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  1. 1. Osteogenesis imperfectaAuthor: Doctor Guillaume Chevrel1Creation Date: October 2002Update: June 2004Scientific Editor: Doctor Martine Le Merrer1 Service de rhumatologie et de pathologies osseuses, CHU Hôpital Edouard Herriot, 5 Place dArsonval,69437 Lyon Cedex 3, France. Guillaume.CHEVREL@wanadoo.frAbstractKeywordsDisease name and synonymsDefinition/Diagnosis criteriaDifferential diagnosisFrequencyClinical descriptionEtiologyDiagnostic methodsManagementTreatmentGenetic counsellingReferencesAbstractOsteogenesis imperfecta (OI) is a group of inherited diseases responsible for varying degrees of skeletalfragility. Minimal trauma is sufficient to cause fractures and bone deformities. A classification with 5 typesis most widely used.Type I: moderate form with autosomal dominant transmission, characterized by blue sclerae ordentinogenesis imperfecta and sometimes late hearing loss, but no growth retardation.Type II: lethal form, with autosomal dominant transmission.Type III: severe form with autosomal dominant or recessive transmission, characterized by blue scleraeand dentinogenesis imperfecta.Type IV: intermediate form with autosomal dominant transmission, characterized by normal sclerae andwith or without dentinogenesis imperfecta.Type V: form with hypertrophic calluses and calcification of interosseous membrane.Type V does not seem to be related to the COL1A1 or COL1A2 genes.OI is caused by mutations in the COL1A1 or COL1A2 gene, which encode the alpha1 and alpha2 chainsof type 1 collagen, respectively. These mutations are responsible for the production of quantitatively orqualitatively deficient fibrils. Accurate incidence and prevalence of the disease are currently unknown. Thediagnosis is often readily made in infancy; some cases, however, go unrecognized until adulthood.Lifelong multidisciplinary management is imperative. Pamidronate therapy in childhood is the mostextensively studied treatment and has been proved beneficial. Prevention of vitamin D and calciumdeficiency is essential throughout life. Various orthopedic and surgical techniques are available forreducing the fractures and correcting the deformities. Pain is common and should be given adequateattention.KeywordsOsteogenesis imperfecta, trauma, fracture, bone deformities, blue sclerae, dentinogenesis imperfecta,COL1A1 or COL1A2, Pamidronate, vitamin D and calcium supplementationChevrel G; Osteogenesis imperfecta. Orphanet encyclopedia, June 2004.http://www.orpha.net/data/patho/GB/uk-OI.pdf 1
  2. 2. Disease name and synonyms and long bone fractures at birth, severe skeletal-Osteogeneis imperfecta deformities, dark sclera. Type III Severely-Glass bone disease (1) deforming: autosomal dominant; glycine-Brittle bone disease substitutions in COL1A1 or COL1A2. Very short-Lobsteins disease (2) stature, triangular face, severe scoliosis, greyish-Porak and Durantes disease (3) sclera, dentinogenesis imperfecta. Type IV Moderately deforming: autosomal dominant;Definition/Diagnosis criteria glycine substitutions in COL1A1 or COL1A2.Osteogenesis imperfecta (OI) is a group of Moderately short stature, mild to moderateorphan diseases characterized by varying scoliosis, greyish or white sclera, dentinogenesisdegrees of skeletal fragility. Fractures and bone imperfecta. Type V Moderately deforming:deformities occur with trivial trauma. The most autosomal dominant, unknown associatedwidely used system to classify the different types mutations. Mild to moderate short stature,of OI is developed by Sillence et al. (4,5). It is dislocation of radial head, mineralizedbased of clinical, genetic and radiographic interosseous membrane, hyperplastic callus,findings: white sclera, no dentinogenesis imperfecta.-Type I: the most common form, is autosomal Type VI Moderately to severely deforming:dominant and is characterized by blue sclerae, a autosomal dominant, unknown associatedtypical feature of OI (6). The number of fractures mutations. Moderately short stature, scoliosis,is fairly small and the deformities are modest, accumulation of osteoid in bone tissue, fish-causing little loss of stature. scale pattern of bone lamellation, white sclera,-Type II: which is also autosomal dominant, is no dentinogenesis imperfecta. Type VIIthe lethal form of the disease. The sclerae are Moderately deforming: autosomal recessive,blue and death is due primarily to lung unknown associated mutations. Mild shortunderdevelopment caused by rib fractures. stature, short humeri and femora, coxa vara,-Type III: is autosomal dominant or recessive (7) white sclera, no dentinogenesis imperfectaand is the most severe non-lethal form. The (32,33).sclerae are white, the face triangular, and thefractures commonly accompanied with Differential diagnosisprogressive deformities and short stature. In neonates and children, the presence of-Type IV: is autosomal dominant and usually fractures that occurred at various ages cancharacterized by white sclerae, short stature, suggest child abuse. However, the possibility ofand skeletal deformities that are less severe OI should be borne in mind: some parents ofthan those in type III. Type IV is the most children with OI have been wrongly accused ofheterogeneous group because it comprises battering their children. Consequently, whenthose patients who do not meet the criteria for child abuse is suspected, radiologicalthe other three types. abnormalities that can point to OI should be-Type V: characterized by hypertrophic calluses, looked for carefully. However, the radiologicalsometimes mistaken for osteosarcomas, and by changes in OI are nonspecific, although theossification of the interosseous membranes (8). presence of wormian bones is highly suggestive.Type V does not seem to be related to the In some cases, dual-photon X-rayCOL1A1 or COL1A2 genes. absorptiometry is useful in discriminatingAlthough widely accepted, many patients with OI between OI, in which bone mineral densitydo not readily fall into Sillences classification (BMD) is low, from child abuse.due to the broad spectrum of molecular Other causes of osteopenia in infants and youngabnormalities resulting in OI. This has prompted children include immobilization, premature birth,some investigators to propose existence of other vitamin D deficiency, and hematologicalsubtypes of OI believed not to be directly diseases.associated with type I collagen mutations but In older children, the combination of fracturesother yet unidentified macromolecules (32): and osteoporosis during the course of a knownType I Mild, non-deforming, due to premature disease raises no diagnostic problems. Whenstop in COL1A1, autosomal dominant the diagnosis remains in doubt, idiopathicinheritance, characterized by normal height or juvenile osteoporosis (IJO) should be consideredmild short stature, blue sclera, no if rare causes of osteopenia (e.g., leukemia)dentinogenesis imperfecta. Type II Perinatal have been ruled out. In the absence of clinicallethal, autosomal dominant inheritance; glycine evidence of OI, a diagnosis of IJO can be given.substitutions in COL1A1 or COL1A2: Multiple rib IJO is typically discovered during evaluation of aChevrel G; Osteogenesis imperfecta. Orphanet encyclopedia, June 2004.http://www.orpha.net/data/patho/GB/uk-OI.pdf 2
  3. 3. fracture between 8 and 11 years of age (i.e., scars. Many patients have neurologicalbefore puberty) in a boy or girl (see (9) for a abnormalities, of which the most common isreview of reported cases). A common feature is basilar impression (12).pain in the spine, hips, and feet, with difficultwalking. The fractures are typically metaphyseal, Musculoskeletal abnormalities include long bonealthough no segment of the long bones is deformities with anterior bowing of the humerus,exempt. Vertebral fractures are common and tibia and fibula and lateral bowing of the femur,can result in deformities and a slight loss of radius and ulna. The hallmark of OI is boneheight of the trunk. The skull and facial skeleton fragility with fractures occurring with minimal toare normal. There are no characteristic moderate trauma. In general, the earlier thebiochemical abnormalities. IJO improves fractures occur in life, the more severe thespontaneously within 3 to 5 years, although the disease is. The lower limbs are more commonlyvertebral deformities and functional impairment involved. Femural fractures are the mostcan persist. A positive family history should common fractures of long bones, with thesuggest a mild form of OI. fracture located usually at the convexity of theOther skeletal disorders resembling OI (32) that bone, usually transverse and minimallytake place in the differential diagnosis of OI are: displaced. Multiple fractures within the sameHypophosphatasia (mild to severe bone bone often occur. Cranial deformity is alsofragility/deformity; low alkaline phosphatase common. There is flattening of the posterioractivity, autosomal recessive, autosomal cranium with a bulging calvarium and adominant inheritance, ALPL defect); triangular-shaped face (type III).Idiopathic hyperphosphatasia (severe bonefragility/deformity, raised alkaline phosphatase Etiologyactivity, autosomal recessive inheritance, OI is a group of inherited disorders caused byTNFRSF11B genetic defect); mutations in the COL1A1 or COL1A2 gene,Bruck syndrome (moderate to severe bone which encode the alpha1 and alpha2 chains offragility/deformity, congenital joint contractures, type 1 collagen produced by osteoblasts,autosomal recessive inheritance; telopeptide respectively (13). These genes are susceptiblelysyl hydroxylase deficiency); to many mutations responsible for the productionCole-Carpenter syndrome (severe bone of quantitatively or qualitatively deficient fibrilsfragility/deformity, craniosynostosis, unknown (14).genetic defect and inheritance). These mutations are private, ie. specific to a family or to an individual when they occur deFrequency novo.Accurate incidence and prevalence data are notavailable. It was reported to range from one per Diagnostic methods10 000 to one per 20 000 live births (34). If OI is not obvious at birth, the diagnosis is often made when the child starts to walk. However,Clinical descriptionIn addition to the clinical manifestations used in some cases go unrecognized until adulthood. The Sillence classification scheme helps todistinguishing the different types of OI (seechapter Definition/diagnosis criteria), several establish the diagnosis, but only when theother features deserve to be underlined because clinical signs are obvious. The presence of blue sclerae and a positive family history are the mostthey provide diagnostic orientation in patients,particularly adults, with mild bone symptoms. reliable features, although there are exceptions, which can raise problems if a therapeutic trial is being considered.Scoliosis is common. The combination of chestdeformities and scoliosis is responsible for a Histomorphometrylarge number of deaths due to respiratory In a small minority of cases the bone biopsydisorders (10,11). Some forms, most notably shows specific abnormalities, which help totype III, are characterized by dentinogenesis establish the diagnosis of OI. The biopsiesimperfecta manifesting as brittle teeth. Hearing should be of excellent quality and should beloss, which can be sensorineural, conductive or examined by observers who are thoroughlymixed, can develop gradually, particularly in type familiar with OI.I (deafness occurs in approximately 40% of type Routine analysis of bone biopsies from childrenI patients). Ligamentous laxity is common, as are with OI has shown that type IV in the Sillencetrauma-related hematomas and atrophic skin classification scheme encompasses a number ofChevrel G; Osteogenesis imperfecta. Orphanet encyclopedia, June 2004.http://www.orpha.net/data/patho/GB/uk-OI.pdf 3
  4. 4. specific patterns, such as type V individualized collagen (PICP) has been reported (21-23).by Glorieux et al. (8). In comparison to normal However, other bone turnover markers, such aschildren, the increase in trabecular width is less osteocalcin, alkaline phosphatase, and amino-marked in type I and absent in types III and IV. terminal telopeptide of type I collagen are useful for monitoring children with OI (24- 26).Genetic diagnosisThe diversity of the mutations involved in OI is a Managementmajor stumbling block to the genetic diagnosis of The management of patients with OI requires theOI: in theory, identification of the mutation involvement of a multidisciplinary team includingrequires that both type 1 collagen genes be general practitioners and specialists who workanalyzed. The chances of success of this near the home of the patient. Indeed, this rareanalysis depend on both the clinical pattern of disease raises many problems in everyday life.the disease and the technique used. Patient organizations (in France: theUnfortunately, this analysis is not available on a “Association de l’Ostéogenèse Imparfaite”) playroutine basis and remains a research tool. Other a key role in disseminating practical informationgenetic analysis techniques exist, but their about the disease (27). In some cases,applicability is partly conditional on the number management must be started at birth. Theof family members. management of OI involves appropriate rehabilitation therapy directed both at theBone density measurement fracture and at the development of the child.Although bone density measurement (BMD) is Long-term follow-up is essential in patients withnow widely available, few patients with OI have OI. The annual fracture rate decreases atbeen investigated using this method. BMD is puberty but increases subsequently duringnormal in a tiny number of cases, even in the adulthood. In women, fractures are commonabsence of degenerative spinal disease or hip after the menopause as a result of the combinedabnormalities (15). In most cases, however, influence of OI and osteoporosis (28). In men,BMD is far below the normal range, as shown by the fracture rate increase is most markedthe Z-score in children and the T-score in adults between 60 and 80 years of age.(16-18). In some patients, the bone is sotransparent as to interfere with image analysis Treatmentby the absorptiometry device. As inosteoporosis, the low BMD is probably a major Medicationsrisk factor for further fractures. However, the The ultimate goal of medical treatment indefinition of osteoporosis developed by the children with severe osteogenesis imperfectaWorld Health Organization, i.e. a T-score lower should be to reduce fracture rates, prevent long-than 2.5, has not been validated prospectively in bone deformities and scoliosis, and improveadults with OI. Neither BMD measurement using functional outcome.ultrasound has been validated in patients withOI. Bisphosphonates Systematic studies have established thatPhosphate, calcium, and bone turnover bisphosphonates, most notably Pamidronate,markers constitute a breakthrough in the treatment of OI.Serum calcium is normal in patients with OI. (24, 29). Pamidronate therapy has been shownHypercalciuria has been reported in some to cause pain relief and to result in the increasepatients in the absence of prolonged of BMD and size of vertebras, as well as in aimmobilization (19), with no renal dysfunction or decrease of the incidence of fractures, while nonephrocalcinosis (20). adverse effects on growth were reported.Serum 25-hydroxy-vitamin D is often low, The benefits of pamidronate therapy areindicating vitamin D deficiency secondary to lack sufficiently impressive to suggest that routineof exposure to sunlight, which is fairly common use of this agent may be in order in all childrenin these patients (Meunier et al., 7th International with OI, even when the manifestations are mild,Conference on Osteogenesis Imperfecta, although this last point is controversial. The needMontreal, 1999). for intravenous injections may limit the use ofBiochemical markers for bone turnover do not pamidronate. Studies of oral bisphosphonatesprovide accurate information on bone structure (e.g., alendronate Fosamax®) are ongoing inin OI, although a selective decrease in serum children with OI.levels of carboxy-terminal propeptide of type IChevrel G; Osteogenesis imperfecta. Orphanet encyclopedia, June 2004.http://www.orpha.net/data/patho/GB/uk-OI.pdf 4
  5. 5. Hormone replacement therapy or selective Genetic counsellingestrogen receptor modulator therapy is strongly Genetic counselling should be offered to therecommended in postmenopausal women with parents of a child with OI who plan to haveOI. subsequent children. During genetic counselling,Some data show that growth hormone might be the possibility that the parents may harbor newuseful in combination with bisphosphonates. mutations, such as asymptomatic somatic andParathyroid hormone as a potent bone anabolic germline mosaicism, needs to be discussed.agent could be a candidate for treating OI but Parents need special instructions in positioningboth regimens remain to be tested. the child in the crib and handling the child with the least possibility of causing fractures. UprightVitamin D and calcium supplements sitting in infants younger than 1 year should beThe measures taken to protect patients with OI discouraged in order to decrease developmentfrom trauma and the repeated immobilizations of basilar impression later in life. Hip-knee-ankle-required by the fractures often result in vitamin D foot orthosis helps early achievement of uprightand calcium deficiency in children and adults. activity.Prophylactic supplementation is in order, withdosages of about 500 to 1000 mg of calcium and References400 to 800 IU of vitamin D. 1. Apert E., Les hommes de verre. Presse M 51 (1928), pp. 805-808.Analgesics 2. Lobstein J., Von der Knochenbreichigkeit oderPain is common and should receive adequate Osteopsathyrose. In: Lehrbuch derattention. Bone pain responds well to Pathologischen Anatomie (Bd 2 ed.),, Brodhag,bisphosphonate therapy (24,26,29). Other Stuttgart (1835), pp.179-179.causes of pain include deformities and 3. Porak C. and Durante G., Les microméliesdegenerative lesions, both of which are congénitales: achondroplasie et dystrophiecommon: in this situation, the treatment is périostale. Nouv Iconogr Salpêt 18 (1905), pp.symptomatic. 481-538. 4. Sillence D., Senn A. and Danks D., GeneticCell and gene therapies as potential treatments heterogeneity in osteogenesis imperfecta. J Medfor OI are currently actively investigated. The Genet 16 (1979), pp. 101-106.design of gene therapies for OI is however 5. Sillence D., Osteogenesis imperfecta: ancomplicated by the genetic heterogeneity of the expanding panorama of variants. In: ClinOrthopdisease and by the fact that most of the OI 159 (1981), pp. 11-25.mutations are dominant negative where the 6. Leidig-Bruckner G. and Grauer A., Bluemutant allele product interferes with the function sclerae in osteogenesis imperfecta. N Engl J Mof the normal allele. Major obstacles result from 339 (1998), pp. 966-966.the presence of abnormal collagen molecules. 7. Beighton P. and Versfeld G., On theTechniques based on marrow stem cells are paradoxically high relative prevalence ofunder investigation. osteogenesis imperfecta type III in the Black population of South Africa. Clin Genet 27 (1985),Orthopedic treatment pp. 398-401.Orthopedic treatment remains indispensable in 8. Glorieux F., Bishop N., Travers R., RoughleyOI. A careful preoperative evaluation with special P., Chabot G., Lanoue G. et al., Type Vattention to lung function is essential in types III osteogenesis imperfecta. J Bone Miner Res 12and IV. In children, rodding surgery is well Suppl 1 (1997), pp.389-389.standardized (reviewed in 30, 31). The treatment 9. Brumsen C., Hamdy N. and Papapoulos S.,of spinal deformities varies with the angle of the Long-term effects of bisphosphonates on thescoliosis (31). After a fracture or a surgical growing skeleton. Studies of young patients withprocedure, prolonged immobilization should be severe osteoporosis. Medicine 76 (1997), pp.avoided: rehabilitation therapy should be started 266-283.early, and the healthcare staff reassured that the 10. McAllion S. and Paterson C., Causes ofrehabilitation program is designed to reduce the death in osteogenesis imperfecta. J Clin Patholrisk of further fracturing. In children and adults, 49 (1996), pp. 627-630.the goal of fracture management should be to 11. Widmann R., Bitan F., Laplaza F., Burke S.,restore the patient to self-sufficiency as DiMaio M. and Schneider R., Spinal deformity,completely and rapidly as possible. pulmonary compromise, and quality of life inChevrel G; Osteogenesis imperfecta. Orphanet encyclopedia, June 2004.http://www.orpha.net/data/patho/GB/uk-OI.pdf 5
  6. 6. osteogenesis imperfecta. Spine 24 (1999), pp. 23. Cepollaro C., Gonnelli S., Pondrelli C.,1673-1678. Montagnani A., Martini S., Bruni D. et al.,12. Sawin P. and Menezes A., Basilar Osteogenesis imperfecta: bone turn-over, boneinvagination in osteogenesis imperfecta and density, and ultrasound parameters. Calcifrelated-osteochondrodysplasias: medical and Tissue Int 65 (1999), pp. 129-132.surgical management. J Neurosurg 86 (1997), 24. Glorieux F., Bishop N., Plotkin H., Chabot G.,pp. 950-960. Lanoue G. and Travers R., Cyclic administration13. Kuivaniemi H., Tromp G. and Prockop D., of pamidronate in children with severeMutations in fibrillar collagens (type I, II, III, XI), osteogenesis imperfecta. N Engl J M 339 (1998),fibril-associated collagen (type IX), and network- pp. 947-952.forming collagen (type X) cause a spectrum of 25. Shapiro J.R., Copley C., Goldsborough D.,diseases of bone, cartilage, and blood vessels. Gelman R. and Barnhart K., Effect ofHuman Mutat 9 (1997), pp. 300-315. pamidronate on bone turnover and IGF-I in type I14. Coppin C. and Eeckhout Y., Lostéogenèse osteogenesis imperfecta. JBone Min Res 10imparfaite: des mutations aux phénotypes. (1995), pp. 604-604.Médecine/Sciences 11 (1995), pp. 853-859. 26. Aström E. and Söderhäll S., Beneficial effect15. Paterson C. and Moles P., Bone density in of bisphosphonate during five years of treatmentosteogenesis imperfecta may well be normal. of severe osteogenesis imperfecta. ActaPostgrad Med J 70 (1994), pp. 104-107. Paediatr 87 (1998), pp. 64-68.16. Davie M. and Haddaway M., Bone mineral 27. Verhaeghe P, Editor, Lostéogenèsecontent and density in healthy subjects and in imparfaite, maladie des os de verre, Éditionsosteogenesis imperfecta. Arch Dis Child 70 Frison-Roche, Paris (1999).(1994), pp. 331-334. 28. Paterson C., McAllion S. and Stellman J.,17. Glorieux F., Lanoue G., Chabot G. and Osteogenesis imperfecta after the menopause.Travers R., Bone mineral density in N Engl J M 310 (1984), pp. 1694-1696.osteogenesis imparfecta. J Bone Min Res 9 29. Plotkin H., Rauch F., Bishop N., Montpetit K.,(1994), pp. 225-225. Ruck-Gibis J., Travers R. et al., Pamidronate18. Zionts L., Nash J., Rude R., Ross T. and treatment of severe osteogenesis imperfecta inStott N., Bone mineral density in children with children under 3 years of age. J Clin Endocrinolmild osteogenesis imperfecta. J Bone Joint Surg Metab 85 (2000), pp. 1846-1850.77B (1995), pp.143-147. 30. Finidori G., Ostéogenèse imparfaite.19. Chines A., Petersen D., Schranck F. and Indications thérapeutiques chez lenfant. In:Whyte M., Hypercalciuria in children severely Conférences denseignement 1988. Cahieraffected with osteogenesis imperfecta. J Pediatr denseignement de la SOFCOT n° 31,119 (1991), 51-57. Expansion Scientifique Française, Paris (1988),20. Chines A., Boniface A., McAlister W. and pp. 327-345.Whyte M., Hypercalciuria in osteogenesis 31. Fassier F., Ostéogenèse imparfaite deimperfecta: a follow-up study to assess renal lenfant. In: Conférences denseignement 1999.effects. Bone 16 (1995), pp.333-339. Cahier denseignement de la SOFCOT,21. Minisola S., Lina-Piccioni A., Rosso R., Expansion Scientifique Publications, ParisRomagnoli E., Pacitti M., Scarnecchia L. et al., (1999), pp. 235-252.Reduced serum levels of carboxy-terminal 32. Rauch F., Glorieux F.H. Osteogenesispropeptide of human type I procollagen in a imperfecta. Lancet 363 (2004), 1377-1385.family with type I-A osteogenesis imperfecta. 33. Niyibizi C., Wang S., Mi Z., Robbins P.D.Metabolism 42 (1994), pp. 1261-1265. Gene therapy approaches for osteogenesis22. Lund A., Hansen M., Kollerup G., Juul A., imperfecta. Gene Therapy 11 (2004), 408-416.Teisner B. and Skovby F., Collagen-derived 34. Engelbert R.H., Pruijs H.E., Beemer F.A.,markers of bone metabolism in osteogenesis Helders P.J. Osteogenesis imperfecta inimperfecta. Acta Paediatr 87 (1998), pp. 1131- childhood: treatment strategies. Arch Phys Med1137. Rehabil 79 (1998), 1590-1594.Chevrel G; Osteogenesis imperfecta. Orphanet encyclopedia, June 2004.http://www.orpha.net/data/patho/GB/uk-OI.pdf 6