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Orphanet Journal of Rare Diseases Sep 2023Skeletal dysplasias are a diverse group of rare disorders in the chondro-osseous tissue that can have a significant impact on patient's functionality. The worldwide...
BACKGROUND
Skeletal dysplasias are a diverse group of rare disorders in the chondro-osseous tissue that can have a significant impact on patient's functionality. The worldwide prevalence of skeletal dysplasias at birth is approximately 1:5000 births. To date, disease burden and trends of skeletal dysplasias in the Sri Lankan population have not been described in any epidemiological study. Our aim was to evaluate the burden and the current trends in hospital admissions for skeletal dysplasias in the Sri Lankan population. A retrospective evaluation of hospital admissions for skeletal dysplasia during 2017-2020 was performed using population-based data from the eIMMR database which covers government hospitals in the entire country. The trends in hospital admissions for skeletal dysplasias by calendar year, age, and types of skeletal dysplasia were described using appropriate summary statistics.
RESULTS
Respective crude admission rates of skeletal dysplasias in the years 2017, 2018, 2019 and 2020 were 5.2, 8.1, 8.0, and 6.5 per million population. A female predominance (1.4:1) was noted during the studied period. Of all reported cases the majority (n = 268; 44.2%) were children less than 4 years. Each year, 0-4 years age group represented 40-47% of the total hospital admissions. More than half of the cases were reported from Colombo (28.1%) and Kandy (25.4%) districts combined. 60% of cases were diagnosed as osteogenesis imperfecta (OI). Rising trends were observed in the hospital admissions for osteogenesis imperfecta, achondroplasia and osteopetrosis, while other skeletal dysplasia types collectively showed a relatively stable trend.
CONCLUSION
This preliminary study revealed a female predominance of skeletal dysplasias and a relatively high admission rate of osteogenesis imperfecta in the Sri Lankan population. A distinct trend was not visible in the studied years probably due to the impact on hospital services due to COVID- Pandemic. Future research on the healthcare burden on families affected by skeletal dysplasia is required to better understand the overall cost of care and identify therapies that reduce admission rates. This study highlights the value of analysing population-based data on rare diseases to improve healthcare in low-resource countries.
Topics: Infant, Newborn; Child; Female; Humans; Male; Osteogenesis Imperfecta; Sri Lanka; Retrospective Studies; COVID-19; Osteochondrodysplasias; Hospitals
PubMed: 37684696
DOI: 10.1186/s13023-023-02884-2 -
Molecular Therapy. Nucleic Acids Sep 2023Rare skeletal diseases are still in need of proper clinically available transfection agents as the major challenge for first-in-human translation relates to intrinsic...
Rare skeletal diseases are still in need of proper clinically available transfection agents as the major challenge for first-in-human translation relates to intrinsic difficulty in targeting bone without exacerbating any inherent toxicity due to used vector. SiSaf's silicon stabilized hybrid lipid nanoparticles (sshLNPs) constitute next-generation non-viral vectors able to retain the integrity and stability of constructs and to accommodate considerable payloads of biologicals, without requiring cold-chain storage. sshLNP was complexed with a small interfering RNA (siRNA) specifically designed against the human mRNA. When tested via single intraperitoneal injection in pre-puberal autosomal dominant osteopetrosis type 2 (ADO2) mice, carrying a heterozygous mutation of the gene (), sshLNP, this significantly downregulated the related mRNA levels in femurs at 48 h. Confirmatory results were observed at 2 weeks and 4 weeks after treatments (3 intraperitoneal injections/week), with rescue of the bone phenotype and demonstrating safety. The pre-clinical results will enable advanced preclinical development of RNA-based therapy for orphan and genetic skeletal disorders by safely and effectively delivering biologicals of interest to cure human systemic conditions.
PubMed: 37680985
DOI: 10.1016/j.omtn.2023.08.020 -
Skeletal Radiology Apr 2024A 5-month-old infant with bone findings on x-ray presented an apparent contradiction including findings of both diffusely dense bones and rickets in the context of a...
A 5-month-old infant with bone findings on x-ray presented an apparent contradiction including findings of both diffusely dense bones and rickets in the context of a history and laboratory investigation that suggested leukemia. Next generation gene panel sequencing revealed a TCIRG1 mutation which is consistent with autosomal recessive osteopetrosis. The paradoxical x-ray findings underscore a recently elucidated mechanism for the pathogenesis of a TCIRG mutation. This case highlights the importance of recognizing this radiographic, seeming contradictory, association in the context of a confusing clinical presentation. Failure to recognize this pattern promptly may lead to a delay in diagnosis, thus potentially permanent organ failure.
Topics: Infant; Humans; Osteopetrosis; Rickets; Radiography; Mutation; Vacuolar Proton-Translocating ATPases
PubMed: 37672091
DOI: 10.1007/s00256-023-04443-z -
Intractable & Rare Diseases Research Aug 2023We performed a study to present a phenotypic and genotypic characterization of a patient clinically diagnosed with carbonic anhydrase II (CAII) deficiency syndrome....
We performed a study to present a phenotypic and genotypic characterization of a patient clinically diagnosed with carbonic anhydrase II (CAII) deficiency syndrome. Medical records were reviewed, and oral examination was performed. Sanger sequencing was undertaken for molecular diagnosis. The patient presented with osteopetrosis, renal tubular acidosis, cerebral calcification, blindness, deafness, and development delay. The oral manifestations included anterior open bite, posterior crossbite, tooth eruption impairment, and hypoplastic amelogenesis imperfecta (AI). Molecular analysis revealed a homozygous deletion (c.753delG, p.Asn252Thrfs*14) and confirmed the clinical diagnosis. This study suggests that AI can be another feature of CAII deficiency syndrome. For the first time, a disease-causing variant is reported to be associated with syndromic AI.
PubMed: 37662627
DOI: 10.5582/irdr.2023.01033 -
International Journal of Molecular... Aug 2023Myocyte enhancement factor 2C (MEF2C) is a transcription factor studied in the development of skeletal and smooth muscles. Bone resorption studies have exhibited that...
Myocyte enhancement factor 2C (MEF2C) is a transcription factor studied in the development of skeletal and smooth muscles. Bone resorption studies have exhibited that the reduced expression of MEF2C contributes to osteopetrosis and the dysregulation of pathological bone remodeling. Our current study aims to determine how MEF2C contributes to osteoclast differentiation and to analyze the skeletal phenotype of cKO mice (; ). qRT-PCR and Western blot demonstrated that expression is highest during the early days of osteoclast differentiation. Osteoclast genes, including c, , , and , had a significant reduction in expression, along with a reduction in osteoclast size. Despite reduced CTX activity, female cKO mice were osteopenic, with decreased bone formation as determined via a P1NP ELISA, and a reduced number of osteoblasts. There was no difference between male WT and cKO mice. Our results suggest that is critical for osteoclastogenesis, and that its dysregulation leads to a sex-specific osteopenic phenotype.
Topics: Animals; Female; Male; Mice; Osteoclasts; Osteogenesis; Bone Diseases, Metabolic; MEF2 Transcription Factors; Cell Differentiation
PubMed: 37628864
DOI: 10.3390/ijms241612686 -
JBMR Plus Aug 2023Osteosclerotic metaphyseal dysplasia (OSMD) is a very rare autosomal-recessive disease caused by mutations in the leucine-rich repeat kinase 1 (LRRK1) gene. It is a...
Osteosclerotic metaphyseal dysplasia (OSMD) is a very rare autosomal-recessive disease caused by mutations in the leucine-rich repeat kinase 1 (LRRK1) gene. It is a sclerosing skeletal dysplasia characterized by osteosclerosis of the long bones, predominantly at the metaphyses and vertebrae. Phenotypic features can be short stature, pathological fractures, delayed development, and hypotonia, but they are not uniformly present, and relatively few cases are known from the literature. A 40-year-old man was seen at our bone center because of nonspontaneous multiple peripheral low-energy trauma fractures since puberty. He had no other complaints and his family history was negative. Except for a relatively short stature (167 cm; -1.5 SD), there were no abnormalities on examination, including laboratory tests. Initially, a suspicion was raised of osteogenesis imperfecta, but bone mineral density was high and X-rays of the whole skeleton showed osteosclerosis of the metaphyses of long bones and vertebrae. Whole-exome sequencing showed a homozygous, likely pathogenic, variant (American College of Medical Genetics and Genomics criteria class 4) in the LRRK1 gene, fitting the diagnosis of OSMD. In conclusion, we described a 40-year-old patient with osteosclerotic metaphyseal dysplasia caused by a homozygous variant in the LRRK1 gene, resulting in multiple fractures of the long bones without other features of the disease, adding to the phenotypic variation of OSMD. © 2023 The Authors. published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.
PubMed: 37614307
DOI: 10.1002/jbm4.10755 -
International Journal of Oral Science Aug 2023The biomolecular mechanisms that regulate tooth root development and odontoblast differentiation are poorly understood. We found that Atp6i deficient mice (Atp6i)...
The biomolecular mechanisms that regulate tooth root development and odontoblast differentiation are poorly understood. We found that Atp6i deficient mice (Atp6i) arrested tooth root formation, indicated by truncated Hertwig's epithelial root sheath (HERS) progression. Furthermore, Atp6i deficiency significantly reduced the proliferation and differentiation of radicular odontogenic cells responsible for root formation. Atp6i mice had largely decreased expression of odontoblast differentiation marker gene expression profiles (Col1a1, Nfic, Dspp, and Osx) in the alveolar bone. Atp6i mice sample RNA-seq analysis results showed decreased expression levels of odontoblast markers. Additionally, there was a significant reduction in Smad2/3 activation, inhibiting transforming growth factor-β (TGF-β) signaling in Atp6i odontoblasts. Through treating pulp precursor cells with Atp6i or wild-type OC bone resorption-conditioned medium, we found the latter medium to promote odontoblast differentiation, as shown by increased odontoblast differentiation marker genes expression (Nfic, Dspp, Osx, and Runx2). This increased expression was significantly blocked by anti-TGF-β1 antibody neutralization, whereas odontoblast differentiation and Smad2/3 activation were significantly attenuated by Atp6i OC conditioned medium. Importantly, ectopic TGF-β1 partially rescued root development and root dentin deposition of Atp6i mice tooth germs were transplanted under mouse kidney capsules. Collectively, our novel data shows that the prevention of TGF-β1 release from the alveolar bone matrix due to OC dysfunction may lead to osteopetrosis-associated root formation via impaired radicular odontoblast differentiation. As such, this study uncovers TGF-β1 /Smad2/3 as a key signaling pathway regulating odontoblast differentiation and tooth root formation and may contribute to future therapeutic approaches to tooth root regeneration.
Topics: Female; Animals; Mice; Transforming Growth Factor beta1; Odontoblasts; Culture Media, Conditioned; Cell Differentiation; Signal Transduction; Disease Models, Animal; Tooth Root
PubMed: 37599332
DOI: 10.1038/s41368-023-00235-2 -
BMJ Case Reports Aug 2023Osteopetrosis is a rare genetic disorder resulting in increased bone density and decreased bone remodelling. Bone expansion results in the crowding of neural foramina...
Osteopetrosis is a rare genetic disorder resulting in increased bone density and decreased bone remodelling. Bone expansion results in the crowding of neural foramina causing cranial nerve compression. Here, we describe a female infant in her mid infancy presented with no eye contact since birth, and abdominal distension for 2 months. On CT evaluation, sclerotic bones with bilateral optic canal narrowing were present. A crowded posterior fossa with Arnold Chiari type I malformation was seen on MRI evaluation, suggesting a rare association of osteopetrosis with Arnold Chiari's malformation.
Topics: Humans; Female; Arnold-Chiari Malformation; Osteopetrosis; Osteosclerosis; Magnetic Resonance Imaging; Spine; Cranial Fossa, Posterior
PubMed: 37586757
DOI: 10.1136/bcr-2023-254559 -
International Journal of Surgery Case... Aug 2023Femoral fractures are common in the patients with osteopetrosis and multiple treatment strategies have been described with varying results. However, there is a paucity...
Application of femoral nail, reconstruction locked plate and bone morphogenic protein - 7 in an osteopetrosis patient with a recurrent femoral shaft fracture: A case report.
INTRODUCTION AND IMPORTANCE
Femoral fractures are common in the patients with osteopetrosis and multiple treatment strategies have been described with varying results. However, there is a paucity of literature describing the treatment of recurrent fractures and subsequent deformity.
CASE PRESENTATION
We present detailed revision strategies and long-term follow-up results of a patient with osteopetrosis who suffered unsuccessful operative treatment using the plate-screw system (recurrent femoral shaft fracture and implant failure).
CLINICAL DISCUSSION
The success of revision surgery of osteopetrosis is based on good preoperative planning, appropriate selection of fixation methods, and a meticulous approach during surgery. The combined application of the expert adolescent lateral femoral nail, the reconstruction locked plate, and bone morphogenic protein (BMP)-7 in this patient achieved good clinical results.
CONCLUSION
In the treatment of failed plated and recurrent osteopetrotic femoral shaft fractures, the combination of nails and plating presents an alternative, potentially more successful, revision strategy.
PubMed: 37562280
DOI: 10.1016/j.ijscr.2023.108628 -
L' Orthodontie Francaise Aug 2023The democratization of access to orthodontic treatments and the development of orthodontics in adults lead more and more practitioners to take care of patients with... (Review)
Review
INTRODUCTION
The democratization of access to orthodontic treatments and the development of orthodontics in adults lead more and more practitioners to take care of patients with various general pathologies. The aim of this literature review was to specify the recommendations governing orthodontic treatment in six specific situations: diabetes, patient at risk of endocarditis, haemophilia, osteopetrosis, epidermolysis bullosa and treatment with growth hormone.
MATERIAL AND METHOD
A review of the literature was carried out according to the PRISMA method from the PubMed database. The keywords used were, for diabetes: diabetic, diabetus mellitus, for infective endocarditis: endocarditis, for hemophilia : hemophilia, bleeding disorder, for the use of growth hormone: growth hormone, for epidermolysis bullosa: epidermolysis bullosa and for osteopetrosis: osteopetrosis, associated with the request « orthodontic » or « tooth movement ».
RESULTS AND CONCLUSION
None of these situations constituted an absolute contraindication to orthodontic treatment. However, if surgical procedures with potential for complications were necessary, a compromise should then be discussed in order to provide the best benefit/risk balance for patients.
Topics: Adult; Humans; Hemophilia A; Osteopetrosis; Endocarditis; Epidermolysis Bullosa; Diabetes Mellitus; Growth Hormone
PubMed: 37553886
DOI: 10.1684/orthodfr.2023.127