Variant Of Osteogenesis Imperfecta Research Articles

Mutational Screening of Skeletal Genes in 14 Chinese Children with Osteogenesis Imperfecta Using Targeted Sequencing.

Background As a heterogeneous hereditary connective tissue disorder, osteogenesis imperfecta (OI) is clinically characterized by increased fracture susceptibility. Analysis of genetic pathogenic variants in patients with OI provides a basis for genetic counseling and prenatal diagnosis. Methods In this study, 14 diagnosed OI patients from sporadic Chinese families were enrolled to be screened for potential mutations from these patients by next-generation sequencing technology. Results 34 different variants were identified. 18 variants were from 4 OI-related genes including COL1A1, COL1A2, P3H1, and WNT1, and 10 variants are novel. Most OI patients (11 out of 14, 78%) harbor variants in type I collagen genes. Conclusions Our results support previously established estimates of the distribution and prevalence of OI mutations and highlight both phenotype and genetic heterogeneity among and within families. We report several novel variants of OI, which expands the clinical spectrum of OI. In summary, our data provides disease-causing genes information for genetic counseling towards OI patients and families and also provides a reference for clinicians in the diagnosis of OI, also in prenatal diagnosis of this disease.

Bruck syndrome in 13 new patients: Identification of five novel FKBP10 and PLOD2 variants and further expansion of the phenotypic spectrum.

Bruck Syndrome (BS) is a very rare disorder characterized by osteogenesis imperfecta (OI) associated with congenital contractures and is caused by mutations in FKBP10 or PLOD2 genes. Herein, we describe 13 patients from 9 unrelated Egyptian families with BS. All patients had white sclerae, recurrent fractures, kyphoscoliosis and osteoporosis with variable degrees of severity. Large joint contractures were seen in 11 patients, one patient had contractures of small interphalangeal joints, and one patient had no contractures. Unusual findings noted in individual patients included microcephaly, dental malocclusion, enamel hypoplasia, unilateral congenital dislocation of knee joint, prominent tailbone, and myopathy. Nine different variants were identified in FKBP10 and PLOD2 including five novel ones. FKBP10 variants were found in six families (67%) while PLOD2 variants were identified in three families (33%). The four families, with two affected sibs each, showed inter- and intrafamilial phenotypic variability. In conclusion, we report five novel variants in FKBP10 and PLOD2 thus, expanding the mutational spectrum of BS. In addition, our results expand the phenotypic spectrum, describe newly associated orodental findings, and further illustrate the phenotypic overlap between OI and Bruck syndrome supporting the suggestion of considering BS as a variant of OI rather than a separate entity.

Bruck syndrome: A rare case presentation with isolated lower extremity contractures and multiple postoperative peri-implant fractures

Bruck syndrome, characterized by congenital brittle bones and multiple joint contractures, is a rare variant of osteogenesis imperfecta. Here, we report the case of a 7-year-old male patient who presented with a fractured shaft of the femur following trivial trauma. He was diagnosed case of arthrogryposis multiplex congenital with deformities involving both knees and ankle. He had a history of bilateral femoral fractures during birth. Due to the knee contracture and a narrow canal, we fixed the fracture by plating. However, the patient developed peri-implant fractures proximal to the plate. Due to the presence of multiple peri-implant fractures and joint contractures, we diagnosed the patient with Bruck’s syndrome and initiated intravenous bisphosphonate therapy. Subsequently, the patient developed one more fracture in the contralateral femur. This case signifies the importance of screening all patients with multiple congenital contractures and recurrent fractures for Bruck syndrome.

Bruck Syndrome: A Rare Disorder in New-Born with Fractures and Contractures

Bruck syndrome is a very rare autosomal recessive syndrome consisting of bone fragility and congenital joint contractures. It is considered as a combination of arthrogryposis multiplex congenita and osteogenesis imperfecta, while some consider it as the autosomal recessive variant of osteogenesis imperfecta. According to the genotype, it has been classified into types 1 and 2. To our knowledge, only about 28 patients of this syndrome have been reported so far worldwide with none been reported from Nepal. Here, we present a patient with generalized osteopenia, bilateral femur fracture and congenital joint contractures of distal extremities.

Reply to Letter to the Editor: Unexplained Fractures: Child Abuse or Bone Disease: A Systematic Review

Reply to Letter to the Editor: Unexplained Fractures: Child Abuse or Bone Disease: A Systematic Review

Reply to Letter to the Editor: Unexplained Fractures: Child Abuse or Bone Disease: A Systematic Review

We thank Drs. Karst and van Rijn for bringing to our notice as well as that of the readership, issues regarding the study by Paterson et al. [2]. The fact that the existence of ‘temporary brittle bone disease’ as a variant of osteogenesis imperfecta has been challenged and in some ways shown to be nonscientific was known and of interest to us. We were, however, unaware (as an entire group of coauthors of our study [1]) of the court ruling from the United Kingdom related to the study Paterson et al. [2], and we welcome the clarification provided by Drs. Karst and van Rijn regarding the unscientific basis of ‘temporary brittle bone disease.’ Their point is even more relevant in light of the fact that the MOOSE group (Meta-analysis of Observational Studies in Epidemiology) state in their guidelines that because observational studies are vulnerable to bias confounding and chance, readers should consider explanations for the observations other than the conclusions of the authors [3]. However, had we known a priori about this issue, the study by Paterson et al. [2] still would have met our search criteria and our inclusion and exclusion criteria. As such, strict observation of systematic review technique would dictate that it be included. However, we would have made note of the controversy. Of note of the 914 cases we pooled in our study, the article by Paterson et al. [2] only contributed 39 cases (less than 5%). The omission of their article (based on the facts provided) would not have changed our main conclusion, which is that various bone disorders (primarily osteogenesis imperfecta, rather than temporary brittle bone disease) may be mistaken for child abuse. Again, we thank Drs. Karst and van Rijn again for bringing these facts to our attention.

Expression of type I procollagen genes.

All of the type I collagen in connective tissue is the product of one structural gene for the pro alpha 1(I) chain and another for the pro alpha 2(I) chain of type I procollagen. An intriguing question therefore is how the expression of the two genes differs in mineralizing and non-mineralizing tissues. One approach that our laboratory has pursued to answer this and related questions is to develop a new system whereby one can examine the self-assembly of collagen fibrils de novo by controlled enzymic cleavage of procollagen to collagen under physiological conditions. The system has made it possible for the first time to define thermodynamic parameters for the self-assembly process. We are now using the system to define the normal kinetics for fibril formation. The results should make it possible to study the effects of other components of extracellular matrix on fibril assembly, including the effects of bone-specific components that initiate mineralization. A second approach has been to define mutations in type I procollagen genes that cause increased brittleness of bone. Over a dozen mutations in type I procollagen genes have been found in probands with osteogenesis imperfecta. One of the surprises has been that at least 25% of the probands with lethal variants of osteogenesis imperfecta have mutations in type I procollagen genes. Another surprise has been the observation that a number of the mutations are tissue specific in terms of their phenotypic manifestations even though the same abnormal pro alpha chains are being synthesized in a variety of tissues.

Silicate-substituted calcium phosphate as a bone void filler after kyphoplasty in a young patient with multiple compression fractures due to osteogenesis imperfecta variant

Kyphoplasty can be used to treat compression fractures resulting from a variety of causes. The use of polymethyl methacrylate (PMMA) in conjunction with kyphoplasty has many risks and potential complications, however, particularly in the younger patient population. Silicate-substituted calcium phosphate (Actifuse Synthetic Bone Graft; Apatech, Ltd.) is an alternative to PMMA that provides immediate pain relief and the ability to heal and incorporate within the vertebral body.

Muscle weakness as presenting symptom of osteogenesis imperfecta

A young boy presented with severe muscle weakness of his legs at the age of 2 years. Muscle morphology and computer tomography imaging findings were compatible with a metabolic myopathy. Additional investigation showed an osteopenic skeleton and signs of healing fractures. A skin biopsy showed an abnormal electrophoresis pattern of collagen, consistent with a variant of osteogenesis imperfecta. The patient improved with intravenous treatment with pamidronate.

1025. Therapeutic Effect of a Self-Cleaving Hammerhead Ribozyme in a Mouse Model of Osteogenesis Imperfecta

Hammerhead ribozymes are small catalytic RNA molecules that can be targeted to any RNA molecule containing a putative cleavage site, and can selectively eliminate mutant gene products producing dominant negative effects, such as those found in severe variants of osteogenesis imperfecta (OI). We recently reported that self-cleaving multimeric hammerhead ribozymes targeted to a truncated COL1A1 transcript are extremely effective in cellulo (Peace, B. E., et al.; “Endogenously expressed multimeric self-cleaving hammerhead ribozymes ablate mutant collagen in cellulo”, Molecular Therapy, 2005).

Osteogenesis imperfecta type VII maps to the short arm of chromosome 3

We have identified a novel form of autosomal recessive osteogenesis imperfecta (OI) in a small First Nations community from northern Quebec. Mutation screening of the COL1A1/COL1A2 genes revealed no detectable mutations, and type I collagen protein analyses were also normal. By linkage analysis, we mapped this unique autosomal recessive variant of osteogenesis imperfecta to chromosome 3p22-24.1. Based on the assumption of a founder effect, genome-wide screening was performed on a DNA sample pooled from seven affected individuals. Familial as well as historical recombinations identified within an extended haplotype of 19 markers localized the disease between markers D3S2324 and D3S1561, separated by <5 cM. Based on chromosomal localization to 3p22-24.1, the transforming growth factor-β receptor 2 gene and the parathyroid hormone/parathyroid hormone-related peptide receptor were tested, but were excluded as being associated with the phenotype. This study excludes type I collagen mutations in the pathogenesis of the disease and assigns this form of OI to a locus other than the ones containing the type I collagen genes.

A single amino acid substitution (D1441Y) in the carboxyl-terminal propeptide of the proα1(I) chain of type I collagen results in a lethal variant of osteogenesis imperfecta with features of dense bone diseases

Osteogenesis imperfecta (OI) is characterised by brittle bones and caused by mutations in the type I collagen genes, COL1A1 and COL1A2. We identified a mutation in the carboxyl-terminal propeptide coding...

Cole-Carpenter Syndrome - A case report

Cole-Carpenter Syndrome is a rare variant of osteogenesis imperfecta characterised by features of both osteogenesis imperfecta and craniosynostosis. Since the initial two cases reported in 1987, there have been only a handful of reports of the condition, none of which have displayed features identical to the initial cases.We report a case of Cole-Carpenter syndrome with physical and radiological features remarkably similar to the original two cases. The female infant was noted at delivery to have short limbs, brachycephaly and unusual dysmorphic features. A skeletal survey showed generalised osteopenia with shortened and bowed long bones and moderate metaphyseal irregularity. The ribs were short and flared, with a single fracture noted. Skull X-ray showed multiple wormian bones.At follow-up the infant exhibits startling growth failure and progression of dysmorphic features with marked turricephaly. She has significant gross motor delay but normal fine motor and social development. CT scan shows craniosynostosis involving the sagittal, lambdoid, coronal and metopic sutures. Pathological fractures of the bones on either side of the fused sagittal suture are allowing the skull to grow vertically, accounting for the turricephalic appearance. By the age of 14 months the child has experienced two long bone fractures, both with minor trauma.We present the physical and radiological features of this case and review other reported cases of Cole-Carpenter syndrome.

Osteogenesis imperfecta and other heritable disorders of bone

This chapter summarizes the many recent advances in our understanding of the principal heritable disorders of bone. In the course of little more than a decade many diseases that were recognizable only by their clinical and radiological features have become explicable in molecular terms. Large numbers of mutations of the genes coding for collagen, for alkaline phosphatase, for the cell surface receptors for parathyroid hormone and for calcium, and for a number of other proteins, are recognized. The chapter covers the many variants of osteogenesis imperfecta, the most common heritable cause of fractures. It also covers osteopetrosis, hypophosphatasia, pseudohypoparathyroidism (with Albright's hereditary osteodystrophy), familial benign hypercalcaemia, autosomal dominant hypocalcaemia and the molecular causes of some chondrodysplasias.

Substitution of arginine for glycine at position 154 of the α1 chain of type I collagen in a variant of osteogenesis imperfecta: Comparison to previous cases with the same mutation

A substitution of arginine for glycine at amino acid position 154 of the alpha 1(I) collagen chain was found in a father and his three children. The phenotype of the patients includes manifestations of types I and III/IV osteogenesis imperfecta, but appears to be milder than that of the previously described two unrelated patients that had the identical mutation in the alpha 1(I) collagen chain. The variability in the phenotype raises the possibility of epistatic loci or environmental effects on expression of the disorder.

Substitution of arginine for glycine at position 154 of the α1 chain of type I collagen in a variant of osteogenesis imperfecta: Comparison to previous cases with the same mutation

A substitution of arginine for glycine at amino acid position 154 of the alpha 1(I) collagen chain was found in a father and his three children. The phenotype of the patients includes manifestations of types I and III/IV osteogenesis imperfecta, but appears to be milder than that of the previously described two unrelated patients that had the identical mutation in the alpha 1(I) collagen chain. The variability in the phenotype raises the possibility of epistatic loci or environmental effects on expression of the disorder.

An ultrastructural, microanalytical, and spectroscopic study of bone from a transgenic mouse with a COL1.A1 pro-alpha-1 mutation

A line of transgenic mice have been investigated that expressed moderate levels of an internally deleted human gene for the pro∝(I) chain of type I procollagen. These mice expressed the gene at approximately 50% that of the endogenous gene. The gene construct was modeled after a sporadic in-frame deletion of the human gene that produced a lethal variant of osteogenesis imperfecta by causing biosynthesis of shortened pro∝(I) chains. Periera et al. (1993) reported extensive fracturing in these mice with femurs that were shorter in length and bone that had decreased ash weight, mineral, and collagen content. These workers demonstrated an increased brittleness in bone using biomechanical measurements. The functional consequences of these mutant genes were examined in both transgenic and in normal littermate mice to determine if a valid model at the ultrastructural and analytical level had been produced for OI. X-ray microanalysis of bone mineral demonstrated a significantly lower calcium-to-phosphorus ( Ca P ) molar ratio in transgenic mouse bone than in normal littermates; this was a feature of human OI bone. Fourier transform infrared spectroscopy confirmed that the mineral present was apatitic in nature despite the lower Ca P molar ratio. Alizarin red skeletal staining showed the presence of multiple fracture calluses on the ribs and on the long bones of some of the transgenic mice, this was not seen on normal littermates. No light microscopic differences were observed between normal and transgenic mice; however, many ultrastructural correlates with human OI were observed in the transmission electron microscope. Anomalous fibrils associated with type I collagen, and an amorphous calcified material was observed lining the cartilage, extending beyond the lamina limitans in young transgenic mice.

Substitution of arginine for glycine at position 154 of the α1 chain of type I collagen in a variant of osteogenesis imperfecta: Comparison to previous cases with the same mutation

Substitution of arginine for glycine at position 154 of the α1 chain of type I collagen in a variant of osteogenesis imperfecta: Comparison to previous cases with the same mutation

Substitution of Cysteine for Glycine-946 in the α1(I) Chain of Type I Procollagen Causes Lethal Osteogenesis Imperfecta

Procollagen synthesized by skin fibroblasts from a patient with a lethal variant of osteogenesis imperfecta has been characterized. After pepsin digestion of the type I procollagen, a portion of the alpha 1(I) chains was recovered as a disulfide-bonded dimer. Cyanogen bromide peptide mapping suggested that a new cysteine residue was present in the alpha 1(I)CB6 fragment. Sequencing of cloned cDNAs prepared using mRNA from the proband's fibroblasts demonstrated that some of the clones contained a single base mutation that converted the glycine codon in amino acid position 946 of the alpha 1(I) chain to a cysteine codon. The thermal stability of the molecules was markedly lower than that in the case of the normal control.

Transgenic mice expressing a partially deleted gene for type I procollagen (COL1A1). A breeding line with a phenotype of spontaneous fractures and decreased bone collagen and mineral.

A line of transgenic mice was prepared that expressed moderate levels of an internally deleted human gene for the pro alpha 1(I) chain of type I procollagen. The gene construct was modeled after a sporadic in-frame deletion of the human gene that produced a lethal variant of osteogenesis imperfecta by causing biosynthesis of shortened pro alpha 1(I) chains. 89 transgenic mice from the line were examined. About 6% had a lethal phenotype with extensive fractures at birth, and 33% had fractures but were viable. The remaining 61% of the transgenic mice had no apparent fractures as assessed by x ray examination on the day of birth. Brother-sister matings produced eight litters in which approximately 40% of the mice had the lethal phenotype, an observation indicating that expression of the exogenous gene was more lethal in putative homozygous mice from the line. Examination of femurs from the transgenic mice indicated that the bones were significantly shorter in length and had a decrease in wet weight, mineral content, and collagen content. However, there was no statistically significant change in the mineral to collagen ratio. Biomechanical measurements on femurs from the mice at 6 wk indicated a decrease in force and energy to failure. There was also a decrease in strain to failure and an increase in Young's modulus of elasticity, observations indicating increased brittleness of bone matrix. The results suggested that the transgenic mice may be an appropriate model for testing potential therapies for osteogenesis imperfecta. They may also be a useful model for studying osteoporosis.