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      Clinical perspectives in congenital adrenal hyperplasia due to 3β-hydroxysteroid dehydrogenase type 2 deficiency

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          3β-hydroxysteroid dehydrogenase type 2 deficiency (3βHSD2D) is a very rare variant of congenital adrenal hyperplasia (CAH) causing less than 0.5% of all CAH. The aim was to review the literature.


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          3βHSD2D is caused by HSD3B2 gene mutations and characterized by impaired steroid synthesis in the gonads and the adrenal glands and subsequent increased dehydroepiandrosterone (DHEA) concentrations. The main hormonal changes observed in patients with 3βHSD2D are elevated ratios of the Δ5-steroids over Δ4-steroids but molecular genetic testing is recommended to confirm the diagnosis. Several deleterious mutations in the HSD3B2 gene have been associated with salt-wasting (SW) crisis in the neonatal period, while missense mutations have been associated with a non-SW phenotype. Boys may have ambiguous genitalia, whereas girls present with mild or no virilization at birth. The existence of non-classic 3βHSD2D is controversial. In an acute SW crisis, the treatment includes prompt rehydration, correction of hypoglycemia, and parenteral hydrocortisone. Similar to other forms of CAH, glucocorticoid and mineralocorticoid replacement is needed for long-term management. In addition, sex hormone replacement therapy may be required if normal progress through puberty is failing. Little is known regarding possible negative long-term consequences of 3βHSD2D and its treatments, e.g., fertility, final height, osteoporosis and fractures, adrenal and testicular tumor risk, and mortality.


          Knowledge is mainly based on case reports but many long-term outcomes could be presumed to be similar to other types of CAH, mainly 21-hydroxylase deficiency, although in 3βHSD2D it seems to be more difficult to suppress the androgens.

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          Most cited references 124

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          Overview of steroidogenic enzymes in the pathway from cholesterol to active steroid hormones.

          Significant advances have taken place in our knowledge of the enzymes involved in steroid hormone biosynthesis since the last comprehensive review in 1988. Major developments include the cloning, identification, and characterization of multiple isoforms of 3beta-hydroxysteroid dehydrogenase, which play a critical role in the biosynthesis of all steroid hormones and 17beta-hydroxysteroid dehydrogenase where specific isoforms are essential for the final step in active steroid hormone biosynthesis. Advances have taken place in our understanding of the unique manner that determines tissue-specific expression of P450aromatase through the utilization of alternative promoters. In recent years, evidence has been obtained for the expression of steroidogenic enzymes in the nervous system and in cardiac tissue, indicating that these tissues may be involved in the biosynthesis of steroid hormones acting in an autocrine or paracrine manner. This review presents a detailed description of the enzymes involved in the biosynthesis of active steroid hormones, with emphasis on the human and mouse enzymes and their expression in gonads, adrenal glands, and placenta.
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            High prevalence of testicular adrenal rest tumors, impaired spermatogenesis, and Leydig cell failure in adolescent and adult males with congenital adrenal hyperplasia.

            In male patients with congenital adrenal hyperplasia, testicular tumors, or so-called adrenal rest tumors, have been described, but their presence in well controlled patients is thought to be rare. In this study, the prevalence of testicular tumors in 17 adolescent and adult male patients with congenital adrenal hyperplasia (age, 16-40 yr) was investigated. In 16 of 17 patients, one or more testicular tumors, ranging in maximal length from 0.2-4.0 cm, were found on ultrasonography. In 6 patients, the testicular tumors were palpable. Undertreatment, defined as the presence of a salivary androstenedione level (mean of 6 saliva samples collected over 24 h with intervals of 4 h) above the upper reference morning level, was found in 5 of 17 patients at the time of investigation. The other 12 patients were treated adequately or even over treated at the time of investigation. Nevertheless, 11 of these 12 patients showed testicular tumors on ultrasonography. Neither the presence of undertreatment at the time of investigation nor characteristics of the therapeutic regimen (daily dose of hydrocortisone equivalents per body surface, the use of glucocorticoid medication either two or three times a day, or the time of taking the highest glucocorticoid dose either in the morning or the evening) could predict tumor size (maximal diameter of largest tumor). In patients who were heterozygous or homozygous for the deletion or conversion of the CYP21 gene, tumor size was significantly larger than in patients who did not have this genotype. Impairment of Leydig cell function as manifested by decreased plasma levels of T was found in 6 of 17 patients. Semen analysis in 11 patients revealed azoospermia in 3 patients and poor semen quality in 4 patients. We conclude that, when carefully sought for, testicular adrenal rest tumors are frequently present in adolescent and adult males with congenital adrenal hyperplasia and are often accompanied by impaired spermatogenesis and Leydig cell failure.
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              One hundred years of congenital adrenal hyperplasia in Sweden: a retrospective, population-based cohort study.

              Congenital adrenal hyperplasia due to 21-hydroxylase deficiency results in cortisol and aldosterone deficiency and is, in its most severe form, lethal. We aimed to assess the effect of historical medical improvements in the care of patients with this disorder over time and to assess the effects of neonatal screening in Sweden.

                Author and article information

                +46-851776411 , henrik.falhammar@ki.se
                Springer US (New York )
                4 February 2019
                4 February 2019
                : 63
                : 3
                : 407-421
                [1 ]ISNI 0000 0004 0442 8821, GRID grid.412855.f, Department of Medicine, , Sultan Qaboos University Hospital, ; Muscat, Oman
                [2 ]GRID grid.240634.7, Division of Medicine, , Royal Darwin Hospital, ; Darwin, NT Australia
                [3 ]ISNI 0000 0004 1937 0626, GRID grid.4714.6, Department of Women’s and Children’s Health, , Karolinska Institutet, ; Stockholm, Sweden
                [4 ]ISNI 0000 0000 9241 5705, GRID grid.24381.3c, Department of Paediatric Endocrinology, Astrid Lindgren Children Hospital, , Karolinska University Hospital, ; Stockholm, Sweden
                [5 ]ISNI 0000 0000 9241 5705, GRID grid.24381.3c, Department of Endocrinology, Metabolism and Diabetes, , Karolinska University Hospital, ; Stockholm, Sweden
                [6 ]ISNI 0000 0004 1937 0626, GRID grid.4714.6, Department of Molecular Medicine and Surgery, , Karolinska Institutet, ; Stockholm, Sweden
                [7 ]ISNI 0000 0000 8523 7955, GRID grid.271089.5, Menzies School of Health Research, ; Darwin, NT Australia
                © The Author(s) 2019

                Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits use, duplication, adaptation, distribution, and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.

                Funded by: FundRef http://dx.doi.org/10.13039/501100006285, Magnus Bergvalls Stiftelse;
                Award ID: 2017-02138
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                © Springer Science+Business Media, LLC, part of Springer Nature 2019

                Endocrinology & Diabetes

                3βhsd2d, diagnosis, management, outcomes, mutations, dehydroepiandrosterone


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