1/238. Locus heterogeneity of autosomal dominant osteopetrosis (ADO). Autosomal dominant osteopetrosis (ADO), is a heritable disorder that results from a failure of osteoclast-mediated bone resorption. The etiology of the disorder is unknown. A previous linkage study of one Danish family mapped an ADO locus to chromosome 1p21. We have studied two families from indiana with ADO. The present study sought to determine if the ADO gene in these families was also linked to chromosome 1p21. We used six microsatellite repeat markers, which demonstrated linkage to the 1p21 ADO locus in the Danish study, to perform linkage analysis in the new kindreds. Multipoint analysis excluded linkage of ADO to chromosome 1p21 (logarithm of the odds score < -7.00) in both families. In addition, no haplotype segregated with the disorder in either family. In summary, the present investigation ruled out linkage of ADO to chromosome 1p21 in two families from indiana. Our results demonstrate that there is locus heterogeneity of this disorder; therefore, mutations in at least two different genes can give rise to the ADO phenotype. ( info) |
2/238. Presentation and management of chronic osteomyelitis in an African patient with pycnodysostosis. A case is reported of pycnodysostosis (PCD) with chronic osteomyelitis in the mandible. The clinical and radiological features and the problems of management and follow-up are discussed. ( info) |
3/238. Bone mineral density and laboratory evaluation of a type II autosomal dominant osteopetrosis carrier. Type II autosomal dominant osteopetrosis (ADO2) is an inherited disorder characterized by increased skeletal mass and characteristic abnormalities evident on radiography. Although previous investigators have described nonpenetrant individuals (carriers), it is not known whether carriers manifest subtle abnormalities. We hypothesized that ADO2 carriers would have an abnormality of osteoclast function that would lead to changes in bone mineral density (BMD), in serum tartrate-resistant acid phosphatase (TRAP), or in creatine kinase isoenzyme BB (CK-BB) levels that would permit carrier recognition. We identified a female carrier in a well-established ADO2 family and measured BMD, serum TRAP, and CK-BB concentrations. She had normal BMD, serum TRAP, and CK-BB concentrations. Thus, these measurements cannot be used to exclude carrier status in individuals who are seen for genetic counseling. However, measurements in other asymptotic carriers are necessary before concluding that these measurements are normal in all or most nonpenetrant individuals. ( info) |
4/238. Mechanisms of osteoclast dysfunction in human osteopetrosis: abnormal osteoclastogenesis and lack of osteoclast-specific adhesion structures. osteoclasts from a patient affected by osteopetrosis were examined in vivo and in vitro. Iliac crest biopsy revealed an osteosclerotic pattern, with prominent numbers of osteoclasts noted for hypernuclearity and incomplete adherence to the bone surface. A population comprising tartrate-resistant acid phosphatase (TRAP)-positive, multinucleated and mononuclear cells, and alkaline phosphatase-positive stromal fibroblasts was obtained in vitro from bone marrow. Mononuclear TRAP-positive precursors spontaneously fused in culture to form giant osteoclast-like cells. These cells expressed the osteoclast marker MMP-9 and calcitonin receptor, and lacked the macrophage marker, Fc receptor. Expression and distribution of c-src, c-fms, and CD68, and response to steroid hormones relevant to osteoclast differentiation and function were apparently normal, whereas cell retraction in response to calcitonin was impaired. TRAP-positive multinucleated cells did not form osteoclast-specific adhesion structures (clear zone, podosomes, or actin rings). bone resorption rate was severely reduced in vitro. focal adhesions and stress fibers were observed en lieu of podosomes and actin rings. Adhesion structures contained low levels of immunoreactive vitronectin receptor, most of this integrin being retained in cytoplasmic vesicles. These data provide the first characterization of abnormal differentiation and function of human osteopetrotic osteoclast-like cells. ( info) |
5/238. 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. ( info) |
6/238. 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. ( info) |
7/238. Ultrastructural findings of bone marrow in a case with malignant osteopetrosis following successful allogeneic bone marrow transplantation. A nine-month-old female patient suffering from malignant osteopetrosis was evaluated by light and transmission electron microscopic study before and following allogeneic bone marrow transplantation (BMT). Bone marrow specimens were obtained from iliac crest biopsies. Before BMT, the bone marrow had an irregular appearance and was filled with bridging bony trabeculae devoid of cells. Following BMT, the marrow had an almost normal appearance with no myelofibrosis and a relatively regular distribution of hematopoletic cells. The osteocytes were visible in their lacunae in the bone matrix. Presence of bone resorbing and bone forming cell together demonstrated that the bone was beginning to gain its normal dynamic structure. These findings were in accordance with the clinical, laboratory and radiological data which showed the beneficial effect of the therapy. ( info) |
8/238. osteopetrosis--improvement of hematologic findings with age. A three months old girl was admitted to the hospital for evaluation of pallor and abdominal distension. There was anemia, thrombocytopenia and extramedullary hematopoiesis. In the long bone roentgenogram medullary areas could not be distinguished and bone densities were increased. The patient was diagnosed for osteopetrosis with these findings and prednisolone treatment was begun and then discontinued since it was not effective. In the follow up, the need for blood transfusions decreased and then disappeared. We present a case which was diagnosed as osteopetrosis and followed up by blood transfusions and of which hematologic findings improved with age. ( info) |
| The histopathology of the temporal bone of an eight and one-half-year-old girl with osteopetrosis (Albers-Schonberg disease) was studied to evaluate the pathogenesis of its frequent complications in hearing and facial nerve function. The patient was blind and had acute otitis media, but facial paralysis was not noted. Although the size of the temporal bone pyramid was markedly increased due to enormously thickened periosteal layer, changes in the endosteal and endochondral layers were less marked. Exostotic growth of periosteal bone was seen in the middle ear wall, and the tympanic cavity appeared to be narrowed. At the oval window region, the facial nerve was pushed down towards the stapes due to extreme overgrowth of periosteal bone of the epitympanum, and the superstructure of the stapes was imbedded deeply into the dislocated facial nerve and had strongly compressed it. Although the footplate was free from ankylosis, the crus of the stapes appeared to be immobilized because it was lodged in the facial nerve. Such changes appeared to be the pathogenesis of one form of facial nerve paralysis and conductive hearing loss associated with osteopetrosis. ( info) |
10/238. Dual-energy x-ray absorptiometry in osteopetrosis. We have used dual-energy x-ray absorptiometry (DXA) in evaluation and follow-up of a patient with osteopetrosis, before and after cord blood transplantation. Other methods of follow-up in such cases have been described, but the use of DXA has not previously been reported. We have shown that DXA offers a safe means of assessing disease progression, the timing of treatment, and response after therapy for osteopetrosis. ( info) |