidosis, cerebral Ca²⁺
                                                  • CLCN7 recessive mutations in 17% of ARO
                                              • Osteopetrosis, autosomal dominant type 1 (ADO1)
                                                • Not true osteopetrosis
                                                  • LRP5 mutation → enhanced osteoblast activity → high bone mass
                                                • Universal osteosclerosis but marked at cranial vault while spine is almost unaffected
                                                • Low fracture rate
                                              • Osteopetrosis, autosomal dominant type 2 (ADO2)
                                                • Albers-Schönberg disease, osteoclast rich
                                                • Most common form of osteopetrosis
                                                • CLCN7 mutation in most → ↓ of chloride channel 7
                                                  • Variable penetrance & expressivity; 20-40% are asymptomatic
                                                • Osteosclerosis predominantly involves spine, pelvis, & skull base; mandibular osteomyelitis
                                              • Osteopetrosis, X-linked recessive (very rare)
                                                • IKBKG mutation → osteopetrosis, lymphedema, anhidrotic ectodermal dysplasia, immunodeficiency (OL-EDA-ID)

                                          IMAGING

                                          • General Features

                                            • CT Findings

                                              • MR Findings

                                                • Ultrasonographic Findings

                                                  • Nuclear Medicine Findings

                                                    DIFFERENTIAL DIAGNOSIS

                                                      PATHOLOGY

                                                      • General Features

                                                        • Microscopic Features

                                                          CLINICAL ISSUES

                                                          • Presentation

                                                            • Demographics

                                                              • Natural History & Prognosis

                                                                • Treatment

                                                                  Selected References

                                                                  1. Shapiro G et al: Skeletal changes following hematopoietic stem cell transplantation in osteopetrosis. J Bone Miner Res.35(9):1645-51, 2020
                                                                  2. Chawla A et al: Fractures in patients with osteopetrosis, insights from a single institution. Int Orthop. 43(6):1297-302, 2019
                                                                  3. Stepensky P et al: Stem cell transplantation for osteopetrosis in patients beyond the age of 5 years. Blood Adv. 3(6):862-8, 2019
                                                                  4. Vomero A et al: Malignant Infantile osteopetrosis. Rev Chil Pediatr. 90(4):443-7, 2019
                                                                  5. Ahmadpour A et al: Cervical spine fractures in osteopetrosis: a case report and review of the literature. J Biomed Res. 32(1):68-76, 2018
                                                                  6. Carvalho PHA et al: Maxillary osteomyelitis associated with osteopetrosis: systematic review. J Craniomaxillofac Surg. 46(11):1905-10, 2018
                                                                  7. Palagano E et al: Genetics of osteopetrosis. Curr Osteoporos Rep. 16(1):13-25, 2018
                                                                  8. Boulet C et al: Sclerosing bone dysplasias: genetic, clinical, and radiology update of hereditary and non-heriditary disorders. Br J Radiol. 20150349, 2016
                                                                  9. Simanovsky N et al: Extending the spectrum of radiological findings in patients with severe osteopetrosis and different genetic backgrounds. Pediatr Blood Cancer. 63(7):1222-6, 2016
                                                                  10. Hashemi Taheri AP et al: Radiologic resolution of malignant infantile osteopetrosis skeletal changes following hematopoietic stem cell transplantation. Pediatr Blood Cancer. 62(9):1645-9, 2015
                                                                  11. Kirkland JD et al: Osteopetrosis - classic imaging findings in the spine. J Clin Diagn Res. 9(8):TJ01-2, 2015
                                                                  12. Orchard PJ et al: Hematopoietic stem cell transplantation for infantile osteopetrosis. Blood. 126(2):270-6, 2015
                                                                  13. Saigal A et al: Recurrent osteomyelitis of the mandible in osteopetrosis: a common complication of an uncommon disease. BMJ Case Rep. 2015, 2015
                                                                  14. Zheng LC et al: 99Tcm-MDP imaging of osteopetrosis: case report. Medicine (Baltimore). 94(22):e929, 2015
                                                                  15. Aggarwal S: Skeletal dysplasias with increased bone density: evolution of molecular pathogenesis in the last century. Gene. 528(1):41-5, 2013
                                                                  16. Bollerslev J et al: Autosomal dominant osteopetrosis revisited: lessons from recent studies. Eur J Endocrinol. 169(2):R39-57, 2013
                                                                  17. Gonen KA et al: Infantile osteopetrosis with superimposed rickets. Pediatr Radiol. 43(2):189-95, 2013
                                                                  18. Sobacchi C et al: Osteopetrosis: genetics, treatment and new insights into osteoclast function. Nat Rev Endocrinol. 9(9):522-36, 2013
                                                                  19. Driessen GJ et al: Long-term outcome of haematopoietic stem cell transplantation in autosomal recessive osteopetrosis: an EBMT report. Bone Marrow Transplant. 32(7):657-63, 2003
                                                                  20. Steward CG: Neurological aspects of osteopetrosis. Neuropathol Appl Neurobiol. 29(2):87-97, 2003
                                                                  21. Whyte MP et al: Bisphosphonate-induced osteopetrosis. N Engl J Med. 349(5):457-63, 2003
                                                                  22. Cleiren E et al: Albers-Schönberg disease (autosomal dominant osteopetrosis, type II) results from mutations in the ClCN7 chloride channel gene. Hum Mol Genet. 10(25):2861-7, 2001
                                                                  23. Gerritsen EJ et al: Autosomal recessive osteopetrosis: variability of findings at diagnosis and during the natural course. Pediatrics. 93(2):247-53, 1994
                                                                  24. Elster AD et al: Autosomal recessive osteopetrosis: bone marrow imaging. Radiology. 182(2):507-14, 1992