This is a revised submission of a grant in its 32nd year of funding. The primary emphasis is on the correlation of genotype of phenotype combining molecular and clinical studies. Two monogenic defects will be studied: 21-hydroxylase deficiency, which results in the disease Congenital Adrenal Hyperplasia (CAR), and 11beta-HSD2 deficiency, which is the cause of the disease Apparent Mineralocorticoid Excess (AME). We have recruited a medical informatics specialist who has established a database describing the longitudinal data of patients with CAH followed by Dr. New for over 30 years. The database includes extensive clinical and molecular genetics studies of 357 patients with CAR and will be analyzed to determine the final outcome of patients treated with glucocorticoid. The long term effects of prenatal treatment of CAH with dexamethasone on cognition and behavior will be studied. We have discovered a new mild form of AME in a consanguineous Mennonite family and have an opportunity to investigate whether others in their 2,000- member congregation have mutations in the 11HSDB2 gene similar to our patient. We will also study the effect of mineralocorticoids and glucocorti-coids on collagen synthesis in vivo and in vitro in 11beta- HSD2 deficiency. Overall, we propose to continue the investigation of steroid disorders with our newly constituted team consisting of Drs. New, Wilson, Obeid, Hanauske-Abel, Newfield, and Meyer-Bahlburg. Our recent progress attests that this team is capable of advancing the work started 33 years ago. The strengths of our group are: 1) The rich source of patients referred to our division for diagnosis of steroid disorders and hypertension. 2) We are the only group in the U.S.A. routinely carrying out prenatal diagnosis and treatment of CAR and thus have accumulated a large population of prenatally-treated infants to- study. 3) As Dr. New has remained at NYH-CMC since 1955, patients with steroid disorders from birth to adulthood are followed. Rarely has a group of patients been so carefully documented continuously with clinical, hormonal, and molecular genetics data. 4) Dr. Wilson brings special expertise in molecular genetics and works compatibly with the clinical teams. 5) Dr. Ranauske-Abel adds a new dimension, with the investigation of pro-and antifibrotic effects of steroid hormones in patients and in cultured human cells. 6) The harmonious interaction of molecular geneticists, biochemists, psychoendocrinologists, and clinicians with great experience in dealing with patients.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
7R37HD000072-40
Application #
6773936
Study Section
Special Emphasis Panel (ZRG4-EDC-1 (02))
Program Officer
Winer, Karen
Project Start
1977-06-01
Project End
2007-05-31
Budget Start
2004-06-01
Budget End
2005-05-31
Support Year
40
Fiscal Year
2004
Total Cost
$698,353
Indirect Cost
Name
Mount Sinai School of Medicine
Department
Pediatrics
Type
Schools of Medicine
DUNS #
078861598
City
New York
State
NY
Country
United States
Zip Code
10029
Khattab, Ahmed; Yuen, Tony; Al-Malki, Sultan et al. (2016) A rare CYP21A2 mutation in a congenital adrenal hyperplasia kindred displaying genotype-phenotype nonconcordance. Ann N Y Acad Sci 1364:5-10
New, Maria I; Abraham, Moolamannil; Gonzalez, Brian et al. (2013) Genotype-phenotype correlation in 1,507 families with congenital adrenal hyperplasia owing to 21-hydroxylase deficiency. Proc Natl Acad Sci U S A 110:2611-6
Meyer-Bahlburg, Heino F L; Dolezal, Curtis; Haggerty, Rita et al. (2012) Cognitive outcome of offspring from dexamethasone-treated pregnancies at risk for congenital adrenal hyperplasia due to 21-hydroxylase deficiency. Eur J Endocrinol 167:103-10
Lin-Su, Karen; Harbison, Madeleine D; Lekarev, Oksana et al. (2011) Final adult height in children with congenital adrenal hyperplasia treated with growth hormone. J Clin Endocrinol Metab 96:1710-7
Ba?, Firdevs; Kayserili, Hülya; Darendeliler, Feyza et al. (2009) CYP21A2 gene mutations in congenital adrenal hyperplasia: genotype-phenotype correlation in Turkish children. J Clin Res Pediatr Endocrinol 1:116-28
Wilson, Robert C; Nimkarn, Saroj; Dumic, Miro et al. (2007) Ethnic-specific distribution of mutations in 716 patients with congenital adrenal hyperplasia owing to 21-hydroxylase deficiency. Mol Genet Metab 90:414-21
Nimkarn, Saroj; New, Maria I (2007) Prenatal diagnosis and treatment of congenital adrenal hyperplasia. Horm Res 67:53-60
New, Maria I (2006) Extensive clinical experience: nonclassical 21-hydroxylase deficiency. J Clin Endocrinol Metab 91:4205-14
Nimkarn, Saroj; New, Maria I (2006) Prenatal diagnosis and treatment of congenital adrenal hyperplasia. Pediatr Endocrinol Rev 4:99-105
Nimkarn, S; Cerame, B I; Wei, J Q et al. (1999) Congenital adrenal hyperplasia (21-hydroxylase deficiency) without demonstrable genetic mutations. J Clin Endocrinol Metab 84:378-81

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