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The Journal of Clinical Endocrinology... Apr 2024Autosomal dominant osteopetrosis (ADO) is a rare sclerotic bone disease characterized by impaired osteoclast activity, resulting in high bone mineral density and...
CONTEXT
Autosomal dominant osteopetrosis (ADO) is a rare sclerotic bone disease characterized by impaired osteoclast activity, resulting in high bone mineral density and skeletal fragility. The full phenotype and disease burden on patients' daily lives has not been systematically measured.
OBJECTIVE
We developed an online registry to ascertain population-based data on the spectrum and rate of progression of disease and to identify relevant patient centered outcomes that could be used to measure treatment effects and guide the design of future clinical trials.
DESIGN
Cross-sectional data from participants with osteopetrosis were collected using an online REDCap-based database.
PARTICIPANTS
Thirty-four participants with a confirmed diagnosis of ADO, aged 4-84 years.
MAIN OUTCOME MEASURES
Participants aged 18 years and older completed the PROMIS 57, participants aged 8 to 17 years completed the PROMIS Pediatric 49, and parents of participants aged <18 years completed the PROMIS Parent Proxy 49.
RESULTS
Based on the PROMIS 57, relative to the general population, adults with ADO reported low physical function and low ability to participate in social roles and activities, and high levels of anxiety, fatigue, sleep problems, and pain interference. Daily pain medications were reported by 24% of the adult population. In contrast, neither pediatric participants, nor their parent proxy reported a negative impact on health-related quality of life.
CONCLUSIONS
Data from this registry demonstrate the broad spectrum of ADO disease severity and high impact on health-related quality of life in adults with ADO.
PubMed: 38661205
DOI: 10.1210/clinem/dgae285 -
Pediatric Transplantation May 2024Osteopetrosis is a group of geneticall heterogeneous disorders resulting from impaired osteoclast function and bone resorption. The identification of specific genetic...
BACKGROUND
Osteopetrosis is a group of geneticall heterogeneous disorders resulting from impaired osteoclast function and bone resorption. The identification of specific genetic mutations can yield important prognostic and therapeutic implications. Herein, we present the diagnosis and successful application of hematopoietic stem cell transplantation (HSCT) in a patient with osteopetrosis caused by carbonic anhydrase II deficiency (Intermediate osteopetrosis).
CASE PRESENTATION
Herein, we describe a 2.5-year-old male patient born to consanguineous parents who presented at 8-month-old with hydrocephaly, brain shunt, and developmental delay. Later at 9 months old, he was found to have eye disorder such as nystagmus, fracture of the elbow, abnormal skeletal survey, normal cell blood count (CBC), and severe hypocellularity in the bone marrow. Further evaluation showed renal tubular acidosis type 2. Whole-exome sequencing revealed a pathogenic homozygous variant in intron 2 of the carbonic anhydrase 2 gene (CA2) gene (c.232 + 1 G>T). The diagnosis of intermediate autosomal recessive osteopetrosis was established, and allogenic HSCT from his mother, a full-matched related donor (MRD), was planned. The conditioning regimen included Busulfan, Fludarabine, and Rabbit anti-thymocyte globulin. Cyclosporine and Mycophenolate Mofetil were used for graft-versus-host-disease prophylaxis. He Engrafted on day +13, and 95% chimerism was achieved. He is currently doing well without immunosuppressive therapy, now 12 months post HSCT, with normal calcium level and improving visual quality and FISH analysis revealed complete donor chimerism.
DISCUSSION
HSCT could be a promising curative treatment for intermediate osteopetrosis and can provide long-term survival. Ongoing challenges in various aspects of HSCT remain to be addressed.
Topics: Humans; Male; Osteopetrosis; Hematopoietic Stem Cell Transplantation; Child, Preschool; Iran; Carbonic Anhydrase II; Acidosis, Renal Tubular; Transplantation, Homologous; Carbonic Anhydrases; Urea Cycle Disorders, Inborn
PubMed: 38655726
DOI: 10.1111/petr.14689 -
JBMR Plus May 2024The purpose of this study was to identify new independent significant SNPs associated with osteoporosis using data from the Taiwan Biobank (TWBB).
PURPOSE
The purpose of this study was to identify new independent significant SNPs associated with osteoporosis using data from the Taiwan Biobank (TWBB).
MATERIAL AND METHODS
The dataset was divided into discovery (60%) and replication (40%) subsets. Following data quality control, genome-wide association study (GWAS) analysis was performed, adjusting for sex, age, and the top 5 principal components, employing the Scalable and Accurate Implementation of the Generalized mixed model approach. This was followed by a meta-analysis of TWBB1 and TWBB2. The Functional Mapping and Annotation (FUMA) platform was used to identify osteoporosis-associated loci. Manhattan and quantile-quantile plots were generated using the FUMA platform to visualize the results. Independent significant SNPs were selected based on genome-wide significance ( < 5 × 10) and independence from each other (r < 0.6) within a 1 Mb window. Positional, eQTL(expression quantitative trait locus), and Chromatin interaction mapping were used to map SNPs to genes.
RESULTS
A total of 29 084 individuals (3154 osteoporosis cases and 25 930 controls) were used for GWAS analysis (TWBB1 data), and 18 918 individuals (1917 cases and 17 001 controls) were utilized for replication studies (TWBB2 data). We identified a new independent significant SNP for osteoporosis in TWBB1, with the lead SNP rs76140829 (minor allele frequency = 0.055, -value = 1.15 × 10). Replication of the association was performed in TWBB2, yielding a -value of 6.56 × 10. The meta-analysis of TWBB1 and TWBB2 data demonstrated a highly significant association for SNP rs76140829 (-value = 7.52 × 10). In the positional mapping of rs76140829, 6 genes (, , , , , ) were identified through chromatin interaction mapping in mesenchymal stem cells.
CONCLUSIONS
Our GWAS analysis using the Taiwan Biobank dataset unveils rs76140829 in the gene as a key risk variant associated with osteoporosis. This finding expands our understanding of the genetic basis of osteoporosis and highlights the potential regulatory role of this SNP in mesenchymal stem cells.
PubMed: 38655459
DOI: 10.1093/jbmrpl/ziae028 -
European Journal of Medical Genetics Jun 2024Osteopetrosis refers to a group of related rare bone diseases characterized by a high bone mass due to impaired bone resorption by osteoclasts. Despite the high bone... (Review)
Review
Osteopetrosis refers to a group of related rare bone diseases characterized by a high bone mass due to impaired bone resorption by osteoclasts. Despite the high bone mass, skeletal strength is compromised and the risk of fracture is high, particularly in the long bones. Osteopetrosis was classically categorized by inheritance pattern into autosomal recessive forms (ARO), which are severe and diagnosed within the first years of life, an intermediate form and an autosomal dominant (ADO) form; the latter with variable clinical severity and typically diagnosed during adolescence or in young adulthood. Subsequently, the AD form was shown to be a result of mutations in the gene CLCN7 encoding for the ClC-7 chloride channel). Traditionally, the diagnosis of osteopetrosis was made on radiograph appearance alone, but recent molecular and genetic advances have enabled a greater fidelity in classification of osteopetrosis subtypes. In the more severe ARO forms (e.g., malignant infantile osteopetrosis MIOP) typical clinical features have severe consequences and often result in death in early childhood. Major complications of ADO are atypical fractures with delay or failure of repair and challenge in orthopedic management. Bone marrow failure, dental abscess, deafness and visual loss are often underestimated and neglected in relation with lack of awareness and expertise. Accordingly, the care of adult patients with osteopetrosis requires a multidisciplinary approach ideally in specialized centers. Apart from hematopoietic stem cell transplantation in certain infantile forms, the treatment of patients with osteopetrosis, has not been standardized and remains supportive. Further clinical studies are needed to improve our knowledge of the natural history, optimum management and impact of osteopetrosis on the lives of patients living with the disorder.
Topics: Osteopetrosis; Humans; Osteoclasts; Adult; Chloride Channels; Mutation
PubMed: 38593953
DOI: 10.1016/j.ejmg.2024.104936 -
JBMR Plus May 2024Mutations in cause osteopetrosis in humans and rats. The germline and osteoclast conditional deletions of gene in mice lead to defective osteoclast bone resorption and...
Mutations in cause osteopetrosis in humans and rats. The germline and osteoclast conditional deletions of gene in mice lead to defective osteoclast bone resorption and increased trabecular bone mass without overt abnormalities in other organs. As an adaptor protein, pleckstrin homology and RUN domain containing M1 (PLEKHM1) interacts with the key lysosome regulator small GTPase RAB7 via its C-terminal RUBICON homologous (RH) domain. In this study, we have conducted a structural-functional study of the PLEKHM1 RH domain and RAB7 interaction in osteoclasts in vitro. The single mutations of the key residues in the Plekhm1 RH predicted from the crystal structure of the RUBICON RH domain and RAB7 interface failed to disrupt the Plekhm1-Rab7 binding, lysosome trafficking, and bone resorption. The compound alanine mutations at Y949-R954 and L1011-I1018 regions decreased Plekhm1 protein stability and Rab7-binding, respectively, thereby attenuated lysosome trafficking and bone resorption in osteoclasts. In contrast, the compound alanine mutations at R1060-Q1068 region were dispensable for Rab7-binding and Plekhm1 function in osteoclasts. These results indicate that the regions spanning Y949-R954 and L1011-I1018 of Plekhm1 RH domain are functionally important for Plekhm1 in osteoclasts and offer the therapeutic targets for blocking bone resorption in treatment of osteoporosis and other metabolic bone diseases.
PubMed: 38586475
DOI: 10.1093/jbmrpl/ziae034 -
Paediatrics and International Child... Apr 2024Osteopetrosis encompasses rare inherited metabolic bone disorders with defect in the osteoclast activity. Severe forms of presentation such as malignant infantile...
Osteopetrosis encompasses rare inherited metabolic bone disorders with defect in the osteoclast activity. Severe forms of presentation such as malignant infantile osteopetrosis are seen in infants and milder forms in older children. The clinical presentation includes failure to thrive, severe pallor, optic atrophy and hepatosplenomegaly. The disorder is characterised by dense bone on radiography, hence the name marble bone disease. A 10-month-old boy who presented with developmental delay, failure to thrive, nystagmus (which the mother described as wandering eye movements), splenomegaly of 16 cm and hepatomegaly of 8 cm. Investigations demonstrated severe anaemia (5.7 g/dL) and thrombocytopenia (34 x 109/L). Radiological signs which help in the diagnosis include diffuse sclerosis, bone within bone appearance, sandwich vertebrae and Erlenmeyer flask deformity. Plain radiography is an easily available and cost effective tool which can aid in the diagnosis of osteopetrosis.
PubMed: 38577960
DOI: 10.1080/20469047.2024.2335423 -
Journal of Leukocyte Biology Mar 2024Macrophage and osteoclast proliferation, differentiation and survival are regulated by colony-stimulating factor-1 receptor (CSF1R) signaling. Osteopetrosis associated...
Relative contributions of osteal macrophages and osteoclasts to postnatal bone development in CSF1R-deficient rats and phenotype rescue following wild-type bone marrow cell transfer.
Macrophage and osteoclast proliferation, differentiation and survival are regulated by colony-stimulating factor-1 receptor (CSF1R) signaling. Osteopetrosis associated with Csf1 and Csf1r mutations has been attributed to the loss of osteoclasts and deficiency in bone resorption. Here we demonstrate that homozygous Csf1r mutation in rat leads to delayed postnatal skeletal ossification associated with substantial loss of osteal macrophages (osteomacs) in addition to osteoclasts. Osteosclerosis and site-specific skeletal abnormalities were reversed by intraperitoneal transfer of wild-type bone marrow cells (BMT) at weaning. Following BMT, IBA1+ macrophages were detected before TRAP+ osteoclasts at sites of ossification restoration. These observations extend evidence that osteomacs independently contribute to bone anabolism and are required for normal postnatal bone growth and morphogenesis.
PubMed: 38526212
DOI: 10.1093/jleuko/qiae077 -
International Journal of Surgery Case... Apr 2024Osteopetrosis is a rare hereditary disease that can be transmitted in an autosomal recessive or autosomal dominant.
INTRODUCTION
Osteopetrosis is a rare hereditary disease that can be transmitted in an autosomal recessive or autosomal dominant.
CASE REPORT
Here, we report a case of trochanteric fracture in an 18-year-old boy with an anatomical plate. At the last follow-up, 24 months after surgery, the fracture had healed well, and the patient was not restricted in his activities.
DISCUSSION
Osteopetrosis is a rare bone disease that is mainly caused by osteoclast dysfunction. It results from a remodelling defect that leads to hypermineralization of the skeleton, resulting in bone fragility. Both surgical and nonsurgical management have advantages and disadvantages. Thus, open reduction and anatomic plate fixation remain effective management modalities for trochanteric fractures in osteopetrosis patients.
CONCLUSION
For our patient and as described in the literature, the complication rate decreases as some principles are respected with better consolidation of the osteoporotic fracture.
PubMed: 38513419
DOI: 10.1016/j.ijscr.2024.109568 -
Pediatric Radiology Jun 2024Osteopetrosis describes several types of rare sclerosing bone dysplasias of varying clinical and radiographic severity. The classic autosomal dominant subtype emerges... (Review)
Review
Osteopetrosis describes several types of rare sclerosing bone dysplasias of varying clinical and radiographic severity. The classic autosomal dominant subtype emerges most often in adolescence but can present from infancy through adulthood. The autosomal recessive osteopetrosis, or "malignant infantile osteopetrosis," presents in infancy with a grimmer prognosis, though the autosomal dominant forms (often mislabeled as "benign") actually can have life-threatening consequences as well. Often osteopetrosis is detected due to skeletal findings on radiographs performed to evaluate injury or as an incidental finding during evaluation for illness. Given the varied phenotypic severity and presentations at different ages, radiologists play an integral role in the care of these patients both in diagnosis and in clinical evaluation and monitoring. A deeper understanding of the underlying genetic basis of the disease can aid in the radiologist in diagnosis and in anticipation of unique complications. An overview of current clinical management is also discussed.
Topics: Humans; Osteopetrosis; Child; Diagnosis, Differential; Adolescent; Infant
PubMed: 38483591
DOI: 10.1007/s00247-024-05899-4 -
Calcified Tissue International Apr 2024Autosomal Dominant Osteopetrosis type II (ADO2) is a rare bone disease of impaired osteoclastic bone resorption caused by heterozygous missense mutations in the chloride...
Autosomal Dominant Osteopetrosis type II (ADO2) is a rare bone disease of impaired osteoclastic bone resorption caused by heterozygous missense mutations in the chloride channel 7 (CLCN7). Adenylate cyclase, which catalyzes the formation of cAMP, is critical for lysosomal acidification in osteoclasts. We found reduced cAMP levels in ADO2 osteoclasts compared to wild-type (WT) osteoclasts, leading us to examine whether regulating cAMP would improve ADO2 osteoclast activity. Although forskolin, a known activator of adenylate cyclase and cAMP levels, negatively affected osteoclast number, it led to an overall increase in ADO2 and WT osteoclast resorption activity in vitro. Next, we examined cAMP hydrolysis by the phosphodiesterase 4 (PDE4) proteins in ADO2 versus WT osteoclasts. QPCR analysis revealed higher expression of the three major PDE4 subtypes (4a, 4b, 4d) in ADO2 osteoclasts compared in WT, consistent with reduced cAMP levels in ADO2 osteoclasts. In addition, we found that the PDE4 antagonists, rolipram and roflumilast, stimulated ADO2 and WT osteoclast formation in a dose-dependent manner. Importantly, roflumilast and rolipram displayed a concentration-dependent increase in osteoclast resorption activity which was greater in ADO2 than WT osteoclasts. Moreover, treatment with roflumilast rescued cAMP levels in ADO2 OCLs. The key findings from our studies demonstrate that osteoclasts from ADO2 mice exhibit reduced cAMP levels and PDE4 inhibition rescues cAMP levels and ADO2 osteoclast activity dysfunction in vitro. The mechanism of action of PDE4 inhibitors and their ability to reduce the high bone mass of ADO2 mice in vivo are currently under investigation. Importantly, these studies advance the understanding of the mechanisms underlying the ADO2 osteoclast dysfunction which is critical for the development of therapeutic approaches to treat clinically affected ADO2 patients.
Topics: Humans; Mice; Animals; Rolipram; Phosphodiesterase 4 Inhibitors; Osteoclasts; Adenylyl Cyclases; Bone Resorption; Chloride Channels; Aminopyridines; Benzamides; Cyclopropanes
PubMed: 38483547
DOI: 10.1007/s00223-024-01191-7