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 350 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 recently 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. Our findings to date have broad implications in the use of genetic analysis in the diagnosis and management of CAH. We are currently comparing various methodologies and aim to establish a suggested protocol for performing CYP21A2 genetic analysis and incorporating genetic analysis into the management of CAH. An important concurrent project is the evaluation of neighboring genes in relation to phenotype. In collaboration with scientists from NIA, we are evaluating a novel CAH-Tenascin X Contiguous Gene Deletion Syndrome, we 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. Further studies are underway to better define the clinical, molecular and biochemical aspects of this novel CAH-X syndrome.

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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
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
Hannah-Shmouni, Fady; Morissette, Rachel; Sinaii, Ninet et al. (2017) Revisiting the prevalence of nonclassic congenital adrenal hyperplasia in US Ashkenazi Jews and Caucasians. Genet Med 19:1276-1279
Turcu, Adina F; Mallappa, Ashwini; Elman, Meredith S et al. (2017) 11-Oxygenated Androgens Are Biomarkers of Adrenal Volume and Testicular Adrenal Rest Tumors in 21-Hydroxylase Deficiency. J Clin Endocrinol Metab 102:2701-2710

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