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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 -
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 -
Bone Reports Jun 2022To describe the presenting features, bone characteristics and molecular genetics in a large monocentric cohort of children and young adults with idiopathic primary...
AIM
To describe the presenting features, bone characteristics and molecular genetics in a large monocentric cohort of children and young adults with idiopathic primary osteoporosis.
METHODS
Sixty-six patients (19 children, 47 adults; 28 males, 38 females; age at referral: 3.8 to 65 years) diagnosed with primary osteoporosis were included in this study; patients with features of osteogenesis imperfecta or other known syndromes associated with osteoporosis were excluded. For each patient, the following data were collected by retrospective chart review: family and personal history of fracture and osteoporosis, mineral homeostasis parameters and markers of bone formation and resorption, bone mineral density (BMD) of the lumbar spine (LS-BMD), the total body less head (TB-BMD), and total hip levels (TH-BMD) measured by DXA. As part of the initial assessment process, a bone fragility gene panel sequencing was performed in all of these patients.
RESULTS
There was a higher predominance of males in the children (63%) and of females in the adults (66%) (p = 0.030). Compared to the adults, the children had a significantly lower frequency of vertebral fractures (26 57%, p = 0.022) and a higher frequency of peripheral fractures (84 53%; p = 0.019). Bone fragility gene panel sequencing allowed the identification of the heterozygous pathogenic variant in 27% of patients (most frequently in , and or genes) and the heterozygous p.(Val667Met) variant in 11% of them. The frequency of pathogenic variants tended to be higher in the children compared to the adults without reaching statistical significance (42 19%; p = 0.053). The frequency of the p.(Val667Met) variant was similar in children and adults. No significant differences were found regarding the various clinical, biological and radiological characteristics of the patients according to genotype.
CONCLUSION
In this study, we reported the presenting features and bone characteristics in a large cohort of children and young adults with idiopathic primary osteoporosis. Bone fragility gene panel sequencing allowed the identification of genetic variants in a significant proportion of these patients. Molecular diagnosis in these patients is important in order to be able to offer genetic counselling and organise patient management.
PubMed: 35252483
DOI: 10.1016/j.bonr.2022.101176 -
Annals of Pediatric Endocrinology &... Jan 2024Patients with juvenile-onset systemic lupus erythematosus (JSLE) are at a high risk of entering adulthood with disease-related morbidities such as reduced bone mass and...
PURPOSE
Patients with juvenile-onset systemic lupus erythematosus (JSLE) are at a high risk of entering adulthood with disease-related morbidities such as reduced bone mass and osteoporosis. This study aimed to evaluate the clinical characteristics of JSLE and to analyze the factors associated with low bone mineral density (BMD) in these patients.
METHODS
Children and adolescents diagnosed with JSLE at a single hospital in Korea were included. Demographic, clinical, and laboratory data and use of glucocorticoids and disease-modifying anti-rheumatic drugs were collected. Lumbar spine BMD Z-score was measured using dual energy x-ray absorptiometry, and lumbar spine radiographic data were collected.
RESULTS
A total of 29 patients with JSLE were included in this study. Of these patients, seven had a lumbar spine Z-score of -2.0 or lower and were designated as the low BMD group. The differences in the clinical parameters and treatment variables between the low BMD and non-low BMD groups were compared. Higher cumulative glucocorticoid dose, longer glucocorticoid exposure, and higher cumulative hydroxychloroquine dose were associated with low BMD; the main factor was the duration of exposure. There was no significant correlation between BMD and clinical profile, SLE disease activity, or bone metabolism markers.
CONCLUSION
The duration of glucocorticoid exposure, cumulative glucocorticoid dose, and cumulative hydroxychloroquine dose were risk factors for low BMD in patients with JSLE, with the main factor being duration of glucocorticoid exposure. Thus, patients with JSLE should be routinely monitored for low BMD and potential fracture risks, and glucocorticoid-sparing treatment regimens should be considered.
PubMed: 38291762
DOI: 10.6065/apem.2346060.030 -
Case Reports in Women's Health Jul 2021A 33-year-old primiparous woman with progressive idiopathic juvenile osteoporosis (IJO) who had had multiple vertebral compressions and bilateral femoral neck fractures...
A 33-year-old primiparous woman with progressive idiopathic juvenile osteoporosis (IJO) who had had multiple vertebral compressions and bilateral femoral neck fractures since the age of 15 years presented for perinatal management at 11 weeks of gestation. Her vertebral bone mass was 0.634 g/cm before pregnancy. The target calcium intake was set at 800 mg/day. Cephalopelvic disproportion led to the patient having an elective cesarean section at 39 weeks 3 days of gestation and she delivered a female infant weighing 2785 g. After the delivery, her vertebral bone mass had increased to 0.700 g/cm. At 34 years of age, she conceived her second child. With similar perinatal management, she delivered a female infant weighing 2580 g at 38 weeks of gestation by elective cesarean section. Her vertebral bone mass had increased again after the second pregnancy. Few cases of pregnancy complicated by progressive IJO have been reported. However, an uneventful pregnancy course can be expected with proper management, and pregnancy can be a good opportunity to increase bone mass.
PubMed: 34040998
DOI: 10.1016/j.crwh.2021.e00325 -
Annals of Medicine and Surgery (2012) Feb 2021Hajdu Cheney Syndrome (HCS) is a rare skeletal disease characterized by severe, progressive focal bone loss with osteoporosis, variable craniofacial, vertebral anomalies...
INTRODUCTION AND IMPORTANCE
Hajdu Cheney Syndrome (HCS) is a rare skeletal disease characterized by severe, progressive focal bone loss with osteoporosis, variable craniofacial, vertebral anomalies and distinctive facial features. It is inherited as an autosomal dominant disease although sporadic cases have been described in literature. Identifying these cases in clinical practice is important for proper diagnosis and management.
CASE PRESENTATION
We report a case of a 36-year-old male patient presented at metabolic bone disease clinic at the Aga Khan University Hospital with history of multiple fragility fractures and juvenile osteoporosis since childhood. DNA sequence analysis of the NOTCH2 coding sequence revealed a pathogenic variant in NOTCH 2, Exon 34, c.6426_6427insTT (p.Glu2143Leufs*5), consistent with a NOTCH2 related conditions including HCS.
CLINICAL DISCUSSION
The multitude of presentations associated with HCS are linked to the NOTCH2 gene, as Notch signaling is one of the core signaling pathways that control embryonic development. Hence, mutations in the Notch signaling pathway cause developmental phenotypes that affect various organs including the liver, skeleton, heart, eye, face, kidney, and vasculature.
CONCLUSION
To the best of our knowledge, nucleotide mutations of c.6933delT, c.6854delA, c.6787C.T, and c.64246427delTCTG were all determined to be novel, with c.6428T > C being the most common mutation found in literature. The c.6426_6427insTT mutation our patient was found to have via gene sequencing too appears to be a novel mutation, which has not previously been reported in literature.
PubMed: 33520214
DOI: 10.1016/j.amsu.2021.01.041