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.

Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
U.S. National Inst/Child Hlth/Human Dev
Zip Code
Tella, Sri Harsha; Mallappa, Ashwini; Merke, Deborah P (2018) VISUAL VIGNETTE. Endocr Pract 24:606
Miller, Walter L; Merke, Deborah P (2018) Tenascin-X, Congenital Adrenal Hyperplasia, and the CAH-X Syndrome. Horm Res Paediatr 89:352-361
El-Maouche, Diala; Hargreaves, Courtney J; Sinaii, Ninet et al. (2018) Longitudinal Assessment of Illnesses, Stress Dosing, and Illness Sequelae in Patients With Congenital Adrenal Hyperplasia. J Clin Endocrinol Metab 103:2336-2345
Mallappa, Ashwini; Nella, Aikaterini A; Sinaii, Ninet et al. (2018) Long-term use of continuous subcutaneous hydrocortisone infusion therapy in patients with congenital adrenal hyperplasia. Clin Endocrinol (Oxf) 89:399-407
Hannah-Shmouni, Fady; Chen, Wuyan; Merke, Deborah P (2017) Genetics of Congenital Adrenal Hyperplasia. Endocrinol Metab Clin North Am 46:435-458
Jones, Christopher M; Mallappa, Ashwini; Reisch, Nicole et al. (2017) Modified-Release and Conventional Glucocorticoids and Diurnal Androgen Excretion in Congenital Adrenal Hyperplasia. J Clin Endocrinol Metab 102:1797-1806
El-Maouche, Diala; Arlt, Wiebke; Merke, Deborah P (2017) Congenital adrenal hyperplasia. Lancet :
Karunasena, Nayananjani; Han, Thang S; Mallappa, Ashwini et al. (2017) Androgens correlate with increased erythropoiesis in women with congenital adrenal hyperplasia. Clin Endocrinol (Oxf) 86:19-25
Mallappa, Ashwini; Nella, Aikaterini A; Kumar, Parag et al. (2017) Alterations in Hydrocortisone Pharmacokinetics in a Patient With Congenital Adrenal Hyperplasia Following Bariatric Surgery. J Endocr Soc 1:994-1001
Mallappa, Ashwini; Millo, Corina M; Quezado, Martha et al. (2017) Congenital Adrenal Hyperplasia Presenting as an Adrenal Mass With Increased 18F-FDG Positron Emission Tomography Uptake. J Endocr Soc 1:1110-1112

Showing the most recent 10 out of 30 publications