AUTHOR INFORMATION

Section 1 of 12

Authored by Horacio Plotkin, MD, FAAP, Assistant Professor of Pediatrics and Orthopedic Surgery, University of Nebraska Medical Center; Medical Director, Metabolic Bone Diseases Clinic, Children's Hospital of Omaha

Coauthored by Mandar A Pattekar, MD, MS, Consulting Staff, Department of Radiology, Methodist Hospital, Peoria, Illinois; Alexander A Cacciarelli, MD, FACR, Consulting Staff, Department of Radiology, St Joseph's Hospital and Medical Center, Phoenix

Horacio Plotkin, MD, FAAP, is a member of the following medical societies: American Academy of Pediatrics, American Society for Bone and Mineral Research, and International Bone and Mineral Society

Edited by Erawati V Bawle, MD, FAAP, FACMG, Director, Division of Genetic and Metabolic Disorders, Children's Hospital of Michigan; Professor (Clinician-Educator), Department of Pediatrics, Wayne State University School of Medicine; Mary L Windle, PharmD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy, Pharmacy Editor, eMedicine.com, Inc; Robert Anthony Saul, MD, Senior Clinical Geneticist, Greenwood Genetic Center; Clinical Professor, Department of Pediatrics, University of South Carolina; Daniel Rauch, MD, FAAP, Director, Pediatric Hospitalist Program, Associate Professor, Department of Pediatrics, New York University School of Medicine; and Bruce A Buehler, MD, Professor, Department of Pathology and Microbiology, Chairman, Department of Pediatrics, Director, Hattie B Munroe Center for Human Genetics, University of Nebraska Medical Center

Author's Email:	Horacio Plotkin, MD, FAAP
Editor's Email:	Erawati V Bawle, MD, FAAP, FACMG

eMedicine Journal, July 26 2006, VOLUME 7, Number 7

INTRODUCTION

Section 2 of 12

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

At least 4 types of OI are described: Type I = mild forms, type II = extremely severe; type III = severe; and type IV = undefined. However, precise typing is often difficult. Severity ranges from mild forms to lethal forms in the perinatal period.

In addition, several syndromes resemble OI (SROI) 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 encoding these chains (COL1A1 on band 17q21 and COL1A2 on band 7q22.1, respectively) cause OI. 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 SROIs (see below).

Qualitative defects (eg, an abnormal collagen I molecule) and quantitative defects (eg, decreased production of normal collagen I molecules) are described.

Syndrome resembling osteogenesis imperfecta

SROIs 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 of SROI 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

Patients with this SROI develop hyperplastic calluses in long bones after having a fracture or orthopedic surgery involving osteotomies. Mutations in the type I procollagen genes have not been found in these patients. Inheritance appears to be autosomal dominant.

Their 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 SROI 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 show that the bone lamella are arranged in meshlike fashion, as opposed to the typical parallel arrangement in patients with OI.

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

Osteoporosis pseudoglioma syndrome

This SROI 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 encoding for the low-density lipoprotein receptor-related protein 5.

Other ocular forms of SROI

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

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

Two boys and a girl have been described as having this particular form of SROI. In the boys, diagnosis was made after several months of life, as 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 where nonambulatory, with short stature, severe osteopenia, and bone deformity. They had normal intellectual and neurologic development.

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

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 of SROI is clinically indistinguishable from moderate-to-severe OI. Diagnosis is possible only by means of bone biopsy, 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 of SROI shares several characteristics with fibrogenesis imperfecta ossium, and a mild form of this SROI may exist.

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.

Frequency:

• In the US: The prevalence of OI is estimated to be 1 per 20,000 live births, but the mild form is underdiagnosed, and the actual prevalence may be higher than this.

• Internationally: Prevalences appear to be similar worldwide, though 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 varies widely. 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 12

History: Patients often have a family history of OI, but most cases are due to new mutations.

• Patients most commonly present with fractures after minor trauma.



• In severe cases, prenatal screening sonography performed during 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 type I OI have deafness by the age of 40 years.

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 also may 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 or 2 to 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 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 they 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 and/or micrognathia.
  
  
  
  • All patients have in utero fractures, which may involved the skull, long bones, and/or vertebrae.
  
  
  
  • The ribs are beaded, and 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 it 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 1 child with OI. Syndromes resembling OI may be inherited in recessive fashion.

DIFFERENTIALS

Section 4 of 12

Child Abuse & Neglect: Physical Abuse

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 12

Lab Studies:

• Results from routine laboratory studies are usually within reference ranges, and they are useful to rule 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, though the rate may be about 15%. Results are negative in SROIs.



• 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 sonographic 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.

Imaging Studies:

• Obtain a radiographic skeletal survey after birth.


• • In mild (type I) OI, images may show 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 show beaded ribs, broad bones, and numerous fractures with deformities of the long bones. Platyspondylia may also be found.
  
  
  
  • Moderate and severe (types III and IV) OI, Imaging may show cystic metaphyses, or a popcorn appearance of the growth cartilage. Normal or broad bones are seen early, with thin bones later. Fractures may cause deformities of the long bones. Old rib fractures may be present. Vertebral fractures are common.
  
  
  
• Prenatal ultrasound 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.
  
  
  

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.

Bone formation is quantitatively decreased, but the quality of the bone material is probably most important in the pathogenesis of the disease.

TREATMENT

Section 6 of 12

Medical Care: Because OI is a genetic condition, it has no cure.

• Cyclic administration of intravenous pamidronate reduces the incidence of fracture and increase bone mineral density, while reducing pain and increasing energy levels. Doses vary from 4.5 to 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 1 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 procedure in the long bones of the lower extremities in 1 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

Section 7 of 12

See Treatment.

FOLLOW-UP

Section 8 of 12

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 OI.



• Basilar impression caused by 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, though 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 1 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

Section 9 of 12

Medical/Legal Pitfalls:

• Differentiation between OI and child abuse: 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 also can 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.

TEST QUESTIONS

Section 10 of 12

CME Question 1: Which major neurologic complication can occur a child with osteogenesis imperfecta (OI)?

A: Brainstem compression
B: Demyelination
C: Development of intracranial malignancy
D: Hydrocephalus
E: Spasticity

The correct answer is A: Basilar impression caused by 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.

CME Question 2: Which condition manifests with blue sclerae?

A: Osteogenesis imperfecta
B: Progeria
C: Cleidocranial dysplasia
D: Menkes syndrome
E: All the above

The correct answer is E: Blue sclerae have been observed in a small percentage of patients with any of these conditions.

Pearl Question 1 (T/F): Patients with osteogenesis imperfecta (OI) are prone to have malignant hyperthermia under anesthesia.

The correct answer is False: Patients with OI have a high basal metabolism that may cause hyperthermia during anesthesia, but it is almost never malignant. In fact, only 1 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.

Pearl Question 2 (T/F): Type I collagen is defective in osteogenesis imperfecta (OI).

The correct answer is True: Type I collagen, which constitutes approximately 30% of the human body by weight, is the defective protein. Qualitative defects (eg, abnormal collagen I molecules) and quantitative defects (eg, decreased production of normal collagen I molecules) both exist. Other syndromes resembling OI share clinical characteristics with OI, but they are caused by mutations in genes different from the procollagen genes.

Pearl Question 3 (T/F): Orthopedic surgery should be avoided in patients with OI

The correct answer is False: Orthopedic surgery is 1 of the pillars of treatment for patients with OI. Surgical interventions include intramedullary rod placement, surgery to manage basilar impression, and correction of scoliosis.

Pearl Question 4 (T/F): The 4 types of osteogenesis imperfecta (OI) are inherited in an autosomal recessive manner.

The correct answer is False: OI is inherited as an autosomal dominant condition in the vast majority of cases. 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 1 child with OI. Syndromes resembling OI may be inherited in recessive fashion.

PICTURES

Section 11 of 12

Caption: Picture 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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Caption: Picture 2. Beaded ribs. Multiple fractures are seen in the long bones of the upper extremities.
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Caption: Picture 3. Wormian bones are present in the skull.
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Caption: Picture 4. This newborn has bilateral femoral fractures.
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BIBLIOGRAPHY

Section 12 of 12

• 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.
• Plotkin H, Lutz R: Osteoporosis in pediatrics. In: Deng HW, Liu Y, eds. Current Topics in Osteoporosis. World Scientific. 2005; 362-414.
• Plotkin H: Syndromes with congenital brittle bones. BioMed Central Pediatrics 2004; 4 (16):[Medline][Full Text].
• Plotkin H, Primorac D, Rowe D: Osteogenesis imperfecta. In: Glorieux F, Pettifor J, Juppner J, eds. Pediatric Bone: Biology and Disease. 2003; 443-71.
• Plotkin H: Two questions about osteogenesis imperfecta. J Ped Orthop 2006; 26: 148-149[Medline].
• Plotkin, H: Syndromes with brittle bones, hyperostotic bone disease and fibrous dysplasia of bone. In: Lifshitz F, ed. Pediatric Endocrinology. 5th Edition. 2006; in press.
• Rauch F, Plotkin H, Travers R, Glorieux FH: Is bone resorption increased in children with osteogenesis imperfecta (OI)? Bone 1998; 5(suppl): s462.
• 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].
• Rauch F, Travers R, Parfitt AM, Glorieux FH: Static and dynamic bone hystomorphometry in children with osteogenesis imperfecta. Bone 2000; 26: 581-9[Medline].

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