Skeletal dysplasias

Musculoskeletal diseases are the diseases affecting joints, bones, soft tissues and muscles. There are over 300 well-defined conditions included in this disease group with an overall birth incidence as high as 1 in 130 births. Skeletal dysplasias are genetic disorders of bone formation and homeostasis. There are over 200 distinct phenotypes known with an overall prevalence of 2-5 in 10 000 births. They often result in disproportionate short stature, deformations and malformations and range in severity from relatively mild through to severe and lethal forms. The clinical manifestations of skeletal dysplasias include disproportionate short stature, malformations and deformations.

In the first instance only one skeletal dysplasia phenotype called achondrodysplasia was recognised (Parrot 1878). In the first half of the twentieth century the skeletal dysplasia phenotypes were classified into two groups based on the clinical features: short limb dwarfism (achondroplasia) or short trunk dwarfism (Morquio disease). In years 1950 to 1980 heterogeneity within those groups began to be recognised and in the 1980’s the skeletal dysplasia phenotypes were grouped into families of disorders, presumably bearing the same or similar etiology (Spranger 1985). Currently the criteria for the classification of skeletal dysplasias are mostly the clinical features such as the growth of an individual, age of onset of the disease and altered body proportions and radiographic features. Based on the radiographic features, skeletal dysplasias are characterised using malformations of long bones and vertebrae as nomenclature markers.

skel dysJ Clin Res Pediatr Endocrinol. 2011;3(4):163-78

However, some skeletal dysplasias bear names reflecting the clinical features (for example acromesomelic: acro = extremities, meso = middle, melic = arms and legs, which is therefore a dysplasia affecting hands, feet and long bones), names of the clinicians who have discovered that particular disease (Stickler syndrome, metaphyseal dysplasia type Schmid) or containing Greek terms describing the observed phenotype (for example thanatophoric = lethal, metatropic = changing).

skeletal dysplasiasFrom

Over 200 unique and well-characterized phenotypes are now known, many of which can be grouped into different diagnostic groups. It has also been shown that different mutations in the same gene can result in a spectrum of disease [i.e. allelic series]. In a molecular classification there are seven main types of gene products affected by skeletal dysplasia mutations. These are:

  • extracellular structural proteins,
  • metabolic pathways (including enzymes, transporters and ion channels),
  • folding and degradation of macromolecules,
  • hormones and signal transduction mechanisms,
  • nuclear proteins and transcription factors,
  • oncogenes and tumor suppressor genes,
  • RNA and DNA processing and metabolism.

It is important to note that skeletal dysplasia mutations also influence other non-skeletal organs if their origin is a signalling pathway defect, or mechanically by tightening the tracts in the body due to skeletal defects. Children with skeletal dysplasias frequently have respiratory problems due to thoracic and craniofacial abnormalities. The skull and vertebrae abnormalities can also result in prominent neurological problems and spinal stenosis. Early diagnosis can therefore be life saving and in some cases enable relatively normal growing up and life span.

The skeletal dysplasias curently investigated in our lab are pseudoachondroplasia (PSACH), multiple epiphyseal dysplasia (MED), spondyloepimetaphyseal dysplasia, aggrecan type (SEMD) and spondyloepimetaphyseal dysplasia with joint laxity (SEMD-JL) Hall type. You can find out more about our work on our projects page.