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Osteogenesis Imperfecta

  • Author: Manoj Ramachandran, MBBS, MRCS, FRCS; Chief Editor: Harris Gellman, MD  more...
 
Updated: Nov 24, 2014
 

Background

The earliest known case of osteogenesis imperfecta (OI) 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 OI are Lobstein disease, brittle-bone disease, blue-sclera syndrome, and fragile-bone disease.

OI 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
  • Growth retardation

Additional features, such as constipation and sweating, may also occur. A multidisciplinary approach is required to manage the disease.[1, 2]

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Pathophysiology

In OI, pathologic changes are seen in all tissues of which type 1 collagen is an important constituent (eg, 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 one of the two genes, accounting for approximately 80% of OI cases.[3, 4, 5, 6]

Most cases of OI, 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 proved 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 correlates well with the clinical severity of the disease. The disease affects both endochondral and intramembranous ossification.

In OI 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 OI due to qualitative defects of type 1 collagen, a severe form of the disease occurs. Light microscopy reveals hyperosteocytosis and increased vascular channels. Other findings are reduced 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 OI.

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.

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Etiology

Type 1 collagen is a triple helix formed by two 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.[7]

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 OI 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 frame shift, 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 OI 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 a larger amino acid (eg, cysteine or alanine) for glycine 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.

Wallace et al, in a report on three patients who had type I OI and primary open angle glaucoma (POAG), identified two novel mutations in COL1A1 in these individuals.[8] They suggested that some mutations in COL1A1 may be causative for OI and POAG. Alternatively, susceptibility genes may interact with mutations in COL1A1 to cause POAG.

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Epidemiology

The overall incidence of OI is approximately 1 case for every 20,000 live births; however, the mild form is underdiagnosed, and the actual prevalence may be higher. Prevalence appears to be similar worldwide, though an increased rate has been observed in two major tribal groups in Zimbabwe.

OI can present at any age, though 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.

OI is equally common in males and females. It 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.

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Prognosis

Morbidity and mortality associated with OI vary widely, depending on the genotype. (See also the adapted Sillence classification in Presentation.) 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, though some babies survive for several months. At the other extreme is OI in its mildest form. In this setting, adults who have never sustained a fracture come to medical attention only because their family members are affected. Between these extremes is a smooth continuum of severity.

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. Although patients with lethal OI may die in the perinatal period, individuals with extremely severe OI can survive until adulthood.

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Patient Education

Patients with OI are generally well motivated and keen to achieve as much as possible despite their physical limitations. Education is extremely important, particularly for those patients who may respond to their condition in a more negative way and therefore be prone to low self-esteem and depression.

Education of parents and families of OI patients is also important for helping them deal with the day-to-day implications and ongoing management of the disorder. For example, parents need special instructions in handling affected children. They need to know how to position the child in the crib and how to hold the child so as to minimize the risk of fractures while maintaining bonding and physical stimulation.

Living with ostogenesis imperfecta

The following tips have been developed by the Osteogenesis Imperfecta Foundation for taking care of children with OI:

  • Do not be afraid to touch or hold an infant with OI, but be careful; to lift the infant, spread your fingers apart and put one hand between the legs and under the buttocks, and place the other hand behind the shoulders, neck, and head
  • Never lift a child with OI by holding him or her under the armpits
  • When changing a diaper, do not pull on arms or legs or, in those with severe OI, lift the legs by the ankles
  • Select an infant car seat that reclines; it should be easy to place or remove your child in the seat; consider padding the seat with foam and using a layer of foam between your child and the harness
  • Be sure your stroller is large enough to accommodate casts; do not use a sling- or umbrella-type stroller
  • Follow your doctor's instructions carefully, especially with regard to cast care and mobility exercises; swimming and walking are often recommended as safe exercises
  • Adults with OI should avoid activities such as smoking, drinking, and taking steroids because they have a negative impact on bone density
  • Increasing awareness of child abuse and a lack of awareness about OI may lead to inaccurate conclusions about a family situation; always have a letter from your family doctor and a copy of your child's medical records handy

A crucial point to stress is that parents should not feel guilty if their child breaks a bone. Children must grow and develop, and fractures can occur despite all the care.

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Contributor Information and Disclosures
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

Manoj Ramachandran, MBBS, MRCS, FRCS is a member of the following medical societies: British Orthopaedic Association

Disclosure: Nothing to disclose.

Coauthor(s)

Pramond Achan, MBBS, FRCS Senior Registrar, Royal National Orthopaedic Hospital, UK

Disclosure: Nothing to disclose.

David H A Jones, MBChB, FRCS FRCS Ed(Orth), Consultant Orthopedic Surgeon, Great Ormond Street Hospital for Children; Senior Clinical Lecturer, University College London Hospitals, UK

David H A Jones, MBChB, FRCS is a member of the following medical societies: British Orthopaedic Association

Disclosure: Nothing to disclose.

Vinod K Panchbhavi, MD, FACS Professor of Orthopedic Surgery, Chief, Division of Foot and Ankle Surgery, Director, Foot and Ankle Fellowship Program, Department of Orthopedics, University of Texas Medical Branch School of Medicine

Vinod K Panchbhavi, MD, FACS is a member of the following medical societies: American Academy of Orthopaedic Surgeons, American College of Surgeons, American Orthopaedic Association, American Orthopaedic Foot and Ankle Society, Orthopaedic Trauma Association, Texas Orthopaedic Association

Disclosure: Serve(d) as a speaker or a member of a speakers bureau for: Styker.

Chief Editor

Harris Gellman, MD Consulting Surgeon, Broward Hand Center; Voluntary Clinical Professor of Orthopedic Surgery and Plastic Surgery, Departments of Orthopedic Surgery and Surgery, University of Miami, Leonard M Miller School of Medicine, Clinical Professor, Surgery, Nova Southeastern School of Medicine

Harris Gellman, MD is a member of the following medical societies: American Academy of Medical Acupuncture, American Academy of Orthopaedic Surgeons, American Orthopaedic Association, American Society for Surgery of the Hand, Arkansas Medical Society

Disclosure: Nothing to disclose.

Acknowledgements

Peter R Calder, MBBS, FRCS(Eng), FRCS (Tr&Orth) Consulting Surgeon, Department of Pediatric Orthopedic Surgery, The Royal National Orthopaedic Hospital, UK

Peter R Calder, MBBS, FRCS(Eng), FRCS (Tr&Orth) is a member of the following medical societies: British Medical Association

Disclosure: Nothing to disclose.

Ian D Dickey, MD, FRCSC Adjunct Professor, Department of Chemical and Biological Engineering, University of Maine; Consulting Staff, Adult Reconstruction, Orthopedic Oncology, Department of Orthopedics, Eastern Maine Medical Center

Ian D Dickey, MD, FRCSC is a member of the following medical societies: American Academy of Orthopaedic Surgeons, British Columbia Medical Association, Canadian Medical Association, and Royal College of Physicians and Surgeons of Canada

Disclosure: Stryker Orthopaedics Consulting fee Consulting; Cadence Honoraria Speaking and teaching

Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Medscape Salary Employment

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Acute fractures are observed in radius and ulna. Multiple fractures can be seen in ribs. Old healing humeral fracture with callus formation is observed.
Beaded ribs. Multiple fractures are seen in long bones of upper extremities.
Wormian bones are present in skull.
Newborn has bilateral femoral fractures.
Table 1. Adapted Sillence Classification of Osteogenesis Imperfecta
Type Genetic Teeth Bone Fragility Bone Deformity Sclera Spine Skull Prognosis
IA AD* Normal Variable but less severe than other types Moderate Blue 20% scoliosis and kyphosis Wormian bones Fair
IB AD Dentinogenesis imperfecta NA NA NA NA NA NA
II AD Unknown Very severe Multiple fractures Blue NA Wormian bones with absence of ossification Perinatal death
III AD Dentinogenesis imperfecta Severe Progressive bowing of long bones and spine Bluish at birth but white in adults Kyphoscoliosis Hypoplastic wormian bones Wheelchair-bound, not ambulatory
IVA AD Normal Moderate Moderate White Kyphoscoliosis Hypoplastic wormian bones Fair
IVB AD Dentinogenesis imperfecta NA NA NA NA NA NA
* AD = autosomal dominant; NA = not applicable.
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