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PubMed2000

Long-term follow-up of two children with a variant of mild autosomal recessive osteopetrosis undergoing bone marrow transplantation.

Malignant autosomal recessive (AR) osteopetrosis represents an absolute indication for bone marrow transplantation (BMT). Over the last 15 years, almost 100 BMTs for osteopetrosis have been reported. The median age at transplant of most patients is 4 months. Very few cases of mild AR osteopetrosis have been described. Here, we report the good outcome of two cases of mild AR osteopetrosis with a follow-up of 5 and 6 years, respectively, after an HLA-identical sibling transplant undergone at 5 and 12 years of age, respectively. At the time of BMT, severe visual impairment was present in both children. Bone biopsy demonstrated hypermineralization with virtual obliteration of the medullary spaces, rare microfoci of hematopoiesis and marked deficiency in osteoclastic activity. Successful engraftment was complicated by hypercalcemia, controlled by a combination of bisphosphonate, phosphate infusions, vigorous hydration and calcitonin. Following BMT, radiological and histological findings showed extensive bone resorption with marked augmentation of the osteoclasts in normalized marrow. No improvement was observed in visual acuity, despite complete remodeling of skeletal abnormalities. We conclude that allogeneic BMT is the only chance of curing mild AR osteopetrosis.

Biopsy↗

PubMed1999

Microphthalmia-associated transcription factor (MITF) locus lacks linkage to human vitiligo or osteopetrosis: an evaluation.

The microphthalmia-associated transcription factor (MITF) locus has been mapped to human chromosome 3p12-p14.1, and encodes a basic helix-loop-helix zipper (bHLH-ZIP) protein homologous to a number of transcription factors. Numerous mutations at the mouse microphthalmia (mi) locus have been described, and all have reduced or absent pigmentation of the eyes, ears, and/or pelage, with some genotypes exhibiting small or absent eyes and osteopetrosis. The mivit/vit mutation at the mouse mi locus produces a postnatal depigmentation that resembles human vitiligo. The mice homozygous for this mi allele show a progressive loss of cutaneous, hair and ocular pigmentation with age. Vitiligo, an acquired depigmentary disorder, is characterized by patchy depigmentation of skin that generally begins around puberty and tends to become more progressive over time. There is suggestive evidence that human vitiligo may be inherited; however, the mode of inheritance is still debated and the pathogenesis is not clearly delineated. The human disorder osteopetrosis is characterized by a generalized net accumulation of skeletal mass and results from reduced osteoclast function in the bone. This is an inherited disorder and has been associated with mi in a mutant mouse. Therefore, the possible involvement of the MITF locus in the pathogenesis of either familial vitiligo or osteopetrosis was investigated. Linkage analysis was performed using microsatellite polymorphic markers D3S2465, D3S1261, and D3S1766 on genomic DNA from 26 families with vitiligo/osteopetrosis. D3S1261 is physically located at or near the MITF locus, while D3S2465 and D3S1766 are flanking the locus at about 17.5 cM genetic distance each side. Evidence from LOD score analysis surprisingly indicated that none of the families with vitiligo or osteopetrosis are linked to these short tandem repeat polymorphisms (STRPs). Thus, the human homolog (MITF) of the mouse mi gene, a good candidate gene at the phenotypic level, may not be involved in the pathogenesis of familial human vitiligo or osteopetrosis.

Adolescent↗

PubMed2003

A phenocopy of CAII deficiency: a novel genetic explanation for inherited infantile osteopetrosis with distal renal tubular acidosis.

The rare bone thickening disease osteopetrosis occurs in various forms, one of which is accompanied by renal tubular acidosis (RTA), and is known as Guibaud-Vainsel syndrome or marble brain disease. Clinical manifestations of this autosomal recessive syndrome comprise increased bone density, growth failure, intracerebral calcification, facial dysmorphism, mental retardation, and conductive hearing impairment. The most common cause is carbonic anhydrase II (CAII) deficiency. Several different loss of function mutations in CA2, the gene encoding CAII, have been described. To date, there have been no exceptions to the finding of CAII deficiency in patients with coexistent osteopetrosis and RTA. Most often, the RTA is of mixed proximal and distal type, but kindreds are reported in which either distal or proximal RTA predominates. We report the molecular genetic investigation of two consanguineous kindreds where osteopetrosis and distal RTA (dRTA) were both manifest. One kindred harbours a novel homozygous frameshift alteration in CA2. In the other, CAII levels were normal despite a similar clinical picture, and we excluded defects in CA2. In this kindred, two separate recessive disorders are penetrant, each affecting a different, tissue specific subunit of the vacuolar proton pump (H(+)-ATPase), providing a highly unusual, novel genetic explanation for the coexistence of osteopetrosis and dRTA. The osteopetrosis is the result of a homozygous deletion in TCIRG1, which encodes an osteoclast specific isoform of subunit a of the H(+)-ATPase, while the dRTA is associated with a homozygous mutation in ATP6V1B1, encoding the kidney specific B1 subunit of H(+)-ATPase. This kindred is exceptional firstly because the coinheritance of two rare recessive disorders has created a phenocopy of CAII deficiency, and secondly because these disorders affect two different subunits of the H(+)-ATPase that have opposite effects on bone density, but which have only recently been determined to possess tissue specific isoforms.

Acidosis, Renal Tubular↗

PubMed2004

Malignant autosomal recessive osteopetrosis caused by spontaneous mutation of murine Rank.

UNLABELLED: We report the first case of lethal autosomal recessive osteopetrosis in mice caused by a spontaneous 8-bp deletion in exon 2 of the Rank gene. The phenotype, including a block in RANKL-dependent osteoclast differentiation and lymph node agenesis, copies that of Rank(-/-) mice, which have been produced by targeted recombination. INTRODUCTION: Commitment of osteoclast progenitors to the osteoclast lineage requires RANKL/RANK-mediated intercellular signals. Gene-targeted defects in this signaling pathway resulted in osteoclast deficiency and severe osteopetrosis in mice, but to date, there have been no reports of spontaneous mutations in Rankl or Rank resulting in osteopetrosis. MATERIALS AND METHODS: Mice with malignant osteopetrosis and absent lymph nodes appeared spontaneously in a highly inbred colony. Appropriate crosses were analyzed to establish the pattern of inheritance. Tissues from affected pups and littermates were evaluated grossly, histopathologically, and radiographically. Osteoclast development from splenocytes was tested in vitro under a variety of conditions, including after infection with RANK-encoding retrovirus. Rank mutational analysis was performed by direct sequencing of RT-PCR products and genomic DNA. RESULTS: The inheritance pattern was consistent with autosomal recessive inheritance, and the phenotype resembled that of either Rankl or Rank knockout mice with the exception of as yet unexplained death of most mice 2-3 weeks after weaning. Osteoclast precursors from the spleens of affected pups failed to form osteoclasts in vitro when stimulated with macrophage-colony stimulating factor (M-CSF) and RANKL, unless they were forced to express wildtype Rank cDNA. Molecular genetic studies identified an 8-bp deletion in exon 2 of the Rank gene. The resulting allele, termed Rank(del8), encodes only a small portion of the RANK extracellular domain, which is probably nonfunctional. CONCLUSIONS: The phenotypic similarities between Rank(del8) and mice previously described with a combined insertion and deletion in Rank confirm the role of this receptor in osteoclastogenesis and lymph node development and suggest that some forms of malignant osteopetrosis in humans could result from a similar defect.

Animals↗

PubMedDate not supplied

[Unusual case of hypercondensing malignant osteodysplasty: osteopetrosis].

Osteopetrosis, known also as Albers-Schonberg disease, is a genetic disorder causing a generalized sclerosis of the bones and the reduction of the marrow. The diagnosis is often secondary to pathologic processes and its usually observed through specific X-ray researches. The principal cause of osteopetrosis is to attribute to a deficit of bone resorption and remodelling. Osteomyelitis is a complication of osteopetrosis. The purpose of this article is based on several point: 1) to know the cause of osteopetrosis, then to classify and check it; 2) to present the case who did not respond to of a patient with osteopetrosis complicated by maxillary and phalanx osteomyelitis common therapies and give an accurate analysis.

Child↗

PubMedDate not supplied

Effects of catecholamines on blood pressure in the long bone marrow cavity in rats with bisphosphonate-induced osteopetrosis.

Osteopetrosis is a congenital metabolic bone disease characterized by skeletal sclerosis resulting from defective osteoclast-mediated bone resorption. The disease may, inter alia, be caused by the administration of bisphosphonates (e.g. pamidronate) particularly in young humans. The issue of the effect of pamindronate-induced osteopetrosis on the function of blood circulation and autonomic nervous system remains open. In order to clarify this problem, the present study concentrated on the effect of catecholamines on blood pressure in the marrow cavity in rats with pamindronate-induced osteopetrosis. The experiments consisted in pamidronate administration to young male Wistar rats at doses of 3 mg/kg sc, for 3 or 6 weeks. Norepinephrine, epinephrine, isoprenaline as well as adrenoceptor antagonists (phentolamine and propranolol) were administered to the controls and the rats with pamindronate-induced osteopetrosis. The examinations demonstrated that rats with pamidronate-induced osteopetrosis displayed increased blood pressure in the marrow cavity. In addition, a disorder in the effect of catecholamines on blood pressure in the marrow cavity of osteopetrotic bone was observed.

Adrenergic alpha-Antagonists↗

PubMed1981

Influence of bursectomy on bone growth and anemia induced by avian osteopetrosis viruses.

This study examines the contribution of the bursa of Fabricius to the pathogenic manifestations of two myeloblastosis-associated viruses which primarily cause osteopetrosis [MAV-1(O) and MAV-2(O)]. MAV-2(O) infection of surgically bursectomized 1-month-old chicks resulted in a rapidly fatal anemia whereas infection of untreated chicks of the same age resulted in a transient drop in hematocrit. Surgical bursectomy of embryos before or after embryonal infection with MAV-2(O) did not alter the course of osteopetrosis, indicating that the bursa was not a source of target cells. Bursectomy prolonged the period of susceptibility to MAV-2(O) induced osteopetrosis until one day posthatching; untreated chicks were not susceptible to osteopetrosis induction at that age. MAV-1(O) infection of eight-day-old bursectomized chicks resulted in osteopetrosis in the absence of anemia; untreated eight-day-old chicks infected with MAV-1(O) showed no effects of virus infection. A role for the bursa in MAV-2(O) infection was found in the participation of neutralizing antibodies in the recovery from anemia. A single dose of antiviral antibody was found to prevent the appearance of anemia. The protective effect of antiviral antibody was dose dependent, and antiserum administration had to be initiated within three days after virus in order to be effective. Antiviral antibody against MAV-1(O) did not protect against MAV-2(O)-induced anemia, suggesting subgroup specificity. These results suggest that the bursa does not provide a stem cell which participates in the bone hyperplasia induced by MAV-1(O) and MAV-2(O). Rather, the humoral antibodies provided by cells derived from the bursa may serve to eliminate viremia and limit virus-specific cytopathogenic effects.

Age Factors↗

PubMed1998

Aberrant regulation of bone trace elements in motheaten and osteopetrosis mutant mice.

Increasing numbers of genetic diseases involving bone development and models for these diseases have been identified recently. Analysis of these bone diseases have revealed that regulated action of multiple growth factors and subsequent signal transduction are essential for normal bone formation. In this paper, two murine mutant mice viable motheaten and osteopetrosis are analyzed. Mice with the recessive 'viable motheaten' mutation express a severe immunodeficiency syndrome and bone defects. Mutations at the motheaten locus were shown to be the result of aberrant splicing of the gene encoding hematopoietic cell phosphatase (Hcph). Mice homozygous for the osteopetrosis mutation develop congenital osteopetrosis due to a severe deficiency of osteoclasts. It has been recognized that bone trace element composition analysis helps to define bone-related physiological conditions. We have analyzed bone trace element composition in viable motheaten and osteopetrosis mutant animal models in this study. In order to gain insights into the effects of particular genetic defects on bone trace element composition, inductively coupled plasma atomic emissions spectrometry (ICP-AES) analysis was performed. Marked changes in bone trace element levels were found in limb bones of viable motheaten and osteopetrosis mutant mice. An assessment of these trace element spectrum in the two mutant models with respect to each genetic defects are discussed in this paper.

Animals↗

PubMed1977

Osteopetrosis in the toothless (t1) rat: presence of osteoclasts but failure to respond to parathyroid extract or to be cured by infusion of spleen or bone marrow cells from normal littermates.

Osteoclast have been observe for the first time in toothless (t1) rats, a mutation with inherits osteopetrosis as an autosomal recessive. The ability of t1 rats to raise the serum calcium concentration after injection of parathyroid extract was severely limited when compared with normal littermates. In addition, osteopetrosis in t1 rats is not cured by radiation and infusion of normal spleen or bone marrow cells from normal littermates, a method know to cure osteopetrosis in mutants of this and other species. This indirect evidence for a reduction in bone resorption as a cause of osteopetrosis in this mutation and the failure of transplanted cells to cure the disease are discussed in relation to the development and function of osteoclasts.

Animals↗

PubMed1984

Osteoclast populations in congenital osteopetrosis: additional evidence of heterogeneity.

Osteopetrosis is a metabolic bone disease characterized by excessive accumulation of skeletal mass due to a reduction in bone resorption. The pathogenesis of osteopetrosis is reduced osteoclast function. Reports of osteoclast numbers in several mammalian mutations exhibiting osteopetrosis have shown them to be increased, decreased, or normal in numbers. The present investigation quantitated the osteoclast populations and examined the cytology of osteoclasts by light microscopy in calvarial and tibial sites in one rabbit and two mouse mutations and compared them with their normal littermates. Our observations show that osteoclast numbers are, depending on the particular mutation, increased, decreased, or comparable to those found in normal littermates. In each mutation, however, osteoclasts fail to exhibit the cytoplasmic vacuolization next to bone surfaces seen in normal osteoclasts. These data provide additional evidence of heterogeneity in the congenital mammalian osteopetrosis and suggest that these mutations may be significant sources of new information about the biology of osteoclasts.

Animals↗

PubMed1996

Animal models of osteopetrosis: the impact of recent molecular developments on novel strategies for therapeutic intervention.

Osteopetrosis comprises a group of rare metabolic diseases of skeletal development that are characterized by a generalized increase in skeletal mass resulting from reduced osteoclast-mediated bone resorption. Specific immune regulators and growth factors that influence osteoclast ontogeny and/or activation have been implicated in the pathogenesis of some of the naturally occurring mutations associated with osteopetrosis in animals. Most recently, loss-of-function experiments using transgenic mice with targeted disruptions of the c-src or c-fos proto-oncogenes have resulted in different osteoclast abnormalities that produce osteopetrosis. The information gained from these mutations in animals should continue to provide new understanding of the molecular defects associated with osteopetrosis, and to broader aspects of skeletal pathology; this should result in more effective therapeutic intervention in humans.

Animals↗

PubMedDate not supplied

Neonatal reductions in osteoclast number and function account for the transient nature of osteopetrosis in the rat mutation microphthalmia blanc (mib).

We have examined the general and skeletal manifestations of osteopetrosis in a new, mild osteopetrotic mutation in the rat, microphalmia blanc (mib). Newborn mutant (mib) rats exhibit the typical skeletal deformities and sclerosis of osteopetrosis at birth, which are reduced significantly during the first postnatal month but don't disappear entirely up to 8 months later. Osteoclast numbers, staining for TRAP and TraATPase, and bone resorption are reduced in mutants during the first 2 postnatal weeks but improve by 1 month. In mutants, serum concentrations of calcium and phosphorus are normal, but 1,25(OH)2 D levels are higher at 1 week than those in normal littermates. Neonatally, mutants exhibit extramedullary hemopoiesis in the spleen. These results are interpreted to mean that the transient perinatal skeletal sclerosis in mib rats is caused by reduced production and function of osteoclasts in this period. The recent description of transient, perinatal osteopetrosis in a child suggests that analyses of the early differences between mild and severe animal mutations might distinguish those children with osteopetrosis who need treatment from those who do not.

Aging↗

PubMed2005

Total joint arthroplasty in patients with osteopetrosis: a report of 5 cases and review of the literature.

Osteopetrosis, an inherited disorder of bone metabolism, is associated with multiple musculoskeletal complications. Two of these problems, osteoarthritis and periarticular nonunions, may be considered for treatment with total joint arthroplasty. However, there is little information on the early and longer-term results, complications, and technical difficulties related to performing arthroplasty in patients with osteopetrosis. We report the results of 3 total hip arthroplasties and 2 total knee arthroplasties in patients with osteopetrosis. These cases in combination with a literature review provide further insight into results, complications, and technical challenges of performing total joint arthroplasty in patients with osteopetrosis.

Adult↗

PubMed1996

Managing osteopetrosis in children: a nutrition challenge.

Osteopetrosis, a rare condition caused by a failure of osteoclasts to resorb bone, results in dense and deformed bones, growth failure, anemia, hypoplastic dentition, chronic infection, blindness, and massive splenomegaly. Children with infantile osteopetrosis have disease-related complications that affect nutritional status. Altered calcium and phosphorus intake has been reported in these patients, but previous studies did not include an assessment of dietary adequacy or nutrition-related complications. A prospective study of six children with severe infantile osteopetrosis was conducted to identify specific nutrition-related problems and effective nutrition intervention strategies. Patients were monitored by a registered dietitian while they participated in a clinical research protocol at St Jude Children's Research Hospital. Dietary records for each patient were obtained at set intervals during the 4-month study period. Because most patients lacked adequate dentition, they had difficulty obtaining adequate nutrition through normal oral intake. Three children required nutrition supplementation (enteral feedings for one and oral supplements for two). We conclude that oral and enteral nutrition support can provide nutrients needed for improved growth and response to treatment in patients with osteopetrosis.

Adolescent↗

PubMed1999

Human malignant osteopetrosis: pathophysiology, management and the role of bone marrow transplantation.

Osteopetrosis is a heterogeneous group of diseases characterized by lack of osteoclast function. Osteopetrosis is found spontaneously in most mammalian species and many transgenic animals have been created, but so far no animal model has been found that genetically corresponds to human malignant autosomal recessive osteopetrosis. The only curative treatment for malignant osteopetrosis is bone marrow transplantation. A review of the literature and preliminary data from IBMTR shows that infants transplanted with marrow from an HLA-identical sibling or unrelated volunteer donor have an actuarian five-year survival with a functioning graft of 50-70%, while those transplanted with a T-cell-depleted mismatched marrow have a very poor survival of only about 10%.

Animals↗

PubMed1998

Hematopoietic stem cell transplantation for infantile osteopetrosis.

Infantile osteopetrosis is a lethal disorder resulting from a severe defect in the ability of osteoclasts to resorb bone. The only therapy shown to be capable of providing lasting benefit is allogeneic hematopoietic stem cell transplantation (HCT). We report the outcome of 10 patients with infantile malignant osteopetrosis treated with HCT from an HLA A, B, DRB1 matched (n=6) or A or B locus mismatched (n=4) family member or unrelated donor at the University of Minnesota between 1978 and 1997. Eight of 10 patients achieved primary engraftment; secondary graft failure was seen in two patients. Five of 10 patients survive; three with full or partial donor chimerism and two with autologous hematological recovery. Transient or partial donor chimerism can be sufficient to correct the hematological manifestations of osteopetrosis. We recommend early referral for consideration of HCT with a related or unrelated donor as neurosensory manifestations of osteopetrosis are generally not reversible. Donor engraftment may be easier to achieve early in the course of the disease.

Child, Preschool↗

PubMed1998

Early VEP and ERG evidence of visual dysfunction in autosomal recessive osteopetrosis.

Autosomal recessive (AR) osteopetrosis has a rapid course and manifests in the first months of life. Visual loss occurs because of optic nerve compromise, and more rarely retinal dysfunction (which may be a part of a primary neurodegeneration). The only curative treatment currently available is bone marrow transplantation (BMT). It has been suggested that BMT is contraindicated if AR osteopetrosis is associated with a primary neurodegeneration. Visual impairment tends to be irreversible after BMT. The young age of the patients makes reliable, objective tests of visual function especially important. We have reviewed the flash electroretinograms (ERGs) and flash and pattern visual evoked potentials (VEPs) recorded without sedation from 15 patients with AR osteopetrosis, 11 of whom were recorded longitudinally. The most frequent, early indication of visual dysfunction was a delay in the pattern or flash VEP latency. This first affects the pattern reversal VEP to small checks. Importantly this often preceded fundal changes of optic disc pallor, and evidence of optic nerve compression on neuroimaging. Only two patients had ERG evidence of retinal dysfunction affecting both rods and cones. One of these patients had a distinctive fundal appearance, but did not have evidence of associated neuronal degenerative disease. The other patient was lost to follow-up. In the patients reviewed in this study successful BMT and optic nerve decompression did not result in VEP improvement. Fundoscopy, VEP and ERG testing are indicated when the diagnosis of AR osteopetrosis is suspected and provide a useful means of monitoring visual involvement.

Bone Marrow Transplantation↗

PubMed1995

Long-term treatment of osteopetrosis with recombinant human interferon gamma.

BACKGROUND: Congenital osteopetrosis is a rare osteosclerotic bone disease characterized by both a defect in osteoclastic function and reduced generation of superoxide by leukocytes. The disease is frequently fatal during the first decade of life. A six-month trial of therapy with recombinant human interferon gamma-1b in eight patients with osteopetrosis provided evidence of benefit, prompting this study of more prolonged therapy. METHODS: We studied 14 patients with severe osteopetrosis treated with subcutaneous injections of recombinant human interferon gamma-1b (1.5 micrograms per kilogram of body weight per dose) three times per week for at least 6 months; 11 patients were treated for 18 months. We assessed the effect of therapy by evaluating the patients' clinical status, measuring blood counts and biochemical markers of bone turnover, and performing bone marrow imaging and bone biopsies. RESULTS: After 6 months of therapy, all 14 patients had decreases in trabecular-bone area (determined by histomorphometric analysis of bone-biopsy specimens) and increases in bone marrow space (determined by marrow imaging), and the improvement was sustained in the 11 patients treated for 18 months. The mean (+SD) hemoglobin concentration increased from 7.5 +/- 2.9 to 10.5 +/- 0.3 g per deciliter (P = 0.05), and superoxide generation by granulocyte-macrophage colonies increased (P < 0.001) after 18 months of therapy. In six patients for whom pretreatment data were available, there was a 96 percent decrease in the frequency of infections requiring antibiotic therapy during interferon treatment. There were no side effects necessitating the discontinuation of therapy. CONCLUSIONS: Long-term therapy with interferon gamma in patients with osteopetrosis increases bone resorption and hematopoiesis and improves leukocyte function.

Adult↗