Congenital adrenal hyperplasia: Molecular genetics and alternative approaches to treatment

Several autosomal recessive disorders affecting the adrenal cortex and its development and leading to defective cortisol biosynthesis are known under the collective term "congenital adrenal hyperplasia" (CAH). Over the last t wo decades, the genes causing most of these disorders have been identified and molecular genetics may supplement their clinical and biochemical diagno sis. In addition, new treatments have emerged; although gene therapy has ye t to be applied in humans, studies are ongoing in gene transfer in adrenoco rtical cell lines and animal models. In this review, after a brief introduc tion on the developmental biology and biochemistry of the adrenal cortex an d its enzymes, we will list the new developments in the genetics and treatm ent of diseases causing CAH, starting with the most recent findings. This o rder happens to follow adrenal steroidogenesis from the mitochondrial entry of cholesterol to cortisol synthesis; it is unlike other presentations of CAH syndromes that start with the most frequently seen syndromes, because t he latter were also the first to be investigated at the genetic level and h ave been extensively reviewed elsewhere. We will start with the latest synd rome to be molecularly investigated, congenital lipoid adrenal hyperplasia (CLAH), which is caused by mutations in the gene coding for the steroidogen ic acute regulatory (StAR) protein. We will then present new developments i n the genetics of 3-beta-hydroxysteroid dehydrogenase (3 beta HSD), 17 hydr oxylase and 17,20-lyase (P450c17), 11 hydroxylase (P450c11 beta), and 21 hy droxylase (P450c21) deficiencies. Alternative treatment approaches and gene therapy experiments are reviewed collectively in the last section, because they are still in their infantile stages.