Heterogeneity of osteogenesis imperfecta. Biochemical and morphological findings in a case of type III according to Sillence

A male infant with pale-blue sclerae, who died at the age of 6 weeks through the aspiration of food, presented multiple fractures and deformation of the long tubular bones. The clinical and radiological findings and the course indicated osteogenesis imperfecta, type III, according to Sillence's classification. The family history was unremarkable. Light and electron microscopic studies of iliac crest bone obtained postmortem, showed an abrupt interruption of endochondral ossification, with an active periosteal ossification. In the region of the fractures, a mixed desmochondral callus was seen. The endoplasic reticulum of the osteoblasts was markedly dilated, the mitochondria were swollen. The osteoid was reduced in quantity. A postmortem analysis of the collagen types I, II and III obtained from skin, cartilage and bone yielded chromatographically normal collagen constituents. An analysis of the amino acids of the collagen -chains showed an increased hydroxylysine content. The radiological findings and the clinical course both indicated type III osteogenesis imperfecta: identical biochemical findings have been described only for type II. The morphological and biochemical findings described here may be a manifestation of a variable expressivity of type III osteogenesis imperfecta. On the other hand, heterogeneity of type II osteogenesis imperfecta cannot be ruled out.Abbreviation OI osteogenesis imperfecta Supported by the Stiftung Volkswagenwerk, research project: Skeletal Dysplasia and by a grant of the Deutsche Forschungsgemeinschaft (Po 189/3-1)     

Anthropometry of patients with osteogenesis imperfecta.

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.     

AN ARTHOROPATHIC FROM OF OSTEOGENESIS IMPERFECTA

Abstract. Penttinen, R., Sipola, E., Kouvalainen, K., Similä, S. and Remes, M. (Department of Medical Chemistry, University of Turku, and Department of Paediatrics, University of Oulu, Finland). Arthropathic osteogenesis imperfecta. Acta Paediatr Scand, 69:263, 1980.—A 14-year-old girl gradually developed severe osteoporosis and destructive generalized joint disease, resulting in joint stiffness and anchyloses. She also had moderate hydroxyprolinemia and hydroxyprolinuria. Rheumatoid arthritis was highly unlikely. Anamnestic data revealed two long bone fractures. Collagen biosynthesis was studied in fibroblasts cultured from the patient's skin. Chromatograms of ³H-labelled culture media proteins on ion exchange celluloses revealed an increased ratio of type III collagen to type I collagen when compared with the chromatograms of age-matched control fibroblasts. This finding is typical of certain cell strains in osteogenesis imperfecta. The patient might thus express a new variety of osteogenesis imperfecta with chronic arthropathy.     

Glykosaminoglykan- und Kollagenanalysen bei Osteogenesis imperfecta

Comparative studies on cartilage, bone, skin, and aorta in a case of osteogenesis imperfecta (male, three and a half year), and a healthy control (male, three and a half year) showed the following results:

1. The content of collagen in cartilage and skin in osteogenesis imperfecta is about 12–38 percent higher in the acetone dried tissue than in the control; however, in aorta and demineralized bone it is lower compared to the control (21 and 25 percent respectively). The amount of acidic glycosaminoglycans in costal and femur-kondyle cartilage in osteogenesis imperfecta exceeds that of the control by about 50 and 300 percent respectively.
2. The mineral content of bone (diaphysis of femur) was found to be 34.1 percent in osteogenesis imperfecta, and 54.7 percent in the control (dry weight of tissue). In two collagen preparations isolated from the citrate soluble and insoluble fraction of demineralized bone (femur diaphysis) the proline and hydroxyproline content was found to be the same in osteogenesis imperfecta and control. In contrast the content of hydroxylysine was increased in osteogenesis imperfecta. The lysine: hydroxylysine ratio was accordingly reduced: 0.9 in osteogenesis imperfecta compared to 1.7 in the control.
3. From the data presented it may be concluded that the biochemical defect in osteogenesis imperfecta is either an abnormally high glycosylation of the hydroxylysine residues of collagen, or a deficient desamination of hydroxylysine. The result in both cases will be a deficiency in the cross linking reactions of collagen.

     

Defective collagen fibril formation and mineralization in osteogenesis imperfecta with congenital joint contractures (Bruck syndrome)

We describe a male patient with osteogenesis imperfecta (OI) who was born with contractures of the knee, elbow and ankle joints. During the first 4 years he suffered from recurrent fractures. He has white sclerae, mild dentinogenesis imperfecta, multiple wormian bones, severe scoliosis and short stature. Morphological analysis of cortical bone revealed typical characteristics of OI including varying width of the osteoid, swollen mitochondria and a dilated endoplasmic reticulum of the osteoblasts. Collagen fibrils of the osteoid had a varying diameter, a feature not found in typical OI patients. Analysis of compact bone showed that the size of apatite crystals and the extractability of collagen with pepsin were markedly elevated compared to controls and other OI type III and IV patients. Lysyl hydroxylation of collagen from the organic bone matrix and the electrophoretic mobility of collagen 1(I)- and 2(I)-chains were normal. Our results provide evidence that this patient belongs to a subtype of OI. The biochemical studies indicate that the underlying defect involves defective fibril-formation of collagen type I leading to an altered mineralization of bone.Part of the results was presented at the IVth International Conference on Osteogenesis imperfecta in Pavia, Italy, 1990     

A probable new type of osteopenic bone disease

A probable new type of osteopenic bone disease in two sisters and one female cousin is described. In infancy, the radiological findings were osteopenia, coxa vara, periosteal cloaking, bowing of the long bones, and flaring of the metaphyses. During growth, spinal pathology developed with compression of the vertebral bodies and scoliosis in one girl and kyphosis in another. All three children had genu valgum and two developed severe S-shaped bowing of the tibiae. Growth was stunted. Inheritance of this disorder is probably recessive. Type I and III collagen biosynthesis was normal. This condition is probably a hitherto undescribed form of osteogenesis imperfecta type III or a new bone disease.     

Child abuse or osteogenesis imperfecta: how can we tell?

Osteogenesis imperfecta may be difficult to differentiate from nonaccidental trauma. Social history may prejudice the physician in favor of or against considering the diagnosis of child abuse. Three cases of osteogenesis imperfecta that were initially diagnosed as nonaccidental trauma are presented. The availability of biochemical analysis of type I collagen was instrumental in confirming the diagnosis of osteogenesis imperfecta in all three cases.     

Serum concentrations of procollagen I C-terminal propeptide,osteocalcin and insulin-like growth factor-I in patients with non-lethal osteogenesis irnperfecta

Serum concentrations of procollagen I C-terminal propeptide (PICP) were studied in 74 patients with various forms of non-lethal osteogenesis imperfecta and 27 unaffected family members. Using the standard deviation (SD) score, PICP concentrations were found to be ≤— 1 SD in 16%, between — 1 and —2 SD in 26% and ≤— 2 SD in 58% of the patients with osteogenesis imperfecta compared to healthy controls. PICP values were lowest in osteogenesis imperfecta type I (- 2.4 ± 0.4 SD, n= 37) followed by type III (-1.9 ± 0.5 SD, n = 13) and type IV (- 1.3 ± 0.7 SD, n= 20). Four patients with osteogenesis imperfecta with an atypical clinical course had normal or even elevated levels which may indicate heterogeneity in the underlying primary defects. In osteogenesis imperfecta type I, PICP concentrations proved to be a helpful serum marker for pedigree screening. Osteocalcin was high in 25 of 28 patients with osteogenesis imperfecta in the first decade but only in 1 of 18 older patients. Insulin-like growth factor-I was within the normal range in 53 cases of osteogenesis imperfecta, decreased in 2 and elevated in 3 patients. We conclude that PICP concentration is a useful parameter in the clinical management of osteogenesis imperfecta, including the assessment of future therapeutic interventions.     

Parental mosaicism and autosomal dominant mutations causing structural abnormalities of collagen I are frequent in families with osteogenesis imperfecta type III/IV

Abstract 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.     

A comparison of oral and intravenous bisphosphonate therapy for children with osteogenesis imperfecta

Bone mineral density and fracture rates in children with osteogenesis imperfecta improve with intravenous bisphosphonates. The efficacy of oral bisphosphonates has not been established. This report is an analysis of an open-label, prospective, randomized clinical trial of oral compared to intravenous bisphosphonate medications in children with osteogenesis imperfecta. Children were stratified according to bone age, pubertal stage, and type of osteogenesis imperfecta and then randomized to receive intravenous pamidronate, 3 mg/kg over 3 days every 4 months, or oral alendronate 1 mg/kg, from a minimum of 10 mg to a maximum of 20 mg daily. The primary efficacy outcome was change in bone mineral density. Secondary outcomes included change in biomarkers of bone turnover, fracture incidence, and growth rate. Ten children were randomized (6 oral and 4 intravenous). Two other children were assigned to intravenous treatment due to chronic abdominal pain. In each group, three patients had type III/IV osteogenesis imperfecta, while three had type I. All 12 children completed 8 months of therapy; nine completed 12 months. Bone mineral density increased in both oral and intravenous groups equally and beyond that expected with normal growth. All children had a decrease in biochemical markers of bone turnover. Linear growth showed a moderate increase above that for age. There was a non-significant decrease in fracture incidence in both groups.     

Collagen peptides in osteogenesis imperfecta, idiopathic juvenile osteoporosis and Ehlers–Danlos syndrome

We evaluated the potential of the carboxy-terminal propeptide of type I procollagen (PICP), the carboxy-terminal telopeptide of collagen I (ICTP), and the amino-terminal propeptide of type III procollagen (PIIINP) to differentiate osteogenesis imperfecta (OI) from Ehlers Danlos syndrome (EDS) and idiopathic juvenile osteoporosis (IJO) in paediatric patients. Markedly decreased serum concentrations of PICP were found in type I OI, while in IJO they were much less diminished, and in EDS they were near to normal. In type III and IV OI, the serum PICP level was lowered in prepubertal patients, whereas at puberty it was comparable to that in controls. Serum ICTP and PIIINP levels in patients with OI did not differ significantly from the levels in EDS and IJO. Measurements of scrum PICP levels seem to be useful in discriminating OI from EDS and IJO in prepubertal children. In pubertal children, however, they lose their diagnostic power.     

Type III osteogenesis imperfecta associated with hypophosphatemic vitamin D-resistant rickets

In a 7 year old girl presenting with bone deformities, dwarfism, and a history of recurrent fractures osteogenesis imperfecta had been diagnosed at birth. Although she had been hospitalized several times, radiologic signs of rickets remained unnoticed. Laboratory data proved existence of hypophosphatemic vitamin D-resistant type of rickets, which was effectively treated with 1 alpha-hydroxycholecalciferol and phosphorus substitution. The combination of osteogenesis imperfecta type III and hypophosphatemic rickets may be coincident. It proves, however, the necessity to consider the possible simultaneous occurrence of two rare diseases. The therapeutic consequences could be important.     

Postural balance,handgrip strength and mobility in Brazilian children and adolescents with osteogenesis imperfecta

ObjectiveTo describe postural balance, handgrip strength and mobility in children and adolescents with different types of osteogenesis imperfecta.MethodsCross-sectional study. Fifty selected subjects diagnosed with types I (n = 11), III (n = 21), and IV (n = 18), followed up at Brazilian reference center for osteogenesis imperfecta in the Midwest region, aged 2–21 years (9.2 ± 5.0), were enrolled in this study. Children and adolescents were evaluated for postural balance in the upright position with eyes-open and eyes-closed conditions, handgrip strength and the mobility domain (Pediatric Dysfunction Assessment Inventory). Data normality and difference between groups was verified.ResultsHandgrip strength was significantly lower in people with type III of osteogenesis imperfecta when compared to the osteogenesis imperfecta types I and IV, and to the age-specific reference data. Center of pressure length and mean velocity in the condition with eyes closed were worse compared to the open-eyes condition for children and adolescents with type I of osteogenesis imperfecta. There were worse results in the mobility domain for the participants classified with the most severe type of osteogenesis imperfecta.ConclusionsIt was observed that the severity of the osteogenesis imperfecta disease affected handgrip strength and locomotor function assessed by the mobility domain. Comparing osteogenesis imperfecta types, the higher the severity of osteogenesis imperfecta, the lower the handgrip strength. These results can contribute to new strategies of treatment focused on improving functional capacity and quality of life in people with osteogenesis imperfecta.     

Biochemical bone markers in the assessment and pamidronate treatment of children and adolescents with osteogenesis imperfecta

Aim: To assess the role of biochemical bone markers in classification of children with osteogenesis imperfecta (OI), their possible association with vertebral compression fractures in milder forms of OI and their role in monitoring of intravenous pamidronate (APD) treatment. Methods: Serum total alkaline phosphatase (ALP), bone ALP isoforms (in a subgroup), osteocalcin, type I procollagen carboxy‐terminal propeptide, carboxy‐terminal telopeptide of type I collagen, and urine deoxypyridinoline (DPD) were measured in a cross‐sectional study of 130 untreated individuals, 0.25–20.9 years (median 6.7), with OI types I, III and IV. Of those, sixty‐nine were also assessed longitudinally during monthly APD treatment. Bone mineral density (BMD) was measured by dual‐energy X‐ray absorptiometry. Results: Significant differences in bone markers, however not sufficient for individual clinical use, were found in the larger untreated group but not between subgroups with or without vertebral compressions. All bone markers decreased during treatment for 1.0–12.5 years, but with different relative amounts. Changes were not correlated to the improvement in BMD, mobility or pain. Conclusion: Bone markers are, despite significant differences, not useful for the classification of OI type in the individual child and are not associated with vertebral compressions. Serum ALP and urinary DPD are sensitive in monitoring bisphosphonate treatment.     

Osteogenesis imperfecta: a new, early therapeutic approach with biphosphonates. A case report]

Management of type III osteogenesis imperfecta (O.I.) (brittle bone disease) is primarily supportive; early introduction of cyclic intravenous pamidronate administration in children younger than 2 years of age is an innovative and promising therapeutic approach. CASE REPORT: We present the case of a 6-month-old infant, whose preliminary data have already been partly published, with severe type III O.I. referred because of aching and crumbling from multiple fractures. Cyclic intravenous disodic pamidronate administration improved the clinical status (fracture incidence, pain, growth curve) and biological status (bone density, osseous alkaline phosphatases, urinary desoxypiridoline excretion), allowing a remarkable recovery. CONCLUSION: Biphosphonates are a new and innovative therapeutic agent in O.I. Clinical safety, easy administration, and overall efficacy are likely to extend their use in severe type III O.I. from the very first months of life, the time of best efficacy.     

Osteogenesis imperfecta: contribution to pathobiochemistry

Osteogenesis imperfecta (OI) is a hereditary disease characterized by increased bone fragility and marked skeletal deformities. As a generalized connective tissue disorder, many patients present with other typical symptoms, such as blue sclerae, dentinogenesis imperfecta, impaired hearing, joint laxity, and easy bruising of the skin. According to clinical and genetic characteristics, Sillence classified four different groups. Metabolic alterations of connective tissue components are thought to be responsible for the pathogenesis of OI. Collagen, the main constituent of connective tissue, was analyzed in autoptic tissue and/or skin fibroblasts from patients with OI. In fibroblast culture of patients with OI group I, the range of synthesized collagen type III is elevated to 15-48% (normal up to 15%). Patients in groups II and III show an increased presence of hydroxylysine in alpha-chains of collagen types I and III. The hydroxylation of lysyl residues of the cartilage specific collagen type II is slightly elevated. In both groups, the hydroxypyroline content in all tested collagen types was normal. In our investigation, the collagen of patients with OI group IV appeared normal. Although the clinical features of patients with OI of all groups were not homogeneous, OI group III and some subtypes of group II had similar clinical courses and biochemical findings. In addition, there are patients with OI who present with clinical symptoms, but who cannot be classified into any of the known groups. For a better differentiation, biochemical examination of collagen should be performed complementary to clinical and genetic criteria.     

Chest compressions in an infant with osteogenesis imperfecta type II: No new rib fractures

The case report of a newborn female with osteogenesis imperfecta type II who underwent cardiopulmonary resuscitation (CPR) with manual chest compressions for several minutes is presented. Chest radiographs taken before and after the chest compressions were administered were reviewed by several radiologists from 3 different hospitals and demonstrated no new radiographically visible rib fractures. Collagen analysis, the patient's clinical appearance, and clinical course, as well as a consultant's opinion aided in confirmation of the diagnosis of osteogenesis imperfecta type II. A review of 4 previous studies concerning rib fractures and CPR is included. This unique case supports previous articles that have concluded that rib fractures rarely, if ever, result from CPR in pediatrics, even in children with a lethal underlying bone disease, such as osteogenesis imperfecta type II. cardiopulmonary resuscitation, chest compressions, osteogenesis imperfecta, rib fractures, bone disease.     

Collagen-derived markers of bone metabolism in osteogenesis imperfecta

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.     

Osteogenesis imperfecta: profiles of motor development as assessed by a postal questionnaire

This study was performed to achieve more detailed information regarding the age and sequence in the development of motor milestones in the different types of osteogenesis imperfecta (OI). The parents of 98 patients with a diagnosis of OI were sent a questionnaire regarding the age at which patients achieved motor milestones. All patients were attending the outpatient clinic for children with OI at the Wilhelmina Children's Hospital. The motor milestones were classified into static motor milestones and dynamic motor milestones and all data were checked with health care records. The age of development of motor milestones was compared to reference values of the healthy population. The severity of the disease was classified according to Sillence based on clinical, genetic and radiological data. The age of intramedullary rodding of the first nail in the lower and upper extremity and the localisation was noted. A total of 76 parents responded to the 98 questionnaires (78%). In OI type I, a delay exists in achieving motor milestones, comparable to the 95th percentile of the normal population. In type III, the development of all motor milestones was significantly delayed compared to types I and IV with a discrepancy between static and dynamic milestones. In OI type IV, a retardation in motor development developed after the milestone `sitting without support' was achieved. Motor development in types I and IV was not influenced by intramedullary rodding of the lower extremities, since rodding was rarely performed before the milestone `unsupported standing' was achieved. In type III, the influence of intramedullary rodding on the age of achieving motor milestones remains questionable. Conclusion The severity of osteogenesis imperfecta has a large influence on the age and sequence in the development of motor milestones. No influence of intramedullary rodding of the lower extremities on motor development was found in osteogenesis imperfecta types I and IV, whereas the influence in type III remains questionable. Received: 11 November 1999 and in revised form: 9 February 2000 and 24 February 2000 Accepted: 24 February 2000     

Bone mineral content and collagen defects in osteogenesis imperfecta

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.