Guidelines for Laboratory Testing for OSTEOGENESIS IMPERFECTA

  1. If your patient has the clinical diagnosis of osteogenesis imperfecta (OI) and laboratory confirmation is needed, Collagen Screening provides the least costly way to confirm the diagnosis. It takes approximately 3 weeks from the time fibroblasts arrive in the laboratory to complete the study, which identifies a biochemical abnormality in approximately 87-90% of clinically affected individuals. Alternatively, DNA sequencing of COL1A1 and COL1A2 from blood is also is also available. Genomic DNA sequencing takes up to 3 months to complete and is greater than 90% sensitive.

    OI TABLE: Clinical Classification of Osteogenesis Imperfecta

    OI Type

    Clinical Features

    Inheritance

    Biochem Abn

    Mutation

    I

    Normal stature, little or no deformity, blue sclerae, hearing loss.

    AD (new mutations are common)

    50% reduction in type I collagen synthesis

    COL1A1

    II

    Lethal in perinatal period; minimal calvarial mineralization, beaded ribs, compressed femurs, long bone deformity, platyspondyly

    AD (new mutations; recurrence due to parental mosaicism)
    AR (rare)

    Structrual alteration in type I collagen chains - overmodification

    COL1A1 & COL1A2

    III

    Progressively deforming bones, moderate deformity at birth, sclerael hue varies, dentinogenesis imperfecta , hearing loss, very short.

    AD
    AR (rare)

    Structrual alteration in type I collagen chains

    COL1A1 & COL1A2

    IV

    Normal sclerae in adults, mild/moderate deformity, variable short stature, DI, some hearing loss

    AD

    Structrual alteration in type I collagen chains

    COL1A1 & COL1A2

    V

    Similar to OI IV plus calcification of interosseous membrane of forearm, anterior radial head dislocation, hyperplastic callus formation (Gorieux et al 2001)

    AD

    None identified

    Unknown

    VI

    Similar to OI IV with early onset vertebral compression fractures; mineralization defect (Glorieux et al 2002)

    ?

    None identified

    Unknown

    Modified from Sillence, 1978

  2. If your patient has some of the clinical features of OI and diagnostic testing for the "possibility" of OI is considered, Collagen Screening is the most cost effective way to establish the diagnosis. The sensitivity of collagen screening and DNA sequencing are similar.

    If collagen screening studies detect an abnormal collagen and you wish to identify the COL1A1 or COL1A2 gene mutation, either direct genomic DNA sequencing or directed cDNA sequencing may be available.

    If collagen screening studies are normal or equivocal but you still suspect that your patient has OI, molecular studies may be indicated. Genomic DNA Sequencing of COL1A1 and COL1A2 may identify mutations that lead to OI. In some instances directed cDNA sequencing derived from fibroblasts will be recommended.

  3. We are receiving an increasing number of requests for testing to exclude OI in children with "unexplained fractures" who are also being evaluated for non-accidental injury. In such instances, the child should first be examined by a clinical geneticist or other clinician experienced in the recognition of OI. Then, if testing is recommended, Collagen Screening is the best test to pursue. In the event of equivocal collagen results, molecular testing will be suggested.

    For an explanation about OI testing in instances of infants evaluated for non-accidental injury (NAI), see Frequently Asked Questions about OI v NAI. The sensitivity of collagen screening alone in this setting (OI v NAI) is thought to be close to 98%. (References: Steiner et al, Marlowe et al).

  4. There are instances when Genomic DNA Sequencing is the best test choice. If your patient is an adult with the biochemical diagnosis of OI type I and he/she wishes to consider prenatal diagnosis it will be necessary to identify the underlying gene mutation to offer testing in pregnancy. Skin fibroblasts from individuals with OI type I usually synthesize half the normal amount of type I collagen. However, chorionic villus cells synthesize less type I collagen than skin fibroblasts making it very difficult to interpret. Instead, direct mutation detection is necessary. Prenatal diagnosis of OI type II, III and IV by biochemical studies is possible by examination of cultured CVS cells. (References: Pepin, et al)

  5. Prenatal diagnosis of OI is possible using biochemical studies for OI type II, III and IV if the diagnosis has been identified in cells from a previous affected family member. Biochemical prenatal diagnosis is only possible by studying cultured CVS cells and cannot be done with amniocytes. Prenatal diagnosis of OI is possible using DNA-based techniques for all forms of OI if a previous affected family member has had their mutation identified. DNA-based prenatal diagnosis is possible by studying DNA extracted from CVS cells or amniocytes.

    Samples should NOT be submitted for prenatal diagnosis unless a previous affected family member has been tested in our laboratory and their mutation or biochemical abnormality has been identified. It is helpful for the clinician to phone ahead and discuss the patient with Dr. Peter Byers or a genetic counselor, Melanie Pepin or Dru Leistritz, to determine appropriate testing (206-543-5464).