Search

OBJECTIVE: Hemophagocytic lymphohistiocytosis is a hyperinflammatory syndrome that often requires critical care support and remains difficult to diagnose. These guidelines are meant to aid in the early recognition, diagnosis, supportive care, and treatment of patients with hemophagocytic lymphohistiocytosis in ICUs. DATA SOURCES: The literature searches were performed with PubMed (MEDLINE). STUDY SELECTION: Keywords and medical subject headings terms for literature search included "macrophage activation syndrome," hemophagocytic lymphohistiocytosis," and "hemophagocytic syndrome." DATA EXTRACTION: The Histiocyte Society developed these consensus recommendations on the basis of published reports and expert opinions with level of evidence provided for each recommendation. They were endorsed by the Society of Critical Care Medicine. DATA SYNTHESIS: Testing for hemophagocytic lymphohistiocytosis should be initiated promptly in all patients admitted to ICUs with an unexplained or disproportionate inflammatory response, especially those with rapid clinical deterioration. Meeting five or more of eight hemophagocytic lymphohistiocytosis 2004 diagnostic criteria serves as a valuable diagnostic tool for hemophagocytic lymphohistiocytosis. Early aggressive critical care interventions are often required to manage the multisystem organ failure associated with hemophagocytic lymphohistiocytosis. Thorough investigation of the underlying triggers of hemophagocytic lymphohistiocytosis, including infections, malignancies, and autoimmune/autoinflammatory diseases, is essential. Early steroid treatment is indicated for patients with familial hemophagocytic lymphohistiocytosis and is often valuable in patients with acquired hemophagocytic lymphohistiocytosis (i.e., secondary hemophagocytic lymphohistiocytosis) without previous therapy, including macrophage activation syndrome (hemophagocytic lymphohistiocytosis secondary to autoimmune/autoinflammatory disease) without persistent or relapsing disease. Steroid treatment should not be delayed, particularly if organ dysfunction is present. In patients with macrophage activation syndrome, whose disease does not sufficiently respond, interleukin-1 inhibition and/or cyclosporine A is recommended. In familial hemophagocytic lymphohistiocytosis and severe, persistent, or relapsing secondary macrophage activation syndrome, the addition of prompt individualized, age-adjusted etoposide treatment is recommended. CONCLUSIONS: Further studies are needed to determine optimal treatment for patients with hemophagocytic lymphohistiocytosis in ICUs, including the use of novel and adjunct therapies.

Spatial abilities contribute to life and occupational competencies, and certain spatial skills differ, on average, between males and females, typically favoring males when differences occur. Factors contributing to spatial skills could include prenatal as well as experiential/cultural influences, with biological and social influences likely interacting and difficult to disentangle. This meta-analysis examined the potential influence of prenatal androgen exposure on spatial skill by examining studies of patients with congenital adrenal hyperplasia (CAH). CAH involves elevated adrenal androgens prenatally, with overall androgen concentrations higher for females with CAH versus same-sex controls but with little overall difference between males with CAH versus controls. We hypothesized that, if androgens contribute prenatally to neurobehavioral development in humans as in many other species, females with CAH would show spatial enhancement versus control females, but with no definitive hypothesis for males. Meta-analysis of 12 studies examining overall spatial skill and three spatial subcategories failed to support enhanced spatial performance for females with CAH; males with CAH showed lower spatial ability compared to control males, at least for the category of overall spatial skill. Although statistical logic precludes accepting the null hypothesis for females, the meta-analysis failed to support the idea that prenatal exposure to androgens explains spatial gender/sex differences in humans. Alternative explanations for average gender/sex differences in some spatial tasks could include androgen exposure at other times, such as mini-puberty, or different social factors experienced by males and females. We also discuss possible explanations for the different outcomes seen in females versus males with CAH.

Chimeric antigen receptor T-cell (CAR T-cell) therapy is associated with significant toxicities secondary to immune activation, including a rare but increasingly recognised severe toxicity resembling haemophagocytic lymphohistiocytosis (carHLH). We report the development of carHLH in 14·8% of paediatric patients and young adults treated with CD19-specific CAR T-cell therapy with carHLH, occurring most commonly in those with high disease burden. The diagnosis and treatment of carHLH required a high index of suspicion and included multidrug immunomodulation with variable response to therapies. Compared to patients without carHLH, patients with carHLH had both reduced response to CAR T-cell therapy (P-value = 0·018) and overall survival (P-value = < 0·0001).

Preferences for pink and blue were tested in children aged 4–11 years in three small-scale societies: Shipibo villages in the Peruvian Amazon, kastom villages in the highlands of Tanna Island, Vanuatu, and BaYaka foragers in the northern Republic of Congo; and compared to children from an Australian global city (total N = 232). No sex differences were found in preference for pink in any of the three societies not influenced by global culture (ds − 0.31–0.23), in contrast to a female preference for pink in the global city (d = 1.24). Results suggest that the pairing of female and pink is a cultural phenomenon and is not driven by an essential preference for pink in girls.

Introduction and importance: Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening hyperinflammatory syndrome as a result of dysregulation of the immune system. Physicians in the intensive care unit (ICU), especially pediatricians, need to know how to recognize the diagnostic criteria and spectrum of HLH clinical presentations because early detection and timing of initial therapy affect the survival rate of the patient. Case presentation A 7-year-old female patient was referred to the pediatric ICU (PICU) at our tertiary hospital because of the suspicion of severe sepsis with shock and disseminated intravascular coagulation. On the fifth day of treatment, the patient was intubated and given a mechanical ventilator after experiencing respiratory failure. On the seventh day in the PICU, high fever persisted and the patient developed worsening acute kidney injury with oliguria. When worsening conditions continued, the patient experienced hypotension and cardiac arrest. The patient died on the 8th day of treatment at PICU due to severe shock and multiorgan failure. Clinical discussion HLH complications can be life-threatening with documented ICU mortality of 35%, even with an appropriate initial therapeutic approach. Patients with HLH can have rapid progression of disease and often require a significant amount of ICU supportive care, including vasopressor support, significant amount of blood products, ventilator support, and renal replacement therapy. Conclusion The diagnosis of HLH should be considered if there are cases with persistent, prolonged fever, organomegaly, cytopenias and evolving Multi Organ Dysfunction Syndrome. It is important for pediatricians to know the diagnostic criteria and possible clinical presentations of HLH., Highlights • A low-resource setting has its own challenges in handling hemophagocytic lymphohistiocytosis • Hemophagocytic lymphohistiocytosis is a life-threatening hyperinflammatory syndrome • The diagnostic criteria and clinical presentations of HLH need to be known by physicians

Phoenix et al. (1959) reported that treating pregnant guinea pigs with testosterone had enduring effects on the sex-related behavior of their female offspring. Since then, similar enduring effects of early testosterone exposure have been found in other species, including humans, and for other behaviors that show average sex differences. In humans, the affected outcomes include gender identity, sexual orientation, and children's sex-typical play behavior. The evidence linking early testosterone exposure to sex-typed play is particularly robust, and sex-typed play is also influenced by many other factors, including socialization by parents and peers and self-socialization, based on cognitive understanding of gender. In addition to influencing behavior, testosterone and hormones produced from testosterone affect mammalian brain structure. Studies using human autopsy material have found some sex differences in the human brain similar to those seen in other species, and have reported that some brain sex differences correlate with sexual orientation or gender identity, although the causes of these brain/behavior relationships are unclear. Studies that have imaged the living human brain have found only a small number of sex differences, and these differences are generally small in magnitude. In addition, they have not been linked to robust psychological or behavioral sex differences. Future research might benefit from improved imaging technology, and attention to other brain characteristics. In addition, it might usefully explore how different types of factors, such as early testosterone exposure and parental socialization, work together in the developmental system that produces sex/gender differences in human brain and behavior.

Hemophagocytic lymphohistiocytosis (HLH) is a fatal disorder of immune hyperactivation that has been described as a cytokine storm. Sepsis due to known or suspected infection has also been viewed as a cytokine storm. Although clinical similarities between these syndromes suggest similar immunopathology and may create diagnostic uncertainty, distinguishing them is critical as treatments are widely divergent. We examined T-cell profiles from children with either HLH or sepsis and found that HLH is characterized by acute T-cell activation, in clear contrast to sepsis. Activated T cells in patients with HLH were characterized as CD38(high)/HLA-DR(+) effector cells, with activation of CD8(+) T cells being most pronounced. Activated T cells were type 1 polarized, proliferative, and displayed evidence of recent and persistent activation. Circulating activated T cells appeared to be broadly characteristic of HLH, as they were seen in children with and without genetic lesions or identifiable infections and resolved with conventional treatment of HLH. Furthermore, we observed even greater activation and type 1 polarization in tissue-infiltrating T cells, described here for the first time in a series of patients with HLH. Finally, we observed that a threshold of >7% CD38(high)/HLA-DR(+) cells among CD8(+) T cells had strong positive and negative predictive value for distinguishing HLH from early sepsis or healthy controls. We conclude that the cytokine storm of HLH is marked by distinctive T-cell activation whereas early sepsis is not, and that these 2 syndromes can be readily distinguished by T-cell phenotypes.

Funder: National Institute for Health Research Cambridge Biomedical Research Centre, Background: Autism is more prevalent in males than in females. Hypotheses related to the extreme male brain theory of autism suggest that heightened androgen exposure during early development contributes to autistic traits. Whilst prior research focused mostly on the prenatal period, the current study tests the influences of androgen exposure during both the prenatal and the early postnatal periods on autistic traits during childhood. Methods: Anthropometric measures that are putative biomarkers of early androgen exposure were employed. Anogenital distance (AGD) was measured at birth and 3 months of age in boys and girls. Penile length at birth and 3 months of age was also measured in boys. When the children were 9–13 years old, a parent‐reported questionnaire (the 10‐item children’s version of the Autism Spectrum Quotient; AQ‐10 Child) was used to assess autistic traits in 97 boys and 110 girls. Results: There were no significant associations between any of the AGD or penile length measures and scores on the AQ‐10 Child in boys, girls or the entire sample. Conclusions: The current study provides the first test of whether early measurements of AGD and/or penile length predict subsequent autistic traits. The current findings do not support a relationship between prenatal or early postnatal androgen exposure and autistic traits. The current study augments prior research showing no consistent relationship between early androgen exposure and autistic traits.

Human gender-related behavior/psychology is shaped by a developmental system that involves numerous influences interacting over time. Understanding of the full range of elements in the system and how they interact is currently incomplete. The available evidence suggests, however, that early exposure to testosterone, postnatal socialization, e.g., by parents and peers, and self-socialization related to cognitive understanding of gender are important elements. This article focuses on prenatal and early neonatal influences of testosterone on gender-related psychological/behavioral outcomes, and contextualizes these hormonal influences within an understanding of socialization influences. There is consistent evidence that early testosterone exposure influences childhood gender role behavior, including sex-typical toy play, as well as gender identity and sexual orientation. Evidence for similar hormonal influences on spatial ability and on traits related to autism, or autistic spectrum disorder, is inconsistent. Evidence from girls exposed to elevated testosterone prenatally suggests that they experience alterations in processes of external socialization, as well as self-socialization, and that these, along with early testosterone exposure, shape gender-related outcomes.

We report findings from two studies investigating possible relations of prenatal androgen exposure to a broad measure of children's gender-typed behavior, as well as specifically to children's toy and playmate preferences. Study 1 investigated these outcomes for 43 girls and 38 boys, aged 4 to 11 years, with congenital adrenal hyperplasia (CAH, a genetic condition causing increased adrenal androgen production beginning prenatally) compared to similarly-aged, unaffected relatives (41 girls, 31 boys). The predicted sex differences were found for all of the outcome measures. Furthermore, girls with CAH showed increased male-typical and decreased female-typical behavior and toy and playmate preferences compared to unaffected girls. Study 2 investigated the relationship of amniotic fluid testosterone to gender-typed behavior and toy and playmate preferences in typically developing children (48 girls, 44 boys) aged 3 to 5 years. Although the predicted sex differences were found for all of the outcome measures, amniotic fluid testosterone was not a significant correlate, in the predicted direction, of any outcome measure for either sex. The results of study 1 provide additional support for an influence of prenatal androgen exposure on children's gender-typed behavior, including toy and playmate preferences. The results of study 2 do not, but amniotic fluid testosterone may be an insufficiently sensitive measure of early androgen exposure. A more sensitive and reliable measure of prenatal androgen exposure may be needed to consistently detect relations to later gender typed behavior in non-clinical populations.

Isolated neuroinflammatory disease has been described in case reports of familial hemophagocytic lymphohistiocytosis (FHL), but the clinical spectrum of disease manifestations, response to therapy and prognosis remain poorly defined. We combined an international survey with a literature search to identify FHL patients with (i) initial presentation with isolated neurological symptoms; (ii) absence of cytopenia and splenomegaly at presentation; and (iii) systemic HLH features no earlier than 3 months after neurological presentation. Thirty-eight (20 unreported) patients were identified with initial diagnoses including acute demyelinating encephalopathy, leukoencephalopathy, CNS vasculitis, multiple sclerosis, and encephalitis. Median age at presentation was 6.5 years, most commonly with ataxia/gait disturbance (75%) and seizures (53%). Diffuse multifocal white matter changes (79%) and cerebellar involvement (61%) were common MRI findings. CSF cell count and protein were increased in 22/29 and 15/29 patients, respectively. Fourteen patients progressed to systemic inflammatory disease fulfilling HLH-2004 criteria at a mean of 36.9 months after initial neurological presentation. Mutations were detected in PRF1 in 23 patients (61%), RAB27A in 10 (26%), UNC13D in 3 (8%), LYST in 1 (3%), and STXBP2 in 1 (3%) with a mean interval to diagnosis of 28.3 months. Among 19 patients who underwent HSCT, 11 neurologically improved, 4 were stable, one relapsed, and 3 died. Among 14 non-transplanted patients, only 3 improved or had stable disease, one relapsed, and 10 died. Isolated CNS-HLH is a rare and often overlooked cause of inflammatory brain disease. HLH-directed therapy followed by HSCT seems to improve survival and outcome.

Funder: Gates Cambridge Trust; doi: http://dx.doi.org/10.13039/501100005370, It is generally recognized that there are gender-related differences in children’s toy preferences. However, the magnitude of these differences has not been firmly established. Furthermore, not all studies of gender-related toy preferences find significant gender differences. These inconsistent findings could result from using different toys or methods to measure toy preferences or from studying children of different ages. Our systematic review and meta-analysis combined 113 effect sizes from 75 studies to estimate the magnitude of gender-related differences in toy preferences. We also assessed the impact of using different toys or methods to assess these differences, as well as the effect of age on gender-related toy preferences. Boys preferred boy-related toys more than girls did, and girls preferred girl-related toys more than boys did. These differences were large (d ≥ 1.60). Girls also preferred toys that researchers classified as neutral more than boys did (d = 0.29). Preferences for gender-typical over gender-atypical toys were also large and significant (d ≥ 1.20), and girls and boys showed gender-related differences of similar magnitude. When only dolls and vehicles were considered, within-sex differences were even larger and of comparable size for boys and girls. Researchers sometimes misclassified toys, perhaps contributing to an apparent gender difference in preference for neutral toys. Forced choice methods produced larger gender-related differences than other methods, and gender-related differences increased with age.

Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening hyperinflammatory syndrome requiring aggressive immunosuppressive therapy. Following 2 large international studies mainly targeting pediatric patients with familial disease and patients without underlying chronic or malignant disease, the HLH-94 protocol is recommended as the standard of care when using etoposide-based therapy by the Histiocyte Society. However, in clinical practice, etoposide-based therapy has been widely used beyond the study inclusion criteria, including older patients and patients with underlying diseases (secondary HLH). Many questions remain around these extended indications and published reports do not address several practical issues. To tackle these concerns, the HLH Steering Committee of the Histiocyte Society decided to issue guidance for use of the HLH-94 protocol. The group convened in a structured consensus finding process to define recommendations that are based largely on expert opinion backed up by available data from the literature. The recommendations address all main elements of HLH-94 including corticosteroids, cyclosporin, etoposide, intrathecal therapy, and hematopoietic stem cell transplantation (HSCT) and consider various forms of HLH and all age groups. Aspects covered include indications, applications, dosing, side effects, duration of therapy, salvage therapy, and HSCT. These recommendations aim to provide a framework to guide treatment decisions in this severe disease.

Rotating mental representations of objects is accompanied by widespread bilateral brain activations. Thus, interhemispheric communication channels may play a relevant part when engaging in mental rotation tasks. Indeed, links between mental rotation and dimensions of the corpus callosum-the brain's main commissure system-have been reported. However, existing findings are sparse and inconsistent across studies. Here we set out to further characterize the nature of any such links, including their exact location across the corpus callosum. For this purpose, we applied an advanced image analysis approach assessing callosal thickness at 100 equidistant points in a sample of 38 healthy adults (19 men, 19 women), aged between 22 and 45 years. We detected a sex interaction, with significant structure-performance relationships in women, but not in men. Specifically, better mental rotation performance was linked to a thicker female corpus callosum within regions of the callosal splenium, posterior midbody, and anterior third. These findings may suggest sex differences in problem solving strategies where in women, more than in men, stronger interhemispheric connectivity-especially between occipitoparietal, frontal, and prefrontal regions-is associated with improved task performance. © 2018 Wiley Periodicals, Inc.

Background Cancer treatment can lead to left ventricular (LV) dysfunction in female cancer survivors of reproductive age, and pregnancy-related hemodynamic stress may result in LV dysfunction or heart failure (HF). Objectives We performed a systematic review and meta-analysis to determine the incidence of LV systolic dysfunction or HF during or soon after pregnancy in cancer survivors and evaluated the impact of history of cancer therapeutics-related cardiac dysfunction (CTRCD). Methods We systematically searched electronic databases (MEDLINE and EMBASE) from inception to January 2020 to identify cohort studies that examined cardiac disease in pregnant cancer survivors. Meta-analysis was performed using the inverse-variance fixed effects method. Potential sources of heterogeneity were explored using subgroup analyses and meta-regression. Results Of 13,782 identified articles, 6 studies consisting of 2,016 pregnancies, predominantly in childhood cancer survivors, were included. Overall, there were 33 cardiac events. The total weighted incidence of LV dysfunction or HF with pregnancy was 1.7% (95% confidence interval [CI]: 0.9% to 2.7%) overall; 28.4% (95% CI: 14.6% to 43.9%) in those with a history of CTRCD and 0.24% (95% CI: 0% to 0.81%) in those without, translating into an odds ratio of 47.4 (95% CI: 17.9 to 125.8). Interstudy heterogeneity was low (I2 = 17.5%). Metaregression did not reveal significant sources of heterogeneity. Conclusions The incidence of LV dysfunction or HF during pregnancy in cancer survivors was low. Although risk estimates are limited by the small number of events, women with a history of CTRCD compared to those without had a 47.4-fold higher odds of experiencing pregnancy-related LV dysfunction or HF., Central Illustration

Secondary hemophagocytic syndrome (HPS) has been described after autologous hematopoietic cell transplant (AutoHCT). We report two cases of secondary HPS after novel consolidation therapy for high-risk neuroblastoma as part of an institutional phase 2 trial incorporating immunotherapy into a "standard" AutoHCT regimen. Both patients developed liver dysfunction beyond expected course of hepatic veno-occlusive disease, coagulopathy, hyperferritinemia, and when evaluated, elevated soluble interleukin-2 receptor and hemophagocytosis. These cases highlight the need for clinicians to have a high index of suspicion for immune-related complications in patients receiving immune therapies.

Hemophagocytic lymphohistiocytosis (HLH) is a syndrome of pathologic immune activation, often associated with genetic defects of lymphocyte cytotoxicity. Though a distinctive constellation of features has been described for HLH, diagnosis remains challenging as patients have diverse presentations associated with a variety of triggers. We propose two concepts to clarify how HLH is diagnosed and treated: within the broader syndrome of HLH, "HLH disease" should be distinguished from "HLH disease mimics" and HLH subtypes should be categorized by specific etiologic associations, not the ambiguous dichotomy of "primary" and "secondary." We provide expert-based advice regarding the diagnosis and initiation of treatment for patients with HLH, rooted in improved understanding of its pathophysiology.

Hemophagocytic lymphohistiocytosis (HLH) is a rare but life-threatening condition characterized by uncontrolled inflammation. The management of HLH is challenging, in part, due to the multiple etiologies of the disease, the variations in presentations, and the rapidity of the progression of the disease. Due to the severity of their disease, these patients often require significant critical care support. HLH can be due to familial (genetic) causes or can be secondary to triggers such as infections, autoimmune disorders, and malignancy. Underlying conditions such as sepsis or malignancy could pose as major confounders while applying universal diagnostic criteria and therefore could lead to delay in diagnosis. This chapter focuses on the characteristics of the disease, pathophysiology, diagnostic criteria, treatment, and intensive care management of pediatric patients with HLH.

BACKGROUND: Langerhans cell histiocytosis (LCH) is a rare myeloid neoplasm characterized by the presence of abnormal CD1a-positive (CD1a(+))/CD207(+) histiocytes. Hemophagocytic lymphohistiocytosis (HLH) represents a spectrum of hyperinflammatory syndromes typified by the dysregulated activation of the innate and adaptive immune systems. Patients with LCH, particularly those with multisystem (MS) involvement, can develop severe hyperinflammation mimicking that observed in HLH. Nevertheless, to the authors' knowledge, little is known regarding the prevalence, timing, risk factors for development, and outcomes of children and young adults who develop HLH within the context of MS-LCH (hereafter referred to LCH-associated HLH). METHODS: To gain further insights, the authors conducted a retrospective, multicenter study and collected data regarding all patients diagnosed with MS-LCH between 2000 and 2015. RESULTS: Of 384 patients with MS-LCH, 32 were reported by their primary providers to have met the diagnostic criteria for HLH, yielding an estimated 2-year cumulative incidence of 9.3% +/- 1.6%. The majority of patients developed HLH at or after the diagnosis of MS-LCH, and nearly one-third (31%) had evidence of an intercurrent infection. Patient age

Background: There is a marked male preponderance in autism spectrum conditions. The extreme male brain theory and the fetal androgen theory of autism suggest that elevated prenatal testosterone exposure is a key contributor to autistic traits. The current paper reports findings from two separate studies that test this hypothesis. \ud Methods: A parent-report questionnaire, the Childhood Autism Spectrum Test (CAST), was employed to measure autistic traits in both studies. The first study examined autistic traits in young children with congenital adrenal hyperplasia (CAH), a condition causing unusually high concentrations of testosterone prenatally in girls. 81 children with CAH (43 girls) and 72 unaffected relatives (41 girls), aged 4 to 11 years, were assessed. The second study examined autistic traits in relation to amniotic testosterone in 92 typically-developing children (48 girls), aged 3 to 5 years. \ud Results: Findings from neither study supported the association between prenatal androgen (testosterone) exposure and autistic traits. Specifically, young girls with and without CAH did not differ significantly in CAST scores and amniotic testosterone concentrations were not significantly associated with CAST scores in boys, girls, or the whole sample. \ud Conclusions: These studies do not support a relationship between prenatal testosterone exposure and autistic traits. These findings augment prior research suggesting no consistent relationship between early androgen exposure and autistic traits.

Sex-typed behavior in childhood is significantly related to sexual orientation in adulthood. In addition, same-sex attractions in early adolescence are more non-exclusive than in adulthood and can differ from later same-sex orientations. However, little research has focused on romantic attractions as they emerge during early adolescence. Drawing a sample from the Avon Longitudinal Study of Parents and Children (197 girls, 204 boys), the current study examined whether same-sex romantic attractions at age 13 years were exclusive, and whether they were predicted by sex-typed behavior at age 3.5 years. No young adolescents in this sample reported exclusive same-sex attractions, and increased same-sex attractions were not significantly related to reduced other-sex sexualities. Childhood sex-typed behavior did not significantly predict early same-sex attractions, suggesting that early same-sex attractions differ from later same-sex orientations. The current study highlights the importance of studying the development of sexuality beginning prior to adulthood. Electronic supplementary material The online version of this article (doi:10.1007/s10508-016-0726-2) contains supplementary material, which is available to authorized users.

The popularity of using the ratio of the second to the fourth digit (2D:4D) to study influences of early androgen exposure on human behavior relies, in part, on a report that the ratio is sex-dimorphic and stable from age 2 years (Manning etal., 1998). However, subsequent research has rarely replicated this finding. Moreover, although 2D:4D has been correlated with many behaviors, these correlations are often inconsistent. Young children's 2D:4D–behavior correlations may be more consistent than those of older individuals, because young children have experienced fewer postnatal influences. To evaluate the usefulness of 2D:4D as a biomarker of prenatal androgen exposure in studies of 2D:4D–behavior correlations, we assessed its sex difference, temporal stability, and behavioral correlates over a 6- to 8-month period in 126, 2- to 3-year-old children, providing a rare same-sample replicability test. We found a moderate sex difference on both hands and high temporal stability. However, between-sex overlap and within-sex variability were also large. Only 3 of 24 correlations with sex-typed behaviors—scores on the Preschool Activities Inventory (PSAI), preference for a boy-typical toy, preference for a girl-typical toy, were significant and in the predicted direction, all of which involved the PSAI, partially confirming findings from another study. Correlation coefficients were larger for behaviors that showed larger sex differences. But, as in older samples, the overall pattern showed inconsistency across time, sex, and hand. Therefore, although sex-dimorphic and stable, 2D:4D–behavior correlations are no more consistent for young children than for older samples. Theoretical and methodological implications are discussed.

Hemophagocytic lymphohistiocytosis (HLH) is a severe hyperinflammatory syndrome induced by aberrantly activated macrophages and cytotoxic T cells. The primary (genetic) form, caused by mutations affecting lymphocyte cytotoxicity and immune regulation, is most common in children, whereas the secondary (acquired) form is most frequent in adults. Secondary HLH is commonly triggered by infections or malignancies but may also be induced by autoinflammatory/autoimmune disorders, in which case it is called macrophage activation syndrome (MAS; or MAS-HLH). Most information on the diagnosis and treatment of HLH comes from the pediatric literature. Although helpful in some adult cases, this raises several challenges. For example, the HLH-2004 diagnostic criteria developed for children are commonly applied but are not validated for adults. Another challenge in HLH diagnosis is that patients may present with a phenotype indistinguishable from sepsis or multiple organ dysfunction syndrome. Treatment algorithms targeting hyperinflammation are frequently based on pediatric protocols, such as HLH-94 and HLH-2004, which may result in overtreatment and unnecessary toxicity in adults. Therefore, dose reductions, individualized tailoring of treatment duration, and an age-dependent modified diagnostic approach are to be considered. Here, we present expert opinions derived from an interdisciplinary working group on adult HLH, sponsored by the Histiocyte Society, to facilitate knowledge transfer between physicians caring for pediatric and adult patients with HLH, with the aim to improve the outcome for adult patients affected by HLH.

It has been suggested that atypical hormone environments during early development may contribute to subsequent development of psychopathology. Also, it has been suggested that individuals with the autosomal recessive genetic variant, classic congenital adrenal hyperplasia (CAH), might be at increased risk of psychopathology. The present study examined emotional and behavioral adjustment in young children with CAH and their unaffected siblings in the United Kingdom. The parent-reported version of the Strengths and Difficulties Questionnaire (SDQ) was employed to assess adjustment in children aged 4 to 11 years. There were 38 boys with CAH, 43 girls with CAH, 23 unaffected brothers, and 31 unaffected sisters. No differences in emotional or behavioral problems were found between boys or girls with CAH and unaffected same-sex siblings. In addition, affected and unaffected boys in the current sample generally did not differ from boys in the general population. However, compared with girls in the general population, girls with CAH had more difficulties related to conduct problems, hyperactivity/ inattention, and prosocial behavior, and unaffected sisters had more difficulties related to peer problems, conduct problems, and prosocial behavior. These findings suggest that both girls with CAH and unaffected sisters of girls or boys with CAH may be at increased risk of developing behavioral problems. Potential influences related to the early hormone environment, familial process, and social stigma are considered.

This chapter describes the role of early testosterone exposure in gender development. It discusses these hormonal influences and how they relate to genetic influences, socialization by others, and self-socialization, in shaping gender development. To illustrate these influences, it focuses primarily on childhood play behavior. This focus is used because childhood play behavior shows large differences between the sex categories boy and girl to which children are assigned at birth. Also, childhood play behavior has been studied extensively, providing perhaps the best example of how a gender-related behavior can be influenced by a range of factors at levels of organization from the cellular to the societal working in concert over time.

Many gender differences are thought to result from interactions between inborn factors and sociocognitive processes that occur after birth. There is controversy, however, over the causes of gender-typed preferences for the colors pink and blue, with some viewing these preferences as arising solely from sociocognitive processes of gender development. We evaluated preferences for gender-typed colors, and compared them to gender-typed toy and activity preferences in 126 toddlers on two occasions separated by 6-8 months (at Time 1, M = 29 months; range 20-40). Color preferences were assessed using color cards and neutral toys in gender-typed colors. Gender-typed toy and activity preferences were assessed using a parent-report questionnaire, the Preschool Activities Inventory. Color preferences were also assessed for the toddlers' parents using color cards. A gender difference in color preferences was present between 2 and 3 years of age and strengthened near the third birthday, at which time it was large (d > 1). In contrast to their parents, toddlers' gender-typed color preferences were stronger and unstable. Gender-typed color preferences also appeared to establish later and were less stable than gender-typed toy and activity preferences. Gender-typed color preferences were largely uncorrelated with gender-typed toy and activity preferences. These results suggest that the factors influencing gender-typed color preferences and gender-typed toy and activity preferences differ in some respects. Our findings suggest that sociocognitive influences and play with gender-typed toys that happen to be made in gender-typed colors contribute to toddlers' gender-typed color preferences.

Individuals with classic congenital adrenal hyperplasia (CAH) experience impaired glucocorticoid production and are treated postnatally with glucocorticoids. Prior research with animals and other human populations indicates that glucocorticoids can influence memory, particularly working memory. We tested the hypothesis that children with CAH would show reduced working memory. Children in the United Kingdom, aged 7-11 years, with classical CAH (31 girls, 26 boys) were compared to their unaffected relatives (30 girls, 20 boys) on a test of working memory, the Digit Span test. Vocabulary was also assessed to measure verbal intelligence for control purposes. Children with CAH showed reduced working memory performance compared to controls, on both components of the Digit Span test: p = .008 for Digit Span Forward, and p = .027 for Digit Span Backward, and on a composite score, p = .004. These differences were of moderate size (d = .53 to .70). Similar differences were also seen in a subset of 23 matched pairs of children with CAH and their relatives (d = .78 to .92). There were no group differences on Vocabulary. Glucocorticoid abnormality, including treatment effects, could be responsible for the reduced Digit Span performance in children with CAH. Other factors related to CAH, such as salt-wasting crises, could also be involved. Additional research is needed to identify the cause of the memory reduction, which will help to determine if more rapid diagnosis or more precise glucocorticoid treatment would help prevent memory reduction. Educational interventions might also be considered for children with CAH.

Some human behaviors, including aggression and activity level, differ on average for males and females. Here we report findings from two studies investigating possible relations between prenatal androgen and children’s aggression and activity level. For study 1, aggression and activity level scores for 43 girls and 38 boys, aged 4 to 11 years, with congenital adrenal hyperplasia (CAH, a genetic condition causing increased adrenal androgen production beginning prenatally) were compared to those of similarly-aged, unaffected relatives (41 girls, 31 boys). Girls with CAH scored higher on aggression than unaffected girls, d = 0.69, and unaffected boys scored higher on activity level than unaffected girls, d = 0.50. No other group differences were significant. For study 2, the relationship of amniotic fluid testosterone to aggression and activity level was investigated in typically-developing children (48 girls, 44 boys), aged 3 to 5 years. Boys scored higher than girls on aggression, d = 0.41, and activity level, d = 0.50. However, amniotic fluid testosterone was not a significant predictor of aggression or activity level for either sex. The results of the two studies provide some support for an influence of prenatal androgen exposure on children’s aggressive behavior, but not activity level. The within-sex variation in amniotic fluid testosterone may not be sufficient to allow reliable assessment of relations to aggression or activity level.

Gender differences in play behavior and physical aggression have been consistently reported. Theoretical perspectives concerning evolutionary, social, and social-cognitive mechanisms suggest that male-typical play behavior during childhood increases subsequent physical aggression. The evidence supporting these connections is limited, however. The present study investigated the association between gender-typed play behavior in early childhood and physical aggression in early adolescence using a sample drawn from a longitudinal, population study, the Avon Longitudinal Study of Parents and Children. Based on gender-typed play behavior as measured by the Pre-School Activities Inventory at age 3.5 years, samples of masculine (64 boys, 60 girls), feminine (80 boys, 66 girls), and randomly selected control children (55 boys, 67 girls) were recruited at age 13 years and administered the Reinisch Aggression Inventory. After controlling for a range of sociodemographic variables, maternal characteristics, and behavioral problems, including hyperactivity and conduct problems at age 3.5, significant group differences in physical aggression at age 13 were found among children classified as masculine, control, and feminine at age 3.5. Masculine children exhibited significantly more physical aggression than control children or feminine children, and control children exhibited significantly more physical aggression than feminine children. The association between gender-typed play behavior and physical aggression was not moderated by sex. These results suggest that the degree of childhood gender-typed play behavior independently predicts the degree of physical aggression at adolescence in boys and in girls.

Lesbian and gay individuals have been reported to show more interest in other-sex, and/or less interest in same-sex, toys, playmates, and activities in childhood than heterosexual counterparts. Yet, most of the relevant evidence comes from retrospective studies or from prospective studies of clinically referred, extremely gender nonconforming children. In addition, findings are mixed regarding the relation between childhood gender-typed behavior and the later sexual orientation spectrum from exclusively heterosexual to exclusively lesbian/gay. The current study drew a sample (2,428 girls and 2,169 boys) from a population-based longitudinal study, and found that the levels of gender-typed behavior at ages 3.5 and 4.75 years, although less so at age 2.5 years, significantly and consistently predicted adolescents' sexual orientation at age 15 years, both when sexual orientation was conceptualized as 2 groups or as a spectrum. In addition, within-individual change in gender-typed behavior during the preschool years significantly related to adolescent sexual orientation, especially in boys. These results suggest that the factors contributing to the link between childhood gender-typed behavior and sexual orientation emerge during early development. Some of those factors are likely to be nonsocial, because nonheterosexual individuals appear to diverge from gender norms regardless of social encouragement to conform to gender roles. (PsycINFO Database Record

The Good Practice Guidelines for the Assessment and Treatment of Adults with Gender Dysphoria is a publication of the Intercollegiate Committee of the Royal College of Psychiatrists. The overall goal of the Good Practice Guidelines is to provide clinical guidance for health professionals to assist transsexual, transgender, and gender nonconforming people with safe and effective pathways to achieving lasting personal comfort with their gendered selves, in order to maximize their overall health, psychological well-being, and self-fulfillment. This assistance may include primary care, gynaecologic and urologic care, reproductive options, voice and communication therapy, mental health services (e.g., assessment, counselling, psychotherapy), and hormonal and surgical treatments. The Good Practice Guidelines are based on the best available science and expert professional consensus. The Good Practice Guidelines articulate standards of care while acknowledging the role of making informed choices and the value of ...

Experimental research in non-human mammals indicates that testosterone exposure during early periods of rapid brain development has enduring influences on brain and behaviour. These influences are exerted when testosterone is higher in developing males than females, and the affected characteristics are those that differ by sex. Testosterone is higher in males than in females from about weeks 8 to 24 of human gestation and then again during early infancy, and both of these periods are times of rapid brain development. Substantial evidence suggests that testosterone prenatally influences human neurobehavioral development. Emerging evidence suggests that the early postnatal period is important too. This early postnatal period could provide a window for studying testosterone interacting with experience to shape human gender development.

Convincing evidence indicates that prenatal exposure to the gonadal hormone, testosterone, influences the development of children's sex-typical toy and activity interests. In addition, growing evidence shows that testosterone exposure contributes similarly to the development of other human behaviors that show sex differences, including sexual orientation, core gender identity, and some, though not all, sex-related cognitive and personality characteristics. In addition to these prenatal hormonal influences, early infancy and puberty may provide additional critical periods when hormones influence human neurobehavioral organization. Sex-linked genes could also contribute to human gender development, and most sex-related characteristics are influenced by socialization and other aspects of postnatal experience, as well. Neural mechanisms underlying the influences of gonadal hormones on human behavior are beginning to be identified. Although the neural mechanisms underlying experiential influences remain largely uninvestigated, they could involve the same neural circuitry as that affected by hormones.

Male and female fetuses differ in testosterone concentrations beginning as early as week 8 of gestation. This early hormone difference exerts permanent influences on brain development and behavior. Contemporary research shows that hormones are particularly important for the development of sex-typical childhood behavior, including toy choices, which until recently were thought to result solely from sociocultural influences. Prenatal testosterone exposure also appears to influence sexual orientation and gender identity, as well as some, but not all, sex-related cognitive, motor and personality characteristics. Neural mechanisms responsible for these hormone-induced behavioral outcomes are beginning to be identified, and current evidence suggests involvement of the hypothalamus and amygdala, as well as interhemispheric connectivity, and cortical areas involved in visual processing.