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Introduction to Skeletal Dysplasias

Andreas Zankl
June 05, 2019
110

Introduction to Skeletal Dysplasias

Genetics Fellow Teaching June 2019

Andreas Zankl

June 05, 2019
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Transcript

  1. Skeletal Dysplasias • individually rare • group prevalence at least

    1:5000 individuals1 • ca. 2’000’000 cases worldwide • ca. 5000 in Australia 1. Wynne-Davies R,:Bone Joint Surg Br 1985, 67:133–137. 2. Stevenson DA, Am J Med Genet 2012, 158A:1046–1054.
  2. Complex Medical Problems • skeletal deformities • early arthritis •

    bone fragility • neurological damage • respiratory failure • …
  3. Bone Dysplasia Clinic Multidisciplinary care • Genetics • Endocrinology •

    Rehabilitation Medicine • Physio/OT • Orthopaedics
  4. nd Mundlos: Genetic Disorders of the Skeleton 457 good models

    to study bone and cartilage biology cleidocranial dysplasia osteogenesis imperfecta osteoporosis-pseudoglioma osteopetrosis juvenile Paget disease metaphyseal anadysplasia osteoporosis-pseudoglioma Pfeiffer syndrome MCD Schmid type acrocapitalfemoral dysplasia Achondroplasia Campomelic dysplasia spondyloepiphyseal dysplasia MCD Jansen type
  5. Knowledge from rare diseases can be applied to common diseases

    • mutations in cathepsin K cause pycnodysostosis • Cathepsin K is a protease involved in matrix degradation by osteoclasts • Blocking cathepsin K activity should increase bone density • Cathepsin K inhibitor (Odanacatib) as a treatment for osteoporosis • (failed in clinical trials due to side effects)
  6. Classification 1878 Description of “Achondroplasia” 1929 Description of “Morquio Syndrome”

    1970 First International Nosology of 
 Constitutional Diseases of Bone 2010 7th Revision of the Nosology: 456 disorders 2015 8th Revision: 436 disorders 1970 1929 1878 2010 2015
  7. knowing the diagnosis is important • different recurrence risks •

    different types of complications • different management • specific treatments
  8. Diagnosis of Skeletal Dysplasias • History • Physical exam •

    Radiographs • Investigations • Genetic testing
  9. onset and progression of symptoms: • prenatal: TD, ACG, OI,

    SRP • birth: ACH, SEDC • first years of life: PSACH, HCH, CHH • after 3 years: MED, brachyolmia, SED tarda → important to have good growth charts! history
  10. history associated medical problems: • cleft palate, myopia, hearing loss:

    type II collagenopathies • intellectual impairment: LSD, Dyggve-Melchior-Clausen • hematological abnormalities: CHH, Shwachman
  11. Consanguinity • Amish • Ellis van Creveld • cartilage-hair hypoplasia

    • Finnish • cartilage-hair hypoplasia • diastrophic dysplasia • Puerto Rican • Jarcho-Levin
  12. Basic Skeletal Survey • skull lateral • thorax AP •

    spine lateral • pelvis AP (including lower spine and proximal femurs) • knees AP • hand AP (including wrists)
  13. Extended Skeletal Survey • skull AP • spine AP •

    knees lateral • upper extremity AP • lower extremity AP • cervical spine lateral (extension, flexion)
  14. what to look for • bone structure • timing of

    ossification • primary sites of involvement • bone shape • specific signs • the big picture
  15. D dysostosis multiplex in the skull. (A) normal J-shaped sella

    turcica, (B) ab the skull of a patient with normal diploic plates and mildly abnormal J-shap loic plates and severe J-shaped sella (arrows) A B x in the thorax. Radiographs showing (A) a normal chest and (B) a chest of an MPS patient showing cles (arrows). en characterized by apering of the ilea the ileum merging of region. Inferior isorders. A newly The hands of MPS patients typically show proximal- ly pointed metacarpals. Metacarpals can be short and thick with thin cortices, even if proximal pointing is not present. Nonspecific findings include hypoplastic and irregular carpal bones, and irregularlyshaped tarsal t a critical aspect in MPS (partic- e if the spinal cord is compressed, result. MRI is more appropriate l cord alterations. hape of vertebral bodies are very attened and rounded vertebrae mbar level the vertebral body can terosuperior corner and, as a con- ongation of the anteroinferior one, ay in an “anterior beaking” aspect. nterior corners occurs, the vertebral LSD
  16. Serum Ca, Ph, PTH, Vitamin D • mostly to exclude

    other causes (e.g. rickets) • normal in most bone dysplasias
  17. Exclude Lysosomal Storage Disorders • quantitative analysis of urinary GAGs

    • qualitative analysis of urinary GAGs 
 (electrophoresis, now Mass-Spec) • enzyme assays
  18. Genetic Testing • Lots of options • Clinical/radiographic review helps

    targeting the testing • Clinical/radiographic review helps interpreting the results
  19. please contact me for Research Whole Genome Sequencing Undiagnosed Bone

    Dysplasia after previous testing (including structural variants, bone specific filters and more…)
  20. please contact me for Research Whole Genome Sequencing Undiagnosed Bone

    Dysplasia after previous testing (including structural variants, bone specific filters and more…)