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Military Medicine Jul 2023Osteogenesis imperfecta (OI) is a heritable, collagen-related disorder with varying degrees of disease severity and systemic involvement. The hallmark of OI is bone...
INTRODUCTION
Osteogenesis imperfecta (OI) is a heritable, collagen-related disorder with varying degrees of disease severity and systemic involvement. The hallmark of OI is bone matrix fragility, but diverse effects related to structural integrity and impaired development of connective tissue can account for hearing loss, blue sclera, dentinogenesis imperfecta, frequent fractures, joint hypermobility, and cardiac valve or vessel fragility in some cases. There is emerging recognition of unique genetic mutations leading to OI including CREB3L1, which codes for an important transcription factor for differentiation of osteoblasts.
CASE PRESENTATION
We present a case of OI diagnosed in an active duty female with multiple prior fractures and heterozygous CREB3L1, a rare cause of OI.
CONCLUSION
This case highlights the importance of consideration of the variable phenotypes of OI and careful assessment of fracture history during evaluation at the Military Entrance Processing Station and subsequent encounters at military treatment facilities to improve readiness.
Topics: Humans; Female; Osteogenesis Imperfecta; Heterozygote; Cyclic AMP Response Element-Binding Protein; Military Personnel; Adult; Nerve Tissue Proteins
PubMed: 35978537
DOI: 10.1093/milmed/usac245 -
Bone Nov 2022Mutations in CRTAP lead to an extremely rare form of recessive osteogenesis imperfecta (OI). CRTAP deficient mice have a brachycephalic skull, fusion of facial bones,...
Mutations in CRTAP lead to an extremely rare form of recessive osteogenesis imperfecta (OI). CRTAP deficient mice have a brachycephalic skull, fusion of facial bones, midface retrusion and class III dental malocclusion, but in humans, the craniofacial and dental phenotype has not been reported in detail. Here, we describe craniofacial and dental findings in two 11-year-old girls with biallelic CRTAP mutations. Patient 1 has a homozygous c.472-1021C>G variant in CRTAP intron 1 and a moderately severe OI phenotype. The variant is known to create a cryptic splice site, leading to a frameshift and nonsense-mediated RNA decay. Patient 1 started intravenous bisphosphonate treatment at 2 years of age. At age 11 years, height Z-score was +0.6. She had a short and wide face, concave profile and class III malocclusion, with a prognathic mandible and an antero-posterior crossbite. A panoramic radiograph showed a poor angulation of the second upper right premolar, and no dentinogenesis imperfecta or dental agenesis. Cone-beam computed tomography confirmed these findings and did not reveal any other abnormalities. Patient 2 has a homozygous CRTAP deletion of two amino acids (c.804_809del, p.Glu269_Val270del) and a severe OI phenotype. As previously established, the variant leads to instability of CRTAP protein. Intravenous bisphosphonate treatment was started at the age of 15 months. At 11 years of age her height Z-score was -9.7. She had a long and narrow face and convex profile, maxillary retrusion leading to a class III malocclusion, an edge-to-edge overjet and lateral open bite. Panoramic radiographs showed no dental abnormalities. Cone-beam computed tomography showed occipital bossing, platybasia and wormian bones. In these two girls with CRTAP mutations, the severity of the skeletal phenotype was mirrored in the severity of the craniofacial phenotype. Class III malocclusion and antero-posterior crossbite were a common trait, while dental agenesis or dentinogenesis imperfecta were not detected.
Topics: Amino Acids; Animals; Child; Diphosphonates; Extracellular Matrix Proteins; Female; Humans; Infant; Malocclusion; Mice; Molecular Chaperones; Mutation; Osteogenesis Imperfecta; Phenotype; RNA Splice Sites; Skull
PubMed: 35970273
DOI: 10.1016/j.bone.2022.116516 -
Molecular Genetics & Genomic Medicine Sep 2022Osteogenesis imperfecta type I (OI-I) is a rare genetic disorder characterized by skeletal deformity, bone fragility, blue sclerae, dentinogenesis imperfecta, and...
BACKGROUND
Osteogenesis imperfecta type I (OI-I) is a rare genetic disorder characterized by skeletal deformity, bone fragility, blue sclerae, dentinogenesis imperfecta, and hearing loss. The current study aimed to confirm the clinical diagnosis and genetic cause of OI-I in a four-generation Chinese family.
METHODS
Clinical investigation and pedigree analysis were conducted to characterize the phenotypic manifestations of a Chinese family with OI-I. Follow-up audiometry and imaging tests were used to evaluate the postoperative outcomes of stapes surgery in the proband with otosclerosis. Whole-exome sequencing (WES) and Sanger sequencing were used to identify the pathogenic gene variants and for cosegregating analysis.
RESULTS
We described in detail the clinical features of the collected family with autosomal dominant OI-I, and firstly identified a pathogenic splicing variant (c.2344-1G>T) in intron 33 of COL1A1 in a Chinese family. The molecular analysis suggested that the mutation might cause splice site changes that result in a loss of gene function. The proband, who suffered from otosclerosis and presented two-side middle-severe conductive hearing loss, benefitted significantly from successive bilateral middle ear surgery.
CONCLUSIONS
The diagnosis of OI-I in a Chinese family was established by clinical and genetic investigation. A heterozygous pathogenic splicing variant in COL1A1 was directly responsible for the bone fragility and hearing loss of this family. Otosclerosis surgery should be suggested to rehabilitate conductive hearing impairment in OI patients.
Topics: China; Collagen Type I; Hearing Loss; Humans; Osteogenesis Imperfecta; Otosclerosis; Pedigree
PubMed: 35855543
DOI: 10.1002/mgg3.2019 -
Journal of Personalized Medicine Jun 2022Hereditary dentin defects are conventionally classified into three types of dentinogenesis imperfecta (DGI) and two types of dentin dysplasia (DD). Mutations in the...
Hereditary dentin defects are conventionally classified into three types of dentinogenesis imperfecta (DGI) and two types of dentin dysplasia (DD). Mutations in the dentin sialophosphoprotein (DSPP) gene have been identified to cause DGI type II and III and DD type II; therefore, these are not three different conditions, but rather allelic disorders. In this study, we recruited three families with varying clinical phenotypes from DGI-III to DD-II and performed mutational analysis by candidate gene analysis or whole-exome sequencing. Three novel mutations including a silent mutation (NM_014208.3: c.52-2del, c.135+1G>C, and c.135G>A; p.(Gln45=)) were identified, all of which affected pre-mRNA splicing. Comparison of the splicing assay results revealed that the expression level of the DSPP exon 3 deletion transcript correlated with the severity of the dentin defects. This study did not only expand the mutational spectrum of DSPP gene, but also advanced our understanding of the molecular pathogenesis impacting the severity of hereditary dentin defects.
PubMed: 35743786
DOI: 10.3390/jpm12061002 -
Journal of Prosthodontics : Official... Oct 2022Type II dentinogenesis imperfecta is an autosomal dominant condition that affects dentin which increases the complexity of the predictability of restorative treatment....
Type II dentinogenesis imperfecta is an autosomal dominant condition that affects dentin which increases the complexity of the predictability of restorative treatment. Computer-aided design and computer-aided manufacturing (CAD-CAM) technologies permit the creation of highly accurate devices and dental prostheses that simplify the planning and execution of advanced implant surgery and full-mouth rehabilitation. This clinical report presents the interdisciplinary management of a 20-year-old male with dentinogenesis imperfecta type II. In this article, a combination of analog and CAD-CAM technologies were used to fabricate devices that aided planning, assisted intermaxillary fixation and implant placement, served as interim prostheses, and permitted the accurate establishment of esthetics and occlusion of the definitive full-arch prostheses.
Topics: Adult; Humans; Male; Young Adult; Computer-Aided Design; Dental Prosthesis Design; Dental Prosthesis, Implant-Supported; Dentinogenesis Imperfecta; Esthetics, Dental; Mouth Rehabilitation; Tooth
PubMed: 35675448
DOI: 10.1111/jopr.13556 -
Genes May 2022Mutations in Dentin Sialophosphoprotein (DSPP) are known to cause, in order of increasing severity, dentin dysplasia type-II (DD-II), dentinogenesis imperfecta type-II...
Mutations in Dentin Sialophosphoprotein (DSPP) are known to cause, in order of increasing severity, dentin dysplasia type-II (DD-II), dentinogenesis imperfecta type-II (DGI-II), and dentinogenesis imperfecta type-III (DGI-III). DSPP mutations fall into two groups: a 5′-group that affects protein targeting and a 3′-group that shifts translation into the −1 reading frame. Using whole-exome sequence (WES) analyses and Single Molecule Real-Time (SMRT) sequencing, we identified disease-causing DSPP mutations in 12 families. Three of the mutations are novel: c.53T>C/p.(Val18Ala); c.3461delG/p.(Ser1154Metfs*160); and c.3700delA/p.(Ser1234Alafs*80). We propose genetic analysis start with WES analysis of proband DNA to identify mutations in COL1A1 and COL1A2 causing dominant forms of osteogenesis imperfecta, 5′-DSPP mutations, and 3′-DSPP frameshifts near the margins of the DSPP repeat region, and SMRT sequencing when the disease-causing mutation is not identified. After reviewing the literature and incorporating new information showing distinct differences in the cell pathology observed between knockin mice with 5′-Dspp or 3′-Dspp mutations, we propose a modified Shields Classification based upon the causative mutation rather than phenotypic severity such that patients identified with 5′-DSPP defects be diagnosed as DGI-III, while those with 3′-DSPP defects be diagnosed as DGI-II.
Topics: Animals; Dentinogenesis Imperfecta; Extracellular Matrix Proteins; Humans; Mice; Mutation; Pedigree; Phosphoproteins; Sialoglycoproteins
PubMed: 35627243
DOI: 10.3390/genes13050858 -
Endocrine Practice : Official Journal... Aug 2022To evaluate the genotype-phenotype relationship and the effect of treatment on the clinical course of osteogenesis imperfecta (OI).
OBJECTIVE
To evaluate the genotype-phenotype relationship and the effect of treatment on the clinical course of osteogenesis imperfecta (OI).
METHODS
We established a Chinese hospitalized cohort with OI and followed them up for an average of 6 years. All patients were confirmed as having OI using whole-exome sequencing. We analyzed the genotype-phenotype relationship based on different types, pathogenic mechanisms, and gene inheritance patterns of OI. Additionally, we assessed whether there was a difference in treatment efficacy based on genotype.
RESULTS
One hundred sixteen mutations in 6 pathogenic genes (COL1A1, COL1A2, IFITM5, SERPINF1, FKBP10, and WNT1) were identified in 116 patients with type I, III, IV, V, VI, XI, or XV OI. Compared with patients with COL1A1 mutations, patients with COL1A2 mutations were younger at the time of the first fracture, whereas other phenotypes were similar. When 3 groups (helical, haploinsufficiency, and non-collagen I gene mutations) were compared, patients with helical mutations were the shortest and most prone to dentinogenesis imperfecta. Patients with haploinsufficiency mutations were the oldest at the time of the first fracture. Moreover, patients with non-collagen I gene mutations were least susceptible to blue sclerae and had the highest fracture frequency. Furthermore, there were some minor phenotypic differences among non-collagen I gene mutations. Interestingly, pamidronate achieved excellent results in the treatment of patients with OI, and the treatment effect appeared to be unrelated to their genotypes.
CONCLUSION
Our findings indicated a genotype-phenotype relationship and a similar effect of pamidronate treatment in patients with OI, which could provide a basis for guiding clinical treatment and predicting OI prognosis.
Topics: China; Collagen Type I; Follow-Up Studies; Genotype; Humans; Mutation; Osteogenesis Imperfecta; Pamidronate; Phenotype
PubMed: 35550181
DOI: 10.1016/j.eprac.2022.05.003 -
The Nigerian Postgraduate Medical... 2022Dental anomalies are craniofacial abnormalities in the size, structure or number of the teeth. This study was conducted to assess the prevalence of dental anomalies...
BACKGROUND
Dental anomalies are craniofacial abnormalities in the size, structure or number of the teeth. This study was conducted to assess the prevalence of dental anomalies among children aged 0-16 years attending the Paediatric Dental Clinic at the Lagos University Teaching Hospital, Lagos, Nigeria.
METHODS
A cross-sectional design was used and data were obtained from the dental records of the Dental Clinic from January 2014 to August 2019 by two calibrated examiners, who are co-authors of the manuscript. To test for statistical differences, Chi-squared test was utilised for the categorical variables. The prevalence of the different dental anomalies was estimated and presented with frequencies. P < 0.05 was considered statistically significant.
RESULTS
Among the 6175 patients' dental records reviewed, 50.85% (n = 3150) were male and the highest proportion of 45.4% (n = 2807) were aged between 6 and 10 years, with a mean age of 8.62 ± 3.85 years. A total of 1090 (17.52%) had dental anomalies; 465 (7.53) anomalies were in the maxilla, 263 (4.6) were in the mandible while 360 (5.83) were in both. The most common anomaly was hypoplasia 550 (9.06%), followed by retained primary tooth 546 (8.84%) and hypodontia 84 (1.36%). Dentinogenesis imperfecta 1 (0.02) and transposition 1 (0.02) were the least prevalent anomalies. Retained primary teeth (5.8%) and the cusp of Carabelli (0.4%) were slightly more prevalent among males. However, females had a higher prevalence of natal/neonatal teeth (0.4%), fusion/germination (0.4%), hypodontia (1.5%) and peg-shaped lateral incisors (0.9%).
CONCLUSION
Dental anomalies' prevalence in this study was 17.52%, with a higher occurrence of anomalies in the maxilla. Hypoplasia was the most prevalent anomaly, after which was retained primary tooth, then hypodontia. Prompt diagnosis and preventive interventions are crucial for the appropriate management of these dental anomalies.
Topics: Anodontia; Child; Cross-Sectional Studies; Female; Humans; Infant, Newborn; Male; Nigeria; Prevalence; Tooth Abnormalities
PubMed: 35488587
DOI: 10.4103/npmj.npmj_23_22 -
Hua Xi Kou Qiang Yi Xue Za Zhi = Huaxi... Mar 2022To construct the three-dimensional structure of the isolated teeth of patients with dentinogenesis imperfecta type Ⅱ (DGI-Ⅱ) and dentin dysplasia type Ⅰ (DD-Ⅰ)...
OBJECTIVES
To construct the three-dimensional structure of the isolated teeth of patients with dentinogenesis imperfecta type Ⅱ (DGI-Ⅱ) and dentin dysplasia type Ⅰ (DD-Ⅰ) by using Micro-CT and explore internal structure and hard tissue mineralization density.
METHODS
The three-dimensional structures of the third molars collected from patients with DGI-Ⅱ and DD-Ⅰ and healthy individuals of the same age were reconstructed by using Micro-CT (Mimics 17.0). The internal structures of the affected teeth along the sagittal and transverse planes were observed. The grayscale values of the enamel, crown dentin, and root dentin were calculated. Then, the mineralization densities of the different parts of the teeth of the three groups were analyzed.
RESULTS
The detailed three-dimensional models of the mandibular third molars with hereditary dentin defects were successfully constructed. The models contained the models of the enamel cap, dentin core, and pulp cavity. Sagittal and transverse section scans revealed that in patients with DGI-Ⅱ, the pulp cavity was incompletely calcified and the root canal was narrow, whereas in those with DD-Ⅰ, the pulp cavity and root canal were obliterated and the root of the tooth was absent. The analysis of the grayscale values showed that compared with those in the healthy group, the grayscale values of the enamel, crown dentin, and root dentin were lower in the DGI-Ⅱ and DD-Ⅰ groups (<0.01). No significant differences in the grayscale values of the enamel and crown dentin were found between the DGI-Ⅱ and DD-Ⅰ groups (>0.05), whereas the grayscale value of the root dentin showed statistically significant differences between the two groups (<0.01).
CONCLUSIONS
The application of Micro-CT provided a simple and accurate method for the three-dimensional structure reconstruction and quantitative analysis of the mineralization density of isolated teeth with hereditary dentin defects. Although the dentin mineralization density of DGI-Ⅱ and DD-Ⅰ teeth decreased, the decrement shown by DD-Ⅰ teeth was more significant than that shown by DGI-Ⅱ teeth. The pulp cavity had abnormal calcifications, and the root canal was narrow or even occluded.
PubMed: 38597048
DOI: 10.7518/hxkq.2022.02.006 -
Bone Reports Jun 2022Metaphyseal corner fractures and posterior rib fractures are thought to only occur in settings of inflicted injury. We describe a case of siblings who presented with...
PURPOSE
Metaphyseal corner fractures and posterior rib fractures are thought to only occur in settings of inflicted injury. We describe a case of siblings who presented with metaphyseal corner fractures and multiple posterior rib fractures who were later found to carry mutations, a rare cause of Osteogenesis Imperfecta (OI) known as Bruck syndrome. This clinical presentation led to a literature review examining fracture types in OI and inflicted injury.
CASES
A 15-month-old male presented with multiple healing fractures of varying ages including posterior rib and metaphyseal corner fractures with no history of significant trauma. He had joint laxity, short stature and Wormian bones. His diagnosis of Bruck Syndrome led to investigations in his sibling at birth, which demonstrated the same fracture pattern including multiple posterior rib and metaphyseal corner fractures. They both had pathogenic compound heterozygous variants.
LITERATURE REVIEW AND RESULTS
We performed a literature review evaluating the fracture pattern in cases investigated for inflicted injury and found to have OI. Fourteen articles reported 78 children with OI initially diagnosed as inflicted injury. Of these children, 71 (91%) were diagnosed with milder forms of OI (Sillence type I and IV). Sixty-four children (81%) had clinical signs of OI including blue sclera, dentinogenesis imperfecta, short stature, joint laxity and limb bowing. Fifteen (19%) children had fractures of high specificity for inflicted injury including metaphyseal corner fractures and posterior rib fractures and 58 (74%) had fractures of moderate specificity for inflicted injury such as bilateral fractures and fractures of different ages.
CONCLUSION
Metaphyseal corner fractures and posterior rib fractures are highly associated with inflicted injury, but they have been reported in children with OI. Bruck syndrome, a rare and severe form of OI can present with metaphyseal and posterior rib fractures, including at birth. When features of OI are present in children with metaphyseal corner fractures and/or posterior rib fractures are present, genetic testing may be warranted.
PubMed: 35242891
DOI: 10.1016/j.bonr.2022.101171