Severe Salt-Losing 3β-Hydroxysteroid Dehydrogenase Deficiency: Treatment and Outcomes of<i>HSD3B2</i>c.35G&gt;A Homozygotes

Benkert, Abigail R.; Young, Millie; Robinson, Donna L.; Hendrickson, Christine; Lee, Peter A.; Strauss, Kevin A.

doi:10.1210/jc.2015-2098

Cited by 30 publications

(53 citation statements)

References 44 publications

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“…The human type I isoenzyme 3βHSD is the isoenzyme, encoded by HSD3B1 gene and is expressed in peripheral tissue including skin, mammary glands, and placenta [9,11,14]. It has 372 amino acids and shares more than 90% homology with the type II isoenzyme [27,28].…”

Section: Pathophysiologymentioning

confidence: 99%

“…It has 372 amino acids and shares more than 90% homology with the type II isoenzyme [27,28]. The human type I isoenzyme 3βHSD catalyzes transformation of DHEA into sex steroids including testosterone and estradiol [9].…”

Section: Pathophysiologymentioning

confidence: 99%

“…3β-hydroxysteroid dehydrogenase type 2 deficiency (3βHSD2D) [8,9], is a very rare type of CAH affecting <0.5% of all CAH [4,5], and with <1/1,000,000 estimated prevalence at birth [10]. This disorder is caused by HSD3B2 gene mutations and characterized by impairment of steroid synthesis in the gonads and the adrenal glands [11].…”

Section: Introductionmentioning

confidence: 99%

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

2019

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Purpose 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. Methods PubMed was searched for relevant articles. Results 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 saltwasting (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. Conclusion 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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Section: Pathophysiologymentioning

confidence: 99%

Section: Pathophysiologymentioning

confidence: 99%

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

2019

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“…3βHSD2 deficiency accounts for less than 5% of CAH worldwide [7]. Its prevalence is too low to be accurately estimated, although rates are much higher in populations with high rates of consanguinity.…”

Section: Epidemiologymentioning

confidence: 99%

Adrenarche unmasks compound heterozygous 3β-hydroxysteroid dehydrogenase deficiency: c.244G>A (p.Ala82Thr) and the novel 931C>T (p.Gln311*) variant in a non-salt wasting, severely undervirilised 46XY

Teasdale

Morton

2017

Journal of Pediatric Endocrinology and Metabolism

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3β-Hydroxysteroid dehydrogenase type II deficiency (3βHSD2) congenital adrenal hyperplasia is a rare cause of ambiguous genitalia, resulting in abnormal virilisation in both 46XY and 46XX. We describe a case of 46XY ambiguous genitalia that was misdiagnosed as androgen insensitivity syndrome. The correct diagnosis was made after adrenarche. Genotyping demonstrated compound heterozygosity in two alleles, the previously described c.244G>A (p.Ala82Thr), and a novel 931C>T(p.Gln311*) variant. We suggest that adrenarche unmasked the condition by driving cortisol production to rates that caused the mutant 3bHSD2 enzyme to become rate limiting for cortisol production. This case illustrates how markedly different the effects of this condition may be on androgen production compared with glucocorticoid and mineralocorticoid production. It also demonstrates how current guidelines based on urinary steroids and cortisol sufficiency may not arrive at the correct diagnosis, and underlines the importance of gene testing in the work-up of disorders of sexual differentiation.

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“…Synthesis of steroid hormones, using cholesterol as starting material, requires several enzymes ( Fig. 1) (Benkert et al, 2015;Lundqvist et al, 2010). The first step of this synthesis forms pregnenolone, which is then metabolized into various types of hormones via different pathways.…”

Section: Introductionmentioning

confidence: 99%

Expression and regulation of CYP17A1 and 3β-hydroxysteroid dehydrogenase in cells of the nervous system: Potential effects of vitamin D on brain steroidogenesis

Emanuelsson

Almokhtar

Wikvall

et al. 2018

Neurochemistry International

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Steroids are reported to have diverse functions in the nervous system. Enzymatic production of steroid hormones has been reported in different cell types, including astrocytes and neurons. However, the information on some of the steroidogenic enzymes involved is insufficient in many respects. Contradictory results have been reported concerning the relative importance of different cell types in the nervous system for expression of CYP17A1 and 3β-hydroxysteroid dehydrogenase (3β-HSD). 3β-HSD is important in all basic steroidogenic pathways and CYP17A1 is required to form sex hormones. In the current investigation we studied the expression of these enzymes in cultured primary rat astrocytes, in neuron-enriched cells from rat cerebral cortex and in human neuroblastoma SH-SY5Y cells, a cell line often used as an in vitro model of neuronal function and differentiation. As part of this study we also examined potential effects on CYP17A1 and 3β-HSD by vitamin D, a compound previously shown to have regulatory effects in steroid hormone-producing cells outside the brain. The results of our study indicate that astrocytes are a major site for expression of 3β-HSD whereas expression of CYP17A1 is found in both astrocytes and neurons. The current data suggest that neurons, contrary to some previous reports, are not involved in 3β-HSD reactions. Previous studies have shown that vitamin D can influence gene expression and hormone production by steroidogenic enzymes in some cells. We found that vitamin D suppressed CYP17A1-mediated activity by 20% in SH-SY5Ycells and astrocytes. Suppression of CYP17A1 mRNA levels was considerably stronger, about 50% in SH-SY5Y cells and 75% in astrocytes. In astrocytes 3β-HSD was also suppressed by vitamin D, about 20% at the enzyme activity level and 60% at the mRNA level. These data suggest that vitamin D-mediated regulation of CYP17A1 and 3β-HSD, particularly on the transcriptional level, may play a role in the nervous system.

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Severe Salt-Losing 3β-Hydroxysteroid Dehydrogenase Deficiency: Treatment and Outcomes ofHSD3B2c.35G>A Homozygotes

Cited by 30 publications

References 44 publications

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

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

Adrenarche unmasks compound heterozygous 3β-hydroxysteroid dehydrogenase deficiency: c.244G>A (p.Ala82Thr) and the novel 931C>T (p.Gln311*) variant in a non-salt wasting, severely undervirilised 46XY

Expression and regulation of CYP17A1 and 3β-hydroxysteroid dehydrogenase in cells of the nervous system: Potential effects of vitamin D on brain steroidogenesis

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