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INTRODUCTION: Hydrocolpos, a rare condition characterized by cystic dilatation of the vagina, can arise from various etiologies, including isolated imperforate hymen and vaginal atresia. Genetic conditions, such as Bardet-Biedl syndrome (BBS), may also manifest with hydrocolpos as part of urogenital malformations. METHODS: We present a case of neonatal hydrocolpos associated with BBS. Sequencing of 19 BBS genes was performed to elucidate the genetic basis of the syndrome. RESULTS: Genetic analysis revealed a novel frameshift indel variant (c.1546_1547insGATA p.Thr516Argfs*7) in the BBS10 gene. This finding expands the spectrum of BBS mutations and underscores the importance of genetic evaluation in patients with hydrocolpos, particularly when associated with additional clinical features suggestive of syndromic etiology. CONCLUSION: Pediatric urologists should maintain a high index of suspicion for underlying genetic conditions, including BBS, in neonates presenting with hydrocolpos, given the potential for more severe associated complications such as renal and retinal diseases, obesity, and polydactyly.

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BACKGROUND: Androgen insensitivity syndrome (AIS) is a common condition among individuals with differences of sexual development (DSD) and results from germline allelic variants in the androgen receptor (AR) gene. Understanding the phenotypic consequences of AR allelic variants that disrupt the activation function 2 (AF2) region is essential to grasping its clinical significance. OBJECTIVES: This study aims to provide insights into the phenotypic characteristics and clinical impact of AR mutations affecting the AF2 region in AIS patients. We achieve this by reviewing reported AR variants in the AF2 region among individuals with AIS, including identifying a new phenotype associated with the c.2138T>C variant (p.Leu713Pro) in the AR gene. MATERIALS AND METHODS: We comprehensively reviewed AR variants within the AF2 region reported in AIS and applied molecular dynamics simulations to assess the impact of the p.Leu713Pro variant on protein dynamics. RESULTS: Our review of reported AR variants in the AF2 region revealed a spectrum of phenotypic outcomes in AIS patients. Molecular dynamics simulations indicated that the p.Leu713Pro variant significantly alters the local dynamics of the AR protein and disrupts the correlation and covariance between variables. DISCUSSION: The diverse phenotypic presentations observed among individuals with AR variants in the AF2 region highlight the complexity of AIS. The altered protein dynamics resulting from the p.Leu713Pro variant further emphasize the importance of the AF2 region in AR function. CONCLUSION: Our study provides valuable insights into AR mutations' phenotypic characteristics and clinical impact on the AF2 region in AIS. Moreover, the disruption of protein dynamics underscores the significance of the AF2 region in AR function and its role in the pathogenesis of AIS.

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In mammals, the development of male or female gonads from fetal bipotential gonads depends on intricate genetic networks. Changes in dosage or temporal expression of sex-determining genes can lead to differences of gonadal development. Two rare conditions are associated with disruptions in ovarian determination, including 46,XX testicular differences in sex development (DSD), in which the 46,XX gonads differentiate into testes, and 46,XX ovotesticular DSD, characterized by the coexistence of ovarian and testicular tissue in the same individual. Several mechanisms have been identified that may contribute to the development of testicular tissue in XX gonads. This includes translocation of SRY to the X chromosome or an autosome. In the absence of SRY, other genes associated with testis development may be overexpressed or there may be a reduction in the activity of pro-ovarian/antitesticular factors. However, it is important to note that a significant number of patients with these DSD conditions have not yet recognized a genetic diagnosis. This finding suggests that there are additional genetic pathways or epigenetic mechanisms that have yet to be identified. The text will provide an overview of the current understanding of the genetic factors contributing to 46,XX DSD, specifically focusing on testicular and ovotesticular DSD conditions. It will summarize the existing knowledge regarding the genetic causes of these differences. Furthermore, it will explore the potential involvement of other factors, such as epigenetic mechanisms, in developing these conditions.

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Context: Genetic analysis of sporadic medullary thyroid carcinoma (MTC) has revealed somatic variants in RET, RAS, and occasionally other genes. However, around 20% of patients with sporadic MTC lack a known genetic driver. Objective: To uncover potential new somatic or germline drivers, we analyze a distinct cohort of patients with sporadic, very early-onset, and aggressive MTC. Methods: Germline and somatic DNA exome sequencing was performed in 19 patients, previously tested negative for germline RET variants. Results: Exome sequencing of 19 germline samples confirmed the absence of RET and identified an NF1 pathogenic variant in 1 patient. Somatic sequencing was successful in 15 tumors revealing RET variants in 80%, predominantly p.Met918Thr, which was associated with disease aggressiveness. In RET-negative tumors, pathogenic variants were found in HRAS and NF1. The NF1 germline and somatic variants were observed in a patient without a prior clinical diagnosis of neurofibromatosis type 1, demonstrating that the loss of heterozygosity of NF1 functions as a potential MTC driver. Somatic copy number alterations analysis revealed chromosomal alterations in 53.3% of tumors, predominantly in RET-positive cases, with losses in chromosomes 9 and 22 being the most prevalent. Conclusion: This study reveals that within a cohort of early-onset nonhereditary MTC, RET remains the major driver gene. In RET-negative tumors, NF1 and RAS are drivers of sporadic MTC. In addition, in young patients without a RET germline mutation, a careful clinical evaluation with a consideration of germline NF1 gene analysis is ideal to exclude Neurofibromatosis type 1 (NF1).

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PURPOSE: This study aims to analyze the trends in mortality rates from penile cancer (PeC) and the treatment modalities adopted in Brazil over recent years. MATERIALS AND METHODS: Death records for PeC cases (International Classification of Diseases, version 10 C60) and treatment modalities were extracted from the DATASUS database. A joinpoint regression analysis was conducted to examine the data. RESULTS: A total of 7,848 deaths due to PeC were recorded in Brazil between 1996 and 2020. Increasing mortality trends were observed, with an average annual percentage change (AAPC) of 0.91 (0.6-1.2; P < .001). The North and Northeast regions had the highest age-standardized mortality rates (ASMRs) and AAPCs. From 2008 to 2020, the ASMR in the Northeast region remained stable, whereas the North region surpassed it. The Southeast region exhibited a significant downward trend, with an AAPC of -0.91 (-1.3 to -0.5; P < .001). Penile biopsies declined and were more frequent in the southeastern region. A total of 8,498 penile amputations were performed, with 39.4% and 29.1% conducted in the Southeast and Northeast regions, respectively. CONCLUSION: Brazil has experienced increasing mortality trends in PeC over the past 2 decades. Low schooling, married, and young men from the North or Northeast regions represent the majority of deaths. Urgent efforts are needed to enhance the diagnosis and treatment of PeC to prevent and reduce mortality rates in the country.

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BACKGROUND: Right ventricular (RV) dysfunction is the main cause of death in patients with normotensive acute pulmonary embolism (PE). The optimal management for this subset of patients remains uncertain. This systematic review and meta-analysis focused on the comparison of diuretics and fluid expansion in patients with acute PE presenting with RV dysfunction and haemodynamic stability. METHODS: A systematic review was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines considering only RTCs. The authors searched the traditional and grey literature through 1 November 2022. Meta-analysis used open source packages in R. Inverse variance fixed-effects models with OR as the effect measure were used for primary analyses. The main outcomes defined in this review protocol included pulmonary arterial systolic pressure (PASP), creatinine value changes and N-terminal pro-B-type natriuretic peptide during the first 24 hours. RESULTS: Four studies with a total of 452 patients met the inclusion criteria. The baseline characteristics of patients were similar across all studies. Overall, patients receiving diuretics had a significant 24 hours reduction in pro-B-type natriuretic peptide (standard mean difference of -41.97; 95% CI -65.79 to -18.15), and PASP (standard mean difference of -5.96; 95% CI -8.06 to -3.86). This group had significantly higher creatinine levels (standard mean difference of 7.74; 95% CI 5.04 to 10.45). The quality of the studies was heterogeneous; two had a low risk of bias, and the other two had a high risk of bias. CONCLUSIONS: Very few studies have compared the efficacy and safety of diuretics and fluid expansion in normotensive patients with acute PE with RV failure. Overall, furosemide appears to reduce RV dysfunction in this subset of patients compared with fluid expansion. Further research is required to confirm these findings.

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Water availability is a limiting factor for the cultivation of sour passion fruit. Soil management techniques and the use of water-retaining polymers can increase soil water retention, reducing the frequency of irrigation in the crop. In this context, the objective of the research was to evaluate the gas exchange, the chlorophyll index, and the yield of the sour passion fruit cv. BRS GA1 as a function of irrigation depths, pit volumes, and doses of water-retaining polymer. The experiment was carried out in randomized blocks, in plots subdivided in a 2 × (2 × 5) arrangement, with irrigation depths of 70 and 100% of the crop evapotranspiration (ETc) as the main plot, the subplots with the volumes of pit of 64 and 128 dm3, and doses of the water-retaining polymer of 0, 0.5, 1.0, 1.5, and 2.0 g dm-3. The interaction of irrigation depths × pit volumes × doses of water-retaining polymer influences chlorophyll indexes, gas exchange, and water productivity, with positive impacts on yield of the sour passion fruit. The water depth of 70% of ETc increased the yield of sour passion fruit, in pits of 64 dm3. The application of doses of up to 1.1 g dm-3 of the water-retaining polymer and irrigation with water of 70% of ETc is recommended, and a dose of 2.0 g dm-3 of the water-retaining polymer in a pit volume of 128 dm3, associated with an irrigation depth of 100% ETc causes stress in sour passion fruit plants due to excess water.

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BACKGROUND: The incidence of spontaneous intracerebral hemorrhage (SICH) is highest in very old elderlies (≥75 years). The increasing use of antithrombotic drugs is shifting the epidemiology of SICH towards predominance of lobar subtype, suggesting an incremented propensity of bleeding associated with underlying cerebral amyloid angiopathy. With population aging and antithrombotic use, a parallel raise of proportion of lobar SICH is occurring. Improvement of prognostication in this specific age group and SICH type is needed. Routine blood biomarkers can contribute to prediction of short-term mortality after SICH. OBJECTIVE: Our aim was to investigate the contribution of routine blood biomarkers for short-term mortality (30-days) in elderly patients with lobar SICH. METHODS: Retrospective analysis of consecutive 130 patients with ≥ 75 years and lobar SICH. The outcome was 30-day mortality. Logistic regression analysis was used to investigate whether admission routine biomarkers can be used as predictors. RESULTS: The case fatality was 40.8%. Admission glycaemia level, neutrophil to lymphocyte ratio and mean platelet volume were significantly different between groups (p = 0.001, p = 0.024, p = 0.038, respectively). There was no significant difference in all other routine biomarkers. On multivariate analysis, admission higher mean BG level (odds ratio [OR]: 1.010, 95% confidence interval [CI]: 1.001-1.019, p = 0.026) and neutrophil to lymphocyte ratio (OR: 1.070, 95% CI: 1.008-1.136, p = 0.027) emerged as predictors. CONCLUSION: In very old patients with lobar SICH, higher BG level and neutrophil to lymphocyte ratio are associated with increased risk of short-term death.

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CONTEXT: Despite high abundance of small indels in human genomes, their precise roles and underlying mechanisms of mutagenesis in Mendelian disorders require further investigation. OBJECTIVE: To profile the distribution, functional implications, and mechanisms of small indels in the androgen receptor (AR) gene in individuals with androgen insensitivity syndrome (AIS). METHODS: We conducted a systematic review of previously reported indels within the coding region of the AR gene, including 3 novel indels. Distribution throughout the AR coding region was examined and compared with genomic population data. Additionally, we assessed their impact on the AIS phenotype and investigated potential mechanisms driving their occurrence. RESULTS: A total of 82 indels in AIS were included. Notably, all frameshift indels exhibited complete AIS. The distribution of indels across the AR gene showed a predominance in the N-terminal domain, most leading to frameshift mutations. Small deletions accounted for 59.7%. Most indels occurred in nonrepetitive sequences, with 15.8% situated within triplet regions. Gene burden analysis demonstrated significant enrichment of frameshift indels in AIS compared with controls (P < .00001), and deletions were overrepresented in AIS (P < .00001). CONCLUSION: Our findings underscore a robust genotype-phenotype relationship regarding small indels in the AR gene in AIS, with a vast majority presenting complete AIS. Triplet regions and homopolymeric runs emerged as prone loci for small indels within the AR. Most were frameshift indels, with polymerase slippage potentially explaining half of AR indel occurrences. Complex frameshift indels exhibited association with palindromic runs. These discoveries advance understanding of the genetic basis of AIS and shed light on potential mechanisms underlying pathogenic small indel events.

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BACKGROUND: Cytogenomic methods have gained space in the clinical investigation of patients with disorders/differences in sexual development (DSD). Here we evaluated the role of the SNP array in achieving a molecular diagnosis in Brazilian patients with syndromic DSD of unknown etiology. METHODS: Twenty-two patients with DSD and syndromic features were included in the study and underwent SNP-array analysis. RESULTS: In two patients, the diagnosis of 46,XX SRY + DSD was established. Additionally, two deletions were revealed (3q29 and Xp22.33), justifying the syndromic phenotype in these patients. Two pathogenic CNVs, a 10q25.3-q26.2 and a 13q33.1 deletion encompassing the FGFR2 and the EFNB2 gene, were associated with genital atypia and syndromic characteristics in two patients with 46,XY DSD. In a third 46,XY DSD patient, we identified a duplication in the 14q11.2-q12 region of 6.5 Mb associated with a deletion in the 21p11.2-q21.3 region of 12.7 Mb. In a 46,XY DSD patient with delayed neuropsychomotor development and congenital cataracts, a 12 Kb deletion on chromosome 10 was found, partially clarifying the syndromic phenotype, but not the genital atypia. CONCLUSIONS: The SNP array is a useful tool for DSD patients, identifying the molecular etiology in 40% (2/5) of patients with 46,XX DSD and 17.6% (3/17) of patients with 46,XY DSD.

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INTRODUCTION: Glycemic control is important to avoid diabetes complications in individuals with cancer. There is no evidence for HbA1c and fructosamine as reliable biomarkers in these conditions. There are particularities in caring for patients with diabetes and cancer that can alter these biomarkers. OBJECTIVE: The aim of this study was to evaluate HbA1c and fructosamine as glycemic biomarkers in people with type 2 diabetes and cancer, undergoing clinical or surgical oncological treatment. METHODS: The authors conducted a single-center, retrospective analysis with people who have cancer and diabetes. Comparison of glycemic biomarkers (HbA1c, fructosamine, and Self-Monitoring of Blood Glucose [SMBG]) was performed including evaluation in individuals undergoing chemotherapy, using glucocorticoids, with anemia, hypoproteinemia or with reduced estimated Glomerular Filtration Rate (eGFR). RESULTS: There was a strong positive correlation between fructosamine and HbA1c (n = 318, r = 0.66, p < 0.001) in people with diabetes and cancer even in those under chemotherapy (n = 101, r = 0.61, p < 0.001) or using glucocorticoids (n = 96, r = 0.67, p<0.001). There was a strong correlation between HbA1c and fructosamine in subjects with anemia (n = 111, r = 0.66, p < 0.001), hypoproteinemia (n = 54, r = 0.67, p < 0.001), or with eGFR ≥ 60 mL/min/1.73 m2 (n = 189, r = 0.70, p < 0.001), and moderate correlation with hypoalbuminemia (n = 21, r = 0.54, p = 0.001) and with reduced eGFR (n = 67, r = 0.57, p < 0.001). The correlations between fructosamine and HbA1c with SMBG were moderate (n = 164, r = 0.49, p < 0.001; n = 111, r = 0.55, p < 0.001, respectively), strong in subjects undergoing chemotherapy, with hypoalbuminemia or hypoproteinemia, and at least moderate, if eGFR < 60 mL/min/1.73 m2 or with anemia. CONCLUSIONS: Fructosamine and HbA1c can be used as glycemic biomarkers in people with diabetes and cancer, even in those with anemia, hypoproteinemia, or undergoing chemotherapy.

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The origin of the diffuse gamma-ray background (DGRB), the one that remains after subtracting all individual sources from observed gamma-ray sky, is unknown. The DGRB possibly encompasses contributions from different source populations such as star-forming galaxies, starburst galaxies, active galactic nuclei, gamma-ray bursts, or galaxy clusters. Here, we combine cosmological magnetohydrodynamical simulations of clusters of galaxies with the propagation of cosmic rays (CRs) using Monte Carlo simulations, in the redshift range z ≤ 5.0, and show that the integrated gamma-ray flux from clusters can contribute up to 100% of the DGRB flux observed by Fermi-LAT above 100 GeV, for CRs spectral indices α = 1.5 - 2.5 and energy cutoffs [Formula: see text] eV. The flux is dominated by clusters with masses 1013 ≲ M/M⊙ ≲ 1015 and redshift z ≲ 0.3. Our results also predict the potential observation of high-energy gamma rays from clusters by experiments like the High Altitude Water Cherenkov (HAWC), the Large High Altitude Air Shower Observatory (LHAASO), and potentially the upcoming Cherenkov Telescope Array (CTA).

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OBJECTIVE: To analyze aspects of sexual life and fertility desire among 46, XY DSD people, including those who changed their gender. METHODS: It is a cross-sectional study including 127 adults (> 16 years of age) with 46, XY DSD (83 females; 44 males) from a Single Brazilian Tertiary-Care Medical Center. RESULTS: Sexual fantasies and masturbation were more frequent in 46, XY DSD males, whereas orgasm and sexual life satisfaction were similar in both genders. More 46, XY DSD men than women had a long-term romantic relationship. 46, XY DSD women with prenatal androgen exposure reported more fear of being romantically rejected. External genitalia appearance at birth did not impact the sexuality of 46, XY DSD women after surgical genital treatment had been completed. Overall, the sexual life was similar between 46, XY men assigned as males and those who changed to the male gender. Regarding sexual orientation, most self-reported as heterosexual (91% and 92% of women and men, respectively). The desire for fertility had a similar prevalence in both genders, but more women than men considered infertility a barrier to a long-term romantic relationship. Twelve individuals (7 males) had children; 10 out of 12 have adopted children. CONCLUSION: Fertility desire was shared among 46, XY DSD people, regardless of gender. Prenatal androgen exposure reduced the desire for motherhood in 46, XY women. 46, XY DSD people who changed from female to male gender presented similar sexual parameters as those assigned as males. Among females, virilized genitalia at birth did not affect sexuality once the surgical treatment is completed.

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CONTEXT: Invasive and somatostatin receptor ligand (SRL)-resistant pituitary tumors represent a challenge in the clinical practice of endocrinologists. Efforts have been made to elucidate reliable makers for both. Survivin and eukaryotic translation initiation factor-binding protein 1 (4EBP1) are upregulated in several cancers and involved in apoptosis and cell proliferation. OBJECTIVE: We explored the role of these markers in somatotropinomas. METHODS: Immunostains for survivin and 4EBP1, and also for somatostatin receptor type 2 (SSTR2), Ki-67, and cytokeratin 18, were analyzed in tissue microarrays containing 52 somatotropinoma samples. Tumor invasiveness was evaluated in all samples while drug resistance was evaluated in 34 patients who received SRL treatment. All these parameters were correlated with first-generation SRL (fg-SRL) responsiveness and tumor invasiveness. RESULTS: Low survivin expression (P = 0.04), hyperintense signal on T2 weighted image (T2WI) (P = 0.01), younger age (P = 0.01), sparsely granular adenomas (SGA) (P = 0.04), high postoperative growth hormone (GH) and insulin-like growth factor-1 (IGF-1) levels (P = 0.049 and P < 0.001, respectively), and large postoperative tumor size (P = 0.02) were associated with resistance to fg-SRL. Low survivin and SSTR2 expression and high 4EBP1 expression were associated with SGA (P = 0.04, P = 0.01, and P = 0.001, respectively). Younger age (P = 0.03), large tumor pre- and postoperative (P = 0.04 and P = 0.006, respectively), low SSTR2 expression (P = 0.03), and high baseline GH and IGF-1 (P = 0.01 and P = 0.02, respectively) were associated with tumor invasiveness. However, survivin, 4EBP1, Ki-67, and granulation patterns were not associated with tumor invasion. CONCLUSION: This study suggests that low survivin expression is predictive of resistance to fg-SRL in somatotropinomas, but not of tumor invasiveness.

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Abstract Objective: To analyze aspects of sexual life and fertility desire among 46, XY DSD people, including those who changed their gender. Methods: It is a cross-sectional study including 127 adults (> 16 years of age) with 46, XY DSD (83 females; 44 males) from a Single Brazilian Tertiary-Care Medical Center. Results: Sexual fantasies and masturbation were more frequent in 46, XY DSD males, whereas orgasm and sexual life satisfaction were similar in both genders. More 46, XY DSD men than women had a long-term romantic relationship. 46, XY DSD women with prenatal androgen exposure reported more fear of being romantically rejected. External genitalia appearance at birth did not impact the sexuality of 46, XY DSD women after surgical genital treatment had been completed. Overall, the sexual life was similar between 46, XY men assigned as males and those who changed to the male gender. Regarding sexual orientation, most self-reported as heterosexual (91% and 92% of women and men, respectively). The desire for fertility had a similar prevalence in both genders, but more women than men considered infertility a barrier to a long-term romantic relationship. Twelve individuals (7 males) had children; 10 out of 12 have adopted children. Conclusion: Fertility desire was shared among 46, XY DSD people, regardless of gender. Prenatal androgen exposure reduced the desire for motherhood in 46, XY women. 46, XY DSD people who changed from female to male gender presented similar sexual parameters as those assigned as males. Among females, virilized genitalia at birth did not affect sexuality once the surgical treatment is completed.

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Abstract Introduction Glycemic control is important to avoid diabetes complications in individuals with cancer. There is no evidence for HbA1c and fructosamine as reliable biomarkers in these conditions. There are particularities in caring for patients with diabetes and cancer that can alter these biomarkers. Objective The aim of this study was to evaluate HbA1c and fructosamine as glycemic biomarkers in people with type 2 diabetes and cancer, undergoing clinical or surgical oncological treatment. Methods The authors conducted a single-center, retrospective analysis with people who have cancer and diabetes. Comparison of glycemic biomarkers (HbA1c, fructosamine, and Self-Monitoring of Blood Glucose [SMBG]) was performed including evaluation in individuals undergoing chemotherapy, using glucocorticoids, with anemia, hypoproteinemia or with reduced estimated Glomerular Filtration Rate (eGFR). Results There was a strong positive correlation between fructosamine and HbA1c (n = 318, r= 0.66, p < 0.001) in people with diabetes and cancer even in those under chemotherapy (n = 101, r= 0.61, p < 0.001) or using glucocorticoids (n = 96, r= 0.67, p<0.001). There was a strong correlation between HbA1c and fructosamine in subjects with anemia (n = 111, r= 0.66, p < 0.001), hypoproteinemia (n = 54, r= 0.67, p < 0.001), or with eGFR ≥ 60 mL/min/1.73 m2 (n = 189, r= 0.70, p < 0.001), and moderate correlation with hypoalbuminemia (n = 21, r= 0.54, p = 0.001) and with reduced eGFR (n = 67, r= 0.57, p < 0.001). The correlations between fructosamine and HbA1c with SMBG were moderate (n = 164, r= 0.49, p < 0.001; n = 111, r= 0.55, p < 0.001, respectively), strong in subjects undergoing chemotherapy, with hypoalbuminemia or hypoproteinemia, and at least moderate, if eGFR < 60 mL/min/1.73 m2 or with anemia. Conclusions Fructosamine and HbA1c can be used as glycemic biomarkers in people with diabetes and cancer, even in those with anemia, hypoproteinemia, or undergoing chemotherapy.

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ABSTRACT Central adrenal insufficiency (CAI) is a life-threatening disorder. This occurs when ACTH production is insufficient, leading to low cortisol levels. Since corticosteroids are crucial to many metabolic responses under organic stress and inflammatory conditions, CAI recognition and prompt treatment are vital. However, the diagnosis of CAI is challenging. This is not only because its clinical presentation is usually oligosymptomatic, but also because the CAI laboratory investigation presents many pitfalls. Thus, the clarification of when to use each test could be helpful in many contexts. The CAI challenge is also involved in treatment: Several formulations of synthetic steroids exist, followed by the lack of a biomarker for glucocorticoid replacement. This review aims to access all available literature to synthesize important topics about who should investigate CAI, when it should be suspected, and how CAI must be treated.

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The 5α-reductase type 2 enzyme catalyzes the conversion of testosterone into dihydrotestosterone, playing a crucial role in male development. This enzyme is encoded by the SRD5A2 gene, which maps to chromosome 2 (2p23), consists of 5 exons and 4 introns, and encodes a 254 amino acid protein. Disruptions in this gene are the molecular etiology of a subgroup of differences of sex development (DSD) in 46,XY patients. Affected individuals present a large range of external genitalia undervirilization, ranging from almost typically female external genitalia to predominantly typically male external genitalia with minimal undervirilization, including isolated micropenis. This is an updated review of the implication of the SRD5A2 gene in 5α-reductase type 2 enzyme deficiency. For that, we identified 451 cases from 48 countries of this particular 46,XY DSD from the literature with reported variants in the SRD5A2 gene. Herein, we present the SRD5A2 mutational profile, the SRD5A2 polymorphisms, and the functional studies related to SRD5A2 variants to detail the molecular etiology of this condition.

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OBJECTIVE: Mild androgen insensitivity syndrome (MAIS) belongs to the androgen insensitivity syndrome (AIS) spectrum, an X-linked genetic disease that is the most common cause of differences in sex development. Unfortunately, AIS studies mainly focus on the partial and complete phenotypes, and the mild phenotype (MAIS) has been barely reported. Our purpose is to explore the MAIS facets, clinical features, and molecular aspects. METHODS: We collected all reported MAIS cases in the medical literature and presented them based on the phenotype and molecular diagnosis. RESULTS: We identified 49 different androgen receptor (AR) mutations in 69 individuals in the literature. We compared the AR mutations presented in individuals with MAIS with AR mutations previously reported in other AIS phenotypes (partial and complete) regarding the type, location, genotype-phenotype correlation, and functional studies. CONCLUSION: This review provides a landscape of the mild phenotype of AIS. Most patients with MAIS present with male factor infertility. Therefore, AR gene sequencing should be considered during male factor infertility investigation, even in males with typically male external genitalia. In addition, MAIS can be part of other medical conditions, such as X-linked spinal and bulbar muscular atrophy (Kennedy disease).

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Central adrenal insufficiency (CAI) is a life-threatening disorder. This occurs when ACTH production is insufficient, leading to low cortisol levels. Since corticosteroids are crucial to many metabolic responses under organic stress and inflammatory conditions, CAI recognition and prompt treatment are vital. However, the diagnosis of CAI is challenging. This is not only because its clinical presentation is usually oligosymptomatic, but also because the CAI laboratory investigation presents many pitfalls. Thus, the clarification of when to use each test could be helpful in many contexts. The CAI challenge is also involved in treatment: Several formulations of synthetic steroids exist, followed by the lack of a biomarker for glucocorticoid replacement. This review aims to access all available literature to synthesize important topics about who should investigate CAI, when it should be suspected, and how CAI must be treated.

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