Our recruitment of patients continues to be excellent and represents the largest cohort of CAH and FMPP patients ever seen at one center. To date, we have enrolled over 400 patients with CAH, and 15 patients with FMPP. Comprehensive clinical phenotyping of patients with CAH due to 21-hydroxylase deficiency has been performed. Detailed clinical evaluations reveal great variation in treatment approaches of referred patients, especially amongst adults, with only 30% of patients in acceptable disease control based on adrenal hormones. Adult short stature, abnormal growth and development of children, cardiovascular risk factors, reduced bone mineral density and adrenal and testicular tumor formation are common. Further studies exploring these adverse outcomes are underway. Patients with CAH and other forms of adrenal insufficiency have been reported to have poor quality-of-life. Cognition, emotional processing, memory and quality-of-life is being evaluated. Genotyping and genetic counseling are important in the management of CAH, and genotyping has been suggested as a potential second tier screen to hormonal measurements in neonatal screening programs. The gene encoding 21-hydroxylase, CYP21A2, is mapped to the short arm of chromosome 6 (6p21.3) within the HLA complex. The high rate of genetic variability at this locus, the presence of CYP21A2 gene duplications, and the presence of the CYP21A1P pseudogene complicate the determination of disease and carrier status. In our large cohort of patients with CAH due to 21-hydroxylase deficiency, we reported that the widely used PCR-based CYP21A2 analysis that targets most common mutations failed to identify mutations in 10 percent of our patients, more often than expected. We also found that unusual duplicated CYP21A2 haplotypes sometimes interferes with genotyping and may result in erroneous results reported by commercial laboratories. In addition, we found that junction site analysis of large gene deletions is clinically relevant and can explain why some patients with large deletions have a mild phenotype. An important concurrent project is the evaluation of neighboring genes in relation to phenotype. We described a novel CAH-Tenascin X Contiguous Gene Deletion Syndrome, termed CAH-X Syndrome. Tenascin-X deficiency, in recessive or dominant form, has been proposed as a cause of hypermobility type Ehlers-Danlos Syndrome (EDS). In the first ever systematic study tenascin deficiency in CAH patients, we found that 14 (7 percent) of 193 consecutive unrelated CAH patients have the novel CAH-X Syndrome. We subsequently identified a novel chimeric gene as a cause of CAH-X, broadening the spectrum of this syndrome. Approximately 10 percent of CAH patients are now estimated to be affected by CAH-X. We also described TGF-beta pathway dysregulation in CAH-X. Further studies are underway to better define the clinical, molecular and biochemical aspects of this novel CAH-X syndrome.
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