Endocrine Abstracts (2017) 49 EP7 | DOI: 10.1530/endoabs.49.EP7

Molecular variability determines subtle adrenal biosynthetic defect in non-classical congenital adrenal hyperplasia due to 21-hydroxylase deficiency

Livia Mermejo1, Fernanda Coeli-Lacchini1, Wendy Turatti1, Marcia Elamid2, Renata Parente2, Carlos Martinelli2, Sonir Antonini2, Margaret Castro1 & Ayrton Moreira1


1Department of Internal Medicine Ribeirao Preto Medical School, University of Sao Paulo, Brazil, Ribeirao Preto/SP, Brazil; 2Department of Pediatrics Ribeirao Preto Medical School, University of Sao Paulo, Brazil, Ribeirao Preto/SP, Brazil.


There is a clinical spectrum of non-classical congenital adrenal hyperplasia due to 21-hydroxylase deficiency (NC-CAH). In addition, CYP21A2 gene mutations analysis present in homozygosis or as compound heterozygosis.

Objectives: To evaluate the relationship between the genotype and biochemical profiles and also compare with clinical severity in NC-CAH.

Patients and methods: Clinical, hormonal and molecular data of 57 patients (47 female,10 male; 47 children,10 adults) with NC-CAH were retrospectively analyzed.

Results: The majority of children (76%) presented with premature pubarche at the diagnosis and 12% showed clitoromegaly. Among adult patients, hirsutism (90%) and menstrual abnormalities (66%) were observed at diagnosis. The basal and ACTH-stimulated 17OHP mean levels were 1115±919 (97–4125) and 4245±2059 (1115–10648) ng/dl. The most frequent mutation was p.V281L (68% of alleles) being 42% in homozygosis and 39% of the patients were compound heterozygotes for one classic and one non-classical mutation (C/NC).The severe mutations were p.I172N, IVS2-13A/C>G, Δ8, CL6, p.Q318X, p.R356W and LGC. Basal and ACTH-stimulated 17OHP values were higher in patients carrying the C/NC genotype group compared to NC/NC genotype (1549±250 vs 806±162; P=0.01 and 4740±577 vs 3355±345 ng/dl; P=0.04, respectively). Moreover, ROC curve analyses showed that the basal and ACTH-stimulated 17OHP levels of 610 and 3,913 ng/dl were the best cutoffs to identify NC-CAH patients carrying compound heterozygosis with severe mutations. We observed a higher DHEAS (182±150 vs 85±69 μg/dl, P=0.03) and a bone age advancement trend (P=0.05) in C/NC genotype group compared to NC/NC. There were no differences in age, height, weight, androstenedione and testosterone levels at diagnosis.

Conclusion: Although no phenotype difference was observed between NC/NC and C/NC genotypes, the present study showed graded severities of adrenal biosynthetic defect reflecting the molecular variability in NC-CAH.