Gender Variance in Children and Adolescents with Neurodevelopmental and Psychiatric Conditions from Australia.

Gender variance is a broad term used to describe gender non-conforming behaviors. Past studies have used the parental response to Child Behavior Checklist (CBCL) Item 110, which asks whether a child "Wishes to be of opposite sex" as an indicator of gender variance. The population prevalence of gender variance in children and adolescents using this metric was found to be 1.2% in birth-assigned females and 0.4% in birth-assigned males (Achenbach & Rescorla, 2001). However, in those referred for psychiatric evaluation, it was higher (5.4% of birth-assigned females and 2.8% of birth-assigned males) (Achenbach & Rescorla, 2001). The aim of this study was to use the CBCL to estimate the prevalence of gender variance among children and adolescents with neurodevelopmental and psychiatric conditions and assess whether this was higher compared to controls. The response to the CBCL and the child's neurodevelopmental and/or psychiatric diagnosis were extracted from the clinical notes of 1553 children and adolescents referred to an outpatient psychiatry clinic in Australia. This was compared to data from 181 control participants as well as to the CBCL standardization sample of 1605 controls. Of the 1553 young people, whose mean age was 10.9 years, gender variance was reported in 3.1% compared to 1.7% in local control participants (p > .05) and 0.7% in the CBCL controls (p < .0001). Rates varied depending upon the underlying diagnosis (ASD 5.2%; ADHD 2.5%, intellectual disability 4.7%; depression 2.6%; and anxiety 4.7%). In this way, our findings support past observations that young people with neurodevelopmental and psychiatric conditions have high rates of gender variance.

LMP2 immunoproteasome promotes lymphocyte survival by degrading apoptotic BH3-only proteins.

The role of the immunoproteasome is perceived as confined to adaptive immune responses given its ability to produce peptides ideal for MHC Class-I binding. Here, we demonstrate that the immunoproteasome subunit, LMP2, has functions beyond its immunomodulatory role. Using LMP2-deficient mice, we demonstrate that LMP2 is crucial for lymphocyte development and survival in the periphery. Moreover, LMP2-deficient lymphocytes show impaired degradation of key BH3-only proteins, resulting in elevated levels of pro-apoptotic BIM and increased cell death. Interestingly, LMP2 is the sole immunoproteasome subunit required for BIM degradation. Together, our results suggest LMP2 has important housekeeping functions and represents a viable therapeutic target for cancer.

Case Report: Successful Use of Minoxidil to Promote Facial Hair Growth in an Adolescent Transgender Male.

Increasing numbers of trans and gender diverse young people are presenting to health services seeking gender-affirming medical care. While testosterone therapy in transgender males is generally effective in inducing masculinization, some adolescents encounter barriers to accessing such treatment or may not wish to experience all the changes that usually accompany testosterone. Here, we describe the case of a 17 year old trans male who presented with gender dysphoria but was initially unable to start testosterone therapy. Due to a desire for facial hair, he was therefore treated with topical minoxidil, an easily accessible, over-the-counter medication that has been used to treat androgenic alopecia for several decades. In this case, minoxidil was applied regularly to the lower face and, after three months of treatment, he developed obvious pigmented facial hair that was sufficient to help him avoid being misgendered. The only reported side effect was excessive skin dryness. Unexpectedly, despite no direct application to other areas, there was also an increase in pigmented body hair, suggestive of systemic absorption and effect. Given its long-standing use and safety record in the management of alopecia, minoxidil might thus represent a useful treatment option for trans males who desire an increase in facial hair.

Measurement tools for gender identity, gender expression, and gender dysphoria in transgender and gender-diverse children and adolescents: a systematic review.

Increasing numbers of children and adolescents are being referred to gender services for gender-related concerns. Various instruments are used with these patients in clinical care, but their clinical validity, strengths, and limitations have not been systematically reviewed. In this systematic review, we searched MEDLINE, PubMed, and PsycINFO databases for available tools that assess gender identity, gender expression, or gender dysphoria in transgender and gender-diverse (TGD) children and adolescents. We included studies published before Jan 20, 2020, that used tools to assess gender identity, expression, or dysphoria in TGD individuals younger than 18 years. Data were extracted from eligible studies using a standardised form. We found 39 studies that met the inclusion criteria, from which we identified 24 tools. The nature of tools varied considerably and included direct observation, child and adolescent self-report, and parent-report tools. Many methods have only been used with small samples, include outdated content, and lack evaluation of psychometric properties. In summary, a paucity of studies in this area, along with sparse reporting of psychometric properties, made it difficult to compare the relative use of tools, and current tools have substantial limitations. Future research is required to validate existing measures and create more relevant, culturally appropriate tools.

Hormonal Treatment in Young People With Gender Dysphoria: A Systematic Review.

CONTEXT: Hormonal interventions are being increasingly used to treat young people with gender dysphoria, but their effects in this population have not been systematically reviewed before. OBJECTIVE: To review evidence for the physical, psychosocial, and cognitive effects of gonadotropin-releasing hormone analogs (GnRHa), gender-affirming hormones, antiandrogens, and progestins on transgender adolescents. DATA SOURCES: We searched Medline, Embase, and PubMed databases from January 1, 1946, to June 10, 2017. STUDY SELECTION: We selected primary studies in which researchers examined the hormonal treatment of transgender adolescents and assessed their psychosocial, cognitive, and/or physical effects. DATA EXTRACTION: Two authors independently screened studies for inclusion and extracted data from eligible articles using a standardized recording form. RESULTS: Thirteen studies met our inclusion criteria, in which researchers examined GnRHas (n = 9), estrogen (n = 3), testosterone (n = 5), antiandrogen (cyproterone acetate) (n = 1), and progestin (lynestrenol) (n = 1). Most treatments successfully achieved their intended physical effects, with GnRHas and cyproterone acetate suppressing sex hormones and estrogen or testosterone causing feminization or masculinization of secondary sex characteristics. GnRHa treatment was associated with improvement across multiple measures of psychological functioning but not gender dysphoria itself, whereas the psychosocial effects of gender-affirming hormones in transgender youth have not yet been adequately assessed. LIMITATIONS: There are few studies in this field and they have all been observational. CONCLUSIONS: Low-quality evidence suggests that hormonal treatments for transgender adolescents can achieve their intended physical effects, but evidence regarding their psychosocial and cognitive impact are generally lacking. Future research to address these knowledge gaps and improve understanding of the long-term effects of these treatments is required.

XIAP Loss Triggers RIPK3- and Caspase-8-Driven IL-1ß Activation and Cell Death as a Consequence of TLR-MyD88-Induced cIAP1-TRAF2 Degradation.

X-linked Inhibitor of Apoptosis (XIAP) deficiency predisposes people to pathogen-associated hyperinflammation. Upon XIAP loss, Toll-like receptor (TLR) ligation triggers RIPK3-caspase-8-mediated IL-1ß activation and death in myeloid cells. How XIAP suppresses these events remains unclear. Here, we show that TLR-MyD88 causes the proteasomal degradation of the related IAP, cIAP1, and its adaptor, TRAF2, by inducing TNF and TNF Receptor 2 (TNFR2) signaling. Genetically, we define that myeloid-specific cIAP1 loss promotes TLR-induced RIPK3-caspase-8 and IL-1ß activity in the absence of XIAP. Importantly, deletion of TNFR2 in XIAP-deficient cells limited TLR-MyD88-induced cIAP1-TRAF2 degradation, cell death, and IL-1ß activation. In contrast to TLR-MyD88, TLR-TRIF-induced interferon (IFN)ß inhibited cIAP1 loss and consequent cell death. These data reveal how, upon XIAP deficiency, a TLR-TNF-TNFR2 axis drives cIAP1-TRAF2 degradation to allow TLR or TNFR1 activation of RIPK3-caspase-8 and IL-1ß. This mechanism may explain why XIAP-deficient patients can exhibit symptoms reminiscent of patients with activating inflammasome mutations.