Natural History Study of Patients with Excess Androgen

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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 500 patients with CAH, and 19 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 among 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. An important concurrent project is the evaluation of neighboring genes, including TNXB and C4, 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, is 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 have subsequently identified novel chimeric genes as a cause of CAH-X, broadening the spectrum of this syndrome. Approximately 10 to 15 percent of CAH patients are now estimated to be affected by CAH-X. Further studies are underway to better define the clinical, molecular and biochemical aspects of CAH.