A novel COL1A1 gene-splicing mutation (c. 1875+1G > C) in a Brazilian patient with osteogenesis imperfecta

Osteogenesis imperfecta is a heterogeneous genetic disorder characterized by bone fragility and deformity, recurrent fractures, blue sclera, short stature, and dentinogenesis imperfecta. Most cases are caused by mutations in COL1A1 and COL1A2 genes. We present a novel splicing mutation in the COL1A1 gene (c. 1875+ 1G>C) in a 16-year-old Brazilian boy diagnosed as a type III osteogenesis imperfecta patient. This splicing mutation and its association with clinical phenotypes will be submitted to the reference database of COL1A1 mutations, which has no other description of this mutation.

The role of dentists in-diagnosing osteogenesis imperfecta in patients with dentinogenesis imperfecta

Background. Osteogenesis imperfecta (OI), also known as ""brittle bone disease,"" can be difficult to diagnose in its mild form. The authors describe a clinical case of a diagnosis of dentinogenesis imperfecta (DI), In which a literature review combined with an analysis of dental alterations led to indications of OI involvement. Case Description. Since DI can be associated with OI, the authors reviewed correlated studies and obtained a new medical history from the patient. They then conducted a radiographic and clinical examination of the dentition and submitted an affected third molar to scanning electron microscopy analysis. They compared their findings with descriptions of OI type I dental alterations in the literature and confirmed their diagnosis by means of a medical evaluation. Clinical Implications. In cases in which DI is diagnosed, patients should be examined carefully and the occurrence of OI should be considered `since, in its mild form, it might be misdiagnosed.

Mutations in FKBP10 cause recessive osteogenesis imperfecta and Bruck syndrome.

Osteogenesis imperfecta (OI) is a genetic disorder of connective tissue characterized by bone fragility and alteration in synthesis and posttranslational modification of type I collagen. Autosomal dominant OI is caused by mutations in the genes (COL1A1 or COL1A2) encoding the chains of type I collagen. Bruck syndrome is a recessive disorder featuring congenital contractures in addition to bone fragility; Bruck syndrome type 2 is caused by mutations in PLOD2 encoding collagen lysyl hydroxylase, whereas Bruck syndrome type 1 has been mapped to chromosome 17, with evidence suggesting region 17p12, but the gene has remained elusive so far. Recently, the molecular spectrum of OI has been expanded with the description of the basis of a unique posttranslational modification of type I procollagen, that is, 3-prolyl-hydroxylation. Three proteins, cartilage-associated protein (CRTAP), prolyl-3-hydroxylase-1 (P3H1, encoded by the LEPRE1 gene), and the prolyl cis-trans isomerase cyclophilin-B (PPIB), form a complex that is required for fibrillar collagen 3-prolyl-hydroxylation, and mutations in each gene have been shown to cause recessive forms of OI. Since then, an additional putative collagen chaperone complex, composed of FKBP10 (also known as FKBP65) and SERPINH1 (also known as HSP47), also has been shown to be mutated in recessive OI. Here we describe five families with OI-like bone fragility in association with congenital contractures who all had FKBP10 mutations. Therefore, we conclude that FKBP10 mutations are a cause of recessive osteogenesis imperfecta and Bruck syndrome, possibly Bruck syndrome Type 1 since the location on chromosome 17 has not been definitely localized.

Phenotypic and molecular characterization of Bruck syndrome (Osteogenesis imperfecta with contractures of the large joints) caused by a recessive mutation in PLOD2

Le Syndrome de Bruck (Bruck Syndrome; BS) est une maladie autosomique récessive assemblant la combinaison inhabituelle de fragilité osseuse semblable à celle de l'Ostéogenèse Imparfaite (0I) avec des contractures congénitales tendineuses et cutanées des grandes articulations («ptérygia»). Les cas décrits jusqu'à ce jour mettent en évidence une grande hétérogénéité du tableau clinique, liée en partie au manque d'un diagnostic biochimique ou moléculaire. Nous savons que dans le BS les gènes codant pour le collagène 1 ne sont pas mutés, mais savons néanmoins, grâce à l'étude du collagène extrait de biopsies osseuses, qu'il y a un déficit d'hydroxylation des résidus de lysine dans les télopeptides du collagène 1 qui servent à la formation des liens intermoléculaires (crosslinks) et donc à la stabilisation des fibres de collagène. Un locus génétique du BS à été mappé sur 17q12, mais le gène responsable sur ce locus reste inconnu; plus récemment, deux mutations dans le gène de la lysyl hydroxylase 2 (PLOD2, position chromosomique 3q23-q24) ont été identifiées, démontrant l'hétérogénéité génétique du ES. La proportion de ES liée à 17p22 (BS type 1) et celle liée à une mutation dans PLOD2 (BS type 2) est encore incertaine et nous manquons de données sur la corrélation phenotype-génotype. Nous avons étudié le cas d'un garçon avec des contractures et des ptérygia dès la naissance, combinées à une ostéopénie sévère de type OI menant à des fractures multiples. Ses urines contenaient une quantité élevée d'hydroxyproline, indiquant un remaniement important du tissu osseux, mais peu de produits de dégradation des crosslinks du collagène, indiquant donc une réduction de la proportion de crosslinks dans le collagène in vivo. Nous avons pu démontrer chez lui la présence d'une nouvelle mutation homozygote dans le gène PLOD2 menant à une substitution Arg598His; les deux parents du sujet étaient hétérozygotes pour la mutation et celle-ci était absente dans notre population témoin. La mutation est adjacente aux deux mutations rapportées précédemment (Gly601Val et Thr608Ile), ce qui suggère la présence d'un ''hotspot'' mutationnel mais aussi d'une région de grande importance fonctionnelle sur PLOD2 : cette observation est importante pour la création d'inhibiteurs de PLOD2, recherchés en ce moment pour le traitement de la fibrose. La combinaison de ptérygia et de fragilité osseuse, comme illustrée par notre patient est apparemment contradictoire et donc difficilement explicable mais indique que l'hydroxylation des résidus lysyl des télopeptides est importante non seulement pour la stabilité osseuse mais aussi dans la morphogénèse et la formation des articulations dans la période prénatale. Finalement, la mesure des produits de dégradation du collagène dans l'urine et l'analyse de mutation de PLOD2 permet le diagnostic du syndrome de Bruck et permet de le différencier de l'Osteogénèse Imparfaite. -- Bruck syndrome (BS) is a recessively-inherited phenotypic disorder featuring the unusual combination of skeletal changes resembling osteogenesis imperfecta (0I) with congenital contractures of the large joints. Clinical heterogeneity is apparent in cases reported thus far. While the genes coding for collagen 1 chains are unaffected in BS, there is biochemical evidence for a defect in the hydroxylation of lysine residues in collagen 1 telopeptides. One BS locus has been mapped at 17p12, but more recently, two mutations in the lysyl hydroxylase 2 gene (PLOD2, 3q23-q24) have been identified in BS, showing genetic heterogeneity. The proportion of BS cases linked to 17p22 (BS type 1) or caused by mutations in PLOD2 (BS type 2) is still uncertain, and phenotypic correlations are lacking. We report on a boy who had congenital contractures with pterygia at birth and severe 0I-like osteopenia and multiple frac-tures. His urine contained high amounts of hydroxyproline but low amounts of collagen crosslinks degradation products; and he was shown to be homozygous for a novel mutation leading to an Arg598His substitution in PLOD2. The mutation is adjacent to the two mutations previously reported (Gly601Val and Thr608Ile), suggesting a functionally important hotspot in PLOD2. The combination of pterygia with bone fragility, as illustrated by this case, is difficult to explain; it suggests that telopeptide lysyl hydroxylation must be involved in prenatal joint formation and morphogenesis. Collagen degradation products in urine and mutation analysis ofPLOD2 maybe used to diagnose BS and differentiate it from M.

Type I osteogenesis imperfecta and multiple osteochondromas in the same child.

A male infant showed a humeral diaphysis fracture at 5 months of age and a distal tibial physis fracture at 2 years of age. A specialized consultant ruled out child abuse. This child had the characteristic features of type I osteogenesis imperfecta: blue sclerae, osseous fragility, and presumably autosomal dominant inheritance, as his father suffered from similar disorders. Later on, multiple painful osteochondromas were also found and some of these were surgically treated. The child's mother showed several peripheral osteochondromas. We describe the follow-up of this patient up to the age of 18 years. To our knowledge, the fortuitous association of these two inherited conditions has not been reported in medical literature.

Urinary pyridinoline cross-links as biomarkers of osteogenesis imperfecta.

Osteogenesis imperfecta (OI) is a group of genetic heterogeneous connective tissue disorders characterized by increased bone fragility and susceptibility to fractures. Laboratory diagnosis relies on time-consuming and cost-intensive biochemical and molecular genetics analyses. Therefore, it is desirable to identify and establish new diagnostic markers for OI that are reliable, cost-effective and easily accessible. In our study we have identified the ratio of the urinary pyridinoline cross-links lysyl-pyridinoline and hydroxylysyl-pyridinoline as a promising, time- and cost-effective biomarker for osteogenesis imperfecta, that could be used furthermore to investigate cases of suspected non-accidental injury in infants.

Bone structure assessed by HR-pQCT, TBS and DXL in adult patients with different types of osteogenesis imperfecta.

UNLABELLED: Bone microarchitecture by high-resolution peripheral quantitative computed tomography (HR-pQCT) was assessed in adult patients with mild, moderate, and severe osteogenesis imperfecta (OI). The trabecular bone score (TBS), bone mineral density (BMD) by dual-energy X-ray absorptiometry (DXA), and dual X-ray and laser (DXL) at the calcaneus were likewise assessed in patients with OI. Trabecular microstructure and BMD in particular were severely altered in patients with OI. INTRODUCTION: OI is characterized by high fracture risk but not necessarily by low BMD. The main purpose of this study was to assess bone microarchitecture and BMD at different skeletal sites in different types of OI. METHODS: HR-pQCT was performed in 30 patients with OI (mild OI-I, n = 18 (41.8 [34.7, 55.7] years) and moderate to severe OI-III-IV, n = 12 (47.6 [35.3, 58.4] years)) and 30 healthy age-matched controls. TBS, BMD by DXA at the lumbar spine and hip, as well as BMD by DXL at the calcaneus were likewise assessed in patients with OI only. RESULTS: At the radius, significantly lower trabecular parameters including BV/TV (p = 0.01 and p < 0.0001, respectively) and trabecular number (p < 0.0001 and p < 0.0001, respectively) as well as an increased inhomogeneity of the trabecular network (p < 0.0001 and p < 0.0001, respectively) were observed in OI-I and OI-III-IV in comparison to the control group. Similar results for trabecular parameters were found at the tibia. Microstructural parameters were worse in OI-III-IV than in OI-I. No significant differences were found in cortical thickness and cortical porosity between the three subgroups at the radius. The cortical thickness of the tibia was thinner in OI-I (p < 0.001), but not OI-III-IV, when compared to controls. CONCLUSIONS: Trabecular BMD and trabecular bone microstructure in particular are severely altered in patients with clinical OI-I and OI-III-IV. Low TBS and DXL and their significant associations to HR-pQCT parameters of trabecular bone support this conclusion.

Nouveautés dans l'ostéogenèse imparfaite: de la recherche à la prise en charge multidisciplinaire [News in osteogenesis imperfecta: from research to clinical management]

Osteogenesis imperfecta (OI) is a rare genetic disease. Today we are able to propose an adapted and efficient management to the patients with this rare disorder (and their families) thanks to a strong collaboration of clinicians and researchers. Recent knowledge regarding the genetics of OI permits an accurate diagnosis of the specific type of OI and its own molecular mechanism, a genetic counseling for family planning and prenatal diagnosis, and in addition more targeted therapeutic options. A specific support with re-education for patients with OI is necessary and efficient. To optimize patient care, a multidisciplinary consultation is proposed at the CHUV, moreover a web site is available for patients, families and therapists: www.infomaladiesrares.ch

Effect of osteogenesis imperfecta on orthodontic tooth movement in a mouse model

Thesis written in co-mentorship with director: Nelly Huynh; co-directors: Frank Rauch and Jean-Marc Retrouvey; collaborators: Clarice Nishio, Duy-Dat Vu and Nathalie Alos

Variable expressivity of osteogenesis imperfecta in a Brazilian family due to p.G1079S mutation in the COL1A1 gene

Osteogenesis imperfecta (OI) is a Mendelian disease with genetic heterogeneity characterized by bone fragility, recurrent fractures, blue sclerae, and short stature, caused mostly by mutations in COL1A1 or COL1A2 genes, which encode the pro-alpha 1(I) and pro-alpha 2(I) chains of type I collagen, respectively. A Brazilian family that showed variable expression of autosomal dominant OI was identified and characterized. Scanning for mutations was carried out using SSCP and DNA sequence analysis. The missense mutation c.3235G>A was identified within exon 45 of the COL1A1 gene in a 16-year-old girl diagnosed as having OI type I; it resulted in substitution of a glycine residue (G) by a serine (S) at codon 1079 (p.G1079S). The proband's mother had the disease signs, but without bone fractures, as did five of nine uncles and aunts of the patient. All of them carried the mutation, which was excluded in four healthy brothers of the patient's mother. This is the first description in a Brazilian family with OI showing variable expression; only one among seven carriers for the c.3235G>A mutation developed bone fractures, the most striking clinical feature of this disease. This finding has a significant implication for prenatal diagnosis in OI disease.

Do patients with osteogenesis imperfecta need individualized nutritional support?

Objective: Information regarding nutrition and body composition in patients diagnosed with osteogenesis imperfecta (OI) is scarce. In the present study, nutritional status, bone mineral density, and biochemical parameters of subjects with Of were evaluated. Methods: Patients with type I OI (n = 13) and type III OI (n = 13) and healthy controls (n = 8) were selected. Nutritional status and bone mineral density were assessed by a 3-d food diary and dual-energy X-ray absorptiometry at the lumbar spine, respectively. Body mass index, serum albumin, calcium, creatinine, cross-linked C-telopeptide, parathyroid hormone, and 25-hydroxivitamin D-3 were also evaluated. Results: Patients with OI had lower bone mineral density (P < 0.05 versus controls). Patients with type III OI had the highest body mass index (P < 0.05 versus patients with type I OI and controls) and the lowest lean body mass (P < 0.05 versus patients with type I OI and controls). In patients with OI, the number of fractures was positively correlated with body mass index (r = 0.581, P = 0.002) and the percentage of body fat (r = 0.451, P = 0.027) and negatively correlated to lean body mass (r = -0.523, P = 0.009). Even when taking dietary supplements, 58% and 12% of subjects with OI did not achieve the calcium and vitamin D recommendations, respectively. Conclusions: Body composition is a risk factor for bone fractures in subjects with OI. Individualized nutritional support is recommended not only to improve body composition but also to potentiate pharmacologic and physical therapies. (C) 2012 Elsevier Inc. All rights reserved.

A Missense Mutation in the SERPINH1 Gene in Dachshunds with Osteogenesis Imperfecta

Osteogenesis imperfecta (OI) is a hereditary disease occurring in humans and dogs. It is characterized by extremely fragile bones and teeth. Most human and some canine OI cases are caused by mutations in the COL1A1 and COL1A2 genes encoding the subunits of collagen I. Recently, mutations in the CRTAP and LEPRE1 genes were found to cause some rare forms of human OI. Many OI cases exist where the causative mutation has not yet been found. We investigated Dachshunds with an autosomal recessive form of OI. Genotyping only five affected dogs on the 50 k canine SNP chip allowed us to localize the causative mutation to a 5.82 Mb interval on chromosome 21 by homozygosity mapping. Haplotype analysis of five additional carriers narrowed the interval further down to 4.74 Mb. The SERPINH1 gene is located within this interval and encodes an essential chaperone involved in the correct folding of the collagen triple helix. Therefore, we considered SERPINH1 a positional and functional candidate gene and performed mutation analysis in affected and control Dachshunds. A missense mutation (c.977C>T, p.L326P) located in an evolutionary conserved domain was perfectly associated with the OI phenotype. We thus have identified a candidate causative mutation for OI in Dachshunds and identified a fifth OI gene.

[Experiences with the early treatment of osteogenesis imperfecta]

Between 1973 and 1988 twenty children with osteogenesis imperfecta were treated in the Department of Paediatric Surgery at the University of Berne, Switzerland. Our initial experience with the first 15 children, who had virtually no treatment during infancy and early childhood showed that they later developed severe soft tissue and skeletal deformities. Since resulting contractures and curvatures of the long bones are difficult to correct, we changed our therapeutic approach. Traditional therapy in OI was limited to the correction of bony malformations. Considering the fact, that the different elements of the locomotor system are part of a functional entity, we began early treatment combining physiotherapy and surgery.