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Most disorders of steroidogenesis, such as forms of congenital adrenal hyperplasia (CAH) are caused by mutations in genes encoding the steroidogenic enzymes and are often recognized clinically by cortisol deficiency, hyper- or hypo-androgenism, and/or altered mineralocorticoid function. Most steroidogenic enzymes are forms of cytochrome P450. Most P450s, including several steroidogenic enzymes, are microsomal, requiring electron donation by P450 oxidoreductase (POR); however, several steroidogenic enzymes are mitochondrial P450s, requiring electron donation via ferredoxin reductase (FDXR) and ferredoxin (FDX). POR deficiency is a rare but well-described form of CAH characterized by impaired activity of 21-hydroxylase (P450c21, CYP21A2) and 17-hydroxylase/17,20-lyase (P450c17, CYP17A1); more severely affected individuals also have the Antley-Bixler skeletal malformation syndrome and disordered genital development in both sexes, and hence is easily recognized. The 17,20-lyase activity of P450c17 requires both POR and cytochrome b5 (b5), which promote electron transfer. Mutations of POR, b5, or P450c17 can cause selective 17,20-lyase deficiency. In addition to providing electrons to mitochondrial P450s, FDX, and FDXR are required for the synthesis of iron-sulfur clusters, which are used by many enzymes. Recent work has identified FDXR mutations in patients with visual impairment, optic atrophy, neuropathic hearing loss, and developmental delay, resembling the global neurologic disorders seen with mitochondrial diseases. Many of these patients have had life-threatening events or deadly infections, often without an apparent triggering event. Adrenal insufficiency has been predicted in such individuals but has only been documented recently. Neurologists, neonatologists, and geneticists should seek endocrine assistance in evaluating and treating patients with mutations in FDXR. [ABSTRACT FROM AUTHOR]

Context Steroidogenic factor 1 (NR5A1 /SF-1) is a nuclear receptor that regulates sex development, steroidogenesis, and reproduction. Genetic variants in NR5A1 /SF-1 are common among differences of sex development (DSD) and associate with a wide range of phenotypes, but their pathogenic mechanisms remain unclear. Objective Novel, likely disease-causing NR5A1 /SF-1 variants from the SF1next cohort of individuals with DSD were characterized to elucidate their pathogenic effect. Methods Different in silico tools were used to predict the impact of novel NR5A1 /SF-1 variants on protein function. An extensive literature review was conducted to compare and select the best functional studies for testing the pathogenic effect of the variants in a classic cell culture model. The missense NR5A1 /SF-1 variants were tested on the promoter luciferase reporter vector -152CYP11A1 _pGL3 in HEK293T cells and assessed for their cytoplasmic/nuclear localization by Western blot. Results Thirty-five novel NR5A1 /SF-1 variants were identified in the SF1next cohort. Seventeen missense NR5A1 /SF-1 variants were functionally tested. Transactivation assays showed reduced activity for 40% of the variants located in the DNA binding domain and variable activity for variants located elsewhere. Translocation assessment revealed 3 variants (3/17) with affected nuclear translocation. No clear genotype-phenotype, structure-function correlation was found. Conclusion Genetic analyses and functional assays do not explain the observed wide phenotype of individuals with these novel NR5A1 /SF-1 variants. In 9 individuals, additional likely disease-causing variants in other genes were found, strengthening the hypothesis that the broad phenotype of DSD associated with NR5A1 /SF-1 variants may be caused by an oligogenic mechanism. [ABSTRACT FROM AUTHOR]

3β-Hydroxysteroid dehydrogenase 2 deficiency (3βHSD2D) is a rare form of congenital adrenal hyperplasia (CAH) with variable clinical presentation. We describe a 46, XY child with ambiguous genitalia and CAH without apparent adrenal insufficiency due to 2 novel heterozygous variants in the HSD3B2 gene (c.779C > T/p.Pro260Leu and c.307 + 1G > A/p.Gly103Asp,fs29X). The disease-causing effect of the novel variants was assessed by genetic and functional studies informing on positive genotype-phenotype correlation. Sex registration was female, and no gender dysphoria has been noted until the present age of 7 years, but psychological assessments have been difficult with a concomitant diagnosis of autism spectrum disorder. Virilization that already progresses prepubertally through peripheral conversion of androgen precursors by 3β-hydroxysteroid dehydrogenase 1 will pose an increasing challenge during puberty. [ABSTRACT FROM AUTHOR]

Background Steroidogenic Factor 1/Nuclear Receptor Subfamily 5 Group A Member 1 (SF-1/ NR5A1) is critical for the development and function of sex organs, influencing steroidogenesis and reproduction. While rare deleterious NR5A1 /SF-1 variants have been identified in individuals with various differences of sex development (DSD), primary ovarian insufficiency, and infertility, their impact on the general population remains unclear. Methods We analyzed health records and exome sequencing data from up to 420 162 individuals (227 858 women) from the UK Biobank study to assess the impact of rare (frequency < 0.1%) predicted deleterious NR5A1 /SF-1 variants on age at menopause and 26 other traits. Results No carriers of rare protein truncating variants in NR5A1 /SF-1 were identified. We found that the previously reported association of rare deleterious missense NR5A1 /SF-1 variants with earlier age at menopause is driven by variants in the DNA binding domain (DBD) and ligand binding domain (LBD) (combined test: beta = −2.36 years/allele, [95% CI: 3.21, −1.51], N = 107 carriers, P = 4.6 × 10−8). Carriers also had a higher risk of adult obesity (OR = 1.061, [95% CI: 1.003, 1.104], N = 344, P =.015), particularly among women (OR = 1.095 [95% CI: 1.034, 1.163, P = 3.87 × 10−3], N = 176), but not men (OR = 1.019, [95% CI: 0.955, 1.088], P =.57, N = 168). Conclusion Deleterious missense variants in the DBD and LBD likely disrupt NR5A1 /SF-1 function. This study broadens the relevance of deleterious NR5A1 /SF-1 variants beyond rare DSDs, suggesting the need for extended phenotyping and monitoring of affected individuals. [ABSTRACT FROM AUTHOR]

Steroidogenic factor 1 (SF-1) is a nuclear receptor that regulates steroidogenesis and reproductive development. NR5A1/SF-1 variants are associated with a broad spectrum of phenotypes across individuals with disorders of sex development (DSDs). Oligogenic inheritance has been suggested as an explanation. SF-1 interacts with numerous partners. Here, we investigated a constellation of gene variants identified in a 46,XY severely undervirilized individual carrying an ACMG-categorized 'pathogenic' NR5A1/SF-1 variant in comparison to the healthy carrier father. Candidate genes were revealed by whole exome sequencing, and pathogenicity was predicted by different in silico tools. We found variants in NR1H2 and INHA associated with steroidogenesis, sex development, and reproduction. The identified variants were tested in cell models. Novel SF-1 and NR1H2 binding sites in the AR and INHA gene promoters were found. Transactivation studies showed that wild-type NR5A1/SF-1 regulates INHA and AR gene expression, while the NR5A1/SF-1 variant had decreased transcriptional activity. NR1H2 was found to regulate AR gene transcription; however, the NR1H2 variant showed normal activity. This study expands the NR5A1/SF-1 network of interacting partners, while not solving the exact interplay of different variants that might be involved in revealing the observed DSD phenotype. It also illustrates that understanding complex genetics in DSDs is challenging. [ABSTRACT FROM AUTHOR]

Biallelic variants of steroidogenic acute regulatory protein (STAR/STARD1) may cause primary adrenal insufficiency and 46,XY disorder of sex development. STAR plays a pivotal role in transporting cholesterol into mitochondria where cholesterol serves as an essential substrate for initiating steroid biosynthesis by its conversion to pregnenolone. Generally, loss-of-function mutations of STAR cause the classic form of lipoid congenital adrenal hyperplasia (LCAH) where steroidogenesis of the adrenal cortex and the gonads is severely affected. By contrast, partial activity of STAR causes a less severe phenotype, the non-classic LCAH, which is characterized by later onset and initial manifestation with isolated adrenal insufficiency only. Disease-causing STAR variants are very rare. Numerous variants of all types have been described worldwide. Prevailing variants have been reported from Japan and Korea and in some population clusters where STAR is more common. Genotype–phenotype correlation is pretty good for STAR variants. While the exact mechanisms of cholesterol transport into mitochondria for steroidogenesis are still under investigation, the important role of STAR in this process is evident by inactivating STAR variants causing LCAH. The mechanism of disease with STAR deficiency is best described by a two-hit model: the first hit relates to impaired cholesterol import into mitochondria and thus lack of substrate for all steroid hormone biosynthesis; the second hit then relates to massive cytoplasmic lipid overload (evidenced by typically enlarged and fatty adrenal glands) leading to cell death and organ destruction. This review summarizes phenotype and genotype characteristics of human STAR variants found through the ClinVar database. [ABSTRACT FROM AUTHOR]

Objective Adrenal cortisol production occurs through a biosynthetic pathway which depend on NADH and NADPH for energy supply. The mitochondrial respiratory chain and the reactive oxygen species (ROS) detoxification system are therefore important for steroidogenesis. Mitochondrial dysfunction leading to oxidative stress has been implicated in the pathogenesis of several adrenal conditions. Nonetheless, only very few patients with variants in one gene of the ROS detoxification system, Thioredoxin Reductase 2 (TXNRD2), have been described with variable phenotypes. Design Clinical, genetic, structural, and functional characterization of a novel, biallelic TXNRD2 splice variant. Methods On human biomaterial, we performed whole exome sequencing to identify and RNA analysis to characterize the specific TXNRD2 splice variant. Amino acid conservation analysis and protein structure modeling were performed in silico. Using patient's fibroblast-derived human induced pluripotent stem cells, we generated adrenal-like cells (iALC) to study the impact of wild-type (WT) and mutant TXNRD2 on adrenal steroidogenesis and ROS production. Results The patient had a complex phenotype of primary adrenal insufficiency (PAI), combined with genital, ophthalmological, and neurological features. He carried a homozygous splice variant c.1348-1G > T in TXNRD2 which leads to a shorter protein lacking the C-terminus and thereby affecting homodimerization and flavin adenine dinucleotide binding. Patient-derived iALC showed a loss of cortisol production with overall diminished adrenal steroidogenesis, while ROS production was significantly increased. Conclusion Lack of TXNRD2 activity for mitochondrial ROS detoxification affects adrenal steroidogenesis and predominantly cortisol production. [ABSTRACT FROM AUTHOR]

Context Small birth size and increased postnatal growth have been associated with earlier timing of adrenarche and puberty, but it is not well known whether these factors alone or together lead to earlier maturation. Objective This work aimed to search for different growth trajectories using a clustering approach to analyze the effects of birth size and postnatal growth on adrenarchal and pubertal development. Methods Altogether 351 children (48% girls) were examined prospectively at ages 6 to 9 and 9 to 11 years. Birth and early-growth data were collected retrospectively. Main outcome measures included clinical signs of adrenarche and puberty, and serum androgen concentrations (dehydroepiandrosterone, dehydroepiandrosterone sulfate, androstenedione, testosterone). Results We detected 4 clusters with different birth sizes and postnatal growth trajectories: 1) children with average birth size and increased postnatal growth (AI), 2) children with small birth size and increased postnatal growth (SI), 3) children with average birth size and postnatal growth (AA), and 4) children with small birth size and average postnatal growth (SA). Thelarche at age 9 to 11 was most common and serum androgens at ages 6 to 9 and 9 to 11 years were highest in girls belonging to the AI and SI groups. Similar patterns in the onset of puberty and in androgen levels were not seen in the SA group. Conclusion Increased early growth and weight gain predict higher serum androgen concentrations and earlier onset of puberty in girls. Adrenarche and puberty do not appear to be shifted earlier in children with small birth size who do not have catch-up growth. [ABSTRACT FROM AUTHOR]

This document is a response to a letter from Dr. Menno Hoekstra regarding a study titled "Adrenal Abcg1 Controls Cholesterol Flux and Steroidogenesis" published in the journal Endocrinology. The authors of the response address discrepancies between their findings and Dr. Hoekstra's previous research on the same topic. They suggest that further investigation is needed to understand the reasons for these discrepancies, including the impact of systemic vs adrenal-specific deletion of Abcg1, the effects of Abcg1 deletion on adrenal cortex function and development, and the degree of Abcg1 recombination. The authors also address concerns raised by Dr. Hoekstra about the suitability of the aldosterone synthase-regulated Cre system used in their experiments. They express gratitude for the opportunity to clarify their findings and encourage further collaborative research in this area. [Extracted from the article]