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PubMed2004

Post operative diagnosis of osteopetrosis.

Osteopetrosis is a rare hereditary disease that was first described by a German Albert Schonberg in 1904. At least five types of osteopetrosis have been described. Among them osteopetrosis congenita (autosomal recessive) and osteopetrosis tarda (autosomal dominant) are most common. Here we are reporting a case of osteopetrosis tarda, who is a female of fifty years of age presented with fracture femur. Preoperatively there was no suspicion of osteopetrosis. She was only suspected while introducing an IM Nail during her fracture reduction. Diagnosis of osteopetrosis was confirmed post operatively by histopathology of medullary cavity of her femur.

Female↗

PubMed1983

Rapid induction of osteopetrosis by subgroup E recombinant viruses.

Avian osteopetrosis is a proliferative bone disorder initiated at high frequency by MAV-2(O), a subgroup B avian myeloblastosis-associated virus. To examine the role of the MAV-2(O) genome in osteopetrosis induction, a series of recombinant viruses between MAV-2(O) and RAV-O was constructed. Recombinant viruses were selected for rapid growth and subgroup E envelopes. The T1 oligonucleotide fingerprint patterns of viruses selected in this manner demonstrated that they were recombinants and were clonally pure because they had oligonucleotides from each parent, and each oligonucleotide was present in single molar yield. When injected into 10-day-old chicken embryos, approximately 50% of the recombinant viruses induced osteopetrosis within 3 weeks after hatch. Therefore, subgroup E envelope did not inhibit osteopetrosis induction. The osteopetrosis that was induced varied from slight to severe, but none of the recombinant viruses induced osteopetrosis as severe as the MAV-2(O) parent.

Animals↗

PubMed1985

Avian leukosis virus-induced osteopetrosis is associated with the persistent synthesis of viral DNA.

DNAs from 19 cases of avian leukosis virus-induced osteopetrosis have been analyzed for viral sequences. Among these were instances of rapid, intermediate, and slow onset osteopetrosis. The DNAs from osteopetrotic bone contained no evidence for osteopetrosis being caused by proviral insertions into or viral transductions of a host protooncogene. Instead, DNAs from osteopetrotic bone displayed evidence for osteopetrosis being associated with the persistent synthesis of viral DNA. Each of the 19 DNAs contained unintegrated as well as integrated viral DNA. Rapid onset osteopetrosis contained about 3X more viral and proviral DNA than intermediate or late onset osteopetrosis. Unintegrated viral DNA could not be detected in DNAs extracted from the bursa bone marrow of osteopetrotic chickens or in DNA extracted from the normal bones of an avian leukosis virus-infected chicken. Thus, the persistent synthesis of unintegrated viral DNA was observed in osteopetrotic but not normal tissues of avian leukosis virus-infected chickens.

Animals↗

PubMed1985

Sequences in the gag-pol-5'env region of avian leukosis viruses confer the ability to induce osteopetrosis.

DNA sequences encoding the genomes of three subgroup E avian leukosis viruses have been molecularly cloned. Virus recovered from one of these cloned DNAs (pRAV-0) caused no osteopetrosis while virus recovered from the second (lambda NY203) caused late onset osteopetrosis and virus recovered from the third (lambda NTRE-2) caused intermediate onset osteopetrosis. Restriction endonuclease fragments of the cloned viral DNAs were used to construct recombinant viruses that could be used to test for the role of gag-pol-5'env and 3'env-LTR sequences in the induction of osteopetrosis. The results of the pathogenicity tests indicate that gag-pol-5'env sequences confer the ability to induce osteopetrosis while 3'env-LTR sequences influence the time of onset and the severity of osteopetrosis.

Animals↗

PubMed1999

Increased induction of osteopetrosis, but unaltered lymphomagenicity, by murine leukemia virus SL3-3 after mutation of a nuclear factor 1 site in the enhancer.

SL3-3 is a murine leukemia virus which is only weakly bone pathogenic but highly T-cell lymphomagenic. A major pathogenic determinant is the transcriptional enhancer comprising several transcription factor binding sites, among which are three identical sites for nuclear factor 1 (NF1). We have investigated the pathogenic properties of NF1 site enhancer mutants of SL3-3. Two different mutants carrying a 3-bp mutation either in all three NF1 sites or in the central site alone were constructed and assayed in inbred NMRI mice. The wild type and both mutants induced lymphomas in all mice, with a mean latency period of 9 weeks. However, there was a considerable difference in osteopetrosis induction. Wild-type SL3-3 induced osteopetrosis in 11% of the mice (2 of 19), and the triple NF1 site mutant induced osteopetrosis in none of the mice (0 of 19), whereas the single NF1 site mutant induced osteopetrosis in 56% (10 of 18) of the mice, as determined by X-ray analysis. A detailed histological examination of the femurs of the mice was carried out and found to support this diagnosis. Thus, the NF1 sites of SL3-3 are major determinants of osteopetrosis induction, without determining lymphomagenesis. This conclusion was further supported by evaluation of the bone pathogenicity of other SL3-3 enhancer variants, the lymphomagenicity of which had been examined previously. This evaluation furthermore strongly indicated that the core sites, a second group of transcription factor binding sites in the viral enhancer, are necessary for the osteopetrosis induction potential of SL3-3.

Animals↗

PubMed2000

Complete visual recovery in osteopetrosis by early optic nerve decompression.

Visual loss with optic atrophy is common in osteopetrosis. The efficacy of optic nerve decompression in patients with osteopetrosis is still controversial. The purpose of this study is to report that visual deterioration in osteopetrosis can be completely reversed by early optic nerve decompression. An 8-year-old female patient with osteopetrosis was found to have reduced visual acuity on routine ophthalmologic examination. Extensive optic nerve decompression was performed. It not only included unroofing the optic canal, but also drilling away bone on both sidewalls of the optic nerve. Both optic nerves were decompressed during the same surgical procedure. Progressive loss of vision associated with osteopetrosis can be prevented by optic nerve decompression in the early stage of visual deterioration. When managing patients with osteopetrosis, the importance of careful and regular assessment of visual function should be stressed.

Child↗

PubMed1997

Pathogenesis of osteosclerosis in autosomal dominant osteopetrosis.

OBJECTIVE: The purpose of this study was to determine if the generalized osteosclerosis seen on skeletal radiographs of patients with osteopetrosis is associated with an increase in bone density. SUBJECTS AND METHODS: Five children (three girls, two boys, 6-12 years old) with autosomal dominant osteopetrosis who had sustained a fracture with minimal trauma had the density and area of cortical bone at the midshaft of the femur and the amount of cancellous vertebral bone per voxel measured by quantitative CT. Values for five children with osteopetrosis were compared with measurements for two control groups of healthy subjects matched for age, sex, Tanner stage of sexual development, race, weight, and height. RESULTS: Both the area of femoral cortical bone and the amount of cancellous vertebral bone per voxel were significantly greater in the children with osteopetrosis than in the healthy children. The density of bone in the children with osteopetrosis was the same as the density in the healthy subjects. Neither sex, age, height, or weight influenced bone density, and values were similar for all 15 children. CONCLUSION: The osteosclerosis depicted on skeletal radiographs of patients with osteopetrosis results from an increase in the amount of bone, not from an increase in the percentage of mineralized bone per unit volume of tissue.

Bone Density↗

PubMed2003

Osteopetrosis.

Osteopetrosis is a rare skeletal condition characterized by skeletal sclerosis caused by aberrant osteoclast-mediated bone resorption. Three clinically distinct forms of osteopetrosis are recognized--the infantile malignant autosomal recessive form, the intermediate autosomal recessive form, and the adult benign autosomal dominant form. The disease represents a spectrum of clinical variants because of the heterogeneity of genetic defects resulting in osteoclast dysfunction. The pathogenic defects may be intrinsic to either the osteoclast-monocyte lineage or the mesenchymal cells that constitute the microenvironment that supports osteoclast ontogeny and activation. Implicated factors include specific proto-oncogenes, growth factors, and immune regulators. A subset of patients with the intermediate autosomal recessive form has been characterized with carbonic anhydrase II isoenzyme deficiency. Management of patients with osteopetrosis requires a comprehensive approach to characteristic clinical problems including hematologic and metabolic abnormalities, fractures, deformity, back pain, bone pain, osteomyelitis, and neurologic sequelae. Medical treatment of osteopetrosis is based on efforts to stimulate host osteoclasts or provide an alternative source of osteoclasts. Stimulation of host osteoclasts has been attempted with calcium restriction, calcitrol, steroids, parathyroid hormone, and interferon. Bone marrow transplant has been used with cure for infantile malignant osteopetrosis. As osteopetrosis likely represents a spectrum of underlying etiologies resulting in osteoclast dysfunction, effective therapies most likely need to be individualized.

Humans↗

PubMed2025

A novel frameshift variant leads to familial osteopetrosis with variable phenotypes in a Chinese Han consanguineous family.

Osteopetrosis, a group of highly heterogeneous genetic bone disorders, is characterized by deafness, increased bone density, hepatosplenomegaly, pancytopenia and intellectual disability. Osteopetrosis can be divided into three subtypes: autosomal recessive osteopetrosis (ARO), intermediate autosomal recessive osteopetrosis (IARO), and autosomal dominant osteopetrosis (ADO). CLCN7 has been reported to be the most common gene responsible for the ADO-II subtype. In this study, a novel variant, c.175dupA (p.Met59Asnfs*8), of CLCN7 was identified in a Chinese Han consanguineous family with suspected ADO-II. The proband was homozygous for the p.Met59Asnfs*8 variant and exhibited multiple severe phenotypes, including deafness, short stature, brittle bones, optic atrophy, hepatosplenomegaly, intellectual disability, cleft palate and recurrent infection. However, except for the mother of the proband, who presented a series of clinical phenotypes caused by bone marrow failure, all the other family members who were heterozygous had no obvious abnormal phenotypes. Our study suggested that the novel variant p.Met59Asnfs*8 in CLCN7 was very likely pathogenic factor in our suspected ADO-II family. The phenotypes of heterozygous carriers may be affected by incomplete penetrance. Loss of function of CLCN7 caused by nonsense-mediated mRNA decay (NMD) due to the frameshift variant was likely the underlying pathogenic mechanism. This study broadened the mutation spectrum of CLCN7, provided a foundation for timely and effective clinical intervention for related diseases, and demonstrates the importance of genetic counselling.

Adult↗

PubMed1989

Treatment of congenital osteopetrosis in the rabbit with high-dose 1,25-dihydroxyvitamin D.

Osteopetrosis is a congenital metabolic bone disease characterized by skeletal sclerosis resulting from defective osteoclast-mediated bone resorption. Osteopetrosis has been described in several animal species (mouse, rat, and rabbit) and in children. Bone marrow transplantation, originally shown to reverse the skeletal sclerosis in some animal mutations, has been effective in curing osteopetrosis in some children. Unfortunately, not all children with osteopetrosis are candidates for or respond to bone marrow transplantation. Recent studies have shown that several animal mutations and some children inheriting osteopetrosis have significantly elevated serum levels of 1,25-(OH)2D. Based on the possibility that there may be a resistance to 1,25-(OH)2D, high-dose calcitriol therapy has been used to treat some children and stimulated some parameters of resorption. In this study, we have examined the effects of high-dose calcitriol therapy on various serum and skeletal parameters in the osteopetrotic rabbit. Mutant rabbits and normal littermates were given continuous infusions of calcitriol via subcutaneously implanted osmotic minipumps for 2 weeks at a dose of 0.5, 2.5, or 25 micrograms/kg/per day. Untreated mutant rabbits are hypocalcemic and hypophosphatemic in the presence of elevated serum 1,25-(OH)2 levels in comparison with their normal littermates. Calcitriol infusions resulted in dose-dependent increases in circulating 1,25-(OH)2D levels in both normal and mutant rabbits. However, evaluation of other serum parameters and the skeletal response demonstrated significant differences between osteopetrotic and normal rabbits. At the highest dose, normal animals rapidly became hypercalcemic and osteoporotic, accompanied by weight loss and a failure to thrive; mutants remained hypocalcemic and osteopetrotic but did not exhibit the deleterious physical effects seen in treated normal littermates. Although the number of osteoclasts increased in both mutants and normals, osteoclast phenotype in the former remained abnormal. These data indicate that although very high levels of circulating 1,25-(OH)2D were achieved in osteopetrotic mutants, activation of osteoclast-mediated bone resorption with subsequent improvement of skeletal sclerosis was not observed.

Animals↗

PubMed1994

Replication of an osteopetrosis-inducing avian leukosis virus in fibroblasts, osteoblasts, and osteopetrotic bone.

Avian leukosis virus (ALV)-induced osteopetrosis is caused by the abnormal growth and differentiation of osteoblasts. To evaluate the role of infection in osteopetrosis induction, the replication of an osteopetrosis-inducing virus (Br21) has been compared in osteopetrotic bone, calvarial-derived osteoblasts, and chick embryo fibroblasts. Much higher levels of infection occurred in diseased bone than in the cultures. Severe cases of osteopetrosis contained 10 times more viral DNA, 30 times more mature capsid protein, 5 to 10 times more Gag precursor protein, and 2 to 3 times more Env protein than the infected cultures. Virus replication in the cultured osteoblasts was similar to that in fibroblasts except for a distinctive asymmetric localization of Gag proteins. In osteopetrotic chickens, bones became atypically enlarged and sera contained elevated levels of osteoblast differentiation markers (alkaline phosphatase and osteocalcin). In cultures, infections did not affect the growth or differentiation of osteoblasts. Thus, the infected cultures lacked aspects of the bone environment that support both the high levels of infection and the aberrant function of osteoblasts characteristic of ALV-induced osteopetrosis.

Animals↗

PubMed1988

The association of infantile osteopetrosis and neuronal storage disease in two brothers.

Neurological manifestations in infantile osteopetrosis are common and varied, and not always attributable to the skeletal pathology. An unusual association of osteopetrosis with neuronal storage of ceroid lipofuscin is reported in two infant brothers born of nonconsanguinous parents. The first child became symptomatic at age 5 days with weight loss and vomiting. He had poor head control, hypertonia, and persistent fisting, and died at age 2 months. In the second infant, the diagnosis of osteopetrosis was confirmed at age 2 days. His neurological symptoms included blindness, deafness, and recurrent seizures. The infant died at 7 months of age. In both cases, autopsy confirmed the diffuse bony sclerosis with hepatosplenomegaly and extramedullary hematopoiesis. Neuropathological examination revealed cerebral atrophy with ventricular dilation, neuronal loss, and astrogliosis. The most striking finding was widespread accumulation of neuronal ceroid lipofuscin associated with formation of axonal spheroids. The optic nerves were compressed at the optic foramina and showed loss of myelinated axons and gliosis. Rapid Golgi impregnations of neurons from the calcarine cortex in the second infant were analyzed quantitatively, showing a reduction in the total dendritic length and number of branches. The primary defect in osteopetrosis is thought to be a lysosomal dysfunction involving the monocyte cell line from which osteoclasts are derived. Thus, the association in two brothers of osteopetrosis with accumulation of neuronal ceroid lipofuscin may not be fortuitous. The neuronal storage disorder in this instance probably reflects lysosomal dysfunction.

Brain↗

PubMed2001

Human osteopetrosis and other sclerosing disorders: recent genetic developments.

Osteopetroses are rare human genetic disorders due to markedly decreased bone resorption. To date, the only gene whose inactivation was known to be responsible for human osteopetroses was that encoding carbonic anhydrase type II. Recessive malignant osteopetrosis is linked to decreased osteoclast function, unlike several osteopetroses in rodents that are caused by the inactivation of genes stimulating osteoclast differentiation. Recent advances in genetics have shown that some patients affected with recessive malignant osteopetrosis have inactivating mutations in a subunit of the vacuolar proton pump that is actively produced in the osteoclast brush border, but not in the lysosomes of other cells. The same gene is mutated in osteopetrotic oc/oc mice. The genes responsible for autosomal dominant osteopetrosis (ADO) have not yet been identified. Also, different localizations have been observed for ADO II, the type with sandwich vertebrae, and ADO I, presenting with diffuse osteocondensation. Less data than in malignant osteopetrosis are avaible on the cellular mechanism of decreased bone resorption in ADO but there is also genetic heterogeneity in ADO II. Pycnodysostosis is also due to a decreased resorption, and is quite close to osteopetrosis. Pycnodysostosis is linked to an inactivating mutation in the gene encoding cathepsin K, which is required for osteoclastic resorption. Decreased bone resorption is not the only defect inducing osteosclerosis, and Camurati-Engelmann disease is due to increased bone formation. Recently it has been shown that it is associated with a mutation in the propeptide of TGFbeta1. Thus, human osteosclerosing disorders have a wide range of phenotypes and genotypes and knowledge of them will contribute to a better understanding of the remodeling of normal bone.

Animals↗

PubMed2003

Osteopetrosis and Glanzmann's thrombasthenia in a child.

Autosomal recessive osteopetrosis is a rare, fatal disease characterized by accumulation of excessive bone mass due to defective bone resorption. The pathogenesis of osteopetrosis is controversial. Osteoblast-osteoclast interaction defects, incorrect differentiation of osteoclasts, abnormal contact between osteoclast and extracellular matrix, and abolished signaling are included in this process. Recently, mutations in the gene of the vacuolar proton pump have been described in some cases of recessive osteopetrosis. Glanzmann's thrombasthenia (GT) is a rare hereditary qualitative platelet disorder characterized by a lifelong bleeding tendency due to quantitative and qualitative abnormalities of the platelet integrin alpha(IIb) beta3. Several mutations on either integrin alpha(IIb) [glycoprotein (GP) IIb] or integrin beta(3) (GP IIIa) were reported in GT. We report on a patient with autosomal recessive osteopetrosis concurrently diagnosed with variant type Glanzmann's thrombasthenia. To our knowledge, our patient was the first case reported in the literature in which osteopetrosis and Glanzmann's thrombasthenia were diagnosed together.

Genes, Recessive↗

PubMed2002

Chloride channel 7 (CLCN7) gene mutations in intermediate autosomal recessive osteopetrosis.

Osteopetrosis is a heterogeneous group of inherited disorders that includes a malignant autosomal recessive form, an intermediate autosomal recessive form and autosomal dominant forms of the disease. Most malignant osteopetroses have been ascribed to mutations in the OC116 gene encoding the human a3 subunit of vacuolar H(+)-ATPase. Few cases of autosomal recessive malignant osteopetrosis have been ascribed to mutations in the chloride channel 7 gene (CLCN7), which accounts for all autosomal dominant type II cases reported to date. Up until now, however, nothing has been known regarding the molecular basis of the intermediate form of osteopetrosis (IARO). Our study of two Portuguese IARO families shows that homozygosity for ClCN7 mutations also accounts for this form of osteopetrosis. The two patients presented with spontaneous fractures in the first years of life and generalised increase of bone density. Direct sequencing of the ClCN7 gene in both patients revealed homozygosity for two mutations (G203D and P470Q). We conclude therefore that ClCN7 mutations not only account for some dominant and malignant forms but also for intermediate forms of osteopetrosis.

Alleles↗

PubMed1991

Evaluation of carbonic anhydrase isozymes in disorders involving osteopetrosis and/or renal tubular acidosis.

Carbonic anhydrase II (CA II) deficiency in man is an autosomal recessive disorder manifest by osteopetrosis, renal tubular acidosis, and cerebral calcification. Other features include growth failure and mental retardation. Complications of the osteopetrosis include frequent bone fractures, cranial nerve compression symptoms, and dental malocclusion. The anemia and leukopenia seen in the recessive, lethal infantile form of osteopetrosis are not seen in CA II deficient patients. The renal tubular acidosis usually includes both proximal and distal components. Symptoms of metabolic acidosis respond to therapy, but no specific treatment is available for the osteopetrosis or cerebral calcification. We review here the role of carbonic anhydrases in bone resorption and renal acidification, and discuss clinical features and laboratory findings which distinguish CA II deficiency from other disorders producing osteopetrosis, renal tubular acidosis, or brain calcification. Methods to evaluate patients with pure proximal renal tubular acidosis for deficiency of CA IV are also discussed.

Acidosis, Renal Tubular↗

PubMed1988

Serum vitamin D metabolites and nuclear uptake of (3H)-1,25-dihydroxyvitamin D3 in monocytes from patients with autosomal dominant osteopetrosis: a study of two radiological types.

The nuclear uptake of (3H)-1,25 dihydroxyvitamin D3 in freshly isolated human monocytes and the serum levels of 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D were investigated in 13 patients with autosomal dominant osteopetrosis and in sex- and age-matched controls. Seven patients had type I osteopetrosis characterized by diffuse, symmetrical osteosclerosis with pronounced sclerosis of the skull and increased thickness of the cranial vault. The other six patients had type II with "Rugger Jersey Spine" and "endobones" as characteristic findings. In type I osteopetrosis the serum 1,25-dihydroxyvitamin D was significantly reduced (p less than 0.05), whereas serum 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D receptor binding were normal. In type II osteopetrosis the serum vitamin D metabolites were normal, as was the maximal binding capacity (Bmax) of 1,25-dihydroxyvitamin D to the nuclear receptor. The dissociation constant (Kd), however, was significantly increased (p less than 0.01) indicating a modest resistance to 1,25-dihydroxyvitamin D. It is concluded that a general end-organ resistance to 1,25-dihydroxyvitamin D at the receptor level does not exist in type I osteopetrosis, but may contribute to some of the radiological and biochemical findings in type II.

Adult↗

PubMed1998

The protein tyrosine kinase p60c-Src is not implicated in the pathogenesis of the human autosomal recessive form of osteopetrosis: a study of 13 children.

Osteopetrosis has been described in mice generated by homozygous gene disruption of c-src gene encoding for the p60c-Src protein tyrosine kinase (Src-/- mice). The similarities of bone histologic findings in this murine model to those observed in some patients first seen with autosomal recessive osteopetrosis, "malignant" osteopetrosis, led us to investigate the potential role of p60c-Src in the pathogenesis of malignant osteopetrosis in 13 children. In 4 patients a c-src mutation was ruled out by an intragenic microsatellite segregation study. In the other 9 we analyzed p60c-Src expression and function, as well as c-src sequence. The expression was normal in all of the patients tested. In addition, the tyrosine phosphorylation and kinase activity of p60c-Src were also normal in all of the patients. Moreover, in these patients, sequences of the coding region of c-src were identical to the published sequence of the human c-src complementary DNA. These results exclude a role for c-src in the pathogenesis of human malignant osteopetrosis in the 13 patients analyzed.

Antibodies, Monoclonal↗