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American Journal of Human Genetics Sep 2021Coatomer complexes function in the sorting and trafficking of proteins between subcellular organelles. Pathogenic variants in coatomer subunits or associated factors...
Coatomer complexes function in the sorting and trafficking of proteins between subcellular organelles. Pathogenic variants in coatomer subunits or associated factors have been reported in multi-systemic disorders, i.e., coatopathies, that can affect the skeletal and central nervous systems. We have identified loss-of-function variants in COPB2, a component of the coatomer complex I (COPI), in individuals presenting with osteoporosis, fractures, and developmental delay of variable severity. Electron microscopy of COPB2-deficient subjects' fibroblasts showed dilated endoplasmic reticulum (ER) with granular material, prominent rough ER, and vacuoles, consistent with an intracellular trafficking defect. We studied the effect of COPB2 deficiency on collagen trafficking because of the critical role of collagen secretion in bone biology. COPB2 siRNA-treated fibroblasts showed delayed collagen secretion with retention of type I collagen in the ER and Golgi and altered distribution of Golgi markers. copb2-null zebrafish embryos showed retention of type II collagen, disorganization of the ER and Golgi, and early larval lethality. Copb2 mice exhibited low bone mass, and consistent with the findings in human cells and zebrafish, studies in Copb2 mouse fibroblasts suggest ER stress and a Golgi defect. Interestingly, ascorbic acid treatment partially rescued the zebrafish developmental phenotype and the cellular phenotype in Copb2 mouse fibroblasts. This work identifies a form of coatopathy due to COPB2 haploinsufficiency, explores a potential therapeutic approach for this disorder, and highlights the role of the COPI complex as a regulator of skeletal homeostasis.
Topics: Animals; Ascorbic Acid; Bone and Bones; Brain; Child; Child, Preschool; Coat Protein Complex I; Coatomer Protein; Collagen Type I; Developmental Disabilities; Embryo, Nonmammalian; Endoplasmic Reticulum; Female; Fibroblasts; Gene Expression Regulation, Developmental; Golgi Apparatus; Haploinsufficiency; Humans; Intellectual Disability; Male; Mice; Osteoporosis; RNA, Small Interfering; Severity of Illness Index; Zebrafish
PubMed: 34450031
DOI: 10.1016/j.ajhg.2021.08.002 -
Archives of Disease in Childhood Feb 1971Two cases of idiopathic juvenile osteoporosis are described; one with the mild form of the disease, and the other with the severe form. The common findings were pain in...
Two cases of idiopathic juvenile osteoporosis are described; one with the mild form of the disease, and the other with the severe form. The common findings were pain in the feet or in the lumbar spine, with a negative calcium balance. Phosphorus balance was negative only in the child with the severe form of the disease.
Topics: Adolescent; Back Pain; Calcium; Child; Female; Foot Diseases; Humans; Lumbar Vertebrae; Osteoporosis; Pain; Phosphorus; Radiography
PubMed: 4252209
DOI: 10.1136/adc.46.245.66 -
Turkish Archives of Pediatrics May 2023Primary osteoporosis is a rare and essential problem in childhood that can cause severe skeletal deformities. We aimed to reveal the spectrum of primary osteoporosis and...
OBJECTIVE
Primary osteoporosis is a rare and essential problem in childhood that can cause severe skeletal deformities. We aimed to reveal the spectrum of primary osteoporosis and assess the effectiveness and safety of bisphosphonates in increasing bone mineral density and reducing fractures.
MATERIALS AND METHODS
Patients with primary osteoporosis who received at least one course of pamidronate or zoledronic acid were included in the study. Patients were divided into 2 groups, osteogenesis imperfecta and non-osteogenesis imperfecta subjects. We evaluated bone densitometer parameters, activation scores, pain status, deformity status, and the number of fractures per year in all patients.
RESULTS
Of the 31 patients, 21 with osteogenesis imperfect, 3 patients with spondyloocular syndromes, 2 with Bruck Syndrome, and 5 with idiopathic juvenile osteoporosis were included. A total of 21 patients had received pamidronate treatment, while only 4 received zoledronic acid, and 6 of them switched from pamidronate to zoledronic acid. At the end of the treatment, the mean bone mineral density height-adjusted Z-score increased from -3.39 ± 1.30 to -0.95 ± 1.34. The number of fractures per year decreased from 2.28 ± 2.67 to 0.29 ± 0.69. The activation score increased from 2.81 ± 1.47 to 3.16 ± 1.48. The pain decreased significantly. There was no difference in bone mineral density increase in patients treated with pamidronate or zoledronic acid.
CONCLUSION
Those with osteogenesis imperfecta were diagnosed at an earlier age with severe deformity and fractures. Pamidronate and zoledronic acid increased bone mineral density in all types of primary osteoporosis.
PubMed: 37144266
DOI: 10.5152/TurkArchPediatr.2023.22248 -
Annals of Pediatric Endocrinology &... Jun 2021Osteoporosis is a skeletal disorder characterized by reduced bone mass that results in increased risk of fractures. Pediatric osteoporosis can be caused by monogenic...
PURPOSE
Osteoporosis is a skeletal disorder characterized by reduced bone mass that results in increased risk of fractures. Pediatric osteoporosis can be caused by monogenic diseases, chronic diseases, and/or their treatment. This study was performed to investigate the effect of pamidronate infusion on osteoporosis in children and adolescents.
METHODS
This study included 13 unrelated pediatric patients (10 males and 3 females) whose bone mineral density (BMD) z-score was <-2.0. Pamidronate was administered intravenously at a dosage of 1 mg/kg for 3 consecutive days every 4 months. Clinical and biochemical findings were reviewed retrospectively. The BMD values of the lumbar spine and femoral neck were assessed by dual energy x-ray absorptiometry at baseline and annually.
RESULTS
The underlying diseases were immobilization (62%), inflammatory bowel disease (23%), protein-losing enteropathy (8%), and idiopathic juvenile osteoporosis (8%). The mean age at the start of treatment was 12.7±4.3 years. Duration of treatment ranged from 12-50 months. The baseline height-standard deviation score (SDS) and weight-SDS were -2.01±2.08 and -2.60±1.62, respectively. The lumbar spine BMD z-scores improved significantly after 1 year of pamidronate treatment, but the femoral neck BMD z-scores did not. However, both z-scores had significantly increased by the end of treatment.
CONCLUSION
This study demonstrated that pamidronate treatment increased BMD in pediatric patients with osteoporosis with no significant adverse events. Further studies are required to better define the long-term efficacy and safety of pamidronate therapy in a large number of pediatric patients.
PubMed: 34218632
DOI: 10.6065/apem.2040150.075 -
BMJ Case Reports Sep 2017Osteoporosis in childhood is uncommon, and it may be secondary to a spectrum of diverse conditions. Idiopathic juvenile osteoporosis is a primary osteoporosis of unknown...
Osteoporosis in childhood is uncommon, and it may be secondary to a spectrum of diverse conditions. Idiopathic juvenile osteoporosis is a primary osteoporosis of unknown aetiology present in previously well children and is a diagnosis of exclusion. We describe a 10-year-old prepubertal boy who presented with back pain of 1-week duration. His spinal X-ray showed generalised loss of vertebral body heights in keeping with osteoporosis. Endocrine and haematological work-up were normal. He was treated with vitamin D supplement and intravenous pamidronate. This case illustrates the general work-up and causes for paediatric osteoporosis, and the management for idiopathic juvenile osteoporosis.
Topics: Administration, Intravenous; Back Pain; Bone Density Conservation Agents; Child; Diagnosis, Differential; Diphosphonates; Humans; Male; Osteoporosis; Pamidronate; Radiography; Spine; Treatment Outcome; Vitamin D
PubMed: 28866630
DOI: 10.1136/bcr-2017-220700 -
International Journal of Surgery Case... 2015Idiopathic Juvenile Osteoporosis is an uncommon condition that has few case reports in the literature. Reported series indicate that it is a condition classically...
INTRODUCTION
Idiopathic Juvenile Osteoporosis is an uncommon condition that has few case reports in the literature. Reported series indicate that it is a condition classically accompanying vertebral and metaphyseal fractures during the immediate pre-puberty years but that seems to develop naturally during puberty. Current clinical treatment is complicated because of lack of understanding on the origins of Idiopathic Juvenile Osteoporosis.
PRESENTATION OF CASE
The 13-year-old female patient with no former complaints had pain in her left hip while walking 2 years ago. Excluding the secondary osteoporosis reasons, the patient was diagnosed with Idiopathic Juvenile Osteoporosis and after the medical treatment she was followed-up.
DISCUSSION
The patient was subjected to a rehabilitation program for muscle weakness. She had difficulty in walking as a result of prolonged immobilization. At the end of a two-year treatment, significant improvement was achieved in muscle strength in the extremities, walking distance, and posture.
CONCLUSION
With this report, we would like to raise awareness about a possible association of persistent fractures with this rare metabolic disorder, Idiopathic Juvenile Osteoporosis, which should be included in differential diagnosis of patients with persistent appendicular skeleton fractures.
PubMed: 25768278
DOI: 10.1016/j.ijscr.2015.02.043 -
Hormone Research in Paediatrics 2015Recent developments in genetic technology have given us the opportunity to look at diseases in a new and more detailed way. This Mini Review discusses monogenetic forms... (Review)
Review
Recent developments in genetic technology have given us the opportunity to look at diseases in a new and more detailed way. This Mini Review discusses monogenetic forms of childhood-onset primary osteoporosis, with the main focus on osteoporosis caused by mutations in WNT1 and PLS3, two of the most recently discovered genes underlying early-onset osteoporosis. The importance of WNT1 in the accrual and maintenance of bone mass through activation of canonical WNT signaling was recognized in 2013. WNT1 was shown to be a key ligand for the WNT-signaling pathway, which is of major importance in the regulation of bone formation. More recently, mutations in PLS3, located on the X chromosome, were shown to be the cause of X-linked childhood-onset primary osteoporosis affecting mainly males. The function of PLS3 in bone metabolism is still not completely understood, but it has been speculated to have an important role in mechanosensing by osteocytes and in matrix mineralization. In this new era of genetics, our knowledge on genetic causes of childhood-onset osteoporosis expands constantly. These discoveries bring new possibilities, but also new challenges. Guidelines are needed to implement this new genetic knowledge to clinical patient care and to guide genetic investigations in affected families.
Topics: Bone Density; Heterozygote; Humans; Membrane Glycoproteins; Microfilament Proteins; Mutation; Osteoporosis; Signal Transduction; Wnt1 Protein
PubMed: 26517534
DOI: 10.1159/000439566 -
Pediatric Rheumatology Online Journal 2013Idiopathic juvenile osteoporosis (IJO) is a rare condition of poorly understood etiology and pathophysiology that affects otherwise healthy children. This condition is...
BACKGROUND
Idiopathic juvenile osteoporosis (IJO) is a rare condition of poorly understood etiology and pathophysiology that affects otherwise healthy children. This condition is characterized clinically by bone pain and vertebral fractures; spontaneous recovery is observed after puberty in the majority of cases. Although decreased trabecular bone turnover has been noted previously, cortical and trabecular bone characteristics as determined by quantitative computed tomography (QCT) and their relationship to bone histomorphometry are unknown.
METHODS
All children with a clinical diagnosis of IJO who were followed in our center since 1995 and who had undergone at least one diagnostic bone biopsy were included in this cross-sectional analysis.
RESULTS
Fifteen patients (11 males/4 females) with median ages of 5.8 and 10.2 years at first symptoms and at referral, respectively, were included in the analysis. Histomorphometric analysis demonstrated decreased trabecular bone turnover (BFR/BS) in the majority of patients with heterogeneous parameters of trabecular mineralization and volume. QCTresults demonstrated that bone mineral density (BMD) was reduced in both trabecular/lumbar and cortical/femoral bone: Z score: -2.1 (-3.6;-1.0) and -0.9 (-8.2;1.4)in the two compartments, respectively. In the eight patients who underwent both bone biopsy and QCT, cortical BMD was associated with trabecular separation and with trabecular bone formation rate (r = 0.898 and -0.881, respectively, both p < 0.05).
CONCLUSIONS
This series confirms that IJO is characterized by impaired trabecular architecture that can be detected by both bone biopsy and QCT. The association between bone biopsy and QCT results may have implications for diagnosis, treatment, and follow-up of these children.
PubMed: 23418950
DOI: 10.1186/1546-0096-11-6 -
Anales de Pediatria (Barcelona, Spain :... Sep 2013
Topics: Child; Humans; Male; Osteoporosis
PubMed: 23490432
DOI: 10.1016/j.anpedi.2013.01.019 -
Postgraduate Medical Journal Aug 1977Osteoporosis is defined as 'too little normal bone', the disorder being rarer in children than adults. The varied forms in childhood can be classified as those secondary...
Osteoporosis is defined as 'too little normal bone', the disorder being rarer in children than adults. The varied forms in childhood can be classified as those secondary to some other disease and primary forms of the disorder which include the genetically determined osteogenesis imperfecta types and idiopathic forms of osteoporosis. A plea is made for greater clinical application in attempting to discriminate differing forms of these primary disorders. Osteogenesis imperfecta it is argued is a heterogeneous condition with the evidence favouring both dominantly and recessively transmitted forms in different kindreds. Another possible osteogenesis imperfecta variant is characterized by dwarfing, scoliosis and peculiar cystic lesions of the proximal humeri. Idiopathic juvenile osteoporosis is a term reserved for the acute osteoporosis beginning in the immediate prepubertal years and may differ in its cause from idiopathic osteoporosis beginning rather earlier in childhood. It is emphasized that immobilization osteoporosis is of very great importance and may become superimposed upon other osseous dysplasias. A complete understanding of these conditions will be helped by elucidation of the basic underlying defects in collagen and other constituents of bone matrix.
Topics: Adolescent; Calcium; Child; Child, Preschool; Humans; Infant; Infant, Newborn; Leukemia; Lymphoma; Osteogenesis Imperfecta; Osteoporosis; Radiography
PubMed: 917959
DOI: 10.1136/pgmj.53.622.450