ESPE Abstracts

Introduction: Congenital Adrenal Hyperplasia (CAH) is an autosomal recessive disorder caused by pathogenic variants in seven genes involved in the cortisol and aldosterone biosynthetic pathway. The second most common cause of CAH, 11β-hydroxylase deficiency (11βOHD), is attributed to pathogenic variants in the CYP11B1gene encoding for the enzyme 11β-hydroxylase (11βOH).

Case presentation: A thirteen-year-old girl was referred to the pediatric endocrinologist due to syncopal episode. She was the third child of a non-consanguineous family. She presented premature adrenarche at the age of 6 years and menarche at the age of 12 years. On physical examination, she presented height of 154.5cm, weight of 50kg, acne, hirsutism, clitoromegaly and normal blood pressure. Laboratory investigations revealed increased androgen levels and poor response of cortisol to ACTH stimulation test. From the family history, the mother was diagnosed with CAH at the age of 10 years and was under treatment with methylprednisolone. Previous molecular investigation of the CYP21A2gene was negative. Due to the increased androstenedione levels in the index patient, the suspicion of 11βOHwas raised. She was then investigated for 11-deoxycortisol and 11-deoxycorticosteronelevels that were found to be significantly raised at 98.1nmol/l(NV: 1.4-5nmol/l)and 1808pg/ml (NV: 40-200pg/ml), respectively.

Methods: PCR and bidirectional sequencing of the 9 exons and flanking intronic sequences of the CYP11B1gene was carried out. Novel variants were evaluated employing 7 bioinformatics software tools and classified according to the ACMG guidelines for the interpretation of Sequence Variants. The frequency of novel variants was searched in the Genome Aggregation Database.

Results: CYP11B1gene sequencing analysis revealed that our patient and her mother harbored two novel variants; the p.K370Q (c.1108A>C) in exon 6 and the p.G379S (c.1135G>A) in exon 7. The father was found to be heterozygote for the p.K370Q variant (p.[K370Q];[=]). Segregation analysis of the two siblings indicated that the patient and her mother were compound heterozygotes for the previously mentioned variants (p.[K370Q];[G379S]). Variant p.K370Q was predicted as pathogenic by the seven bioinformatics tools employed and classified as Variant of Uncertain Significance (VUS) according to ACMG criteria. Variant p.G379S was predicted as pathogenic by 3/7 tools and classified as likely pathogenic according to ACMG criteria. None of thevariants were present in gnomAD database.

Conclusion: We present a case of 11βOHDcaused by two novel pathogenic variants of theCYP11B1gene, in the index patient and her mother, emphasizing the importance of molecular investigation in order to confirm clinical diagnosis and allow propergenetic counseling of the family.