The eight defects described above provide a foundation for the molecular diagnosis of Primary IGFD. Although each of these, in its classic form, appears rare, each defect serves to underscore the critical role of IGF-I in both intrauterine and postnatal growth. The major clinical and biochemical features of each condition are summarized in table 2 . With the exception of bioinactive IGF-I, they are all characterized by low serum concentrations of IGF-I, which fail to rise normally in response to exogenous GH administration. In the case of bioinactive IGF-I, serum concentrations of IGF-I, as measured by conventional radioassays, may be normal or even elevated, but bioassays reveal the underlying abnormality. It seems reasonable to speculate that these 'classic' forms of IGFD represent the tip of the iceberg, and that our understanding of less severe IGFD cases will expand over ensuing years. In addition to the established molecular defects described above, future areas of investigation for molecular etiologies of IGFD might include defects of JAK2, IGFBP-3, and various proteases and phosphatases that might impact GH signal transduction. Since studies suggest that as many as 25-50% of children labeled as 'idiopathic short stature' have reduced serum concentrations of IGF-I in the face of normal or elevated GH, such cases will warrant careful biochemical and molecular investigations, in an effort to identify more subtle defects of the GHR, GH signaling cascade or IGF-I gene expression.
ASJC Scopus subject areas
- Endocrinology, Diabetes and Metabolism