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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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Context: Massively parallel sequencing (MPS) technologies have emerged as a first-tier approach for diagnosing several pediatric genetic syndromes. However, MPS has not been systematically integrated into the diagnostic workflow along with clinical/biochemical data for diagnosing 46,XY differences of sex development (DSD). Objective: To analyze the contribution of phenotypic classification either alone or in association with genetic evaluations, mainly MPS, for diagnosing a large cohort of 46,XY DSD patients. Design/patients: 209 nonsyndromic 46,XY DSD index cases from a Brazilian DSD center were included. Patients were initially classified into 3 subgroups according to clinical and biochemical data: gonadal dysgenesis (GD), disorders of androgen secretion/action, and DSD of unknown etiology. Molecular genetic studies were performed by Sanger sequencing and/or MPS. Results: Clinical/biochemical classification into either GD or disorders of hormone secretion/action was obtained in 68.4% of the index cases. Among these, a molecular diagnosis was obtained in 36% and 96.5%, respectively. For the remainder 31.6% classified as DSD of clinically unknown etiology, a molecular diagnosis was achieved in 31.8%. Overall, the molecular diagnosis was achieved in 59.3% of the cohort. The combination of clinical/biochemical and molecular approaches diagnosed 78.9% of the patients. Clinical/biochemical classification matched with the genetic diagnosis in all except 1 case. DHX37 and NR5A1 variants were the most frequent genetic causes among patients with GD and DSD of clinical unknown etiology, respectively. Conclusions: The combination of clinical/biochemical with genetic approaches significantly improved the diagnosis of 46,XY DSD. MPS potentially decreases the complexity of the diagnostic workup as a first-line approach for diagnosing 46,XY DSD. [ABSTRACT FROM AUTHOR]

Introduction Hypophysitis is a chronic inflammation of the pituitary gland of complex and still incompletely defined pathogenesis. It belongs to the group of non-hormone-secreting sellar masses, sharing with them comparable clinical presentation and radiographic appearance. Objectives Describe the case of immunoglobulin G4 (IgG4)related hypophysitis presenting as a mass in the sphenoid sinus. Resumed Report A 40-year-old Brazilian man had a diagnosis of central diabetes insipidus since 2001 associated with pituitary insufficiency. Pituitary magnetic resonance imaging revealed a centered pituitary stalk with focal nodular thickening and the presence of heterogeneous materials inside the sphenoid sinus. The patient was treated with testosterone replacement therapy. Laboratory results revealed increased IgG4 serum. Conclusion IgG4-related hypophysitis should be considered in patients with pituitary insufficiency associated with sellar mass and/or thickened pituitary stalk. IgG4 serum measurement for early diagnosis of IgG4-related hypophysitis should be performed. [ABSTRACT FROM AUTHOR]