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PubMed1983

Allogeneic bone-marrow transplantation in infantile malignant osteopetrosis.

Two infants with malignant osteopetrosis were treated by allogeneic bone-marrow transplantation after marrow ablation with busulphan and cyclophosphamide. Engraftment without graft-vs-host disease occurred in both cases. The first child established stable chimerism and is clinically well 30 months after receiving a histocompatible sibling bone-marrow graft: haematological, radiological, and biochemical features of osteopetrosis have completely resolved. The second child was non-identical with the marrow donor (his older sister) at a single HLA-B locus and received cyclosporin A as prophylaxis for graft-vs-host disease. 11 months after transplantation haematological abnormalities have resolved and radiological features have improved. The findings indicate that allogeneic bone-marrow transplantation should be considered the treatment of choice for infants with severe osteopetrosis who have histocompatible siblings.

Blood Grouping and Crossmatching↗

PubMed1997

[Value of in vitro study of osteoclast precursors in the case of severe infantile osteopetrosis treated by bone marrow graft].

BACKGROUND: Pathogenesis of osteopetrosis is still debated. Testing the ability of osteoclastic progenitors to support the proliferation of functional cells may be useful in understanding pathogenesis. CASE REPORT AND METHODS: A diagnosis of osteopetrosis was made in a girl 1 month-old, born to consanguuineous parents. Bone marrow transplantation was uneffective at the age of 3 months but a second engraftment was successful at 5 months. Unfortunately, the patient died from severe thrombocytopenia at the age of 8 months. Long-term cultures of mononucleated cells from the patient's blood were performed before and after the bone marrow transplantation, with or without growth factors such as vitamin D3, IL-6 and IL-1. Similar studies were made from the patient's marrow obtained after transplantation; all results were compared with those obtained after culturing control cells from cord blood umbilical. RESULTS: Production of osteoclastic cells was mild in peripheral blood cultures; it was important in bone marrow cultures in presence of growth factors. CONCLUSION: These results suggest that osteopetrosis in our patient resulted from an intrinsic defect in progenitors of osteoclasts.

Blood Cells↗

PubMed2000

Type II autosomal dominant osteopetrosis (Albers-Schönberg disease): clinical and radiological manifestations in 42 patients.

Type II autosomal dominant osteopetrosis (ADO II, Albers-Schonberg disease) is a genetic condition characterized by generalized osteosclerosis predominating in some skeletal sites such as the spine and pelvis. ADO II is rare, and most available clinical descriptions are based on small numbers of patients. We report the clinical and radiological manifestations in 42 ADO II patients. To our knowledge, this is the largest series reported so far. Our inclusion criterion was presence on radiographs of the spine of vertebral endplate thickening, producing the classic sandwich vertebra appearance. We found various patterns of sandwich vertebra, of which we provide a description to assist physicians in diagnosing ADO II. The classic bone-within-bone appearance was present in most but not all skeletal sites. The radiological penetrance of the disease was high (90%) and increased after 20 years of age. As many as 81% of our patients experienced clinical manifestations. Fractures were common (78% of patients) and healed slowly. Hip osteoarthritis developed in 27% of patients and required arthroplasty in 9 of the 16 affected hips. Nonmandibular osteomyelitis occurred in 4 cases (11%). Twenty-four percent of patients had thoracic or lumbar scoliosis. Orthopedic surgery was performed in 52.8% of patients, of whom half had at least three surgical procedures for internal fracture fixation, arthroplasty, limb deformity correction, or treatment of surgical complications. There was a high rate of surgical complications including nonunion, infection, prosthesis loosening, and intraoperative fractures. Nearly two-thirds of patients (64%) had stomatologic manifestations, including mandibular osteomyelitis in 4 patients (11%). Cranial nerve involvement responsible for hearing loss, bilateral optic atrophy, and/or facial palsy was present in 14 patients but was clearly attributable to ADO II in only 6 cases (16%). This large series sheds new light on several aspects of ADO II, most notably the possibility of severe clinical complications. Although other forms of osteopetrosis are considerably more severe, the name "benign osteopetrosis" previously used for ADO II is probably a misnomer.

Adolescent↗

PubMed2001

Linking osteopetrosis and pycnodysostosis: regulation of cathepsin K expression by the microphthalmia transcription factor family.

Various genetic conditions produce dysfunctional osteoclasts resulting in osteopetrosis or osteosclerosis. These include human pycnodysostosis, an autosomal recessive syndrome caused by cathepsin K mutation, cathepsin K-deficient mice, and mitf mutant rodent strains. Cathepsin K is a highly expressed cysteine protease in osteoclasts that plays an essential role in the degradation of protein components of bone matrix. Cathepsin K also is expressed in a significant fraction of human breast cancers where it could contribute to tumor invasiveness. Mitf is a member of a helix-loop-helix transcription factor subfamily, which contains the potential dimerization partners TFE3, TFEB, and TFEC. In mice, dominant negative, but not recessive, mutations of mitf, produce osteopetrosis, suggesting a functional requirement for other family members. Mitf also has been found-and TFE3 has been suggested-to modulate age-dependent changes in osteoclast function. This study identifies cathepsin K as a transcriptional target of Mitf and TFE3 via three consensus elements in the cathepsin K promoter. Additionally, cathepsin K mRNA and protein were found to be deficient in mitf mutant osteoclasts, and overexpression of wild-type Mitf dramatically up-regulated expression of endogenous cathepsin K in cultured human osteoclasts. Cathepsin K promoter activity was disrupted by dominant negative, but not recessive, mouse alleles of mitf in a pattern that closely matches their osteopetrotic phenotypes. This relationship between cathepsin K and the Mitf family helps explain the phenotypic overlap of their corresponding deficiencies in pycnodysostosis and osteopetrosis and identifies likely regulators of cathepsin K expression in bone homeostasis and human malignancy.

Alleles↗

PubMed1997

Localization of a gene for autosomal dominant osteopetrosis (Albers-Schönberg disease) to chromosome 1p21.

Albers-Schönberg disease, the classical form of osteopetrosis, is an autosomal dominant condition with generalized increased skeletal density due to reduced bone resorption. Characteristic radiological findings are generalized osteosclerosis, with, most typically, end-plate sandwichlike thickening of the vertebrae (Rugger-Jersey spine) and the bone-within-bone (endobones) phenomenon. We studied an extended kindred with Albers-Schönberg disease and found linkage with several markers from chromosome 1p21. The Albers-Schönberg gene is located in a candidate region of approximately 8.5 cM flanked by markers D1S486 and D1S2792. A maximum LOD score (Z(max)) of 4.09 was obtained in multipoint analysis at loci D1S239/D1S248. Possible linkage of osteopetrosis to this chromosomal region was analyzed because the CSF-1 gene, which is mutated in the op/op mouse model for osteopetrosis, is located in 1p21. However, SSCP and mutation analysis in patients did not reveal any abnormality, which excludes the CSF-1 gene as the disease-causing gene. This was confirmed by refined physical mapping of the CSF-1 gene outside the candidate region for the Albers-Schönberg gene. The identification of the molecular defect underlying Albers-Schönberg disease will therefore be dependent on the isolation of other genes from an 8.5-cM candidate region on chromosome 1p21.

Chromosomes, Human, Pair 1↗

PubMed2001

Albers-Schönberg disease (autosomal dominant osteopetrosis, type II) results from mutations in the ClCN7 chloride channel gene.

Albers-Schönberg disease, or autosomal dominant osteopetrosis, type II (ADO II), is the most common form of osteopetrosis, a group of conditions characterized by an increased skeletal mass due to impaired bone and cartilage resorption. Following the assignment of the gene causing ADO II to chromosome 16p13.3, we now report seven different mutations in the gene encoding the ClCN7 chloride channel in all 12 ADO II families analysed. Additionally, a patient with the severe, autosomal recessive, infantile form of osteopetrosis (ARO) was identified as being homozygous for a ClCN7 mutation. From genotype-phenotype correlations, it seems that ADO II reflects a dominant negative effect, whereas loss-of-function mutations in ClCN7 do not cause abnormalities in heterozygous individuals. Because some ARO patients have mutations in both copies of the ClCN7 gene, ADO II is allelic with a subset of ARO cases.

Alleles↗

PubMed1998

Human autosomal recessive osteopetrosis maps to 11q13, a position predicted by comparative mapping of the murine osteosclerosis (oc) mutation.

Autosomal recessive osteopetrosis is a rare congenital disorder characterized by the development of abnormally dense bones, acrocephaly, severe anemia, hepatosplenomegaly and progressive deafness and blindness. The clinical course is rapidly progressive and is lethal at a very young age in the absence of a bone marrow transplant. The failure to remodel developing bone that is the basis of the disease process is most likely due to a dysfunction of the bone resorptive cell, the osteoclast. This phenotype is similar to that of the murine mutation osteosclerosis (oc), which is localized to proximal mouse chromosome 19. Given the similarity between the human and murine phenotypes, we tested whether human osteopetrosis maps to a region of conserved synteny. Microsatellite markers in the region of 11q12-13 were found to be linked to osteopetrosis in two consanguineous Bedouin kindreds. Recombination events were used to define the disease interval to an approximately 14 cM region between D11S1983 and D11S2371. A maximum LOD score of 7. 94 was obtained with D11S449 at straight theta = 0.

Animals↗

PubMed2004

Surgical correction of craniosynostosis in malignant osteopetrosis.

In osteopetrosis, bone healing is complicated by progressive sclerosis. A 2-year-old blind boy with malignant osteopetrosis developed increased intracranial pressure secondary to craniosynostosis. Osteopetrosis had already been treated with bone marrow transplantation (BMT), and bone remodeling seemed to be restored. A craniotomy was performed. The postoperative course and bone healing were uneventful. After successful BMT, craniofacial procedures seem to be possible without a high risk for osteomyelitis.

Bone Marrow Transplantation↗

PubMed1984

Osteopetrosis with calcifying tendinitis.

Osteopetrosis is a hereditary disease caused by cellular dysfunction. Calcifying tendinitis is a sequela of stress mediated by multinucleated cells in the tendon fibers. Our patient had both osteopetrosis and calcifying tendinitis. A related cellular dysfunction may predispose individuals with osteopetrosis to calcifying tendinitis.

Adult↗

PubMed2000

Posterior spinal instrumentation and fusion of a neuromuscular scoliosis in a patient with autosomal dominant osteopetrosis.

STUDY DESIGN: A case report of a patient with autosomal dominant osteopetrosis and neuromuscular scoliosis who required surgical instrumentation and fusion of her spine. OBJECTIVE: To illustrate the surgical technique and long-term outcome in this rare form of spinal deformity. SUMMARY OF BACKGROUND DATA: Osteopetrosis is a group of rare skeletal dysplasias characterized clinically by skeletal osteosclerosis that is classically described in appearance as "marble bone." Despite the ubiquitous involvement of the vertebra, clinical manifestations of spinal involvement are uncommon. We present the case of an osteopetrotic patient with neuromuscular scoliosis who required surgical correction of her progressive deformity. There are no prior reports in the literature concerning operative or nonoperative management of scoliosis in this patient population. METHODS: The surgical technique utilized as well as the patient's response to surgical management of her scoliosis is presented with 5 year follow-up. RESULTS: The patient underwent a successful T4 to L1 posterior spine fusion and instrumentation using Luque rods, sublaminar wires and allograft bone augmentation. At 5 years following her index procedure, she is clinically and radiographically fused. CONCLUSION: Patients with osteopetrosis present unique surgical challenges during surgical correction of spinal deformities. The use of segmental sublaminar wires with 1/4-inch rods and crosslinks afforded stable fixation despite poor bone quality. Allograft bone combined with postoperative bracing resulted in a well-maintained correction and a solid fusion. Five year follow-up and continued radiographic evidence of stable fusion indicate that the presented approach can lead to a successful outcome in the osteopetrotic patient population.

Adult↗

PubMed2005

Otologic manifestations of malignant osteopetrosis.

OBJECTIVE: To determine the incidence of hearing loss and describe the neurotologic manifestations over time in a large series of patients with malignant osteopetrosis. STUDY DESIGN: Longitudinal study. SETTING: Tertiary care referral center. PATIENTS: Thirty-two patients, including 19 infants (< 1 yr of age at initial visit) and 13 children (aged 1-7.6 yr at initial visit), with autosomal recessive osteopetrosis were followed-up during a 10-year period from 1991 to 2001. The average length of follow-up was 2.5 years (range, 0-9.1 yr). INTERVENTIONS: Patients underwent annual otologic evaluations including clinical examination, audiologic evaluation (auditory brainstem response, pure-tone thresholds, speech discrimination scores, and tympanograms), and high-resolution computed tomography of the temporal bone. MAIN OUTCOME MEASURES: Incidence of hearing loss, otitis media, and facial paralysis. Serial changes in temporal bone anatomy by computed tomographic scan. RESULTS: Twenty-six percent of infants' ears demonstrated hearing loss during the first year of life, and 78% of children's ears demonstrated hearing loss during the study period. Of the children's ears with hearing loss, 100% had a conductive component and 26% had an additional sensorineural component (mixed hearing loss); VIIIth nerve conduction was normal in 100% of infants and 78% of children. Five patients (16%) had unilateral facial nerve palsy. Common temporal bone findings included thickening and sclerosis of the calvarium; poor pneumatization of the mastoid bone; and narrowing of the external auditory canal, eustachian tube, and internal auditory canal. CONCLUSION: Otologic manifestations are common in malignant osteopetrosis secondary to the formation of dense, brittle bone. Frequent findings include external auditory canal stenosis, otitis media, conductive and sensorineural hearing loss, and facial nerve paralysis.

Child↗

PubMed2004

Recalcitrant osteomyelitis following tooth extraction in a case of malignant osteopetrosis.

Malignant osteopetrosis generally begins in utero and often results in stillbirth. Besides, failure to thrive, increased bone fragility resulting in frequent fractures and recurrent bone infections are the other characteristic features. Infections after tooth extraction and fracture of the sclerotic bone following mild trauma are serious complications, as these ordinarily common problems are very difficult to treat in such patients. Poor bone vascularisation and reduced local defences prolong the defensive response. A rare case of malignant osteopetrosis in a 19-year-old girl, who presented with the complication of osteomyelitis of the mandible following tooth extraction, is presented. The case is of interest for two reasons: it is very rare for a case of malignant osteopetrosis to survive until adulthood and to be aware of the potential dental and oral complications of the disorder.

Adult↗

PubMed1978

Characterization of the immunosuppression accompanying virus-induced avian osteopetrosis.

Infection of chickens with a myeloblastosis-associated virus which induced a high incidence of osteopetrosis was accompanied by immunosuppression. The immunosuppression was manifested in the following ways. The weight of the bursa, spleen, and thymus was depressed in infected chickens. Infected animals had a diminished capacity to form hemolytic plaques in a direct assay. Spleen cells from osteopetrotic animals did not respond to phytohemagglutinin, and the spleen and bursa had a decreased proportion of cells possessing surface immunoglobulin. Osteopetrotic animals failed to show an age-dependent increase in the proportion of cells demonstrating surface immunoglobulin that was observed in normal animals. However, several individual chickens with heavy osteopetrosis responded to antigenic stimulation in a normal fashion, indicating that although immunosuppression usually accompanies avian osteopetrosis, it may not contribute directly to abnormal bone proliferation.

Animals↗

PubMedDate not supplied

Major cerebral arterial and venous disease in osteopetrosis.

Two patients with osteopetrosis were studied in whom severe stenosis of one or both internal carotid arteries was demonstrated. One patient had autosomal dominant osteopetrosis and the other patient had the autosomal recessive form of the disease. In one patient, probable occlusion of one internal jugular vein and retrograde thrombosis of the contributing dural venous sinuses was present. Venous drainage of parts of the brain occurred through dilated emissary and scalp veins. It appears that major extracranial vessels may be impinged upon by dysplastic bone in osteopetrosis, although this is the first report of such an occurrence. A posterior fossa aneurysm was present in one case, and may have been related to abnormal intracranial hemodynamics.

Bone and Bones↗

PubMed1983

Infantile osteopetrosis and neuronal storage disease.

Infantile osteopetrosis often presents with neurologic symptoms that cannot always be attributed to primary bone disease of the skull. We studied an infant with osteopetrosis and pathologic evidence of neuronal and axonal changes. This is the third case in which primary parenchymal disease of the brain was associated with infantile osteopetrosis and the first in which neuronal cytoplasmic storage was documented by light and electronmicroscopy. The simultaneous occurrence of two rare autosomal-recessive disorders, each possibly caused by an inherited lysosomal enzyme deficiency, may not be fortuitous.

Adult↗

PubMed1988

Optic nerve decompression for osteopetrosis in early childhood.

Visual failure in osteopetrosis may result from retinal degeneration or compression of the optic nerve in the narrowed optic canals. We report the evaluation and treatment of five children with osteopetrosis whose optic nerve dysfunction seems to have been related to the latter etiology. Evaluation of visual function was carried out by means of behavioral observation and flash visual evoked responses. Of six nerves evaluated both pre- and postoperatively, the visual evoked responses seemed to improve in four. Three nerves were serially evaluated without an operation, and one showed changes consistent with maturation. One nerve was evaluated with serial postoperative evoked potentials and showed no change. We conclude that surgical decompression of the optic nerve in patients with documented optic nerve dysfunction and osteopetrosis allows improvement in visual function and is, therefore, an important consideration in the evaluation and management of patients with this disease.

Age Factors↗

PubMed2004

Severe malignant osteopetrosis caused by a GL gene mutation.

Infantile malignant autosomal recessive osteopetrosis is a genetically heterogeneous disease caused by the inability of OCLs to resorb and remodel bone, resulting in generalized osteosclerosis and obliteration of marrow spaces and cranial foramina. The classical clinical features are pathological fractures, visual impairment, and bone marrow failure. Two human genes have been described as the cause of this form of osteopetrosis: the T-cell immune-regulator-1 (TCIRG1) gene, which is mutated in >50% of the patients, and the chloride channel 7 (ClCN7) gene, which accounts for approximately 10% of cases. We report the clinical, radiographic, and histopathologic findings of the first human osteopetrosis case caused by a mutation in the grey-lethal (GL) gene. The patient, a 9-day-old male infant, presented with a very severe osteopetrotic phenotype including substantial hepatosplenomegaly since birth, cytopenia, and progressive major liver failure. Skeletal radiographs revealed a generalized increase in bone density with loss of corticomedullary differentiation. Histopathologic bone examination showed the typical osteopetrotic changes, with absence of resorptive activity, and osteoclasts, slightly decreased in number, with evident morphological alterations.

Bone and Bones↗

PubMed2000

Study of the nonresorptive phenotype of osteoclast-like cells from patients with malignant osteopetrosis: a new approach to investigating pathogenesis.

Osteopetrosis manifests as failure of osteoclastic bone resorption. The cause of the disease lies either in the hematopoietic lineage or in the bone marrow stromal microenvironment. It has not been possible to define the cell type involved in the various forms of the human disease because of the inability to form human osteoclasts in vitro. Using the recently described method for generating human osteoclasts from peripheral blood in coculture with rat osteoblastic UMR 106 cells, we demonstrate that a defect lies in the mature osteoclast-like cells in four cases of this disease. Control and osteopetrotic cocultures generated large numbers of osteoclast-like cells (calcitonin and vitronectin receptor positive, and F-actin ring-positive cells) with similar morphology. Bone resorption did not occur in three of the four osteopetrotic cultures. In case 1, in which bone resorption was identified, the area of resorption was negligible compared with the number of osteoclast-like cells in the culture and was detected only by scanning electron microscopy. In contrast, up to 20% of the bone surface in controls was resorbed. The normal and osteopetrotic osteoclast-like cells had a similar phenotype except that two of the osteopetrotic cases did not express CD44 and two expressed CD44 weakly, whereas CD44 was strongly expressed in the controls. This study shows that it is possible to reproduce in vitro the pathological features of human osteopetrosis, and the assay provides a means of acquiring a greater understanding of the pathogenesis of human osteopetrosis.

Animals↗