eMedicine Specialties > Pediatrics: Genetics and Metabolic Disease > Genetics

Osteogenesis Imperfecta

Author: Horacio Plotkin, MD, FAAP, Adjunct Associate Professor of Pediatrics and Orthopedic Surgery, University of Nebraska School of Medicine
Contributor Information and Disclosures

Updated: Oct 15, 2009

Introduction

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 osteogenesis imperfecta 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 osteogenesis imperfecta, 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 osteogenesis imperfecta.

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 osteogenesis imperfecta (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 osteogenesis imperfecta.

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 osteogenesis imperfecta 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 osteogenesis imperfecta with redundant callus formation.

Syndromes Resembling Osteogenesis Imperfecta

Syndromes resembling osteogenesis imperfecta are a group of disorders associated with congenital bone fragility. In many cases, these disorders are diagnosed as osteogenesis imperfecta. Some have even been described in the literature as osteogenesis imperfecta 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 osteogenesis imperfecta is the result of mutations of the CRTAP gene. Inheritance appears to be autosomal dominant.

The initial presentation often resembles that of osteogenesis imperfecta 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 osteogenesis imperfecta.

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 osteogenesis imperfecta. 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 osteogenesis imperfecta 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.

Several other syndromes with congenital brittle bones have been described in humans since the original publication describing syndromes resembling osteogenesis imperfecta (SROI) as a class, including the association of elastosis perforans serpiginosa and congenital bone fragility and the association of severe hypertelorism, midface prominence, prominent/simple ears, severe myopia, borderline intelligence, and bone fragility.

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

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 osteogenesis imperfecta 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 osteogenesis imperfecta have deafness by age 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 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 or more.
  • Height is usually normal in individuals with mild forms of osteogenesis imperfecta.
  • People with osteogenesis imperfecta 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 osteogenesis imperfecta, and they can occur without any signs of pain.
  • Exercise tolerance and muscle strength are significantly reduced in patients with osteogenesis imperfecta, even in the mild forms.
  • Fractures are most common during infancy but may occur at any age.
  • Other possible findings include kyphoscoliosis, hearing loss (at any age),³ 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 osteogenesis imperfecta.
  • 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 osteogenesis imperfecta.
  • Vertigo is common in patients with severe osteogenesis imperfecta.
  • The incidence of congenital malformations of the heart in children with osteogenesis imperfecta is probably similar to that of the healthy population.
  • Hypercalciuria may be present in about 36% of patients with osteogenesis imperfecta but does not appear to affect renal function.
  • Respiratory complications secondary to kyphoscoliosis are common in individuals with severe osteogenesis imperfecta.
  • Constipation and hernias are also common in people with osteogenesis imperfecta.
• Type IV - Undefined
  • This type of osteogenesis imperfecta 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 osteogenesis imperfecta 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 osteogenesis imperfecta is dominant or involves a new dominant mutation, regardless of the clinical form of osteogenesis imperfecta 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 osteogenesis imperfecta.
• Syndromes resembling osteogenesis imperfecta (SROI) may be inherited in recessive fashion.

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