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Male to female sex reversal has been observed in individuals with duplications of the short arm of the X chromosome. Here we demonstrate that sex reversal results from the presence of two active copies of an Xp locus rather than from its rearrangement and that alterations at this locus constitute one of the causes of sex reversal in individuals with a normal 46,XY karyotype. We have named this locus DSS (Dosage Sensitive Sex reversal) and localized it to a 160 kilobase region of chromosome Xp21, adjacent to the adrenal hypoplasia congenita locus. The identification of male individuals deleted for DSS suggests that this locus is not required for testis differentiation. We propose that DSS has a role in ovarian development and/or functions as a link between ovary and testis formation.

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OBJECTIVESome studies have highlighted psychological and neuropsychological difficulties and a potential reduction in health-related quality of life (HRQOL) in patients with pituitary tumors, despite hormone deficits or excess. To the authors’ knowledge, this study is the first prospective longitudinal case-control study with the aim of simultaneously testing whether HRQOL and psychiatric and neuropsychological disabilities are related to neural dysfunction due to hypercortisolism per se, or tumor mass and/or surgery in patients with Cushing’s disease (CD). The authors evaluated a homogeneous cohort of patients with CD and nonfunctioning pituitary adenomas (NFPAs) before and after neurosurgery and compared these patients with healthy controls.METHODSTwenty patients (10 with NFPA and 10 with CD) were evaluated using 3 validated questionnaires (SF-36, Beck Depression Inventory–II [BDI-II], and Minnesota Multiphasic Personality Inventory–II [MMPI-II]) to assess HRQOL and psychological status preoperatively and 12 months after neurosurgery. Neuropsychological tests were assessed preoperatively, 3–7 days postoperatively, and 12 months postoperatively. Twenty healthy matched controls were recruited.RESULTSPreoperatively, the NFPA and CD subgroups had worse HRQOL scores than controls on the basis of SF-36 scores, although the NFPA subgroup experienced significant recovery 12 months postoperatively. Preoperatively, CD patients had depressive symptoms according to the BDI-II and MMPI-II that persisted 12 months postoperatively, together with social introversion and hypochondriasis; NFPA patients were similar to controls except for hypochondriasis scores that were clinically significant at all timepoints. Preoperatively and 3–7 days postoperatively, both subgroups showed significant neuropsychological disabilities compared with controls, but only the CD subgroup did not completely recover over time.CONCLUSIONSHRQOL and neuropsychological impairments were observed in all patients at early timepoints, independent of hypercortisolism, tumor mass, and successful surgery. Over time, CD patients showed persistent changes in HRQOL, in particular in social activities. In this light, CD seems to have a strong impact on HRQOL and to be associated with more psychological and neuropsychological comorbidities than NFPA.

Context COVID-19 represents a global health emergency and infected patients with chronic diseases often present with a severe impairment. Adrenal insufficiency (AI) is supposed to be associated with an increased infection risk which could trigger an adrenal crisis. Objective Our primary aim was to evaluate the incidence of COVID-19 symptoms and complications in AI patients. Design and setting We conducted a retrospective case-control study. All patients were on active follow-up and lived in Lombardy, one of the most affected areas. Patients We enrolled 279 patients with primary and secondary AI and 112 controls (patients with benign pituitary lesions without hormonal alterations). All AI patients had been previously trained to modify their replacement therapy on stress doses. Intervention By administering a standardized questionnaire by phone, we collected data on COVID-19 suggestive symptoms and consequences. Results In February-April 2020, the prevalence of symptomatic patients (complaining at least one symptom of viral infection) was similar between the two groups (24% in AI and 22.3% in controls, p 0.79). Highly suggestive COVID-19 symptoms (at least two including fever and/or cough) also occurred equally in AI and controls (12.5% in both groups). No patient required hospitalization and no adrenal crisis was reported. Few nasopharyngeal swabs were performed (n=12) as indicated by sanitary regulations, limiting conclusions on the exact infection rate (two positive results in AI and none in controls, p 0.52). Conclusions AI patients who are adequately treated and trained, seem to display the same incidence of COVID-19 suggestive symptoms and disease severity as controls.

Inflammatory bowel diseases (IBDs) are characterized by a multifactorial partially unknown etiology that involves genetic, immunological and environmental factors. Up to 50% of IBD patients experience at least one extraintestinal manifestation; among them is the involvement of bone density which is referred to as metabolic bone disease (MBD), including osteopenia and osteoporosis. Bone alterations in IBDs population appear to have a multifactorial etiology: Decreased physical activity, inflammation-related bone resorption, multiple intestinal resections, dietary malabsorption of minerals and vitamin D deficiency, genetic factors, gut-bone immune signaling interaction, steroid treatment, microbiota and pathogenic micro-organisms interaction, and dietary malabsorption of minerals, that, all together or individually, may contribute to the alteration of bone mineral density. This review aims to summarize the prevalence and pathophysiology of metabolic bone alterations in IBD subjects outlining the main risk factors of bone fragility. We also want to underline the role of the screening and prophylaxis of bone alterations in Crohn’s disease and ulcerative colitis patients and the importance of treating appropriately MBD.

Cushing’s Disease (CD) is a rare condition characterized by an overproduction of ACTH by an ACTH-secreting pituitary tumor, resulting in an excess of cortisol release by the adrenal glands. Somatic mutations in the deubiquitinases USP8 and USP48, and in BRAF genes, have been reported in a subset of patients affected by CD. The aim of this study was to characterize the genetic profile of a cohort of 60 patients with ACTH-secreting tumors, searching for somatic mutations in USP8, USP48, and BRAF hotspot regions. Seven patients were found to carry USP8 somatic mutations in the well-characterized 14-3-3 protein binding motif (n = 5 P720R, n = 1 P720Q, n = 1 S718del); 2 patients were mutated in USP48 (M415I); no mutation was identified in BRAF. In addition, a novel USP8 variant, G664R, located in exon 14, upstream of the 14-3-3 protein binding motif, was identified in 1 patient. Functional characterization of USP8 G664R variant was performed in murine corticotroph tumor AtT-20 cells. Transient transfection with the USP8 G664R variant resulted in a significant increase of ACTH release and cell proliferation (+114.5 ± 53.6% and +28.3 ± 2.6% vs. empty vector transfected cells, p < 0.05, respectively). Notably, USP8 proteolytic cleavage was enhanced in AtT-20 cells transfected with G664R USP8 (1.86 ± 0.58–fold increase of N-terminal USP8 fragment, vs. WT USP8, p < 0.05). Surprisingly, in situ Proximity Ligation Assay (PLA) experiments showed a significant reduction of PLA positive spots, indicating USP8/14-3-3 proteins colocalization, in G664R USP8 transfected cells with respect to WT USP8 transfected cells (−47.9 ± 6.6%, vs. WT USP8, p < 0.001). No significant difference in terms of ACTH secretion, cell proliferation and USP8 proteolytic cleavage, and 14-3-3 proteins interaction was observed between G664R USP8 and S718del USP8 transfected cells. Immunofluorescence experiments showed that, contrary to S718del USP8 but similarly to WT USP8 and other USP8 mutants, G664R USP8 displays an exclusive cytoplasmic localization. In conclusion, somatic mutations were found in USP8 (13.3% vs. 36.5% incidence of all published mutations) and USP48 (3.3% vs. 13.3% incidence) hotspot regions. A novel USP8 variant was identified in a CD patient, and in vitro functional studies in AtT-20 cells suggested that this somatic variant might be clinically relevant in ACTH-secreting tumor pathogenesis, expanding the characterization of USP8 functional domains.

Due to the outbreak of Covid-2019 pandemic, the organisation of many Hospitals in Italy, as well as all over the world, has changed dramatically. In our tertiary Endocrinology Unit, we are continuing to deliver urgent care to our patients, trying to grant assistance to chronic and frail subjects, as well. In this Letter, we provide a picture of GH adherence during Covid19 pandemic form one of the first and worst hit Italian region. We aim to share our experience in the management of both paediatric and adult patients with growth hormone deficiency, enlightening that every possible effort is valuable to reduce the risk of therapy discontinuation.