Inherited disorders of bone and cartilage

							 Inherited disorders of bone and
             cartilage

              Skeletal dysplasias

               Ravi Savarirayan
           Introduction and Overview

                Skeletal Biology Research Group
                Genetic Health Services Victoria
                    University of Melbourne
May 2008               Ravi Savarirayan: Bologna
           Melbourne




May 2008   Ravi Savarirayan: Bologna
           Royal Children's Hospital




                                               My office




May 2008           Ravi Savarirayan: Bologna
              Outline of Talk
      •    Significance/Background
      •    Classification
      •    Clinical/Radiographic evaluation
      •    Prenatal diagnosis
      •    Clinical examples
      •    Common disease relevance

May 2008              Ravi Savarirayan: Bologna
           Why is this important?
 • Diseases of the MSK system 2nd most common
   reason for doctor visit in Australia
 • Third leading cause of health care expenditure
   ($3 billion/annum)
 • Significant burden of disease in men and
   women now and over next 20 years in Australia
   and worldwide
     (Mathers et al., Australian Burden of Disease
     Study, 2000)

May 2008             Ravi Savarirayan: Bologna
           Why is this important?

• Jan 2000, Bone and Joint Decade launched
  by WHO (2000-2010)

• "Joint diseases, back complaints,
  osteoporosis……. have an enormous impact on
  individuals and societies, and on healthcare
  services and economies.“
                 Kofi Annan, Former UN Secretary-General



May 2008          Ravi Savarirayan: Bologna
           Why is this so important?


• TIME magazine 2002
• The “age of arthritis”
  (40 million Americans by 2020)
• Ageing populace, obesity
• Political, social, economic impacts


May 2008           Ravi Savarirayan: Bologna
           Background

                                        Seneb and familly




May 2008    Ravi Savarirayan: Bologna
           The Human skeleton
•   complex organ
•   206 bones
•   appendicular (126), axial (74), ossicles (6)
•   functions
•   2 tissues, 3 cell types

May 2008           Ravi Savarirayan: Bologna
           Skeletal dysplasias
• Ancient disorders
• Cultural differences in
  perception of term
  « dwarf »
• Social stigma
  attached to word




May 2008           Ravi Savarirayan: Bologna
           Skeletal dysplasias


  • Abnormalities in the
    development, growth and
    maintenance of the human
    skeleton


May 2008        Ravi Savarirayan: Bologna
              BONE FORMATION


ENDOCHONDRAL                      INTRAMEMBRANOUS
• bones form from cartilage       • mesenchymal cells
  anlagen                           condense
• complex process of              • tissue vascularizes
  chondrogenesis,                 • cells differentiate directly
  hypertrophy, apoptosis,           to osteoblasts
  bone replacement
                                  • Flat skull bones,
• Major mechanism of
                                    clavicles form this way
  skeletogenesis


May 2008             Ravi Savarirayan: Bologna
           Endochondral ossification




May 2008           Ravi Savarirayan: Bologna
   Intramembranous ossification




May 2008    Ravi Savarirayan: Bologna
           Classification




May 2008    Ravi Savarirayan: Bologna
             Classification
• Prior to 1970

• Short limbed-short stature=achondroplasia

• Short trunk-short stature= Morquio
  syndrome


May 2008          Ravi Savarirayan: Bologna
              Classification
• Recognition of clinical and radiographic
  heterogeneity led to the first nomenclature
  meeting 1972, Paris (Maroteaux)

• First classification of these conditions
  purely descriptive (clinical, radiographic,
  and pathological)


May 2008         Ravi Savarirayan: Bologna
           Classification:Terms

  Descriptions based on:
  • Which segments most affected
    (rhizo/meso/acro-melia)
  • What part of skeleton affected
    radiographically (epi-/meta-/dia-
    /spondylo-)
  • Greek prefixes also prevalent
    (-atelo/-geleo/-diastrophic/-ana)
May 2008         Ravi Savarirayan: Bologna
            Classification
• Revised every 4 years by the Nosology
  Group of the International Skeletal
  Dysplasia Society (ISDS)

• Latest nosology meeting in 2005 at 7th
  ISDS meeting in Martigny, Switzerland



May 2008        Ravi Savarirayan: Bologna
           CURRENT NOMENCLATURE
            Am J Med Genet Jan 2007, 143A:1-18.

  • Over 350 well defined entities in 37
    “groups”
  • Many groups now based on common
    etiology (i.e. achondroplasia group, type 2
    collagenopathies, diastrophic sulfate
    transporter group)
  • Other groups still purely descriptive
    (SEMD, acro-mesomelic group) and await
    molecular defect
  • Need for more integrated nosology
May 2008               Ravi Savarirayan: Bologna
     Molecular classification of skeletal
                 dysplasias

Structural cartilage     Collagen type II              Kniest, Stickler,
proteins                                               achondrogenesis 2
Cartilage metabolic      Diastrophic dysplasia         DTD, ATO 2, ACH1B,
pathways                 transporter                   rMED
Local cartilage growth   FGFR3                         Achondroplasia,
regulators                                             hypochondroplasia, TD
Transcription factors    CDMP-1                        BDC, Grebe dysplasia

Cell membrane            WISP3                         PPD
proteins
Tumour suppressor        EXT 1, 2                      Multiple exostoses
genes
Signal transduction      TGFβ-1, ROR2                  Diaphyseal dysplasia,
mechanisms                                             BDB
May 2008                   Ravi Savarirayan: Bologna
           Current nomenclature

  •   Please refer to paper
  •   Groups
  •   Rationale
  •   Future directions




May 2008           Ravi Savarirayan: Bologna