Molecular analysis of CYP21A2 can optimize the follow-up of positive results in newborn screening for congenital adrenal hyperplasia

• Published in: Clinical genetics Vol. 76; no. 6; pp. 503 - 510
• Main Authors: Silveira, EL, Elnecave, RH, Dos Santos, EP, Moura, V, Pinto, EM, Van Der Linden Nader, I, Mendonca, BB, Bachega, TASS
• Format: Journal Article
• Language: English
• Published: Oxford, UK Blackwell Publishing Ltd 01-12-2009; Wiley-Blackwell
• Subjects: 17-alpha-Hydroxyprogesterone - blood; 17OHP level; 21-hydroxylase deficiency; Adrenal Hyperplasia, Congenital - blood; Adrenal Hyperplasia, Congenital - diagnosis; Adrenal Hyperplasia, Congenital - enzymology; Adrenals. Adrenal axis. Renin-angiotensin system (diseases); Biological and medical sciences; Child; Child, Preschool; congenital adrenal hyperplasia; CYP21A2 mutations; Endocrinopathies; Female; Follow-Up Studies; Fundamental and applied biological sciences. Psychology; General aspects. Genetic counseling; Genes; Genetics of eukaryotes. Biological and molecular evolution; Heterozygote; Humans; Infant; Infant, Newborn; Male; Medical genetics; Medical sciences; Medical screening; Molecular and cellular biology; Neonatal care; Neonatal Screening; newborn screening; Non tumoral diseases. Target tissue resistance. Benign neoplasms; Steroid 21-Hydroxylase - genetics; Endocrinopathy; Human; 21-hydroxylase deficiency; Adrenal cortex diseases; Enzyme; Deficiency; Hydroxylase; Hyperadrenocorticism; Medical screening; CYP21 A2 mutations; Enzymopathy; congenital adrenal hyperplasia; Congenital adrenal hyperplasia syndrome; 170HP level; Screening; Newborn; Follow up study; Newborn animal; Adrenal gland diseases; Genetics; Oxidoreductases; Mutation; newborn screening
• ISSN: 0009-9163; 1399-0004
• DOI: 10.1111/j.1399-0004.2009.01274.x

Neonatal screening for congenital adrenal hyperplasia (CAH) is useful in diagnosing salt wasting form (SW). However, there are difficulties in interpreting positive results in asymptomatic newborns. The main objective is to analyze genotyping as a confirmatory test in children with neonatal positive results. Patients comprised 23 CAH children and 19 asymptomatic infants with persistently elevated 17‐hydroxyprogesterone (17OHP) levels. CYP21A2 gene was sequenced and genotypes were grouped according to the enzymatic activity of the less severe allele: A1 null, A2 < 2%, B 3–7%, C > 20%. Twenty‐one children with neonatal symptoms and/or 17OHP levels > 80 ng/ml carried A genotypes, except two virilized girls (17OHP < 50 ng/ml) without CAH genotypes. Patients carrying SW genotypes (A1, A2) and low serum sodium levels presented with neonatal 17OHP > 200 ng/ml. Three asymptomatic boys carried simple virilizing genotypes (A2 and B): in two, the symptoms began at 18 months; another two asymptomatic boys had nonclassical genotypes (C). The remaining 14 patients did not present CAH genotypes, and their 17OHP levels were normalized by 14 months of age. Molecular analysis is useful as a confirmatory test of CAH, mainly in boys. It can predict clinical course, identify false‐positives and help distinguish between clinical forms of CAH.