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PubMed1995

Bone marrow transplantation for infantile malignant osteopetrosis.

PURPOSE: Most patients diagnosed with malignant osteopetrosis die during infancy or early childhood from hemorrhage and infection due to bone marrow failure. Allogeneic bone marrow transplantation (BMT) has been reported to provide curative therapy for this disorder. We report our experience with eight patients with malignant osteopetrosis who underwent BMT. PATIENTS AND METHODS: Between May 1987 and August 1992, eight children with malignant osteopetrosis underwent allogeneic BMT. Median age at BMT was 9 months (range, 2-36 months). Six patients received marrow from HLA-identical sibling donors, one from phenotypically matched father, and one from a one antigen mismatched father. BMT conditioning for all patients was busulfan 16 mg/kg and cyclophosphamide 200 mg/kg each administered over 4 days. Graft versus host disease (GVHD) prophylaxis included cyclosporin A in six patients or cyclosporin A and methotrexate in two patients. RESULTS: Six patients, including those who received bone marrow from their father's, engrafted as documented by bone marrow biopsy showing an increase in osteoclasts in all cases and by chromosomal analysis in four patients. Two patients died without engraftment. Three out of six patients engrafted are alive and well at the follow-up of 48, 63, and 81 months. Serum calcium, alkaline, and acid phosphatase levels normalized within 2 months. These patients have full bone marrow reconstitution. Serial radiologic studies revealed bone marrow remodelling and a new nonsclerotic bone formation. Vision improved dramatically in the youngest patient. CONCLUSION: BMT offers cure to patients with malignant osteopetrosis with reconstitution of bone marrow and correction of metabolic disturbances. In our experience, reversibility in neurosensory deficit is possible when BMT is done at an early age.

Bone Marrow Transplantation↗

PubMed2007

Posterior cervical arthrodesis for subacute odontoid fracture in a patient with osteopetrosis: case report.

STUDY DESIGN: A case of subacute odontoid fracture in a patient with osteopetrosis treated with posterior cervical arthrodesis using transarticular screws and interspinous wiring. OBJECTIVES: To report the first successful cervical arthrodesis in a patient with osteopetrosis and to highlight the potential perioperative pitfalls in this rare surgical population. SUMMARY OF BACKGROUND DATA: Osteopetrosis is a group of skeletal dysplasias characterized by osteoclast dysfunction, impaired bone resorption, and poor bone remodeling. Unique challenges associated with surgical fixation in osteopetrotic bone include a high incidence of nonunion, intraoperative fractures, intraoperative instrumentation failure, infection, and prosthesis loosening. We report the case of a patient with a subacute odontoid fracture treated successfully with posterior cervical arthrodesis using transarticular screws and interspinous wiring. METHODS: The surgical technique, intraoperative pitfalls, and 2-year follow-up data are reported. RESULTS: The patient underwent a successful posterior cervical arthrodesis using transarticular screws and interspinous wiring with autogenous iliac crest graft. At 2 years, a stable fixation was achieved with only mild postoperative limitation in neck range of motion. CONCLUSIONS: Cervical fractures and instability that require surgery in patients with osteopetrosis represent a unique challenge to the orthopedic spine surgeon. Despite the increased potential for perioperative instrumentation complications, nonunion, and infection, posterior cervical arthrodesis can be achieved and should be considered in the treatment armamentarium for this potentially catastrophic injury.

Adult↗

PubMed1986

Sequences near the 5' long terminal repeat of avian leukosis viruses determine the ability to induce osteopetrosis.

Avian leukosis virus (ALV)-induced osteopetrosis is associated with the accumulation of unintegrated viral DNA in osteoblasts. Viruses constructed from the DNAs of an osteopetrosis-inducing ALV (Br21) and a non-osteopetrosis-inducing ALV (RAV-0) have been used to test for the role of viral genes in the induction of osteopetrosis. Our results map osteopetrotic potential to a 1,400-base-pair region near the 5' long terminal repeat. This region contains signals for the splicing, translation, and packaging of viral RNAs and coding sequences for the gag proteins p19 and p10 and the N terminus of p27.

Animals↗

PubMed1991

Sequences from myeloblastosis-associated virus MAV-2(O) and UR2AV involved in the formation of plaques and the induction of osteopetrosis, anemia, and ataxia.

Recombinant viruses were made between myeloblastosis-associated virus MAV-2(O) and UR2AV to examine the relationship between regions of the MAV-2(O) genome and disease induction. The env-long terminal repeat (LTR) portion of MAV-2(O), when substituted into UR2AV, was sufficient to induce osteopetrosis identical to that caused by the parent MAV-2(O). When this region was reduced to the gp37 and LTR of MAV-2(O), osteopetrosis more severe than that caused by the parent virus was induced. Recombinant viruses that contained all or part of the MAV-2(O) env gene in the absence of the MAV-2(O) LTR induced a severe, chronic anemia and late-onset osteopetrosis, leading to the conclusion that the MAV-2(O) LTR, in addition to env, was required for rapid induction of osteopetrosis. A viral recombinant, pEU, which contained the gp85 segment of UR2AV substituted into MAV-2(O), induced an ataxia/cerebellar dysfunction not seen during infection with the other chimeric or parent viruses. In vitro studies of the parent and recombinant viruses demonstrated that the ability to form plaques on chicken embryo fibroblasts correlated with the presence of the MAV-2(O) gp37 and LTR except for construct pEU. When the viruses were inoculated into 10-day-old chickens, chimeras containing the env-LTR of gp37-LTR region of MAV-2(O) induced severe regenerative anemia similar to that induced by MAV-2(O). pEU was the exception, suggesting that the unique configuration of this chimera is responsible for its unusual pathogenic properties.

Anemia↗

PubMed1995

Association of infantile neuroaxonal dystrophy and osteopetrosis: a rare autosomal recessive disorder.

The association of neuroaxonal dystrophy and osteopetrosis is reported in 2 siblings born to non-consanguineous parents. The 1st child was diagnosed as having infantile osteopetrosis shortly after delivery. A computed tomography scan of the head revealed agenesis of the corpus callosum. She died at the age of 9 months. Post-mortem examination showed pneumonia and bony sclerosis. Neuropathological examination revealed cerebral atrophy, ventricular dilation, absence of the corpus callosum, and a small hippocampus. Neuroaxonal spheroids were found in hippocampus, basal ganglia, pons, medulla, spinal cord, cranial nerves, cerebellum, and peripheral nerves. Ultrastructural examination revealed membranous cytoplasmic bodies and electron-dense granular deposits within the neuroaxonal spheroids as well as the soma of neurons. The 2nd child was delivered at 36 weeks of gestation because of intrauterine fetal distress. The diagnosis of osteopetrosis and partial agenesis of the corpus callosum was made shortly after delivery. The child died at 1 month without an autopsy. There are rare cases reported previously with the association of neuroaxonal dystrophy and osteopetrosis. We review these cases and compare them with ours.

Agenesis of Corpus Callosum↗

PubMed2001

[Autosomal-dominant osteopetrosis in Chuvashiya].

A genetic epidemiological study of osteopetrosis was carried out in Chuvashiya. The major signs of this disorder are severe anemia developed in the prenatal or early postnatal life, hepatosplenomegaly, and a progressive loss of sight and hearing. Osteopetrosis showed the autosomal recessive inheritance with a somewhat increased proportion of affected patients in families. The lowest estimate of osteopetrosis frequency in Chuvashiya was 0.00026, one affected patient per 3879 newborns. The osteopetrosis gene occurred at a frequency of 0.016; the proportion of heterozygotes was 3.15%. The gene was shown to be evenly distributed throughout the republic.

Genes, Recessive↗

PubMedDate not supplied

[Recessive osteopetrosis. Identification of a form of medium severity].

BACKGROUND: Several distinct forms of osteopetrosis have been identified. Some of the autosomally recessive inherited forms are benign, much like the autosomal dominant form. Others are more malignant. PATIENTS: The clinical data, skeletal radiographs, histological features and histories of 32 children with osteopetrosis were analyzed retrospectively. RESULTS: The 32 patients, belonging to 20 sibships were divided into two groups. The first group included 24 patients, aged 1 day-11 months (mean 4.5 months), suffering from hepatosplenomegaly, anemia, thrombocytopenia and optic atrophy in early infancy. They also had a generalized increase in bone density, abnormal bone remodeling, rachitic lesions and a "bone-within-bone" appearance. Biopsies showed severe bone resorption and myelofibrosis. 19 of the 20 patients whose outcomes were known died during the first year of life. The second group included 8 patients, aged 40 days-3 years (mean: 11 months). Hepatosplenomegaly appeared later, anemia was less severe and thrombocytopenia occurred in only 1 patient. However, all 8 patients suffered from optic atrophy and 3 were deaf. Radiographs showed bone growth without rachitic lesions. Biopsies from 2 patients showed bone resorption, but no myelofibrosis. The outcome was less severe: 6 patients, now aged 8 months to 8 years, have survived, 3 of them for over 5 years. Genetic investigation showed patterns compatible with autosomal recessive inheritance in both groups, with similar sets of features within each sibship. CONCLUSION: This study reveals a new type of recessively inherited osteopetrosis. It can be classified as an intermediate form, distinct from both the malignant and the benign forms, and also distinct from osteopetrosis with carbonic anhydrase II deficiency.

Child, Preschool↗

PubMed1992

Circulating macrophage colony-stimulating factor is not reduced in malignant osteopetrosis.

Malignant osteopetrosis is a disorder characterized by a deficiency in osteoclast number or function. In one animal model of osteopetrosis, the op/op mouse, macrophage colony-stimulating factor (M-CSF) is absent, and the administration of M-CSF corrects the defects. We evaluated the serum of 13 patients with malignant osteopetrosis by an M-CSF radioimmunoassay to determine if a quantitative M-CSF deficiency existed in these patients. All patients had M-CSF present in levels equal to or higher than control serum. In addition, serum from 6 osteopetrotic patients was tested in a bioassay to determine if the M-CSF present is biologically active, and in all cases there was demonstrable activity in these samples. We provide evidence that deficiency of circulating M-CSF is unlikely to be a major contributor to the etiologic basis for the majority of children with malignant osteopetrosis.

Child, Preschool↗

PubMed1991

Reduction of graft failure by a monoclonal antibody (anti-LFA-1 CD11a) after HLA nonidentical bone marrow transplantation in children with immunodeficiencies, osteopetrosis, and Fanconi's anemia: a European Group for Immunodeficiency/European Group for Bone Marrow Transplantation report.

Forty-six infants and children suffering from either inherited immunodeficiency disorders (Wiskott-Aldrich syndrome, functional T-cell immunodeficiency with or without HLA class II expression deficiency), malignant osteopetrosis, or Fanconi's anemia received HLA-nonidentical bone marrow transplantation (BMT) from related donors. Bone marrow was T-cell depleted to reduce the risk of graft-versus-host disease (GVHD). To prevent graft failure, a mouse monoclonal antibody specific for the CD11a-lymphocyte function-associated antigen 1 (LFA-1) molecule was infused into the patients. Eleven patients received five infusions of 0.1 mg/kg every other day from day -3 to +5. Thirty-five patients received 0.2 mg/kg daily from day -3 to +6. The overall sustained engraftment rate was 72% instead of 26.1% in a historical control group of 24 patients similarly treated except for the infusion of the anti-LFA-1 antibody. No late rejection occurred. The T-cell depletion method (E-rosetting or Campath IM plus complement) resulted in different rate of engraftment (83.3% v 57.9%, respectively, P = .05). Engraftment rate was slightly but not significantly influenced by the degree of HLA incompatibility between donor and recipient. Acute GVHD of grade II or more occurred in 35.5% of the patients and the rate of chronic GVHD was 12.9%. The overall actuarial survival rate with a functional graft is 47.3% with a mean follow-up of 28.0 months for patients with immunodeficiency and osteopetrosis, while none of the four patients with Fanconi's anemia survived. The development of full T-cell functions took on the average 6 months and of full B-cell functions 10 months. Significant infectious problems developed in the majority of the patients during the posttransplant course. Epstein-Barr virus-induced B-cell proliferative syndromes were observed in seven patients, six of whom had Wiskott-Aldrich syndrome. Correction of immunodeficiency was comparable in terms of kinetics and quality with that observed in patients with severe combined immunodeficiency undergoing HLA-nonidentical BMT. Correction of osteopetrosis appears not to be different from what has been observed after HLA-identical BMT. The in vivo use of an anti-CD11a-LFA-1 antibody as an additional immunosuppressive therapy in HLA-nonidentical BMT may thus promote engraftment and survival with correction of the primary disease in a significant number of patients with life-threatening immunodeficiency and osteopetrosis, but not with Fanconi's anemia.

Antibodies, Monoclonal↗

PubMed1985

Craniofacial abnormalities in osteopetrosis with precocious manifestations: report of a case with serial cephalometric roentgenograms.

Serial roentgencephalograms were taken (from the age of 2 to 8 years) of a female patient with malignant osteopetrosis. The roentgencephalograms were compared to those of a control patient with cleft lip and to other normative data. The calvaria of the osteopetrosis patient was very thick, increasing with age. The intracranial space was reduced in volume, resulting in compression of the brain. Roentgencephalometric characteristics of the facial skeleton included orbital hypertelorism, defective horizontal and vertical growth of the middle and lower face, and poorly developed dentoalveolar structures. The mandibular body was short in contrast to the wide ramus, both resulting from defective resorption of the anterior ramal border. A cone-shaped structure in the mandible extending from the condylar process into the ramus was noted. This was believed to consist of remnants of unresorbed, heavily calcified secondary cartilage constituting part of the condylar process present since intrauterine life. Recent treatment of malignant osteopetrosis by bone marrow transplantation early in life has resulted in some cases in normalization of bone structure and marrow. Serial roentgencephalometry provides a sensitive method of assessing craniofacial development in cases of osteopetrosis and presumably can be used to evaluate the effects of therapy.

Cephalometry↗

PubMed1982

[Different radiological, histomorphometrical and biochemical findings in two cases of adult osteopetrosis (author's transl)].

Morphokinetic measurements after tetracycline labeling were performed on bone specimens of the iliac crest in a 30-year-old man and a 38-year-old women. On radiographs, the osteopetrosis (=marble bone disease Albers-Schönberg) was characterized by an almost homogenous osteosclerosis in the man and by variable zones of high and normal density in the woman. Histologically, the man revealed increased rates of bone formation and mineralisation as signs of hyperactivity of the osteoblasts accompanied, biochemically, by an elevation of serum alkaline phosphatase and a high urinary output of hydroxyproline. In the woman increased resorbing bone seams, and elevation of serum acid phosphatase and a slightly lowered urinary output of hydroxyproline were apparent as signs of an osteoclastic deficiency. The cause of osteopetrosis has been generally ascribed to decreased bone resorption. This study shows that the accumulation of bone mass in osteopetrosis may be due also to increased bone formation and that by pathomechanism, probably, two forms of osteopetrosis in the adult may be differentiated.

Acid Phosphatase↗

PubMed1994

Autosomal recessive osteopetrosis: variability of findings at diagnosis and during the natural course.

OBJECTIVE: To determine the variability and the natural course of children suffering from autosomal recessive osteopetrosis to allow optimal counseling and decision making with respect to therapeutic intervention. DESIGN: Retrospective and longitudinal evaluation of clinical symptoms and natural course with emphasis on survival and sensoneurologic and hematologic findings. SETTING: Two large referral-based pediatric bone marrow transplantation units in Europe. PATIENTS: Thirty-three patients with autosomal recessive osteopetrosis admitted to units in Paris and Leiden between 1972 and 1988 were analyzed until last follow-up or the time at which bone marrow transplantation was performed. The great number of patients and unprecedented amount of data make this report one of the single largest clinical studies on autosomal recessive osteopetrosis. MAIN RESULTS: Ocular involvement occurring at a median age of 2 months was the symptom at initial examination in half of the patients. A striking variability between patients was found. Retinal degeneration was present in three patients and associated generalized neurodegeneration was present in two. The probability of survival until the age of 6 years was about 30% for the group as a whole. The cumulative risk of developing visual or hematologic impairment in the first year of life was about 75% and leveled off afterward. Patients with early hematologic impairment, ie, before 3 months of age, especially when combined with early visual impairment, had a very poor prognosis regarding life expectancy. CONCLUSIONS: Autosomal recessive osteopetrosis seems to be a variable disorder with a poor prognosis, especially in children with early visual and hematologic impairment. Allogenic bone marrow transplantation remains the only curative approach.

Bone Marrow Transplantation↗

PubMed1994

Growth hormone and IGF1 profile in short children with osteopetrosis.

Osteopetrosis is commonly associated with short stature. To identify the cause, 8 children with osteopetrosis and short stature were studied. One showed evidence of renal tubular acidosis, none showed evidence of anaemia, and all were clinically and biochemically euthyroid. Growth hormone profile was assessed using night sampling (8 patients), growth hormone provocative testing using insulin-induced hypoglycaemia (6 patients), and L-dopa-propranolol (8 patients). The mean nocturnal growth hormone values taken at 60 and 90 min after onset of sleep and at 4 a.m. were 5.5, 12.8, and 11.5 mu/L respectively. The peak stimulated growth hormone mean values with the insulin-induced hypoglycaemia (glucose 1.6-3.0 mmol/L, mean = 2.2) was 14 mu/L (range 7.3-24.5 mu/L) and with the L-dopa-propranolol was 25.6 mu/L (range 12.3-49 mu/L). IGF1 levels taken at 0 and 120 min of insulin-induced hypoglycaemia (0 min for L-dopa-propranolol), and at 120 min of L-dopa-propranolol, showed normal values for age. We conclude that: (1) growth hormone profiles in these children are normal; (2) tissue unresponsiveness to growth hormone and/or IGF1 is not likely to be the cause of short stature in children with osteopetrosis; and (3) osteopetrosis per se is not an indication for assessment of growth hormone status.

Adolescent↗

PubMed1993

Experimental studies of osteopetrosis in laboratory animals.

Osteopetrosis is a metabolic bone disease characterized by a systemic increase in skeletal mass. It results from a defect in the production or function of osteoclasts and is inherited in nine genetically distinct osteopetrotic animal mutations and man. Studies of these mutations have revealed that osteopetrosis is a complex, heterogeneous disorder in its expression, etiology, and response to treatment by bone marrow transplantation or by hormone/growth factor therapy. These animal mutations have been valuable tools for probing the pathogenesis and treatment of osteopetrosis, and information obtained from these studies has been used clinically for the treatment of humans with osteopetrosis. In addition, studies of these mutations have contributed significantly to understanding normal bone cell biology, including the origin of the osteoclast and the significance of colony-stimulating factor-1 in osteoclast development. The resistance of some of these mutations to cure by stem cell transplantation and hormone therapy, coupled with similar observations and experiences in the human condition, indicates that these animal mutations will continue to serve important roles in the development of alternative therapies to treat resistant forms of the disease. These studies are bound to improve the understanding of normal bone biology by providing additional insights into the regulation of osteoclasts by osteoblasts and their products or by other elements of the skeletal microenvironment.

Animals↗

PubMed1998

Malignant infantile osteopetrosis: otolaryngological complications and management.

OBJECTIVES: To inform otolaryngologists about upper airway obstruction requiring tracheotomy and other otolaryngological manifestations of malignant infantile osteopetrosis (MIOP) and to discuss pathophysiological features, management, and new treatment strategies in MIOP. DESIGN: Ongoing case series combined with a retrospective chart review. SETTING: International tertiary pediatric hospital. INTERVENTIONS: Patients with MIOP were initially referred for treatment and routine follow-up. Tracheotomy was performed to manage obstructive sleep apnea. Audiograms were also performed at regular intervals. RESULTS: The records of 9 patients were examined. The otolaryngological findings of hearing loss, obstructive sleep apnea (sometimes requiring tracheotomy), otitis media, and chronic osteomyelitis with facial fistulas were identified. CONCLUSIONS: Osteopetrosis is a rare condition caused by a failure of the osteoclast to resorb bone. This results in thickened dense, deformed, and easily fractured bone. As a result, growth failure, anemia, hypoplastic dentition, chronic infections, facial fistulas, blindness, hearing loss, nasal congestion, and upper airway obstruction may occur. The management of otolaryngological problems in a child with osteopetrosis is an important component in comprehensive care. To our knowledge, this study represents the largest case series of MIOP in the otolaryngology literature.

Face↗

PubMed1979

Visual loss in osteopetrosis.

We present the clinical and electrophysiological findings in three cases of osteopetrosis with visual loss. In all cases the findings on electroretinography suggested diffuse retinal degeneration, despite normal ophthalmoscopic appearance of the retinas. We suggest that retinal degeneration may be a common finding in osteopetrosis and a major cause of visual loss. Patients with osteopetrosis and poor vision should be examined using electrophysiological techniques to detect unsuspected retinal dysfunction.

Blindness↗

PubMed1986

Lethal osteopetrosis with multiple fractures in utero.

Severe osteopetrosis was diagnosed in utero in two successive pregnancies resulting from an intermarriage. Hydrocephaly and skeletal hyperdensity were detected at 18 weeks of gestation, and fractures at 24 weeks. We report on extensive ultrasound, radiological, and pathological findings, including those on brain and bone. The markedly reduced number of osteoclasts observed in these sibs and the very early fetal involvement suggest that this form of osteopetrosis might represent a new entity: autosomal recessive lethal osteopetrosis.

Adult↗

PubMed2004

Identification of a novel mutation in the coding region of the grey-lethal gene OSTM1 in human malignant infantile osteopetrosis.

Autosomal recessive malignant infantile osteopetrosis (ARO) is characterized by severe osteosclerosis, pathologic fractures, hepatosplenomegaly, and pancytopenia. The pathophysiological basis is inadequate bone resorption due to osteoclast dysfunction. In the majority of cases, mutations in either of two human genes cause this fatal disorder: TCIRG1, encoding a subunit of the osteoclast H(+)-ATPase, and the voltage-gated chloride channel gene CLCN7. We excluded both genes in a small inbred family with malignant infantile osteopetrosis and undertook linkage analysis of several candidate loci that are involved in murine osteopetrosis. A region spanning more than 20 cM between the markers D6S1717 and D6S1608 on chromosome 6q21 was found to be homozygous in the affected child. This locus is syntenic to the genomic region harboring the gene for the osteopetrotic mutant mouse grey-lethal (gl). Recently, mutations in a novel gene of unknown function were described in the grey-lethal mouse and in one human patient. Mutation screening of the grey-lethal gene (OSTM1), revealed a homozygous 2-bp deletion in exon 2 (c.415_416delAG) in the affected child. No mutations could be found in six independent ARO patients who had tested negative for mutations in TCIRG1 and CLCN7. In summary, we describe the identification of a novel mutation in the coding sequence of the human grey-lethal gene, which is the second OSTM1 mutation found in human ARO, confirming the involvement of this gene in the pathogenesis of this severe bone disease.

Amino Acid Sequence↗