eMedicine Specialties > Orthopedic Surgery > Neoplasms

Osteogenesis Imperfecta

Author: Manoj Ramachandran, MBBS, MRCS, FRCS, Consultant Trauma and Orthopaedic Surgeon, Barts and the London NHS Trust; Honorary Senior Lecturer, William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary's, University of London, UK
Coauthor(s): David H A Jones, MB, ChB, FRCS, FRCS Ed(Orth), Consultant Orthopedic Surgeon, Great Ormond Street Hospital for Children; Senior Clinical Lecturer, University College London Hospitals, UK; Pramod Achan, MBBS, FRCS(Orth), Senior Registrar, Royal National Orthopaedic Hospital, UK; Peter R Calder, MBBS, FRCS(Eng), FRCS (Tr&Orth), Consulting Surgeon, Department of Pediatric Orthopedic Surgery, The Royal National Orthopaedic Hospital, UK
Contributor Information and Disclosures

Updated: Nov 20, 2008

Introduction

Background

The earliest known case of osteogenesis imperfecta is in a partially mummified infant's skeleton from ancient Egypt now housed in the British Museum in London. In 1835, Lobstein coined the term osteogenesis imperfecta and was one of the first to correctly understand the etiology of the condition. Other names for osteogenesis imperfecta are Lobstein disease, brittle-bone disease, blue-sclera syndrome, and fragile-bone disease.

Osteogenesis imperfecta is one of the most common skeletal dysplasias. It is a generalized disease of connective tissue that may manifest itself with one or more of the following findings: blue sclerae, triangular facies, macrocephaly, hearing loss, defective dentition, barrel chest, scoliosis, limb deformities, fractures, joint laxity, and growth retardation. Additional features, such as constipation and sweating, may also occur. A multidisciplinary approach is required to manage the disease.^1,2

Pathophysiology

In osteogenesis imperfecta, pathologic changes are seen in all tissues in which type 1 collagen is an important constituent, such as bone, ligament, dentin, and sclera. The basic defect is one of a qualitative or quantitative reduction in type 1 collagen. Mutations in genes encoding type 1 collagen affect the coding of 1 of the 2 genes, accounting for approximately 80% of cases of osteogenesis imperfecta.^3,4,5,6

Most cases of osteogenesis imperfecta, previously thought to be either autosomal dominant or autosomal recessive, are now known to arise from autosomal dominant mutations. These mutations are either genetically inherited or new. The inherited mutations have a recurrence risk in subsequent pregnancies of 50% if a parent is affected, whereas the new mutations have an unpredictable recurrence risk. A small number of cases previously thought to be autosomal recessive have now been proven by molecular and linkage analysis to be secondary to gonadal mosaicism. The recurrence risk for these cases is also unpredictable.

In bone, the degree of histologic change is well correlated with the clinical severity of the disease. The disease affects both endochondral and intramembranous ossification. In osteogenesis imperfecta due to quantitative defects of type 1 collagen, a mild form of the disease occurs. On light microscopy, osteoporotic bone is present, with thick osteoid seams and reduced intercellular matrix. The numbers of osteoclasts and osteocytes are normal. Bone trabeculae are thin and disorganized. Lamellar bone is seen in the diaphysis and metaphysis. On electron microscopy, osteoblasts show distended rough endoplasmic reticulum (possibly because of accumulation of incomplete procollagen molecules), and collagen fibers are of reduced diameter.

In osteogenesis imperfecta that results from qualitative defects of type 1 collagen, a severe form of the disease occurs. Light microscopy reveals hyperosteocytosis and increased vascular channels. Other findings are a reduction in cortical bone thickness, lack of normal cortical bone formation, and disorganization of the growth plate. Woven bone is seen, with minimal osteoid bone and no lamellar bone. Electron microscopy shows poorly preserved osteoblasts and collagen bundles of variable diameter, particularly in the more lethal forms of osteogenesis imperfecta.

The epiphysis and physis tend to be broad and irregular, with disorganization of the proliferative and hypertrophic zones and loss of the typical columnar arrangement. Thinning of the zone of calcified cartilage is evident, along with deficiency of the primary spongiosa of the metaphysis and delay of the secondary centers of ossification in the epiphysis.

With respect to the axial skeleton, scoliosis and kyphosis are common. Vertebral bodies tend to be wedged, translucent, and shallow. Thinning of the skull and multiple ossification centers (wormian bones) are present, particularly in the occiput.

Frequency

International

The birth incidence is approximately 1 case in 20,000 births.

Mortality/Morbidity

Morbidity and mortality associated with osteogenesis imperfecta vary widely depending on the genotype. In addition, variability occurs between individuals with different mutations, and variability has also been observed between unrelated individuals with the same mutations, between members of the same family, and even between identical twins on occasion.

• At one extreme, early stillbirths occur, and virtually every bone in the body has multiple fractures. The severe perinatal form (type II) is usually fatal within hours after birth, although some babies survive for several months.
• At the other extreme is osteogenesis imperfecta in its mildest form. In this setting, adults who have never had a fracture come to medical attention only because their family members are affected.
• Between these extremes is a smooth continuum of severity.

Race

Osteogenesis imperfecta has been described in every human population in which skeletal dysplasias have been studied. The disease appears to have no predilection for a particular race.

Sex

Osteogenesis imperfecta is equally common in males and females.

Age

Osteogenesis imperfecta can present at any age, although the more severe forms tend to become evident at a younger age.

Clinical

History

The most widely used classification is that of Sillence (1979, 1981)^7,8 , which classifies osteogenesis imperfecta into 4 types on the basis of clinical and radiologic features. In addition, dentinogenesis imperfecta is denoted as subtype B, whereas osteogenesis imperfecta without dentinogenesis imperfecta is denoted as subtype A.

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^* AD indicates autosomal dominant.

^† NA indicates not applicable.

Three more types of osteogenesis imperfecta (types V, VI, and VII) have been described, though they have not been incorporated as of yet into the International Classification of the Osteochondrodysplasias (INCO), which uses the Sillence classification. The 7 forms are described in more detail below.

• Type I
  • Type I osteogenesis imperfecta is the mildest and most common form. Patients present with blue sclerae (often described as dark blue with a gray tinge), variable degrees of bone fragility, moderate bone deformity, and premature deafness. Birth weights tend to be normal, although one or more bones may be fractured.
  • Fractures may occur for the first time at a later age, such as when the child starts to walk. These fractures tend to heal well, though sometimes a hypertrophic callus response is seen. Fractures tend to decrease in frequency after puberty, but their occurrence may increase later in life when age- and sex-related osteoporosis is superimposed.
  • Involvement of the axial skeleton in the form of scoliosis and kyphosis is seen in 20% of cases. Dentinogenesis imperfecta is characteristic of osteogenesis imperfecta type IB.
• Type II
  • Severely affected babies with type II disease are born with dwarfism, with blue sclerae and short, bowed limbs.
  • The disease is usually fatal at birth, but some babies survive for several months.
  • Multiple fractures are evident, and the long bones are short and crumpled.
• Type III
  • Babies with type III disease are born with severe bone fragility and suffer multiple fractures at birth, although their birth weight tends to be normal. The sclerae are bluish at birth but fade over the years, becoming white in adulthood. Dentinogenesis imperfecta is frequently seen.
  • The chest and rib cage are usually spared, with few or no fractures of the ribs. Bowing of the limbs is common with growth, and multiple fractures may be seen later in life. The result is a short skeleton and a relatively less affected barrel shaped chest, with a pectus carinatum deformity.
  • The classic radiographic appearance is that of popcorn bones, in which fractures of the physes in several locations result in several islands of endochondral ossification. With age, these ossifications tend to disappear, leaving an enlarged radiolucent epiphysis. The axial skeletal is also involved, with progressive platyspondyly and kyphoscoliosis. Eventually, the wide rib cage overlaps the narrow pelvis.
  • Affected children tend to become wheelchair bound and nonambulatory. Of all types of osteogenesis imperfecta, type III is the one that orthopedic surgeons see most often.
• Type IV
  • Children with type IV disease have white sclerae with moderate bone fragility and deformity. The clinical picture may be similar to that of type I osteogenesis imperfecta, except for the presence of white sclerae.
  • Axial skeletal involvement, in the form of kyphoscoliosis, is also common.
  • Dentinogenesis imperfecta is seen in type IVB osteogenesis imperfecta.
• Type V
  • Type V is an autosomal dominant condition with severity similar to that of type IV disease but with a predisposition to hyperplastic callus formation.
  • Characteristic features include ossification of the interosseous membrane of the forearms and legs, leading to limited pronation and supination and a radiopaque metaphyseal band in growing patients.
• Type VI
  • Type VI is clinically similar to types II and IV, but it has distinctive histology, including hyperosteoid bone due to a mineralization defect, but  it does not have a disturbance of bone mineral metabolism.
• Type VII
  • Type VII disease has been described in an isolated First Nations community in northern Quebec^9,10 and is clinically similar to osteogenesis imperfecta types II and IV but with rhizomelia as a distinctive feature.
  • The gene mutation has been mapped to chromosome region 3p22-24.1.
• Other types of osteogenesis imperfecta
  • Many cases of osteogenesis imperfecta do not fit into the aforementioned categories, with variants such as osteoporosis-pseudoglioma, Bruck syndrome, and Cole-Carpenter syndrome.
  • Osteoporosis-pseudoglioma syndrome is caused by mutations in the gene encoding for the low-density-lipoprotein receptor-related protein 5 (LRP5), with clinical features including blindness and bone fragility. LRP5 is thought to mediate the proliferation and differentiation of osteoblasts.
  • Bruck syndrome is an autosomal recessive condition caused by mutations in the bone-specific collagen type 1 telopeptide lysyl hydroxylase enzyme, with clinical features that include congenital joint contractures and bone fragility.¹¹
  • Cole-Carpenter syndrome is a severe progressive form of osteogenesis imperfecta, with associated multisutural craniosynostosis and growth failure.

Physical

See Clinical, History, above, for findings with the different subtypes.

Causes

Type 1 collagen is a triple helix formed by 2 copies of the alpha1 chain and 1 copy of the alpha2 chain. The COL1A gene on chromosome 17 encodes the pro-alpha1 chain, and the COL2A gene on chromosome 2 encodes the pro-alpha2 chain.

The gene sequence coding for the triple-helix domain has a repeating motif of (Gly-X-Y)(n), where X is commonly hydroxyproline and Y is commonly hydroxylysine. Glycine, being the smallest of all amino acids, fits into the core of the superhelix when the chains wind around each other; therefore, glycine plays an important role in the superhelix formation. In 85-90% of cases, the gene mutation occurs in the region where the exon and intron splice sites are sequenced. All current mutations for type 1 collagen and their associated phenotypes can be found in the Human Type 1 Collagen Mutation Database.

In osteogenesis imperfecta due to quantitative defects of type 1 collagen, mutations are usually found on the COL1A gene. The mutations result in the production of a premature stop codon or a microsense frameshift, which leads to mutant messenger RNA (mRNA) in the nucleus. However, the cytoplasm contains normal alpha1 mRNA; therefore, reduced amounts of structurally normal collagen are produced.

In osteogenesis imperfecta due to qualitative defects of type 1 collagen, autosomal dominant mutations are found on either the COL1A or the COL1B gene. The mutations result in the production of a mixture of normal and mutant collagen chains. Substitution of glycine by a larger amino acid (eg, cysteine, alanine) results in abnormal helix formation, but these chains can combine with normal chains to produce type 1 collagen. The type 1 collagen thus formed is functionally impaired because of the mutant chain; this is the so-called dominant negative mechanism.

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