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Access Microbiology 2023() is a Gram-positive coccus of the family . It can be found in a variety of vegetables and dairy products. is an opportunistic pathogen with intrinsic resistance to...
() is a Gram-positive coccus of the family . It can be found in a variety of vegetables and dairy products. is an opportunistic pathogen with intrinsic resistance to vancomycin and teicoplanin. In this case report, we discuss a rare case of -associated bacteraemia in a patient with osteopetrosis. A 4-year-old girl was admitted to the paediatric emergency department with acute fever without other signs. Blood culture revealed an infection with . Using the streptococcus antibiogram, the isolate was resistant to vancomycin, teicoplanin, rifampicin and sulfamethoxazole-trimethoprim but sensitive to β-lactams, gentamicin, streptomycin, azithromycin, clarithromycin, lincomycin, clindamycin and erythromycin. The patient was treated with intravenous ceftriaxone and gentamicin, and subsequently with oral amoxicillin. After a favourable course, she was discharged from the hospital on the 10th day. The modes of transmission and physiopathology of remain unknown. Factors associated with this infection include compromised immunity, previous antibiotic therapy especially with vancomycin, and application of a central venous catheter. In our patient, the risk factors for infection were pancytopenia and multiple transfusions used to treat bone marrow failure. The source of the bacteraemia could have been the cutaneous route, but it could also have been digestive due to the reservoir of the bacteria. is known as an opportunistic bacterium. Further studies on its pathogenesis and other risk factors are needed to understand the true prevalence of this potentially fatal bacterium in compromised individuals, such as the case of our patient.
PubMed: 37970073
DOI: 10.1099/acmi.0.000439 -
Surgical Neurology International 2023Osteopetrosis is a rare disease characterized by systemic osteosclerosis and hematopoietic disturbances. Childhood-onset cases are often accompanied by hydrocephalus and...
BACKGROUND
Osteopetrosis is a rare disease characterized by systemic osteosclerosis and hematopoietic disturbances. Childhood-onset cases are often accompanied by hydrocephalus and craniosynostosis; however, there have been no established treatments. We performed cranial distraction in a child with osteopetrosis who presented with craniosynostosis and intracranial hypertension.
CASE DESCRIPTION
The patient was a 4-year-1-month-old boy. His pregnancy and birth were normal, but at 4 months of age, he was diagnosed with osteopetrosis based on generalized osteosclerosis and family history. A computed tomography scan of the head revealed early sagittal suture fusion and ventricular enlargement. A ventriculoperitoneal shunt was placed for intracranial hypertension; however, slit ventricle syndrome ensued and pansynostosis developed. To improve uncontrolled high intracranial pressure, cranial distraction was performed for intracranial volume expansion. No perioperative hemorrhagic or infectious complications were observed. After the start of distraction, the intracranial pressure gradually decreased, and clinical findings such as disturbance of consciousness and bradycardia disappeared. Bone regeneration in the defect site was good, and the extension device was removed 6 months after the operation.
CONCLUSION
For osteopetrosis with poorly controlled intracranial hypertension, cranial distraction was considered to be an effective treatment.
PubMed: 37941624
DOI: 10.25259/SNI_623_2023 -
The Journal of Physiology Dec 2023ClC-6 and ClC-7 are closely related, intracellular Cl /H antiporters belonging to the CLC family of channels and transporters. They localize to acidic late endosomes and...
ClC-6 and ClC-7 are closely related, intracellular Cl /H antiporters belonging to the CLC family of channels and transporters. They localize to acidic late endosomes and lysosomes and probably function in ionic homeostasis of these contiguous compartments. ClC-7 transport function requires association with the accessory protein Ostm1, whereas ClC-6 transport does not. To elucidate their roles in endo-lysosomes, we measured Cl - and pH-dependences of over-expressed wild-type ClC-6 and ClC-7, as well as disease-associated mutants, using high-resolution recording protocols. Lowering extracellular Cl (corresponding to luminal Cl in endo-lysosomes) reduced ClC-6 currents, whereas it increased transport activity of ClC-7/Ostm1. Low extracellular Cl activated ClC-7/Ostm 1 under acidic extracellular conditions, as well as under conditions of low intracellular chloride. Activation is conserved in ClC-7 , a variant displaying disrupted PI(3,5)P inhibition. Detailed biophysical analysis of disease-associated ClC-6 and ClC-7 gain-of-function (GoF) variants, ClC-6 and ClC-7 , and the ClC-7 and ClC-6 correlates, identified additional functional nuances distinguishing ClC-6 and ClC-7. ClC-7 recapitulated GoF produced by ClC-6 . ClC-6 displayed transport activation qualitatively similar to ClC-7 , although current density did not differ from that of wild-type ClC-6. Finally, rClC-7 , homologous to hClC-7 , an osteopetrosis variant with fast gating kinetics, appeared indifferent to extracellular Cl , identifying altered Cl sensitivity as a plausible mechanism underlying disease. Collectively, the present studies underscore the distinct roles of ClC-6 and ClC-7 within the context of their respective localization to late endosomes and lysosomes. In particular, we suggest the atypical inhibition of ClC-7 by luminal Cl serves to limit excessive intraluminal Cl accumulation. KEY POINTS: ClC-6 and ClC-7 are late endosomal and lysosomal 2 Cl /1 H exchangers, respectively. When targeted to the plasma membrane, both activate slowly at positive voltages. ClC-6 activity is decreased in low extracellular (i.e. luminal) chloride, whereas ClC-7 is activated by low luminal chloride, even at acidic pH. The functional gain-of-function phenotypes of the ClC-6 and ClC-7 disease mutations ClC-6 and ClC-7 are maintained when introduced in their respective homologues, ClC-7 and ClC-6 , with all mutations retaining chloride dependence of the respective wild type (WT). An osteopetrosis mutation of ClC-7 displaying fast gating kinetics (R762Q) was less sensitive to extracellular chloride compared to WT. The opposing substrate dependences of ClC-6 and ClC-7 Cl / H exchangers point to non-overlapping physiological functions, leading us to propose that inhibition of ClC-7 by luminal chloride and protons serves to prevent osmotic stress imposed by hyper-accumulation of chloride.
Topics: Humans; Chloride Channels; Chlorides; Homeostasis; Lysosomes; Osteopetrosis; Protons
PubMed: 37937509
DOI: 10.1113/JP285431 -
Frontiers in Endocrinology 2023Osteosclerotic metaphyseal dysplasia (OSMD, OMIM 615198) is an extremely rare autosomal recessive osteopetrosis disorder resulting in a distinctive pattern of...
BACKGROUND
Osteosclerotic metaphyseal dysplasia (OSMD, OMIM 615198) is an extremely rare autosomal recessive osteopetrosis disorder resulting in a distinctive pattern of osteosclerosis of the metaphyseal margins of long tubular bones. To date, only thirteen cases have been reported (eight molecularly confirmed). Five homozygous sequence variants in the leucine-rich repeat kinase 1 () gene have been identified to cause OSMD. We present two male siblings with OSMD with a novel variant.
CASES
The index case, now aged 6 years, was referred aged 9 months when diffuse sclerosis of the ribs and vertebral bodies, suggestive of osteopetrosis, was incidentally identified on a chest radiograph for suspected lower respiratory tract infection. Parents were consanguineous and of Pakistani origin. Further evaluation revealed developmental delay, nystagmus with bilateral optic nerve hypoplasia and severe visual impairment. Skeletal survey confirmed typical changes of OSMD, with widespread diffuse sclerosis and Erlenmeyer flask deformity of long bones. His older sibling, now aged 12 years, was 7 years at the time of referral and had similar clinical course and skeletal findings. Additionally, he had a chronic progressive osteonecrosis of the left mandible that required debridement, debulking and long-term antibiotics. Skeletal survey revealed findings similar to his sibling. Neither sibling had significant skeletal fractures or seizures. Unlike most previous reports suggesting sparing of the skull and lack of visual impairment, our patients had evidence of osteosclerosis of the cranium. Genetic screening for the common autosomal recessive and dominant pathogenic variants of osteopetrosis was negative. Whole Exome Sequencing (WES) followed by Sanger sequencing, identified a novel homozygous c.2506C>T p. (Gln836Ter) nonsense variant predicted to result in premature truncation of LRRK1 transcript.
CONCLUSION
Our cases confirm the autosomal recessive inheritance and expand the spectrum of genotype and phenotype of OSMD reported in the literature. Increasing reports of variants in this phenotype raise the question of whether should be included in targeted osteopetrosis panels. Bone histology in previous cases has shown this to be an osteoclast rich form of osteopetrosis raising the possibility that haematopoietic stem cell transplantation may be an appropriate treatment modality.
Topics: Humans; Male; Mutation; Optic Nerve; Osteopetrosis; Osteosclerosis; Protein Serine-Threonine Kinases; Ribs; Sclerosis; Vision Disorders; Child
PubMed: 37920250
DOI: 10.3389/fendo.2023.1258340 -
BMJ Case Reports Oct 2023Osteopetrosis encompasses a spectrum of conditions marked by heightened bone density due to faulty osteoclast-mediated bone resorption, leading to an accumulation of...
Osteopetrosis encompasses a spectrum of conditions marked by heightened bone density due to faulty osteoclast-mediated bone resorption, leading to an accumulation of immature bone and thickened cortical structures. This condition gives rise to bone fragility, blood cell irregularities, nerve entrapment and growth challenges, all stemming from disrupted bone remodelling. Craniofacial distinctiveness, encompassing anomalies in the skull and jaw, is a frequent occurrence. Osteopetrosis presents a range of clinical signs, including facial and dental anomalies. The diagnostic process involves thorough clinical and radiological assessments, often obviating the need for genetic testing. Interestingly, few prior reports have delved into the specifics of craniofacial and dental issues in osteopetrosis. The presented case showcases rare occurrence of maxillary osteomyelitis. The diagnosis was established through a combination of history, clinical, radiographic and laboratory findings. The patient declined surgical intervention, leading to the implementation of conservative management involving regular irrigation alongside systemic antibiotic therapy.
Topics: Humans; Female; Osteopetrosis; Osteomyelitis; Maxilla; Skull; Bone Density
PubMed: 37907307
DOI: 10.1136/bcr-2023-257908 -
Zhonghua Er Ke Za Zhi = Chinese Journal... Nov 2023To investigate the clinical presentation and genetic characteristics of malignant infantile osteopetrosis. This was a retrospective case study. Thirty-seven children...
To investigate the clinical presentation and genetic characteristics of malignant infantile osteopetrosis. This was a retrospective case study. Thirty-seven children with malignant infantile osteopetrosis admitted into Beijing Children's Hospital from January 2013 to September 2022 were enrolled in this study. According to the gene mutations, the patients were divided into the CLCN7 group and the TCIRG1 group. Clinical characteristics, laboratory tests, and prognosis were compared between two groups. Wilcoxon test or Fisher exact test were used in inter-group comparison. The survival rate was estimated with the Kaplan-Meier method and the Log-Rank test was used to compare the difference in survival between groups. Among the 37 cases, there were 22 males and 15 females. The age of diagnosis was 0.5 (0.2, 1.0) year. There were 13 patients (35%) and 24 patients (65%) with mutations in CLCN7 and TCIRGI gene respectively. Patients in the CLCN7 group had an older age of diagnosis than those in the TCIRGI group (1.2 (0.4, 3.6) 0.4 (0.2, 0.6) years, =-2.60, =0.008). The levels of serum phosphorus (1.7 (1.3, 1.8) 1.1 (0.8, 1.6) mmol/L, =-2.59, =0.010), creatine kinase isoenzyme (CK-MB) (457 (143, 610) 56 (37, 82) U/L, =-3.38, =0.001) and the level of neutrophils (14.0 (9.9, 18.1) 9.2 (6.7, 11.1) ×10/L, =-2.07, =0.039) at diagnosis were higher in the CLCN7 group than that in the TCIRG1 group. However, the level of D-dimer in the CLCN7 group was lower than that in the TCIRGI group (2.7 (1.0, 3.1) 6.3 (2.5, 9.7) μg/L, =2.83, =0.005). After hematopoietic stem cell transplantation, there was no significant difference in 5-year overall survival rate between the two groups (92.3%±7.4% 83.3%±7.6%, ²=0.56, =0.456). TCIRGI gene mutations are more common in children with osteopetrosis. Children with TCIRGI gene mutations have younger age, lower levels of phosphorus, CK-MB, and neutrophils and higher level of D-dimer at the onset. After hematopoietic stem cell transplantation, patients with CLCN7 or TCIRGI gene mutations have similar prognosis.
Topics: Child; Male; Female; Humans; Osteopetrosis; Retrospective Studies; Prognosis; Genes, Recessive; Phosphorus; Chloride Channels; Vacuolar Proton-Translocating ATPases
PubMed: 37899344
DOI: 10.3760/cma.j.cn112140-20230822-00124 -
Pediatric Health, Medicine and... 2023Leukoerythroblastosis is rarely encountered in clinical practice and is characterized by the presence of leukocytosis and erythroid and myeloid blast cells in peripheral...
Leukoerythroblastosis is rarely encountered in clinical practice and is characterized by the presence of leukocytosis and erythroid and myeloid blast cells in peripheral blood. The most common causes of leukoerythroblastosis in early childhood are viral infection, juvenile myelomonocytic leukemia, and osteopetrosis. To the best of our knowledge, leukoerythroblastic reactions associated with hemolysis have not been previously reported in newborns. Here, we report a 24-hour-old female term newborn diagnosed with a leukoerythroblastic reaction, severe anemia, and neonatal hyperbilirubinemia secondary to Rh incompatibility based on presentation, laboratory determination, and peripheral morphology. A high index of clinical suspicion is required to avoid life-threatening complications among health professionals in the neonatal care unit.
PubMed: 37872980
DOI: 10.2147/PHMT.S430828 -
International Journal of Molecular... Sep 2023Osteopetrosis is a rare inherited disease caused by osteoclast failure, resulting in increasing bone density in humans. Patients with osteopetrosis possess several...
Osteopetrosis is a rare inherited disease caused by osteoclast failure, resulting in increasing bone density in humans. Patients with osteopetrosis possess several dental and cranial complications. Since carbonic anhydrase II (CA-II) deficiency is a major cause of osteopetrosis, CA-II activators might be an attractive potential treatment option for osteopetrosis patients. We conducted comprehensive label-free quantitative proteomics analysis on Fluconazole-treated Dental Pulp Mesenchymal Stem/Stromal Cells from CA-II-Deficient Osteopetrosis Patients. We identified 251 distinct differentially expressed proteins between healthy subjects, as well as untreated and azole-treated derived cells from osteopetrosis patients. Twenty-six (26) of these proteins were closely associated with osteogenesis and osteopetrosis disease. Among them are ATP1A2, CPOX, Ap2 alpha, RAP1B and some members of the RAB protein family. Others include AnnexinA1, 5, PYGL, OSTF1 and PGAM4, all interacting with OSTM1 in the catalytic reactions of HCO3 and the Cl- channel via CAII regulation. In addition, the pro-inflammatory/osteoclast regulatory proteins RACK1, MTSE, STING1, S100A13, ECE1 and TRIM10 are involved. We have identified proteins involved in osteogenic and immune metabolic pathways, including ERK 1/2, phosphatase and ATPase, which opens the door for some CA activators to be used as an alternative drug therapy for osteopetrosis patients. These findings propose that fluconazole might be a potential treatment agent for CAII- deficient OP patients. Altogether, our findings provide a basis for further work to elucidate the clinical utility of azole, a CA activator, as a therapeutic for OP.
Topics: Humans; Fluconazole; Osteogenesis; Dental Pulp; Osteopetrosis; Azoles; Metabolic Networks and Pathways; Mesenchymal Stem Cells; rap GTP-Binding Proteins
PubMed: 37762144
DOI: 10.3390/ijms241813841 -
Journal of Pediatric Orthopedics Jan 2024The aim of this study is to determine the demographic data, fracture treatment methods, and medical treatments of patients diagnosed with osteopetrosis in the national...
BACKGROUND
The aim of this study is to determine the demographic data, fracture treatment methods, and medical treatments of patients diagnosed with osteopetrosis in the national registry.
METHODS
Patients with International Classification of Diseases (ICD)-10 code Q78.2 for osteopetrosis between January 1, 2016 and April 11, 2023 were retrospectively reviewed. Data on sex, age at time of diagnosis, fracture history, mortality, and use of medications were evaluated for all patients. In addition, open reduction and internal fixation, closed reduction and internal fixation, closed reduction and casting, and conservative treatment methods were noted. The number of patients requiring deformity surgery was determined. The incidence and prevalence of osteopetrosis were also calculated in this cross-sectional study.
RESULTS
A total of 476 patients diagnosed with osteopetrosis were identified. The mean age at time of diagnosis of these patients was 5.79 ± 5.43 years. A total of 101 patients died. As the age at diagnosis decreased, the mortality rate of the patients increased with statistical significance ( P <0.001). A total of 192 fractures were seen in 121 osteopetrosis patients in this study. Femur fractures were most common among these patients with osteopetrosis. A history of fracture was statistically significantly less common in patients using a combination of vitamin D + calcium compared with patients not using such medication ( P <0.001). In this 7-year cross-sectional study, the incidence was found to be 1 in 416,000 and the prevalence was 0.00199% in the population under 18 years of age.
CONCLUSION
Younger age at diagnosis is associated with higher mortality in patients with osteopetrosis. In addition, the combination of vitamin D and calcium were associated with lower fracture incidence.
LEVEL OF EVIDENCE
Prognostic Level II.
Topics: Humans; Adolescent; Infant; Child, Preschool; Child; Retrospective Studies; Osteopetrosis; Cross-Sectional Studies; Calcium; Turkey; Fracture Fixation, Internal; Femoral Fractures; Vitamin D
PubMed: 37728079
DOI: 10.1097/BPO.0000000000002518 -
Bone Dec 2023Osteopetrosis and related osteoclastic disorders are a heterogeneous group of inherited diseases characterized by increased bone density. The aim of this study is to...
BACKGROUND
Osteopetrosis and related osteoclastic disorders are a heterogeneous group of inherited diseases characterized by increased bone density. The aim of this study is to investigate the molecular spectrum and natural history of the clinical and radiological features of these disorders.
METHODS
28 patients from 20 families were enrolled in the study; 20 of them were followed for a period of 1-16 years. Targeted gene analysis and whole-exome sequencing (WES) were performed.
RESULTS
Biallelic mutations in CLCN7 and TCIRG1 were detected in three families each, in TNFRSF11A and CA2 in two families each, and in SNX10 in one family in the osteopetrosis group. A heterozygous variant in CLCN7 was also found in one family. In the osteopetrosis and related osteoclast disorders group, three different variants in CTSK were detected in five families with pycnodysostosis and a SLC29A3 variant causing dysosteosclerosis was detected in one family. In autosomal recessive osteopetrosis (ARO), a malignant infantile form, four patients died during follow-up, two of whom had undergone hematopoietic stem cell transplantation. Interestingly, all patients had osteopetrorickets of the long bone metaphyses in infancy, typical skeletal features such as Erlenmeyer flask deformity and bone-in-bone appearance that developed toward the end of early childhood. Two siblings with a biallelic missense mutation in CLCN7 and one patient with the compound heterozygous novel splicing variants in intron 15 and 17 in TCIRG1 corresponded to the intermediate form of ARO (IARO); there was intrafamilial clinical heterogeneity in the family with the CLCN7 variant. One of two patients with IARO and distal tubular acidosis was found to have a large deletion in CA2. In one family, two siblings with a heterozygous mutation in CLCN7 were affected, whereas the father with the same mutation was asymptomatic. In WES analysis of three brothers from a family without mutations in osteopetrosis genes, a hemizygous missense variant in CCDC120, a novel gene, was found to be associated with high bone mass.
CONCLUSION
This study extended the natural history of the different types of osteopetrosis and also introduced a candidate gene, CCDC120, potentially causing osteopetrosis.
PubMed: 37704070
DOI: 10.1016/j.bone.2023.116897