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This rare disease affects the major connective tissues of the body. Overall, there is a decrease in bone mass and increase in bone brittleness. Patients present with a blue sclera, dental abnormalities, progressive hearing loss, and a positive family history.

Classification of Osteogenesis Imperfecta

I AD Mild fragility without deformity, short stature
II AD OR AR Perinatal lethal
III AD OR AR Severe, progressive deformity
IV AD Skeletal fragility and osteoporosis, bowing


Disease Associations  
Laboratory/Radiologic/Other Diagnostic Testing  
Gross Appearance and Clinical Variants  
Histopathological Features and Variants  
Special Stains/Immunohistochemistry/Electron Microscopy  
Differential Diagnosis  
Prognosis and Treatment  
Commonly Used Terms  
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1/20,000 births



Osteogenesis imperfecta and Paget's disease of bone. Biochemical and morphologic studies.

Shapiro JR, Triche T, Rowe DW, Munabi A, Cattell HS, Schlesinger S.

Arch Intern Med 1983 Dec;143(12):2250-7 Abstract quote

Osteogenesis imperfecta (OI) and Paget's disease of bone occurred in a patient whose brother has Paget's disease. Several other relatives have the dominant variety of OI.

The familial occurrence of the two diseases is presumably due to chance and, to our knowledge, has not been previously reported. Examination of iliac crest bone biopsy specimens showed mild changes of both diseases in the proband. Electron microscopy of the bone collagen demonstrated type I collagen fibers, which are reduced in number, decreased in diameter, and stellate rather than smooth in outline. Three populations of collagen fibers were observed in the bone. The synthesis of type I collagen by dermal fibroblasts was diminished in the proband and affected relatives, but it was normal in the unaffected relatives.

Since collagen fibers with a stellate outline have not been observed in OI bone, an intriguing question is the effect to the putative Paget agent (? viral) on collagen synthesis in OI.



Osteogenesis imperfecta: insufficient collagen synthesis in early childhood as evidenced by analysis of compact bone and fibroblast cultures.

Brenner RE, Vetter U, Nerlich A, Worsdorfer O, Teller WM, Muller PK.

Max Planck Institut fur Biochemie, Martinsried, FRG.

Eur J Clin Invest 1989 Apr;19(2):159-66 Abstract quote

We analysed the composition of compact bone from 30 patients suffering from various forms of osteogenesis imperfecta (OI). Collagen and total protein content per cell of controls increased with the age of the donors, but were generally low in OI.

In fibroblast cultures controls had a maximum of collagen synthesis between 2 and 9 years of age, an observation which was not seen in OI cells. In bone collagen both OI type II patients showed overhydroxylation of lysyl residues as did some patients with OI type III (25%) and OI type IV (33%). The collagen of OI type I patients was never found to be overmodified. In controls, collagen III was found exclusively during fetal time while it was present in significant amounts in bone tissue of all types of OI. The proportion of collagen V was somewhat higher in OI bones (about twice) than in controls.

Our data suggest that the normal increase of collagen synthesis is defective in patients with OI. Perhaps some of these changes are due to specific molecular defects in collagen while others may be due to defective regulation of the maturation process.

Altered collagen metabolism in osteogenesis imperfecta fibroblasts: a study on 33 patients with diverse forms.

Brenner RE, Vetter U, Nerlich A, Worsdorfer O, Teller WM, Muller PK.

Max Planck Institut fur Biochemie, Martinsried, FRG.

Eur J Clin Invest 1990 Feb;20(1):8-14 Abstract quote

The pattern of collagen metabolism was analysed in fibroblast cultures from patients with diverse forms of osteogenesis imperfecta (OI). Generally, OI fibroblasts show an insufficient collagen synthesis which is most obvious in patients between 2 and 9 years of age during which period control fibroblasts have an elevated collagen synthesis. OI fibroblasts remain on a basal level except for fibroblasts from OI type IV patients which seem to approach normal levels. In addition, OI fibroblasts generally show a slightly increased degradation of newly synthesized collagen which again is most obvious between 2 and 9 years.

These differences in collagen degradation, however, only contribute to a minor extent to the lack of net collagen synthesis during early childhood. No correlation could be found between the degree of overmodification of collagen and its degradation since fibroblasts of both OI type I and OI type II have an elevated degradation though only the latter ones produce overmodified collagen molecules. Pulse labelling of collagen with radioactivity labelled sugars was used to distinguish between normal collagen chains or CNBr-derived peptides and those which were overmodified. In all three cases studied (OI II, OI III, OI IV) the entire triple helical domain of alpha 1(I) and alpha 2(I) was overglycosylated. The amount of overmodification, however, was not uniform but rather unique for each patient studied.

We assume that the molecular defects in the majority of OI cases may be located in the mechanisms operating on the control of both the age appropriate synthesis of collagen and its degree of post-translational modification.

Osteogenesis imperfecta: clinical, cephalometric, and biochemical investigations of OI types I, III, and IV.

Jensen BL, Lund AM.

Department of Pediatric Dentistry, Faculty of Health Sciences, School of Dentistry, Copenhagen N, Denmark.

J Craniofac Genet Dev Biol 1997 Jul-Sep;17(3):121-32 Abstract quote

The aim of the study was to analyze craniofacial development in 54 patients with osteogenesis imperfecta (OI), who were classified into OI types I, III, and IV according to clinical criteria, and to relate the findings to the abnormalities in collagen I production.

In 33 patients, analysis of radioactively labelled procollagen was performed. Cephalometric radiographs, facial photographs, and CT-scans (a single case) were analyzed and mean facial diagrams for lateral and frontal films were produced based on registration of 221 reference points. Radiographs of 102 male and 51 female Danish students served as control material. In OI type I, size of the skull and jaws was generally slightly reduced, but morphology was within normal limits. In OI type IV and especially type III more severe abnormalities were found; the cranial base was flattened, the maxilla posteriorly inclined, and nearly all size-measurements were reduced. In OI type III the sagittal jaw relations were reduced and a mandibular overjet recorded. Three OI type I patients, whose fibroblasts produced structurally abnormal collagen I, had the stature and several features in the craniofacial region, which corresponded to those recorded for the OI type IV group. Also, in three OI type IV patients whose fibroblasts produced a reduced amount of normal collagen I, craniofacial morphology showed several features resembling type I patients.

We conclude that structural abnormalities of collagen I generally give rise to more severe alterations of the craniofacial features than a quantitative defect of collagen I. OI type I patients are only slightly affected in their craniofacial region, while patients with OI type IV and especially type III are moderately to severely affected. The combined cephalometric and biochemical findings suggest that future classification of patients with osteogenesis imperfecta should be based on biochemical/molecular and radiological analyses in combination with clinical criteria rather than on clinical features alone.


The mechanical properties of skin in osteogenesis imperfecta.

Hansen B, Jemec GB.

Osteoporosis Research Clinic, Hvidovre University Hospital, University of Copenhagen, Kettegaard Alle 30, DK-2650 Hvidovre, Denmark.

Arch Dermatol 2002 Jul;138(7):909-11 Abstract quote

BACKGROUND: Skin mechanics may be affected by several dermatological and systemic conditions. The skin can act as a marker of generalized disease. Osteogenesis imperfecta (OI) is a heritable disorder characterized by fragile bones caused by a generalized disorder of collagen. The dermis has a relative increase of argyrophil and elastic fibers and a deficiency of adult collagen. The collagen defect is well described, but functional changes in tissue mechanics have not been studied in the skin. The functional changes may reflect general changes and may give insight into the pathogenesis of clinical problems in these patients.

OBJECTIVE: To examine skin mechanics (elasticity, distensibility, and hysteresis) in patients with OI.

METHODS: Ten patients with OI (mean +/- SD age, 45.9 +/- 11.5 years) and 24 age-matched control subjects (mean +/- SD age, 43.3 +/- 13.8 years) were studied. The suction cup technique was used (Dermaflex; Cortex Technology, Hadsund, Denmark).

RESULTS: Significant differences between the patients and controls were found in all measurements (P<.002). Skin elasticity was decreased in patients vs controls (55.5% [range, 50.9%-60.1%] vs 73.8% [range, 70.3%-77.2%]). Similarly, distensibility was decreased (2.10 mm [range, 1.85-2.35 mm] vs 2.50 mm [range, 2.37-2.63 mm]), as was hysteresis (0.19 mm [range, 0.15-0.23 mm] vs 0.28 mm [range, 0.27-0.30 mm]).

CONCLUSIONS: The skin of patients with OI is more stiff and less elastic than normal skin. It is speculated that similar differences may be found in other tissues in patients with OI. The results potentially offer a quantitative standardized measure of OI, which may further our understanding of the underlying physical problems of these patients, provide better case definitions, and assist in predicting the prognosis of patients with OI.




Testing for osteogenesis imperfecta in cases of suspected non-accidental injury.

Marlowe A, Pepin MG, Byers PH.

Public Health Genetics Program, University of Washington, Seattle, WA 98195, USA.

J Med Genet 2002 Jun;39(6):382-6 Abstract quote

To evaluate if laboratory testing for osteogenesis imperfecta (OI) identifies children unrecognised by clinical examination in instances where non-accidental injury (NAI) is suspected as the likely cause of fracture, we carried out a retrospective review of available medical records and biochemical test results from 262 patients.

Cultured fibroblasts were received for biochemical testing for OI from children in whom the diagnosis of NAI was suspected. Eleven of the samples had alterations in the amount or structure of type I collagen synthesised, consistent with the diagnosis of OI, and in 11 others we could not exclude OI. Referring physicians correctly identified children with OI in six of the 11 instances established by biochemical studies, did not identify OI by clinical examination in three, and there was inadequate clinical information to know in two others. Biochemical testing was inconclusive in 11 infants in whom the diagnosis of OI could not be excluded, none of whom were thought to be affected by the referring clinicians. Four children believed to have OI by clinical examination had normal biochemical studies, a false positive clinical diagnosis attributed, in large part, to the use of scleral hue (a feature that is age dependent) as a major diagnostic criterion.

Given the inability to identify all children with OI by clinical examination in situations of suspected NAI, laboratory testing for OI (and other genetic predispositions for fractures) is a valuable adjunct in discerning the basis for fractures and may identify a small group of children with previously undiagnosed OI.



Dental manifestations of osteogenesis imperfecta and abnormalities of collagen I metabolism.

Lund AM, Jensen BL, Nielsen LA, Skovby F.

Department of Clinical Genetics, Rigshospitalet, Copenhagen.

J Craniofac Genet Dev Biol 1998 Jan-Mar;18(1):30-7 Abstract quote

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.


Cardiovascular pathology in osteogenesis imperfecta type IIA with a review of the literature.

Wheeler VR, Cooley NR Jr, Blackburn WR.

University of South Alabama Medical Center, Department of Pathology, Mobile 36617.

Pediatr Pathol 1988;8(1):55-64 Abstract quote

Lethal perinatal osteogenesis imperfecta (OI Type II) is a biochemically diverse collagen disorder characterized by short, crumpled long bones, beaded ribs, blue sclerae and thin, fragile skin.

Cardiovascular abnormalities are rarely described. Using morphometry and light and electron (SEM and TEM) microscopy, we analyzed the hearts and great vessels from 2 fetuses with OI Type IIA and compared the findings with age-matched controls. The heart weights and atrioventricular valve (AVV) circumferences were reduced in OI. The chordae tendineae were short and fragile; both the AVVs and the chordae tendineae were hypercellular. TEM showed relatively little organized collagen in the chordae tendineae of OI fetuses. Furthermore, quantitative evaluation of collagen fibril size revealed a decrease in the cross-sectional diameter. There was also a marked decrease in the adventitial and intramural collagen of the intramyocardial arteries and great vessels in OI.

Our study reports, for the first time, specific lesions in the cardiovascular systems of patients with OI Type II and reviews the cardiovascular pathology in other forms of OI.



Histological investigation of skin biopsies in otosclerosis and osteogenesis imperfecta.

Pedersen U, Sogaard H, Elbrond O.

Arch Otorhinolaryngol 1984;240(1):1-6 Abstract quote

Histological investigation of skin biopsies in four patients with osteogenesis imperfecta, nine patients with otosclerosis and 13 sex- and age-matched normal controls was carried out blindly.

The dermal thickness was markedly reduced in osteogenesis imperfecta and slightly reduced in otosclerosis. Minor degenerative changes in the elastic fibres were seen in otosclerosis, while the elastic fibres were found to be more degenerated and more numerous in osteogenesis imperfecta.

Our study does not support the hypothesis of otosclerosis being a localized form of osteogenesis imperfecta. The minor changes in the elastic fibres in otosclerosis indicate that further studies of the elastic fibres and of collagen will be necessary to determine whether otosclerosis is a localized disease or part of a general connective tissue disorder.



Collagen defect of bone in osteogenesis imperfecta (Type I). An electron microscopic study.

Jones CJ, Cummings C, Ball J, Beighton P

Clin Orthop 1984 Mar;(183):208-14 Abstract quote

Osteogenesis imperfecta (OI) is an inherited disorder of connective tissue metabolism characterized by fragility of the bones, resulting in multiple fractures.

In this study electron microscopic examination of the osteoid region of iliac crest bone biopsy specimens from a 55-year-old man and his three sons (18, 21, and 25 years of age) affected with the common Type I (autosomal dominant) form of OI revealed collagen fibrils consistently smaller in diameter than those from normal age-matched control subjects, with the majority of OI fibrils measuring 0.04-0.06 micron, as opposed to 0.06-0.08 micron in the control subjects.

This defect may be due to the biosynthesis of Type III collagen, not normally found in adult lamellar bone or, more likely, to a failure of maturation of Type I fibrils to their normal diameters, possibly owing to the increased levels of hydroxylysine previously reported in OI collagen, a factor known to be inversely related to fibril diameter.


Achondrogenesis Type I Distinguished from OI by the absent sacrum and narrowed interpediculate distance.
(Melnik-Needles Syndrome)
Distinguished from OI by the bizarre shape of the pelvis.
Short Rib Polydactyl Syndrome
(Saldino-Noonan Syndrome)
Distinguished from OI by absence of fractures and bowing and irregular metaphyses.



Osteogenesis imperfecta in childhood: impairment and disability.

Engelbert RH, van der Graaf Y, van Empelen R, Beemer FA, Helders PJ.

Department of Pediatric Physical Therapy, University Hospital for Children and Youth, "Wilhelmina Children's Hospital", Utrecht, The Netherlands.

Pediatrics 1997 Feb;99(2):E3 Abstract quote

OBJECTIVE: To determine clinical characteristics in children with osteogenesis imperfecta (OI) regarding impairment (range of joint motion and muscle strength) and disability (functional skills) in relation to the different types of the disease, and to study the correlation between characteristics of impairment and disability.

METHODS: In a cross-sectional study 54 children with OI (OI type I: 24; OI type III: 15; OI type IV: 15), the range of joint motion, muscle strength, and functional ability were measured in a standardized way and analyzed statistically.

RESULTS: The range of joint motion in almost all joints differed significantly with respect to the different disease types. In OI type I patients, generalized hypermobility of the joints was present, without decrease in joint motion. In OI type III the extremities were severely maligned, especially the lower limbs. In type IV the upper and lower extremities were equally maligned. Muscle strength differed significantly with respect to the different types of OI. In type I patients, muscle strength was normal except for the periarticular hip muscles. In type III, especially in the lower extremities, muscle strength was severely decreased, with a muscular imbalance around the hip joint. In type IV, muscle strength was mainly decreased in the proximal muscles of the upper and lower extremities. In children </=7.5 years of age, significant differences existed among the different disease types in functional skills regarding mobility. No significant difference was observed in self-care and social function, although the most severely affected children showed a tendency to score better with social function. Older children differed significantly concerning mobility and self-care items. In children </=7.5 years old, a correlation was sometimes observed between impairment and disability items, although in older children a moderate to good correlation was always present (r > .6).

CONCLUSION: In OI, severity-related profiles exist, within the different subtypes of the disease, regarding range of joint motion, muscle strength, and functional skills. In younger children, impairment parameters do not sufficiently correlate for disability. Rehabilitation strategies in younger children should therefore focus on improvement of functional skills and not only on impairment parameters.


Osteogenesis imperfecta in childhood: treatment strategies.

Engelbert RH, Pruijs HE, Beemer FA, Helders PJ.

Department of Pediatric Physical Therapy, University Hospital for Children and Youth, Wilhelmina Children's Hospital, Utrecht, The Netherlands.

Arch Phys Med Rehabil 1998 Dec;79(12):1590-4 Abstract quote

Osteogenesis imperfecta (OI) is a skeletal disorder of remarkable clinical variability characterized by bone fragility, osteopenia, variable degrees of short stature, and progressive skeletal deformities. Additional clinical manifestations such as blue sclerae, dentinogenesis imperfecta, joint laxity, and maturity onset deafness are described in the literature.

OI occurs in about 1 in 20,000 births and is caused by quantitative and qualitative defects in the synthesis of collagen I. Depending on the severity of the disease, a large impact on motor development, range of joint motion, muscle strength, and functional ability may occur.

Treatment strategies should primarily focus on the improvement of functional ability and the adoption of compensatory strategies, rather than merely improving range of joint motion and muscle strength.

Surgical treatment of the extremities may be indicated to stabilize the long bones to optimize functional ability and walking capacity. Surgical treatment of the spine may be indicated in patients with progressive spinal deformity and in those with symptomatic basilar impression.


Beneficial effect of long term intravenous bisphosphonate treatment of osteogenesis imperfecta.

Astrom E, Soderhall S.

Department of Woman and Child Health, Divison of Paediatric Neurology, Astrid Lindgren Children's Hospital and Sodersjukhuset, Stockholm, Sweden.

Arch Dis Child 2002 May;86(5):356-64 Abstract quote

AIM: To find an effective symptomatic treatment for osteogenesis imperfecta (OI).

METHODS: In a prospective observational study disodium pamidronate (APD) was given as monthly intravenous infusions to 28 children and adolescents (aged 0.6-18 years) with severe OI or a milder form of the disease, but with spinal compression fractures.

RESULTS: During treatment for 2-9 years, dual energy x ray absorptiometry measurements of the total body and of the lumbar spine showed a gradual increase in bone density. All bone metabolism variables in serum (alkaline phosphatase, osteocalcin, procollagen 1 C-terminal peptide, collagen 1 teleopeptide) and urine (deoxypyridinoline) indicated that there was a decrease in bone turnover. All patients experienced beneficial effects and the younger patients reported a major improvement in wellbeing, pain, and mobility without significant side effects. Vertebral remodelling was also seen.

CONCLUSIONS: APD seems to be an efficient symptomatic treatment for children and adolescents with OI.

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Weedon D. Weedon's Skin Pathology. Churchill Livingstone. 1997.
Fitzpatrick's Dermatology in General Medicine. 5th Edition. McGraw-Hill. 1999.
Robbins Pathologic Basis of Disease. Sixth Edition. WB Saunders 1999.

Commonly Used Terms

Congenital Metabolic Diseases

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Last Updated 8/1/2002

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