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Osteopetrosis

By Zornitza Stark and Ravi Savarirayan

Abstract

Osteopetrosis ("marble bone disease") is a descriptive term that refers to a group of rare, heritable disorders of the skeleton characterized by increased bone density on radiographs. The overall incidence of these conditions is difficult to estimate but autosomal recessive osteopetrosis (ARO) has an incidence of 1 in 250,000 births, and autosomal dominant osteopetrosis (ADO) has an incidence of 1 in 20,000 births. Osteopetrotic conditions vary greatly in their presentation and severity, ranging from neonatal onset with life-threatening complications such as bone marrow failure (e.g. classic or "malignant" ARO), to the incidental finding of osteopetrosis on radiographs (e.g. osteopoikilosis). Classic ARO is characterised by fractures, short stature, compressive neuropathies, hypocalcaemia with attendant tetanic seizures, and life-threatening pancytopaenia. The presence of primary neurodegeneration, mental retardation, skin and immune system involvement, or renal tubular acidosis may point to rarer osteopetrosis variants, whereas onset of primarily skeletal manifestations such as fractures and osteomyelitis in late childhood or adolescence is typical of ADO. Osteopetrosis is caused by failure of osteoclast development or function and mutations in at least 10 genes have been identified as causative in humans, accounting for 70% of all cases. These conditions can be inherited as autosomal recessive, dominant or X-linked traits with the most severe forms being autosomal recessive. Diagnosis is largely based on clinical and radiographic evaluation, confirmed by gene testing where applicable, and paves the way to understanding natural history, specific treatment where available, counselling regarding recurrence risks, and prenatal diagnosis in severe forms. Treatment of osteopetrotic conditions is largely symptomatic, although haematopoietic stem cell transplantation is employed for the most severe forms associated with bone marrow failure and currently offers the best chance of longer-term survival in this group. The severe infantile forms of osteopetrosis are associated with diminished life expectancy, with most untreated children dying in the first decade as a complication of bone marrow suppression. Life expectancy in the adult onset forms is normal. It is anticipated that further understanding of the molecular pathogenesis of these conditions will reveal new targets for pharmacotherapy

Topics: Review
Publisher: BioMed Central
OAI identifier: oai:pubmedcentral.nih.gov:2654865
Provided by: PubMed Central
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    Citations

    1. (2006). a beta-subunit to support bone resorption and lysosomal function. Nature
    2. (2008). A: Genetics, pathogenesis and complications of osteopetrosis. Bone
    3. (2001). Albers-Schonberg disease (autosomal dominant osteopetrosis, type II) results from mutations in the ClCN7 chloride channel gene. Hum Mol Genet
    4. (1904). Albers-Schonberg: Rontgenbilder einer seltenen Knockenerkrankung. Munch Med Wochenschr
    5. (1995). Alemdaroglu A: Prenatal diagnosis of autosomal recessive osteopetrosis, infantile type, by X-ray evaluation. Prenat Diagn
    6. (2008). Alon R: Kindlin-3: a new gene involved in the pathogenesis of LAD-III. Blood
    7. (2006). and the Nosology Group of the International Skeletal Dysplasia Society: Nosology and Classification of Genetic Skeletal Disorders:
    8. (1992). Artul HJ: Pycnodysostosis. Orthopedic aspects with a description of 14 new cases. Clin Orthop Relat Res
    9. (2001). Aziz Bedair ES, Rizk MM: Pycnodysostosis: clinical, radiologic, and endocrine evaluation and linear growth after growth hormone therapy. Metabolism
    10. (2000). Birth and death of bone cells: basic regulatory mechanisms and implications for the pathogenesis and treatment of osteoporosis. Endocr Rev
    11. (1988). Blinkhorn AS: Pycnodysostosis. A review of reported dental abnormalities and a report of the dental findings in two cases. Br Dent J
    12. Carbonic anhydrase II deficiency.
    13. (2007). Cesare P: Orthopaedic management of the patient with osteopetrosis.
    14. (2008). Clinical and cellular manifestations of OSTM1-related infantile osteopetrosis. J Bone Miner Res
    15. (2006). Clinical, genetic, and cellular analysis of 49 osteopetrotic patients: implications for diagnosis and treatment.
    16. (2002). CM: Dysosteosclerosis: a report of three new cases and evolution of the radiological findings.
    17. (1997). Cooney WP 3rd: Melorheostosis in a patient with familial osteopoikilosis.
    18. (1999). Cowie GH: Melorheostosis in a family with autosomal dominant osteopoikilosis.
    19. (2008). Crimmins DW: Patients with autosomal-recessive osteopetrosis presenting with hydrocephalus and hindbrain posterior fossa crowding.
    20. (2000). de Vernejoul MC: Type II autosomal dominant osteopetrosis (Albers-Schonberg disease): clinical and radiological manifestations in 42 patients.
    21. (1996). Desnick RJ: Pycnodysostosis, a lysosomal disease caused by cathepsin K deficiency. Science
    22. (2002). Econs MJ: Measurement of tartrate-resistant acid phosphatase and the brain isoenzyme of creatine kinase accurately diagnoses type II autosomal dominant osteopetrosis but does not identify gene carriers.
    23. (1999). et al.: Cathepsin K knockout mice develop osteopetrosis due to a deficit in matrix degradation but not demineralization. J Bone Miner Res
    24. (2000). et al.: Defects in TCIRG1 subunit of the vacuolar proton pump are responsible for a subset of human autosomal recessive osteopetrosis. Nat Genet
    25. (2007). et al.: Involvement of PLEKHM1 in osteoclastic vesicular transport and osteopetrosis in incisors absent rats and humans.
    26. (1984). et al.: Treatment of congenital osteopetrosis with high-dose calcitriol.
    27. (2008). Etzioni A: The Clinical Spectrum of Leukocyte Adhesion Deficiency (LAD) III due to Defective CalDAG-GEF1.
    28. (1996). Francomano CA: A nonsense mutation in the cathepsin K gene observed in a family with pycnodysostosis. Genome Res
    29. (2003). Fryns JP: Melorheostosis in a family with autosomal dominant osteopoikilosis: report of a third family.
    30. (2006). Germline LEMD3 mutations are rare in sporadic patients with isolated melorheostosis. Hum Mutat
    31. (2009). Germline mutations in WTX cause a sclerosing skeletal dysplasia but do not predispose to tumorigenesis. Nat Genet
    32. (1992). HC: Recombinant human interferon gamma therapy for osteopetrosis.
    33. (2007). Hofling K, et al.: Deficiency of PORCN, a regulator of Wnt signaling, is associated with focal dermal hypoplasia. Nat Genet
    34. (1968). HR: [Dysosteosclerosis – a special form of generalized osteosclerosis]. Fortschr Geb Rontgenstr Nuklearmed
    35. (2004). Hul W: Localization of the gene causing the osteopetrotic phenotype in the incisors absent (ia) rat on chromosome 10q32.1. J Bone Miner Res
    36. (2008). Human osteoclast-poor osteopetrosis with hypogammaglobulinemia due to TNFRSF11A (RANK) mutations.
    37. (2004). JM: Osteoclast-derived serum tartrate-resistant acid phosphatase 5b in Albers-Schonberg disease (type II autosomal dominant osteopetrosis). Clin Chem
    38. (2000). KC: Complete visual recovery in osteopetrosis by early optic nerve decompression. Pediatr Neurosurg
    39. (2005). Key LL Jr: Otologic manifestations of malignant osteopetrosis. Otol Neurotol
    40. (2004). Kubisch C: Identification of a novel mutation in the coding region of the grey-lethal gene OSTM1 in human malignant infantile osteopetrosis. Hum Mutat
    41. (2000). Kubisch C: Mutations in the a3 subunit of the vacuolar H(+)-ATPase cause infantile malignant osteopetrosis. Hum Mol Genet
    42. (1924). L'image radiologique non encore decrit d'une anomalie du squelette; ses rapports avec la dyschondroplasie et l'osteopathia condensans disseminata. Acta Radiol
    43. (2003). Long-term outcome of haematopoietic stem cell transplantation in autosomal recessive osteopetrosis: an EBMT report. Bone Marrow Transplant
    44. (2005). Loss of the chloride channel ClC-7 leads to lysosomal storage disease and neurodegeneration. Embo J
    45. (2004). Lossof-function mutations in LEMD3 result in osteopoikilosis, Buschke-Ollendorff syndrome and melorheostosis. Nat Genet
    46. (2007). Megarbane A: Electron microscopic findings in skin biopsies from patients with infantile osteopetrosis and neuronal storage disease. Ultrastruct Pathol
    47. (2003). Mixed sclerosing bone dysplasia – a case report with literature review. Clin Imaging
    48. (2003). Neurological aspects of osteopetrosis.
    49. (2007). Osteoclast-poor human osteopetrosis due to mutations in the gene encoding RANKL. Nat Genet
    50. (2006). Osteoclastic bone degradation and the role of different cysteine proteinases and matrix metalloproteinases: differences between calvaria and long bone. J Bone Miner Res
    51. (1997). Osteopathia striata with cranial sclerosis: highly variable phenotypic expression within a family. Clin Genet
    52. (1997). Peptide aldehyde inhibitors of cathepsin K inhibit bone resorption both in vitro and in vivo. J Bone Miner Res
    53. (2001). Physical and transcriptional map of the mouse Chromosome 10 proximal region syntenic to human 6q16-q21. Mamm Genome
    54. (1962). Presse Med
    55. (1996). Proteolytic activity of human osteoclast cathepsin K. Expression, purification, activation, and substrate identification.
    56. (2002). Pycnodysostosis: Toulouse-Lautrec's and Aesop's disease? Hormones (Athens)
    57. (1977). Quesada-Calvo E, Cordero-Chaverri C: Osteopetrosis in children: a report of 26 cases.
    58. (1988). Radiological, biochemical and hereditary evidence of two types of autosomal dominant osteopetrosis.
    59. (1991). Report of a case and review of the Japanese literature, with emphasis on oral and maxillofacial findings. Oral Surg Oral Med Oral Pathol
    60. (2005). Rescue of ATPa3-deficient murine malignant osteopetrosis by hematopoietic stem cell transplantation in utero. Proc Natl Acad Sci USA
    61. (1995). Ries WL: Long-term treatment of osteopetrosis with recombinant human interferon gamma.
    62. (2008). Sobacchi C: Infantile Malignant, Autosomal Recessive Osteopetrosis: The Rich and The Poor. Calcif Tissue Int
    63. (1999). Stashenko P: Atp6i-deficient mice exhibit severe osteopetrosis due to loss of osteoclast-mediated extracellular acidification. Nat Genet
    64. (1998). Svedberg E: Marble brain syndrome: osteopetrosis, renal acidosis and calcification of the brain. Neuroradiology
    65. (1983). Tashian RE: Carbonic anhydrase II deficiency identified as the primary defect in the autosomal recessive syndrome of osteopetrosis with renal tubular acidosis and cerebral calcification. Proc Natl Acad Sci USA
    66. (1973). Tashjian AH Jr: Plasma calcitonin in pycnodysostosis: intermittently high basal levels and exaggerated responses to calcium and glucagon infusions.
    67. The classic: Osteopetrosis cured by temporary parabiosis.
    68. (1965). The Malady of Toulouse-Lautrec. Jama
    69. (2009). The murine mutation osteo-Orphanet Journal of Rare Diseases
    70. (2001). The mutational spectrum of human malignant autosomal recessive osteopetrosis. Hum Mol Genet
    71. (2006). The regulation of cathepsin K gene expression.
    72. (2001). TJ: Loss of the ClC-7 chloride channel leads to osteopetrosis in mice and man. Cell
    73. (2007). Veyver IB Van den: Mutations in X-linked PORCN, a putative regulator of Wnt signaling, cause focal dermal hypoplasia. Nat Genet
    74. (1998). von Figura K: Impaired osteoclastic bone resorption leads to osteopetrosis in cathepsin-K-deficient mice.
    75. (2001). X-linked anhidrotic ectodermal dysplasia with immunodeficiency is caused by impaired NF-kappaB signaling. Nat Genet

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