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Osteogenesis imperfecta is a hereditary connective tissue disorder. Typical manifestations are fragile bones with multiple bone fractures and bone deformities. A history of minimal or no trauma and recurrent fractures is a feature of OI, but is also typical of non-accidental injury (NAI). OI and NAI are relevant differential diagnoses when a child presents with unexplained fractures. The differential diagnostic problems are reviewed, all of which are important for the child both in terms of treatment and for prognosis, socially and medicolegally. We conclude that comprehensive clinical evaluation is adequate for differential diagnosis and that both OI and NAI can be diagnosed by positive anamnestic and objective signs. Mild OI IV without other signs than fracture(s) is very rare and the new entity temporary brittle bone disease is hypothetical; the diagnosis of these two clinical pictures is unacceptable in small children. Routine analysis of collagens should not be performed.

Whole-body and spine dual-energy X-ray absorptiometry was done in 63 patients with osteogenesis imperfecta aged 5 to 63 y, and the results were compared with OI types and collagen defects. Bone mineral content (BMC)-for-age, bone area (BA)-for-age, bone mineral density (BMD)-for-age, and BMC-for-BA were reduced, especially in patients with OI III/IV and/or in those with a qualitative collagen defect. BA-for-height was normal. Some patients with OI I and/or a quantitative collagen defect had BMD at or above -2 z-scores. We conclude (i) that both BMC and BMD differ significantly between OI types and collagen defects, (ii) that reduced BMC-for-age in OI patients is due mainly to reduced height ("short bones") and reduced BMC-for-BA ("light bones"), whereas BA-for-height ("bone width") is normal, (iii) that most OI patients have lower than average BMC, but in some mildly affected patients brittleness may exist with only small reductions in BMC.

Standing height, sitting height, armspan, subischial leg length, head circumference, and growth hormone-insulin-like growth factor I (IGF-I) axis were determined in 86 patients with osteogenesis imperfecta. The aim of this study was to determine standing height and body proportions and their variability among osteogenesis imperfecta types and collagen defects. Mean standing height was reduced in all groups of patients, to the greatest extent and variability in osteogenesis imperfecta type III/IV and in those with qualitative collagen defects. The mean standing height of patients with osteogenesis imperfecta was lower than that of their unaffected first degree family members. Truncal height of patients with osteogenesis imperfecta was reduced; head size was increased, and this was more pronounced in patients with osteogenesis imperfecta type III/IV and qualitative collagen defects than in patients with osteogenesis imperfecta type I and quantitative collagen defects. Mean concentrations of IGF-I and IGF binding protein 3 (IGFBP-3) were low, but most values were within age specific reference values. The reduction of standing height appears to correlate with osteogenesis imperfecta type and the type of collagen defect. A relatively short trunk is typical and head circumference and body length are disproportionate.

Non-lethal OI III (OMIM 259420) is caused by structural aberrations of collagen I. We report four novel glycine substitutions, one in the a1 (I) chain of collagen I (G688S) and three in the a2 (I) chain (G241D, G247C, G883V). In each of two families (G241D and G883V), we found parental mosaicism for the substitution explaining recurrence and intrafamilial variability of OI. The G247C and the G883V are the most N-terminally and C-terminally, respectively, placed cysteine and valine substitutions reported. The new substitutions add important information to the genotype-phenotype map and in particular the importance of a-chain stoichiometry is underlined. Data regarding the G688S substitution may suggest a different effect of the two a-chains in the development of dentinogenesis imperfecta (DI).

Markers of bone formation [C-terminal and N-terminal propeptides of procollagen I (PICP, PINP), osteocalcin and alkaline phosphatase] and bone resorption [C-terminal cross-linked telopeptide of collagen I (ICTP) and hydroxypyridinium cross-links, pyridinoline (Pyr) and deoxypyridinoline (Dpyr)] were measured in 78 osteogenesis imperfecta (OI) patients to investigate bone metabolism in vivo and relate marker concentrations to phenotype and in vitro collagen I defects, as shown by sodium dodecyl sulphate-polyacrylamide gel electrophoresis (SDS-PAGE). PICP and PINP were generally low, and the serum levels were lower in all children and adults with mild OI and a quantitative collagen defect than in patients with severe OI and a qualitative collagen I defect. ICTP, Pyr and Dpyr were generally normal or reduced, but elevated in severely affected adults with a qualitative collagen I defect. The in vivo findings correlated with in vitro results of collagen I SDS-PAGE. Bone turnover is reduced in OI children and mildly affected OI adults, whereas bone resorption is elevated in severely affected adults. These findings may prove helpful for diagnosis and decision-making regarding therapy in OI.

The in vitro protein-chemical features and the molecular background of osteogenesis imperfecta (OI), a heritable disorder of collagen I metabolism, have been elucidated in recent years. The aim of our study was to find the prevalence of dentinogenesis imperfecta (DI) and other dental anomalies in 88 patients with OI, to compare clinical with radiologic abnormalities, and to correlate these clinical/radiologic findings with the results of gel electrophoresis and molecular studies of collagen I. Twenty-eight percent of OI patients had DI. Most patients with DI had radiologic abnormalities, but some patients had radiologic signs compatible with DI, but no clinical signs of DI. OI type I patients with DI were more severely affected by OI than those without DI. In OI type III and IV, in contrast, there was no difference in overall severity between patients with and without DI. DI was not associated with any particular molecular aberration in any OI type. If defining DI from the presence of both clinical and radiologic signs, collagen I produced by cultured fibroblasts was qualitatively abnormal from all OI patients with DI. Some OI patients had dental abnormalities not resembling DI. A qualitative collagen abnormality could not be found in any of these patients. Denticles, i.e., calcifications within the pulpal cavity, were found more frequently in OI patients than in control subjects.

Protein-chemical and molecular studies were conducted on all osteogenesis imperfecta (OI) type III/IV patients referred to our hospital during the last 15 y. Of a total of 16 OI type III/IV patients studied, 15 patients were heterozygous for a mutation in one of the two genes coding for collagen I, COL1A1 or COL1A2. Cultured fibroblasts from these 15 patients produced both normal and abnormal collagen I molecules, pointing to a dominant-negative effect of the mutation. Nine mutations had not been described previously. Parental mosaicism was demonstrated in three families. In the 16th child the causative mutation was not found. In conclusion, OI type III/IV in most patients of Western European ancestry is caused by dominant mutations in the genes for collagen I, and recurrence of OI is caused in most cases by parental gonadal mosaicism.

Osteogenesis imperfecta (OI) is a congenital disease of connective tissue, most often caused by single amino acid substitutions of glycine residues within the triple helical region of collagen I. Collagen I consists of two alpha 1 chains and one alpha 2 chain. Thus, a substitution in the alpha 1(I) chain is thought to affect the function of the collagen molecule more than would a similar substitution in the alpha 2(I) chain, thereby causing more severe OI. Theoretically this hypothesis may be tested by comparing patients with identical substitutions in different alpha-chains. We present a Gly586Val substitution in the alpha 1(I) chain, and compare our findings to those resulting from Gly586Val substitutions in the alpha 2(I) chain (Forlino et al., 1994; Bateman et al., 1991). Our proband had lethal OI type II. Most alpha-chains of collagen I produced by his cultured fibroblasts were overmodified. The denaturation temperature of the abnormal collagen was 1.5 degrees C below normal. Cyanogen bromide cleavage and subsequent sequencing revealed a G-to-T base substitution at nucleotide 2420 of COL1A1, resulting in a Gly586Val substitution. The collagen findings were almost identical to those reported by Bateman et al. (1991) and Forlino et al. (1994), but the clinical phenotypes were different: the patients with the alpha 2(I) substitutions had OI type IV and III and not the lethal OI type II of our proband. It is known that identical biochemical aberrations in the same chain may have different phenotypic effects, both within families and between non-related patients. This must be taken into account in our cautious proposal that substitutions in the alpha 1(I) chain may have more serious consequences than similar substitutions in the alpha 2(I) chain.

We have studied a family with autosomal dominant osteogenesis imperfecta (OI) type IV. Electrophoresis of collagen produced by cultured fibroblasts revealed a slower migrating population of collagen I. Cyanogen bromide peptide mapping localised the structural defect to the area of the alpha 1(1)CB3 peptide. Subsequent sequencing revealed a deletion of nucleotides 1964-1966 in exon 27 of COL1A1. By means of restriction enzyme analysis, the deletion could be detected in all affected family members. This in-frame deletion resulted in the removal of alanine-438 and Glu437Asp substitution in the pro alpha 1(I) collagen chain. Clinical variation was considerable among affected family members. The most consistent clinical features were reduced height and extraosseous manifestations of OI.

In a family with recurrent osteogenesis imperfecta (OI) caused by paternal mosaicism, prenatal diagnosis was made using restriction enzyme analysis for a mutation in COL1A2. Parental mosaicism is important to consider in genetic counselling for OI. Prenatal diagnosis of OI is available currently by means of collagen or gene analyses in the first trimester or by ultrasonography in the second trimester.

We have investigated one member of a family with dominant osteogenesis imperfecta type IV through three generations. In protein-chemical studies of cultured fibroblasts derived from the proband, collagen I was overmodified, with normal processing of procollagen I, normal thermal stability, and a cyanogen bromide peptide map that suggested a C-terminal location of the structural abnormality in the collagen triple helix. Sequencing of the gene encoding the alpha2(I) chain of collagen I (COL1A2) indicated a nine base-pair deletion of nucleotides 3418-3426. When a polymerase chain reaction product containing the nucleotides in question was electrophoresed in a 12% polyacrylamide gel, two bands with a difference in size of nine base pairs could be shown. Sequencing of the molecular weight band confirmed the deletion of the nine base pairs involving codons 1003-1006 of COL1A2. The deletion introduced a SfiI restriction site that was used for confirmation of the deletion in genomic DNA from the proband. The deletion resulted in the removal of three amino acids (Gly-Pro-Pro), but this did not disrupt the Gly-X-Y sequence of the collagen triple helix, as is often the case in the more common glycine substitutions. We discuss the ways in which this deletion could result in osteogenesis imperfecta.

A proband with osteogenesis imperfecta (OI) type III/IV was born to clinically normal parents, who subsequently had two pregnancies terminated because of OI in the fetuses. Cultured fibroblasts from the proband, one fetus and the father produced abnormal collagen I. Cyanogen bromide mapping localised the defect to the region of the alpha 1(I)CB7 peptide. Sequencing revealed a G to A transition at nucleotide 2814 in COL1A2 in the proband, the fetus, and the father, which resulted in a Gly802Asp substitution in the pro alpha 2(I) collagen chain. About 25% of the paternal alleles from fibroblasts and leucocytes and 40% of paternal alleles from spermatocytes carried the mutation consistent with somatic and germinal mosaicism. For genetic counselling, parental mosaicism must be considered in all sporadic cases of OI.

The article focuses on the study of patients affected with Osteogenesis imperfecta (OI) /Ehlers-Danlos sysndrome (EDS). OI is an inherited connective tissue disorders which can intersect other connective tissues such as EDS. The patient underwent skin biopsy and analysis on his cultured fibroblasts. The observation was that, varied clinical phenotypes arises from glycine and that arg-to-cys substitution and theres limited bone involvement.