Clinical-molecular correlations in the skeletal dysplasias
The skeletal dysplasias are a heterogeneous group of disorders that result in disproportionate short stature and/or skeletal deformities. There are over 250 distinct skeletal dysplasias, which must be differentiated one from another for specific genetic counseling, prognosis and treatment. Over the past decade, there has been an explosive increase in the delineation of their biochemical and molecular defects, however the gene locus and/or molecular defect are still not known for many of these disorders. On the basis of the recent molecular findings, they can now be classified on a molecular-pathogenetic basis: Defects in extracellular matrix structural proteins; Defects in metabolic pathways; Defects in folding, processing, transport and degradation of macromolecules; Defects in hormones, growth factors, receptors and signal transduction; Defects in nuclear proteins; Defects in RNA processing and metabolism; and Defects in cytoskeletal proteins.
In the most recent international nomenclature, attempts have been made to consolidate the clinical and molecular classifications and nomenclature. In some instances, the clinically predicted families of disorders have been found to share a common etiology, whereas in other bone dysplasia families, clear locus heterogeneity was defined. It has also become apparent that previous clinical classifications of these disorders, based simply on age of onset, dysplasia versus dysostosis, or presence or absence of a single clinical feature are not valid, because a wide clinical spectrum can result from different mutations in the same gene. Thus a variety of approaches to their nomenclature and classification are necessary. It is clear that a multidimensional electronic cross-referenced classification incorporating clinical, radiological, morphological, biochemical, molecular and developmental criteria will be required for the skeletal dysplasias, as well as for most other groups of genetic syndromes.