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Non-Classic Disorder of Adrenal Steroidogenesis and Clinical Dilemmas in 21-Hydroxylase Deficiency Combined with Backdoor Androgen Pathway. Mini-Review and Case Report

1
Department of Pediatric Diabetes and Obesity, Poznan University of Medical Sciences, 60-527 Poznan, Poland
2
Department of Endocrinology, Metabolism and Internal Medicine, Poznan University of Medical Sciences, 60-653 Poznan, Poland
*
Author to whom correspondence should be addressed.
Int. J. Mol. Sci. 2020, 21(13), 4622; https://doi.org/10.3390/ijms21134622
Received: 3 June 2020 / Revised: 27 June 2020 / Accepted: 28 June 2020 / Published: 29 June 2020
(This article belongs to the Section Molecular Pathology, Diagnostics, and Therapeutics)
Congenital adrenal hyperplasia (CAH) is the most common cause of primary adrenal insufficiency in children and adolescents. It comprises several clinical entities associated with mutations in genes, encoding enzymes involved in cortisol biosynthesis. The mutations lead to considerable (non-classic form) to almost complete (classic form) inhibition of enzymatic activity, reflected by different phenotypes and relevant biochemical alterations. Up to 95% cases of CAH are due to mutations in CYP21A2 gene and subsequent 21α-hydroxylase deficiency, characterized by impaired cortisol synthesis and adrenal androgen excess. In the past two decades an alternative (“backdoor”) pathway of androgens’ synthesis in which 5α-androstanediol, a precursor of the 5α-dihydrotestosterone, is produced from 17α-hydroxyprogesterone, with intermediate products 3α,5α-17OHP and androsterone, in the sequence and with roundabout of testosterone as an intermediate, was reported in some studies. This pathway is not always considered in the clinical assessment of patients with hyperandrogenism. The article describes the case of a 17-year-old female patient with menstrual disorders and androgenization (persistent acne, advanced hirsutism). Her serum dehydroepiandrosterone sulfate and testosterone were only slightly elevated, along with particularly high values for 5α-dihydrotestosterone. In 24 h urine collection, an increased excretion of 16α-OHDHEA—a dehydroepiandrosterone metabolite—and pregnanetriolone—a 17α-hydroxyprogesterone metabolite—were observed. The investigations that we undertook provided evidence that the girl suffered from non-classic 21α-hydroxylase deficiency with consequent enhancement of the androgen “backdoor” pathway in adrenals, peripheral tissues or both, using adrenal origin precursors. The paper presents diagnostic dilemmas and strategies to differentiate between various reasons for female hyperandrogenism, especially in childhood and adolescence. View Full-Text
Keywords: non-classic congenital adrenal hyperplasia; 21-hydroxylase deficiency; backdoor androgen pathway; 16α-hydroxydehydroepiandrosterone (16α-OHDHEA); pregnanetriolone (PTN) non-classic congenital adrenal hyperplasia; 21-hydroxylase deficiency; backdoor androgen pathway; 16α-hydroxydehydroepiandrosterone (16α-OHDHEA); pregnanetriolone (PTN)
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Sumińska, M.; Bogusz-Górna, K.; Wegner, D.; Fichna, M. Non-Classic Disorder of Adrenal Steroidogenesis and Clinical Dilemmas in 21-Hydroxylase Deficiency Combined with Backdoor Androgen Pathway. Mini-Review and Case Report. Int. J. Mol. Sci. 2020, 21, 4622.

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