AUTHOR AND EDITOR INFORMATION

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• Follow-up
• Miscellaneous
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INTRODUCTION

Section 2 of 11  

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• Introduction
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• Follow-up
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Background

Osteogenesis imperfecta (OI) is disorder of congenital bone fragility caused by mutations in the genes that codify for type I procollagen (ie, COL1A1 and COL1A2).

The following 4 types of OI have been reported:¹

• Type I - Mild forms
• Type II - Extremely severe
• Type III - Severe
• Type IV - Undefined

Precise typing is often difficult. Severity ranges from mild forms to lethal forms in the perinatal period. In addition, several syndromes resemble OI, with congenital bone fragility in association with other distinctive clinical or histologic features.

Pathophysiology

Overview

Type I collagen fibers are found in the bones, organ capsules, fascia, cornea, sclera, tendons, meninges, and dermis. Type I collagen, which constitutes approximately 30% of the human body by weight, is the defective protein in OI.

In structural terms, type I collagen fibers are composed of a left-handed helix formed by intertwining of pro-alpha 1 and pro-alpha 2 chains. Mutations in the loci that encode these chains cause OI (ie, COL1A1 on band 17q21 and COL1A2 on band 7q22.1, respectively). Other mutations may cause congenital bone fragility associated with distinctive clinical or histologic features (eg, redundant callus formation, pseudoglioma, defective mineralization of bone). These conditions have been grouped as syndromes resembling OI.

Qualitative defects (eg, an abnormal collagen I molecule) and quantitative defects (eg, decreased production of normal collagen I molecules) are described. Of note, recent studies have reported that quantitative defects can cause very severe (even lethal) syndromes resembling OI through posttranslational modifications of collagen.²

Cartilage-associated protein (CRTAP) is a protein required for prolyl 3-hydroxylation. Loss of CRTAP in mice causes an osteochondrodysplasia characterized by severe osteoporosis and decreased osteoid production. In humans, CRTAP mutations cause excess posttranslational modification of collagen, and may be associated with syndromes resembling osteogenesis imperfecta, including recessive forms of lethal syndromes resembling OI and syndromes resembling OI with redundant callus formation.

Syndromes Resembling Osteogenesis Imperfecta

Syndromes resembling OI are a group of disorders associated with congenital bone fragility. In many cases, these disorders are diagnosed as OI. Some have even been described in the literature as OI types V-VII. Mutations in the procollagen genes cannot be demonstrated in these syndromes. In some cases, a mutation has been identified in a different gene.

Congenital brittle bones with rhizomelia

This particular form with short humerus and femora and recessive inheritance was only described in a First Nations community of Quebec. The severity in terms of fractures and disability is moderate to severe. Fractures may be present at birth. In linkage studies, the genetic defect has been mapped to the short arm of chromosome 3, where no genes codify type I procollagen.

Congenital brittle bones with redundant callus formation

These patients develop hyperplastic calluses in long bones after having a fracture or orthopedic surgery that involves osteotomies. Mutations in the type I procollagen genes have not been found in these patients. This form of syndrome resembling OI is the result of mutations of the CRTAP gene. Inheritance appears to be autosomal dominant.

The initial presentation often resembles that of OI with bone fragility and deformity, but these patients develop hard, painful, and warm swellings over long bones that may initially suggest inflammation or osteosarcoma. Patients with this condition have white sclera and normal teeth.

On radiographs, a redundant callus can be observed around some fractures. The size and shape of the callus may remain stable for many years after a rapid growth period. Histomorphometric studies reveal that the bone lamella are arranged in meshlike fashion, as opposed to the typical parallel arrangement in patients with OI.

A variant of this syndrome is called aspirin-responsible expansile bone disease.

Osteoporosis pseudoglioma syndrome

This condition is inherited in an autosomal recessive fashion. Bone fragility is mild to moderate. Blindness is due to hyperplasia of the vitreous, to corneal opacity, and to secondary glaucoma. The genetic defect has been identified and mapped to chromosomal region 11q12-13. The defect is specifically in the LRP5 gene that encodes for the low-density lipoprotein receptor-related protein 5.

Other ocular forms

At least 2 other forms with ocular involvement are described in the literature. One variant includes optic atrophy, retinopathy, and severe psychomotor retardation; another variant includes microcephaly and cataracts.

Congenital brittle bones with craniosynostosis and ocular proptosis (Cole-Carpenter syndrome)

Two boys and one girl have been described with this particular form. In the boys, diagnosis was made after several months of life, and they were apparently healthy at birth. They developed craniosynostosis, hydrocephalus, ocular proptosis, facial dysmorphism, and several metaphyseal fractures associated with generalized low bone density.

By adulthood, both boys were nonambulatory, with short stature, severe osteopenia, and bone deformity. They had normal intellectual and neurologic development.

No specific mutation has been identified as responsible for this syndrome. Neurologic development is normal in this form.

Congenital brittle bones with joint contractures (Bruck syndrome)

Patients with Bruck syndrome have congenital brittle bones that lead to repeated fractures, as well as joint contractures and pterygia (arthrogryposis multiplex congenita). Wormian bones are present.

Inheritance appears to be recessive. No mutations in the COL1A1 or COL1A2 genes were found in 3 patients with Bruck syndrome who underwent procollagen mutation testing. The basic defect was mapped to locus 17p12 (18-cM interval), where a bone telopeptidyl hydroxylase is located.

Congenital brittle bones with mineralization defect

This rare form is clinically indistinguishable from moderate-to-severe OI. Diagnosis is possible only by means of bone biopsy findings, in which a mineralization defect affecting the bone matrix and sparing growth cartilage is evident. Patients have normal teeth, and they do not have wormian bones. They have no radiologic signs of growth-plate involvement despite the mineralization defect evident on bone biopsy. This form shares several characteristics with fibrogenesis imperfecta ossium, and a mild form may be observed.

The pattern of inheritance is not clear, but cases in 2 siblings from healthy consanguineous parents suggest gonadal mosaicism or a somatic recessive trait. The structure of the collagen molecule appears to be normal, and no mutations of COL1A1 and COL1A2 genes have been found.

Other recessive syndromes resembling osteogenesis imperfecta

Genetic studies of recessive syndromes resembling OI reported in South African blacks reported mutations that involved both the CRTAP gene and the leucine proline-enriched proteoglycan 1 (LEPRE1) gene, which are both involved in collagen proline-3 hydroxylation. Cases of recessive lethal syndromes resembling OI have been found to be caused by mutations in the CRTAP gene.

Frequency

United States

The prevalence of OI is estimated to be 1 per 20,000 live births; however, the mild form is underdiagnosed, and the actual prevalence may be higher.

International

Prevalences appear to be similar worldwide, although an increased rate has been observed in 2 major tribal groups in Zimbabwe.

Race

No differences based on race are reported.

Sex

No differences based on sex are reported.

Age

The age when symptoms (ie, fractures) begin widely varies. Patients with mild forms may not have fractures until adulthood, or they may present with fractures in infancy. Patients with severe cases present with fractures in utero.

CLINICAL

Section 3 of 11  

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History

Patients often have a family history of osteogenesis imperfecta (OI), but most cases are due to new mutations.

• Patients most commonly present with fractures after minor trauma.
• In severe cases, prenatal screening ultrasonography performed during the second trimester may show bowing of long bones, fractures, limb shortening, and decreased skull echogenicity. Lethal OI cannot be diagnosed with certainty in utero.
• Patients may bruise easily.
• Patients may have repeated fractures after mild trauma. However, these fractures heal readily.
• Deafness is another feature. About 50% of patients with type I OI have deafness by the age 40.

Physical

Physical examination can vary depending on the severity. Degrees of severity may vary among different affected members of the same family.

• Type I - Mild forms
• • Patients have no long-bone deformity.
  • The sclera can be blue or white. Blue sclera may also occur in other disorders, such as progeria, cleidocranial dysplasia, Menkes syndrome, cutis laxa, Cheney syndrome, and pyknodysostosis.
  • Dentinogenesis imperfecta may be present.
  • Over a lifetime, numbers of fractures can range from 1-60.
  • Height is usually normal in individuals with mild forms of OI.
  • People with OI have a high tolerance for pain. Old fractures can be discovered in infants only after radiographs are obtained for other reasons other than an assessment of OI, and they can occur without any signs of pain.
  • Exercise tolerance and muscle strength are significantly reduced in patients with OI, even in the mild forms.
  • Fractures are most common during infancy but may occur at any age.
  • Other possible findings include kyphoscoliosis, hearing loss, premature arcus senilis, and easy bruising.
• Type II - Extremely severe
• • Type II is often lethal.
  • Blue sclera may be present.
  • Patients may have a small nose, micrognathia, or both.
  • All patients have in utero fractures, which may involved the skull, long bones, and/or vertebrae.
  • The ribs are beaded, and the long bones are severely deformed.
  • Causes of death include extreme fragility of the ribs, pulmonary hypoplasia, and malformations or hemorrhages of the CNS.
• Type III - Severe
• • Patients may have joint hyperlaxity, muscle weakness, chronic unremitting bone pain, and skull deformities (eg, posterior flattening) due to bone fragility during infancy.
  • Deformities of upper limbs may compromise function and mobility.
  • The presence of dentinogenesis imperfecta is independent of the severity of the OI.
  • The sclera have variable hues.
  • In utero fractures are common.
  • Limb shortening and progressive deformities can occur.
  • Patients may have a triangular face with frontal bossing.
  • Basilar invagination is an uncommon but potentially fatal occurrence in OI.
  • Vertigo is common in patients with severe OI.
  • The incidence of congenital malformations of the heart in children with OI is probably similar to that of the healthy population.
  • Hypercalciuria may be present in about 36% of patients with OI but does not appear to affect renal function.
  • Respiratory complications secondary to kyphoscoliosis are common in individuals with severe OI.
  • Constipation and hernias are also common in people with OI.
• Type IV - Undefined
• • This type of OI is not clearly defined.
  • Whether patient have normal height or whether scleral hue defines the type has not been established in consensus.
  • Dentinogenesis imperfecta may be present. Some have suggested that this sign can be used to divide type IV OI into subtypes a and b.
  • Fractures usually begin in infancy, but in utero fractures may occur. The long bones are usually bowed.

Causes

Osteogenesis is an inherited disorder. In almost all cases, mode of inheritance in OI is dominant or involves a new dominant mutation, regardless of the clinical form of OI observed. A recessive pattern of inheritance has been demonstrated in some families from South Africa. Some have proposed possible germ-cell mosaicism as an explanation for cases occurring in families with healthy parents that have more than one child with OI. Syndromes resembling OI may be inherited in recessive fashion.

DIFFERENTIALS

Section 4 of 11  

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Other Problems to be Considered

Camptomelic dysplasia
Achondrogenesis type I
Congenital hypophosphatasia
Steroid induced osteoporosis
Battered child syndrome (syndrome X)
Idiopathic juvenile osteoporosis

WORKUP

Section 5 of 11  

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Lab Studies

• Results from routine laboratory studies are usually within reference ranges and they are useful in ruling out other metabolic bone diseases.
• Collagen synthesis analysis is performed by culturing dermal fibroblasts obtained during skin biopsy. The occurrence of false-negative results is not clear, although the rate may be about 15%. Results are negative in syndromes resembling osteogenesis imperfecta (OI).
• Prenatal DNA mutation analysis can be performed in pregnancies with risk of OI to analyze uncultured chorionic villus cells. Samples are obtained during chorionic villus sampling performed under ultrasonographic guidance when a mutation in another member of the family is already known.
• Bone mineral density, as measured with dual-energy x-ray absorptiometry (DEXA), is low in children and adults with OI despite the severity. Bone mineral densities can be normal in infants with OI, even in severe cases. In pediatric patients, DEXA results are not useful for predicting the risk of fracture. No reliable published reference data regarding DEXA in infants is available.

Imaging Studies

• Obtain a radiographic skeletal survey after birth.
• • In mild (type I) OI, images may reveal thinning of the long bones with thin cortices. Several wormian bones may be present. No deformity of long bones is observed.
  • In extremely severe (type II) OI, the survey may reveal beaded ribs, broad bones, and numerous fractures with deformities of the long bones. Platyspondylia may also be revealed.
  • Moderate and severe (types III and IV) OI, Imaging may reveal cystic metaphyses, or a popcorn appearance of the growth cartilage. Normal or broad bones are revealed early, with thin bones revealed later. Fractures may cause deformities of the long bones. Old rib fractures may be present. Vertebral fractures are common.
• Prenatal ultrasonography can be used to detect limb-length abnormalities at 15-18 weeks' gestation.
• • Mild forms may result in normal sonogram findings.
  • Features include supervisualization of intracranial contents caused by decreased mineralization of calvaria (also calvarial compressibility), bowing of the long bones, decreased bone length (especially of the femur), and multiple rib fractures.

Histologic Findings

• The width of biopsy cores, the width of the cortex, and the volume of cancellous bone are decreased in all types of OI. The number and thickness of trabeculae are reduced.
• Samples may show evidence of defects in modeling of external bone in terms of the size and shape, the production of secondary trabeculae by endochondral ossification, and the thickening of secondary trabeculae by remodeling. Therefore, OI might be regarded as a disease of the osteoblast.³
• Bone formation is quantitatively decreased, but the quality of the bone material is probably most important in the pathogenesis of the disease.

TREATMENT

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Medical Care

Because osteogenesis imperfecta (OI) is a genetic condition, it has no cure.

• Cyclic administration of intravenous pamidronate reduces the incidence of fracture and increases bone mineral density, while reducing pain and increasing energy levels.⁴ Doses vary from 4.5-9 mg/kg/y, depending on the protocol used.
• Current evidence does not support the use of oral bisphosphonates in patients with OI.
• Nutritional evaluation and intervention are paramount to ensure appropriate intake of calcium and vitamin D. Caloric management is important, particularly in adolescents and adults with severe forms of OI.

Surgical Care

Orthopedic surgery is one of the pillars of treatment for patients with OI. Surgical interventions include intramedullary rod placement, surgery to manage basilar impression, and correction of scoliosis.

• Intramedullary rod placement
• • In patients with bowed long bones, intramedullary rod placement may improve weight bearing and, thus, enable the child to walk at an earlier age that he or she might otherwise. Use of the new extensible Fassier-Duval rods has shown promising results in these patients.
  • In children appropriately treated with bisphosphonates, the percutaneous technique of multiple osteotomy with intramedullary fixation is safe and effective.
  • An experienced team can perform up to 4 rod procedures in the long bones of the lower extremities in one surgical session.
  • Fractures heal normally in about 85% of patients with OI.
  • Postoperative immobilization is significantly shortened with this technique. Prolonged immobilization after a fracture must be avoided.
• Surgery for basilar impression: This procedure is reserved for cases with neurologic deficiencies, especially those caused by compression of brainstem and high cervical cord. A team of orthopedic surgeons and neurosurgeons is required.
• Correction of scoliosis: Correction of scoliosis may be difficult because of bone fragility. Spinal fusion may be helpful. Pretreatment with pamidronate appears to improve the surgical outcome.

Consultations

• Care of OI patients is multidisciplinary. Team members may include an occupational therapist (OT), a physical therapist (PT), nutritionist, an audiologist, an orthopedic surgeon, neurosurgeon, pneumologist, and nephrologist, among others.
• Offer genetic counseling to the parents of a child with OI who plan to have more children. During genetic counseling, the possibility of germline mosaicism must be discussed.

Diet

• Adequate calcium, vitamin D, and phosphorus intake are paramount.
• Caloric management is necessary in nonambulatory patients with severe OI.

Activity

• Parents need special instructions in handling affected children.
• Parents need to know how to position the child in the crib and how hold the child to avoid causing fractures while maintaining bonding and physical stimulation.

MEDICATION

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See Treatment.

FOLLOW-UP

Section 8 of 11  

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• Follow-up
• Miscellaneous
• Multimedia
• References

Further Outpatient Care

• Physical therapy
• • Therapy should be directed toward improving joint mobility and developing muscle strength
  • Overall, emphasize the achievement of functional ability.
  • Independence is the main objective of therapy.
• Periodic nutritional evaluation and intervention
• Periodic evaluation and intervention by an OT and/or a PT

Complications

• Repeated respiratory infections are complications of osteogenesis imperfecta (OI).
• Basilar impression caused by a large head, which causes brainstem compression, is the major neurologic complication in a child with OI. This is most commonly observed in children with severe OI.
• Cerebral hemorrhage caused by birth trauma is another complication.
• Patients with OI should be considered to be at high risk for complications of anesthesia, although they are not particularly prone to have malignant hyperthermia. Patients with OI have a high basal metabolism that may cause hyperthermia during anesthesia, but it is almost never malignant. In fact, only one case of malignant hyperthermia in a child with OI is described in the literature, and that particular patient had a family history of malignant hyperthermia.

Prognosis

• The life expectancy of subjects with nonlethal OI appears to be the same as that for the healthy population, except for those with severe OI with respiratory or neurologic complications.
• Patients with lethal OI may die in the perinatal period, but individuals with extremely severe OI can survive until adulthood.

Patient Education

• Parents need special instructions in positioning the child in the crib and in handling the child while minimizing the risk of fractures.

MISCELLANEOUS

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Medical/Legal Pitfalls

• Differentiating between OI and child abuse is important. Mild OI is most likely to be confused with child abuse. The sclera and teeth are normal in many patients with OI. A family history is often not present.
• Keys to differentiate OI from child abuse if no other stigmata of OI are present include the following:
• • Consider the types of fractures. Although any type of long bone fracture can occur in OI, certain types are rare. Metaphyseal corner fractures, which are common in child abuse, are rare in OI.
  • In children with OI, fractures may continue to occur while they are in protective custody; however, this scenario is hard to evaluate.
  • Child abuse can also be differentiated from OI on the basis of nonskeletal manifestations, such as retinal hemorrhage, visceral intramural hematomas, intracranial bleeds of various ages, pancreatitis, and splenic trauma.
• Collagen analysis is useful in difficult cases, but a negative result does not rule out OI.
• OI and child abuse can coexist.

MULTIMEDIA

Section 10 of 11  

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• Workup
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• Follow-up
• Miscellaneous
• Multimedia
• References

Media file 1:  Acute fractures are observed in the radius and ulna. Multiple fractures can be seen in the ribs. Old healing humeral fracture with callus formation is observed.
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Media type:  Radiograph

Media file 2:  Beaded ribs. Multiple fractures are seen in the long bones of the upper extremities.
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Media type:  Radiograph

Media file 3:  Wormian bones are present in the skull.
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Media type:  Radiograph

Media file 4:  This newborn has bilateral femoral fractures.
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Media type:  Radiograph

REFERENCES

Section 11 of 11

• Authors and Editors
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1. Plotkin H. Syndromes with congenital brittle bones. BioMed Central Pediatrics. 2004;4 (16):[Medline]. [Full Text].
2. Morello R, Bertin TK, Chen Y, Hicks J, Tonachini L, Monticone M, et al. CRTAP is required for prolyl 3- hydroxylation and mutations cause recessive osteogenesis imperfecta. Cell. 2006;127:291-304. [Medline].
3. Rauch F, Travers R, Parfitt AM, Glorieux FH. Static and dynamic bone hystomorphometry in children with osteogenesis imperfecta. Bone. 2000;26:581-9. [Medline].
4. Rauch F, Munns C, Land C, Glorieux FH. Pamidronate in Children and Adolescents with Osteogenesis Imperfecta: Effect of Treatment Discontinuation. J Clin Endocrinol Metab. 2006;91:1268-74. [Medline].
5. Esposito P, Turman K, Scherl S, et al. Percutaneous surgical treatment of multiple lower extremity deformities in children with osteogenesis imperfecta. In: Proceedings of 2006 Annual Meeting of the Pediatric Orthopaedic Society of North America. Rosemont, IL: Pediatric Orthopaedic Society of North America; 2006:103.
6. Plotkin H. Two questions about osteogenesis imperfecta. J Ped Orthop. 2006;26:148-149. [Medline].
7. Plotkin H, Lutz R. Osteoporosis in pediatrics. In: Deng HW, Liu Y, eds. Current Topics in Osteoporosis. World Scientific.; 2005:362-414.
8. Plotkin H, Primorac D, Rowe D. Osteogenesis imperfecta. In: Glorieux F, Pettifor J, Juppner J, eds. Pediatric Bone: Biology and Disease. 2003:443-71.
9. Plotkin, H. Syndromes with brittle bones, hyperostotic bone disease and fibrous dysplasia of bone. In: Lifshitz F, ed. Pediatric Endocrinology. 5^th ed. 2006.
10. Rauch F, Plotkin H, Travers R, Glorieux FH. Is bone resorption increased in children with osteogenesis imperfecta (OI)?. Bone. 1998;5(suppl):s462.

Article Last Updated: May 8, 2008