SAT-LB067 Mutational Spectrum Determines Subtle Adrenal Biosynthetic Defect in Non-Classical Congenital Adrenal Hyperplasia Due to 21-Hydroxylase Deficiency

Abstract

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. Herein we hypothesize that allele combination associates with specific biochemical profiles. Objectives: To evaluate the relationship between the genotype and biochemical profiles in the diagnosis of NC-CAH. Patients and Methods: Clinical, hormonal and molecular data at diagnosis of 63 patients (78% female; 43 children, 20 adults) with NC-CAH followed from 1989 to 2019 were analyzed. Results: At the diagnosis, most children (75% of girls and 71% of boys), presented with premature pubarche. Clitoromegaly was present in 10% of the girls. Among adult patients, hirsutism (75%), menstrual abnormalities (50%), premature pubarche (42%), acne (35%) and clitoromegaly (10%) were observed. Basal and ACTH-stimulated 17OHP mean levels (ng/dL) were 1,329 ± 1,232 (97-5,560) and 4,364 ± 2,340 (1,115-10,648), respectively. The most frequent mutation was p.V281L (60% of alleles) being 31% in homozygosis. Fifty percent of the patients were compound heterozygotes for one classic (C) and one non-classical mutation (NC). C alleles 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 genotypes compared to NC/NC genotypes (1,768±1,333 vs 835±923; p=0.0002 and 5,392±498 vs 3,551±400 ng/dl; p=0.005, respectively). Similarly, basal and ACTH-stimulated 17OHP to cortisol ratios were higher in patients carrying the C/NC compared to NC/NC genotypes (134 ±76 vs 53±34; p=0.0003 and 309±48 vs 199±27; 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 C alleles. According to the severity of the mutation, basal 17OHP (ng/dL) was progressively higher p.V281L/p.V281L vs p.V281L/IVS2-13A/C>G (927 vs 3,094; p<0.01) and p.V281L/p.I172N vs p.V281L/IVS2-13A/C>G (1,011 vs 3,094; p<0.05). This was also observed in ACTH-stimulated 17OHP between p.V281L/p.V281L vs p.V281L/p.R356W (3,265 vs 5,817; p<0.01). There was a trend to early appearance of premature pubarche (5.7±1.8 vs 6.7±1.6 years; p=0.07) in C/NC genotype group compared to NC/NC. There were no differences in age, height, weight, androstenedione, DHEAS and testosterone levels between the C/NC and NC/NC groups at diagnosis. Conclusion: The molecular variability in NC-CAH associates with graded severities of adrenal biosynthetic defect. Unless otherwise noted, all abstracts presented at ENDO are embargoed until the date and time of presentation. For oral presentations, the abstracts are embargoed until the session begins. s presented at a news conference are embargoed until the date and time of the news conference. The Endocrine Society reserves the right to lift the embargo on specific abstracts that are selected for promotion prior to or during ENDO.