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Background Hypogonadism is a key feature of Prader–Willi syndrome (PWS) but clear strategies for hormone replacement are lacking. Objective To evaluate the gonadal status and outcome in patients attending a Scottish PWS clinic from 1991 to 2019. Methods In 93 (35F:56M) patients, median follow-up 11.2 years, gonadal and pubertal status were assessed clinically. Pelvic ultrasound findings and basal/stimulated gonadotrophins were compared with age-matched controls. Results Females:of 22 patients aged > 11, 9 had reached B4–5, while 5 were still at B2–3, and 6 remained prepubertal. Eight patients experienced menarche aged 9.8–21.4 years, none with a normal cycle. Uterine length and ovarian volumes were normal but uterine configuration remained immature, with low follicular counts. Gonadotrophins were unremarkable, serum oestradiol 129 (70–520) pmol/L. Only 5 patients received oestrogen replacement. Males:fifty-four (96%) patients were cryptorchid (9 unilateral). Weekly hCG injections resulted in unilateral/bilateral descent in 2/1 of 25 patients. Of 37 boys aged > 11, 14 (9 with failed/untreated bilateral cryptorchidism) failed to progress beyond G1, 15 arrested at G2–3 (testes 3–10 mL), and 8 reached G4–5. Gonadotrophins were unremarkable except in boys at G2–5 in whom FSH was elevated: 12.3/27.3 vs 3.25/6.26 U/L in controls (P < 0.001). In males aged > 13, testosterone was 3.1 (0.5–8.4) nmol/L. Androgen therapy, given from 13.5 to 29.2 years, was stopped in 4/24 patients owing to behavioural problems. Conclusion Despite invariable hypogonadism, few females and only half the males with PWS in this study received hormone replacement. Double-blind placebo-controlled crossover trials of sex steroids are required to address unproven behavioural concerns.

Objective There is limited knowledge on the onset of comorbidities in congenital adrenal hyperplasia (CAH) during childhood. We aimed to establish the health status of children with CAH in the UK. Design and methods This cross-sectional multicentre study involved 14 tertiary endocrine UK units, recruiting 101 patients aged 8–18 years with classic 21-hydroxylase deficiency and 83 controls. We analysed demographic, clinical and metabolic data, as well as psychological questionnaires (Strengths and Difficulties (SDQ), Paediatric Quality of Life (PedsQL)). Results Patient height SDS in relation to mid-parental height decreased with age, indicating the discrepancy between height achieved and genetic potential height. Bone age was advanced in 40.5% patients, with a mean difference from the chronological age of 1.8 (±2.3) years. Patients were more frequently overweight (27%) or obese (22%) compared to controls (10.8% and 10.8%, respectively, P < 0.001). No consistent relationship between glucocorticoid dose and anthropometric measurements or hormonal biomarkers was detected. A small number of patients had raised total cholesterol (3.0%), low HDL (3.0%), raised LDL (7.0%) and triglycerides (5.0%). SDQ scores were within the ‘high’ and ‘very high’ categories of concern for 16.3% of patients. ‘School functioning’ was the lowest PedsQL scoring dimension with a median (interquartile range) of 70 (55–80), followed by ‘emotional functioning’ with a median of 75 (65–85). Conclusions Our results show an increased prevalence of problems with growth and weight gain in CAH children and suggest reduced quality of life. This highlights the urgent need to optimise management and monitoring strategies to improve long-term health outcomes.

Objectives To determine trends in clinical practice for individuals with DSD requiring gonadectomy. Design Retrospective cohort study. Methods Information regarding age at gonadectomy according to diagnosis; reported sex; time of presentation to specialist centre; and location of centre from cases reported to the International DSD Registry and who were over 16 years old in January 2019. Results Data regarding gonadectomy were available in 668 (88%) individuals from 44 centres. Of these, 248 (37%) (median age (range) 24 (17, 75) years) were male and 420 (63%) (median age (range) 26 (16, 86) years) were female. Gonadectomy was reported from 36 centres in 351/668 cases (53%). Females were more likely to undergo gonadectomy (n = 311, P < 0.0001). The indication for gonadectomy was reported in 268 (76%). The most common indication was mitigation of tumour risk in 172 (64%). Variations in the practice of gonadectomy were observed; of the 351 cases from 36 centres, 17 (5%) at 9 centres had undergone gonadectomy before their first presentation to the specialist centre. Median age at gonadectomy of cases from high-income countries and low-/middle-income countries (LMIC) was 13.0 years (0.1, 68) years and 16.5 years (1, 28), respectively (P < 0.0001) with the likelihood of long-term retention of gonads being higher in LMIC countries. Conclusions The likelihood of gonadectomy depends on the underlying diagnosis, sex of rearing and the geographical setting. Clinical benchmarks, which can be studied across all forms of DSD will allow a better understanding of the variation in the practice of gonadectomy.

Background There is a paucity of tools that can be used in routine clinical practice to assess the psychosocial impact of Disorders/Differences of Sex Development (DSD) on parents and children. Objective To evaluate the use of short Parent Self-Report and Parent Proxy-Report questionnaires that can be used in the outpatient setting. Methods Previously validated DSD-specific and generic items were combined to develop a Parent Self-Report questionnaire and a Parent Proxy-Report questionnaire for children under 7 years. Of 111 children approached at one tertiary paediatric hospital, the parents of 95 children (86%) with DSD or other Endocrine conditions completed these questionnaires. Results Questionnaires took under 10 min to complete and were found to be easy to understand. Compared to reference, fathers of children with DSD reported less stress associated with Clinic Visits (p = 0.02) and managing their child’s Medication (p = 0.04). However, parents of children with either DSD or other Endocrine conditions reported more symptoms of Depression (p = 0.03). Mothers of children with DSD reported greater Future Concerns in relation to their child’s condition (median SDS − 0.28; range − 2.14, 1.73) than mothers of children with other Endocrine conditions (SDS 1.17; − 2.00, 1.73) (p = 0.02). Similarly, fathers of children with DSD expressed greater Future Concerns (median SDS -1.60; − 4.21, 1.00) than fathers of children with other Endocrine conditions (SDS 0.48; − 2.13, 1.52) (p = 0.04). Conclusion DSD was associated with greater parental concerns over the child’s future than other Endocrine conditions. Brief parent-report tools in DSD can be routinely used in the outpatient setting to assess and monitor parent and patient needs.

Purpose: The purpose of the study was to present an endovascular management of a type IIIc endoleak (EL) in a patient with migration of the bridging stent graft of the celiac trunk (CT) after branched aortic aneurysm repair with retrograde cannulation of the superior mesenteric artery (SMA). Technique: The therapy was applied in a 62-year-old man who underwent a branched EVAR 2 years ago. Meanwhile, the patient was treated due to type Ia EL 6 months ago. The patient suffered in the last days from unclear hemorrhage clinically correlated with weakness. In the computed tomography angiography (CTA), an EL IIIc with a migration of the bridging stent graft from the CT branch was displayed. As vascular access, the left axillar artery was used. Due to the misaligned bridging stent graft, an antegrade cannulation was impossible, so cannulation was performed retrograde through the SMA using pancreaticoduodenal and gastroduodenal arteries. Thereafter, the EL could be repaired with bridging stent grafts. The postinterventional control showed a satisfying reconstruction without EL or embolization. Conclusion: Most of the complications such as type IIIc EL after complex endovascular repair can also be treated endovascularly. This sophisticated treatment requires that necessary materials and experience are available.

Aim:Previous evidence suggests that language influences bilinguals’ moral judgements. One explanation for this phenomenon is that using a second language (L2) attenuates emotional arousal, thus leading to more rational decisions. This study examined whether bilinguals’ moral arguments and emotional vocabulary are influenced by the language – first language (L1) or L2 – in which a moral dilemma is presented.Methodology and data analysis:A mixed-methods design was employed. We analysed the emotional vocabulary used by 204 Spanish-English bilinguals when making moral judgements and expressing their emotions in response to a highly emotional moral dilemma, as well as the type of arguments they employed to justify their moral decisions in L1 and L2.Findings:The participants were more emotional in their L1, as reflected in the arguments they used to justify their decisions. This finding was supported by a significantly lower number of emotional words in their L2. Moreover, the effect of language on moral judgements was mediated by the participants’ emotions.Originality:This study is the first to qualitatively examine the types of arguments underlying bilinguals’ moral decision-making in their L1 and in their L2. Moreover, the analysis of verbal emotional expressions in relation to moral decisions adds to the findings of previous research that was based almost exclusively on forced-choice measures and further supports the hypothesis that the reduction of emotional arousal in an L2 modulates individuals’ moral judgements.Implications:The results have implications for L2 teaching and pedagogy. The L2 curriculum should include instruction in emotional vocabulary and should engage learners in discussions that require argumentation and critical thinking about strong emotional content. This may assist bilinguals not only to express their internal affective states more efficiently, but also to experience the intensity of L2 emotionally charged words in a similar way as they do in their L1.

BACKGROUND Gender Dysphoria (GD) refers to the distress that may accompany gender incongruence, often heightened at onset of puberty, with the development of secondary sex characteristics. Children and adolescents may be especially vulnerable to severe stressors, including GD, with potentially irreversible effects if these exposures occur during critical periods of development and brain maturation. SUMMARY We describe the evidence for GD as a chronic stressor, drawing parallels to other established models of stress, activating both innate psychological and biological stress responses. As well as being an inherently distressing experience, a person who experiences GD may also experience minority stress. Minority stress has been demonstrated in young people who experience GD with higher rates of social rejection and internalised stigma and shame. The biological stress response in young people with GD is illustrated through the activation of the Hypothalamic-Pituitary-Adrenal axis, autonomic nervous system, and pro-inflammatory response. The number of young people who report experiencing GD has increased exponentially worldwide in the past decade demanding a change in clinic infrastructure. Paediatric Endocrinologists and specialists in Mental Health work together to both support psychosocial wellbeing and offer individualised treatment to align phenotype with gender identity with the aim of alleviating the distress of GD. Medical interventions may include puberty suppression and gender affirming hormones. Ongoing monitoring is required prior to initiation and during treatment to ensure that the goals of treatment are being achieved. Key Messages: GD has similarities to other examples of chronic stress, with some evidence of both a psychological and biological stress response, but this has yet to be fully evaluated in longitudinal studies of young people with GD. GD, as a chronic stressor, may in part be responsible for reported poorer physical and mental health outcomes in young people. Uncertainties remain on the benefit of treatment in young people with GD highlighting the need for specific measures of GD and stress to be used in both clinical monitoring and future research.

Congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency (21-OHD) is caused by mutations in the CYP21A2 gene. The study refers to CAH patients of Greek-Cypriot ancestry between years 2007 and 2018. One hundred and twenty patients with various degrees of CAH were categorized and genotyped. The patients were categorized in 4 mutation groups based on their clinical and biochemical findings. The majority of patients (85.0%) belonged to the non-classic (NC)-CAH form and the disorder was more often diagnosed in females (71.7%). The most severe classic salt-wasting (SW) form was identified in 11 neonates (9.2%). Seven (5.8%) children were also identified with the simple virilizing (SV) form and a median presentation age of 5 years [interquartile range (IQR) 3.2–6.5]. In the 240 nonrelated alleles, the most frequent mutation was p.Val281Leu (60.0%) followed by c.655 A/C>G (IVS2–13A/C>G) (8.8%), p.Pro453Ser (5.8%), DelEx1–3 (4.6%), p.Val304Met (4.6%), and p.Gln318stop (4.2%). Other less frequent mutations including rare deletions were also identified. Following our recent report that the true carrier frequency of CYP21A2 in Greek-Cypriots is 1:10, this study reports that the CAH prevalence is predicted around 1.7 cases per 10 000 people. Therefore, the up-to-date 120 CAH patients identified by our group make only the 6.9% of the ones estimated (approximately 1750) to exist in the Greek Cypriot population. The compiled data from a coherent population such as the Greek-Cypriot could be valuable for the antenatal diagnosis, management and genetic counselling of the existing and prospect families with CAH.

Background:\ud Anorexia nervosa (AN) during childhood and adolescence has been reported to adversely affect bone health, but few studies have investigated longitudinal changes.\ud \ud Method:\ud DXA-derived bone parameters and body composition were retrospectively assessed in 111 young girls with AN with a median age of 15.4 years (10.9, 19.8). In 68 (61%) vertebral fracture assessment (VFA) was performed and in 31 (28%), a follow-up DXA was performed. Correlations with growth, changes in body composition and effects of illness duration and menstruation were examined. Size adjusted DXA standard deviation scores were calculated for total body (TB) less head bone mineral content (TBLH-BMC) and lumbar spine bone mineral apparent density (LS-BMAD).\ud \ud Results:\ud Mean (range) bone area (BA) for height centile was 27.1 (0–97), and mean lean mass for height centile was 28.8 (0–95) at baseline. Mean (range) LS BMAD was −1.0 (−2.6, 0.8) SDS at first and − 1.2 (−3.0, −0.2) at second DXA (p = 0.023). On follow up, lean mass for height increased from 27th centile (0, 75) to 40th centile (0, 70) (p = 0.006), and fat mass for height increased from 55 g/cm to 67 g/cm (11.3, 124.2) (p

The clinical needs of young people with gender dysphoria (GD) have outpaced the capacity of health services to provide appropriate care. The study aimed to explore the interface of Paediatric Endocrinology and young people with GD, detailing the clinical characteristics and the clinical care provided, in order to inform future service development. Medical records of all young people with GD (n=91, 59 (65%) birth-assigned females and 32 (35%) birth-assigned males) referred to Paediatric Endocrinology during 2011-2019 for puberty suppression were reviewed. Median age at initial assessment was 14.6 years (range 8.8-17.6 years). There was a threefold increase from 2016 (n=22) to 2019 (n=73). Mental health disorders were present in 34 (37%) and autistic spectrum disorder in 21 (23%), while 54 (59%) had at least one comorbidity. Sixty-four (70%) young people fulfilled the criteria for consideration of fertility preservation, with 6 (9%) of them preserving their gametes. Seventy-nine (87%) young people commenced treatment with gonadotrophin-releasing hormone analogue, at a median age of 14.8 years (range 9.7-18.0 years). Six (8%) of those discontinued treatment, following a median duration of 6 months (range 6-18 months). Forty-one young people commenced gender-affirming hormones. One (2%) of those who started gender-affirming hormones discontinued treatment.Conclusions: We have witnessed increasing numbers of young people with GD attending Paediatric Endocrinology, with an over-representation of comorbidities, necessitating provision of an individualised approach to treatment. Addressing young people's acceptability of fertility services and ongoing close collaboration between endocrinology and mental health professionals require innovative models of multidisciplinary care. What is Known: • A worldwide increase in presentation of gender dysphoria has been mirrored in our service, with majority assigned female at birth and post-pubertal. • An over-representation of comorbidities exists, notably mental health disorders and autistic spectrum disorder. What is New: • Coordination of interprofessional care to meet complex needs, at an individual level, while improving efficiency of working, at a systemic level, can be met by the development of specialist centres. • The reasons for low uptake of fertility services demand further exploration.

Objectives To determine the levels of physical activity (PA) in young people with gender dysphoria (GD) and help identify factors which deter participation. Methods Fifty-six young people who attended paediatric endocrinology because of GD, June to October 2019, and were on treatment with gonadotrophin-releasing hormone (GnRH) analogue were approached to participate in a survey. Results A total of 55 young people (98%) responded to the survey. Thirty-eight (69%) participated in PA for >1 h/week. Thirty-two (58%) reported high motivation level for exercise. Those had median age of 15.9 years (10.7, 18.7) at the time of survey, and 13.6 years (9.7, 17.6) at start of GnRH analogue compared to 16.7 years (13.9, 18.5) (p, 0.047) and 15.4 years (11.2, 18.0) (p, 0.009) of the 23 (42%) who reported low motivation. Forty-one (74.5%) reported barriers when accessing PA, such as not being as good as others (75%), revealing sports clothing (73%) and not satisfied with body image (47%). Those were older (16.4 years [10.9, 18.7] vs. 14.7 years [10.7, 18.4] [p, 0.011]) at the time of survey and at start of GnRH analogue (14.9 years [9.7, 18.0] vs. 12.5 years [10.6, 15.2] [p, 0.0001]) than those 14 (25.5%) who reported facing no barriers. Twelve (85.7%) of those reporting no barriers stated high motivation levels compared to 20 (48.8%) of those reporting barriers (p, 0.026). Conclusions Strategies aimed at improving participation are twofold: first to improve motivation, especially in post-pubertal young people, and secondly to achieve societal change to help eliminate barriers.

Over the last decade, we have witnessed a significant rise in the number of transgender young people seeking endocrine treatment, of which clinical service and gender dysphoria terminology have attempted to keep pace both in matching demand and better describing the condition. Although helpful guidelines for pubertal suppression and gender affirming hormones have been developed, uncertainties remain regarding treatment and monitoring during treatment, often because the clinical needs of the transgender population have outpaced medical expertise and training. Recently, multidisciplinary team work has evolved due to the increasing complexity of diagnostic and treatment decision-making and has been instrumental in creating a unique service with input from a range of specialists. In this article, the current approach in clinical management of adolescents with gender dysphoria is reviewed, with focus on the endocrine aspect of care in children and adolescents. Questions on what defines optimal clinical care of children and adolescents with gender dysphoria remain and should be the focus of future research. (www.actabiomedica.it)

Introduction The relationship between serum anti-Müllerian hormone (AMH) and the testosterone response to human chorionic gonadotropin (hCG) stimulation test is unclear. Methods Children who had hCG stimulation tests in one tertiary centre from 2001 to 2018 were included (n = 138). Serum testosterone was measured before (day 1 [D1]) and after 3 days (D4) of hCG stimulation. Sixty-one of these children also had prolonged hCG stimulation for 2 more weeks and serum testosterone measured after 21 days (D22). All children had a serum AMH measured on D1. Results Of the 138 children, D4 testosterone was normal in 104 (75%). AMH was low in 24/138 (17%) children, and 16 (67%) of these had a low D4 testosterone. Median AMH in those who had a normal vs low D4 testosterone was 850 pmol/L (24, 2280) and 54 pmol/L (0.4, 1664), respectively (P < 0.0001). An AMH > 5th centile was associated with a low D4 testosterone in 18/118 (13%; P < 0.0001). Of the 61 children who had prolonged hCG stimulation, D22 testosterone was normal in 39 (64%). AMH was low in 10/61(16%) children and 9 (90%) of these had a low D22 testosterone. Median AMH in children who responded and did not respond by D22 was 639 pmol/L (107, 2280) and 261 pmol/L (15, 1034) (P < 0.0001). Conclusion A normal AMH may provide valuable information on overall testicular function. However, a low AMH does not necessarily predict a suboptimal testosterone response to hCG stimulation.

Introduction: Impaired Quality of Life (QoL) in Congenital Adrenal Hyperplasia (CAH) has been demonstrated in adults, but research in children has yielded variable results. We investigated the impact of CAH on QoL of children and adolescents alongside clinical health outcomes (biometric and biochemical profiles). Method: We collected data from 14 tertiary UK centres to explore current health status of 8-18 year olds with CAH. QoL was assessed by using three different questionnaires; strengths and difficulties questionnaire (SDQ), Paediatric Quality of life (PedsQL) and Self-image profile (SIP), the former two completed by both patients and their parents. Height, weight and blood pressure were converted to age and sex adjusted z-scores. Serum markers included 17OH-progesterone (17OHP), androstenedione (D4), testosterone (T) and 11-ketotestosterone (11KT). Statistical Analysis: Statistical analysis comprised of principal component analysis (PCA) followed by multivariate analysis of variance (MANOVA), and post hoc regression. Results: Of the 107 CAH patients included in the study, median age 12.4 years (IQR 10.0-15.1), 55% were female and 104 completed at least 1 questionnaire. Adequate data for PCA was available from 73/107. Three Principal Components (PCs) with observed eigenvalues > 1 explained 71% of the total variance in the observed variables. PC1 reflected ‘disease control’ comprising 17OHP, D4, T and 11KT. PC2 reflected ‘biometrics’ comprising age, and height and weight z-score. PC3 reflected ‘blood pressure’, comprising systolic and diastolic z-score. PC1 correlated with outcomes in the parent and patient SDQ as well as parent PedsQL. PC2 and PC3 did not correlate with QoL. Regression analysis revealed higher scores (indicating lower QoL) in the SDQ domain of emotional problems and PedsQL domain of emotional health in patients where biomarkers suggested good control or overtreatment. Post hoc regression analysis revealed a rise in Androstenedione of 10nmol/L equated to an improved SDQ emotional problems score of 0.5 points and an improved PedsQL emotional health score of 3 points. Conclusion: The study found an interrelation between QoL and biomarkers of disease control in CAH. There were more emotional problems with higher levels of androgen suppression. Biochemical control within normal ranges did not predict emotional problems. However, unexpectedly, patients with very high levels of androgens were highlighted as reporting fewer problems with their emotional QoL. Further research into QoL in CAH and optimal levels of biochemical control will further understanding.

Introduction: The association between congenital adrenal hyperplasia (CAH) and increased morbidity and mortality in adult life has been well established, however, limited knowledge exists regarding the onset of co-morbidities during childhood. Objective: To establish the health status of children and young persons (CYP) with CAH in the United Kingdom. Methods: This cross-sectional multi-center study involved 14 tertiary endocrine units across the United Kingdom. We recruited 107 patients aged 8-18 years with 21-hydroxylase deficiency and 83 matched controls. We collected and analyzed demographic, clinical, and metabolic data, as well as psychological questionnaires (Strengths and Difficulties [SDQ], Paediatric Quality of Life [PedsQL]and Self-Image Profile [SIP]). Results: The majority of patients (62.2%) were diagnosed within the first month of life, most commonly presenting with ambiguous genitalia (32.7%) or salt losing crisis (25.2%). After diagnosis, 37.3% of patients required admission for adrenal crisis, 11.2% presenting three or more episodes. Of the female patients, 57.6% had undergone urogenital examination under anesthesia and 35.5% had genital surgery. Most CAH patients received glucocorticoid (GC) replacement therapy with hydrocortisone (HC) (94.3%) and the rest with prednisolone, with a mean for relative GC doses of 13.3 (±3.7) mg/m2 per day HC-equivalent. 76.6% of patients received treatment with fludrocortisone, with a mean dose of 105.0 (±50.2) µg/m2 per day. Comparing height-Standard Deviation Score (SDS), patients under 12 years were taller (p=0.011) and patients aged 12-18 years shorter (p=0.031) than controls. Bone age was advanced in patients, with a mean difference from the chronological age of 1.9 (±2.2) years. CAH patients were more frequently overweight (26.4%) or obese (22.6%) compared to controls (10.8% and 10.8% respectively, p

Objectives:\ud To explore the prevalence and anatomic distribution of vertebral fractures in disease groups investigated for primary and secondary osteoporosis, using vertebral fracture assessment (VFA).\ud \ud Study design:\ud VFA was performed independently by 2 nonradiologists, in 165 children (77 males, 88 females) as part of their investigation for osteoporosis. Vertebral bodies from T6 to L4 were assessed for vertebral fractures using the Genant scoring system. The common readings for the presence of vertebral fractures were used for evaluating the prevalence and anatomic distribution of vertebral fractures.\ud \ud Results:\ud The median age of the subjects was 13.4 years (range, 3.6, 18). Of the 165 children, 24 (15%) were being investigated for primary bone disease, and the remainder had a range of chronic diseases known to affect bone health. Vertebral fractures were identified in 38 (23%) children. The distribution of the vertebral fractures was bimodal, with vertebral fractures peaks centered at T9 and L4. Conditions associated with increased odds for vertebral fractures were inflammatory bowel disease (OR, 3.3; 95% CI, 1.4, 8.0; P = .018) and osteogenesis imperfecta (OR, 2.3; 95% CI, 1.04, 5.8; P = .022). Among children with vertebral fractures, those with Duchenne muscular dystrophy (P = .015) and osteogenesis imperfecta (P = .023) demonstrated higher number of vertebral fractures than the other disease groups.\ud \ud Conclusions:\ud VFA identified the presence of vertebral fractures, in a bimodal distribution, in both primary bone disease and chronic disease groups. VFA is a practical screening tool for identification of vertebral fractures in children and adolescents at risk of fragility fractures.

Over the last decade, we have witnessed considerable progress in gender dysphoria (GD) terminology in an attempt to better describe the condition based on certain criteria. The ever-increasing social acceptance and destigmatization of children and adolescents with GD have resulted in an increased number of transgender individuals seeking endocrine care. In addition to terminology and diagnostic criteria, the tremendous progress of genetics and neuroimaging has enabled us to have a deeper understanding of the complex pathogenesis of GD. Although helpful guidelines for treatment with GnRH analogs and gender-affirming hormones have been proposed, several challenges and controversies still exist. In this article, the current knowledge about GD in adolescents is reviewed, with particular emphasis on terminology, clinical manifestations, and epidemiologic data. The neurobiological basis of the condition is presented, and both hormonal treatment and mental issues of transgender individuals are discussed. Undoubtedly, further research will optimize the diagnostic and therapeutic approach of children and adolescents with GD.

BackgroundMonitoring of hormonal control represents a key part of the management of congenital adrenal hyperplasia (CAH). Monitoring strategies remain suboptimal because they rely on frequent blood tests and are not specific for adrenal-derived hormones. Recent evidence suggests the crucial role of adrenal-specific 11-oxygenated-C19 androgens in the pathogenesis of CAH.ObjectiveTo establish a correlation between plasma and salivary adrenal-specific androgens in CAH as a noninvasive monitoring strategy.DesignThis prospective cross-sectional study recruited patients between 2015 and 2018.SettingMulticenter study including 13 tertiary centers in the United Kingdom.ParticipantsSeventy-eight children with CAH and 62 matched healthy controls.MethodsUsing liquid chromatography–tandem mass spectrometry, plasma and salivary concentrations of five steroids were measured: 17-hydroxyprogesterone (17OHP), androstenedione (A4), testosterone (T), 11-hydroxyandrostenedione (11OHA4), and 11-ketotestosterone (11KT). The correlation between plasma and salivary steroids was analyzed to assess their use in clinical practice.ResultsStrong correlations between plasma and salivary steroid concentrations in patients with CAH were detected: 17OHP (rs = 0.871; P < 0.001), A4 (rs = 0.931; P < 0.001), T (rs = 0.867; P < 0.001), 11OH4A (rs = 0.876; P < 0.001), and 11KT (rs = 0.944; P < 0.001). These results were consistent for patient subgroups based on sex and age. Analysis of patient subgroups based on 17OHP concentrations established clear correlations between plasma and salivary concentrations of the adrenal-specific androgen 11KT.ConclusionsThe current study identified tight correlations between plasma and saliva for the adrenal-derived 11-oxygenated C19 androgen 11KT, as well as 17OHP and A4, which are widely used for monitoring treatment in CAH. This combination of steroid hormones will serve as an improved noninvasive salivary test for disease monitoring in patients with CAH.

Purpose There is a need to improve our understanding of the clinical utility of vertebral fracture assessment (VFA) in paediatrics and this requires a thorough evaluation of its readability, reproducibility, and accuracy for identifying VF. Methods VFA was performed independently by two observers, in 165 children and adolescents with a median age of 13.4 years (range, 3.6, 18). In 20 of these subjects, VFA was compared to lateral vertebral morphometry assessment on lateral spine X-ray (LVM). Results 1528 (84%) of the vertebrae were adequately visualised by both observers for VFA. Interobserver agreement in vertebral readability was 94% (kappa, 0.73 [95% CI, 0.68, 0.73]). 93% of the non-readable vertebrae were located between T6 and T9. Interobserver agreement per-vertebra for the presence of VF was 99% (kappa, 0.85 [95% CI, 0.79, 0.91]). Interobserver agreement per-subject was 91% (kappa, 0.78 [95% CI, 0.66, 0.87]). Per-vertebra agreement between LVM and VFA was 95% (kappa 0.79 [95% CI, 0.62, 0.92]) and per-subject agreement was 95% (kappa, 0.88 [95% CI, 0.58, 1.0]). Accepting LVM as the gold standard, VFA had a positive predictive value (PPV) of 90% and a negative predictive value (NPV) of 95% in per-vertebra analysis and a PPV of 100% and NPV of 93% in per-subject analysis. Conclusion VFA reaches an excellent level of agreement between observers and a high level of accuracy in identifying VF in a paediatric population. The readability of vertebrae at the mid thoracic region is suboptimal and interpretation at this level should be exercised with caution.

The level of connection between health care professionals and people who experience a condition that affects sex development is variable. These people and associated support groups need to be included in discussions about research and healthcare delivery. The aim of this study was to understand the experiences of individuals with disorders of sexual development (DSD), their parents, health care providers, and support groups. Workshop planning, preparation, delivery, and evaluation involved members of working groups from the COST Action DSDnet. A coordinator, in collaboration with a support group representative, led the workshop design and delivery. Our successful, facilitated workshop involved 33 attendees from 8 EU countries. The workshop provided individuals with DSD, parents, advisory groups, and professionals with an opportunity for shared learning. Outputs focused on 7 key areas, including diagnosis, childhood, and transition to adult care as well as fostering discussion around registries, future research topics, consent processes, and information needs across the life course. The importance of trustworthy and knowledgeable providers, time to understand such rare conditions, and the place support groups have in a life course approach were valuable learning points for all attendees. In conclusion, workshops can be designed and delivered in meaningful ways for all those involved in care of individuals with rare conditions.

Introduction/aim Children with Prader-Willi syndrome (PWS) show alterations in infantile, childhood and pubertal growth. Growth Hormone (GH) therapy is recommended due to reported improvements in height velocity (HV) and body composition. The aim was to describe the patterns of growth in PWS and the influence of both changes in clinical practice and GH therapy. Methods Height SDS(HSDS), BMISDS and HVSDS of children attending a dedicated PWS clinic, 2000–2017, were analysed. To identify changes in growth we compared growth parameters between 2000–2012 and 2013–2017. In 21 children who received GH(median age at GH start 4.92 years (2.27,8.1)), consecutive measurements were available at −1, 0,+1 and+2 years from GH start. Results Overall, 60 children(31 F/29 M) were included. Three phases of growth after the age of 1 year were identified: 1–5 years, with acceleration in both HSDS(r, 0.310, p, At age 5, children in 2013–2017 (n,12) had higher HSDS [median,−0.08 (-1.74,1.54) vs −1.04(−4.16,0.5)] than those in 2000–2012 (n,18) (p,0.03). At age 12, children in 2013–2017 (n,5) had higher HSDS [median, 1.13 (-0.62,1.59) vs −1.35 (-4.27,0.23)] (p,0.027) and lower BMISDS [median, 1.05 (-0.13,2.14) vs 2.44 (0.13,4.3)] (p,0.032) than those in 2000–2012 (n,11). After 2 years on GH, median HSDS improved from −1.43 (-4.59,0.95) to −0.11(−3.53,1.57) (p, Conclusion We were able to delineate 3 distinct phases of growth in PWS. Changes in our clinical practice have led to improvements in both height and BMI. GH therapy was associated with an increase in height and stabilisation of BMI.

Sodium polystyrene sulfonate (SPS) is a cation-exchanging resin that has been widely used for several decades as first-line therapy of mild chronic hyperkalemia in patients with chronic kidney disease (CKD). However, evidence to prove the long-term tolerability and efficacy of SPS for the treatment of this condition is still missing. In this retrospective, observational study, we enrolled 26 outpatients with stages 3–4 CKD who received oral therapy with low-dose SPS for mild chronic hyperkalemia in the Outpatient Nephrology clinic of our Department during 2010–2016. We obtained medical records on side effects potentially attributable to SPS use, and we analyzed the changes in serum electrolytes before and after the initiation of SPS therapy. Serum potassium levels fell from 5.9 ± 0.4 to 4.8 ± 0.5 mmol/l (P

Myotonic dystrophy type 1 (DM1) is the most common form of adult-onset muscular dystrophy, which is characterised by progressive muscle wasting and the discovery of reliable blood-based biomarkers could be useful for the disease progress monitoring. There have been some reports showing that the presence of specific miRNAs in blood correlates with DM1. In one of these, our group identified four muscle-specific miRNAs, miR-1, miR-133a, miR-133b and miR-206, which correlated with the progression of muscle wasting observed in DM1 patients. The levels of the four muscle-specific miRNAs were elevated in the serum of DM1 patients compared to healthy participants and were also elevated in the serum of progressive muscle wasting DM1 patients compared to disease-stable DM1 patients. The aim of this work was to characterise the ontology of these four muscle-specific miRNAs in the blood circulation of DM1 patients. Here we show that the four muscle-specific miRNAs are encapsulated within exosomes isolated from DM1 patients. Our results show for the first time, the presence of miRNAs encapsulated within exosomes in blood circulation of DM1 patients. More interestingly, the levels of the four exosomal muscle-specific miRNAs are associated with the progression of muscle wasting in DM1 patients. We propose that exosomal muscle-specific miRNAs may be useful molecular biomarkers for monitoring the progress of muscle wasting in DM1 patients. There has been a growing interest regarding the clinical applications of exosomes and their role in prognosis and therapy of various diseases and the above results contribute towards this way.

Background:We aimed to describe the longitudinal changes in bone mineral content and influencing factors, in children with cystic fibrosis (CF).Methods:One hundred children (50 females) had dual X-ray absorptiometry (DXA) performed. Of these, 48 and 24 children had two to three scans, respectively over 10 years of follow-up. DXA data were expressed as lumbar spine bone mineral content standard deviation score (LSBMCSDS) adjusted for age, gender, ethnicity and bone area. Markers of disease, anthropometry and bone biochemistry were collected retrospectively.Results:Baseline LSBMCSDS was >0.5 SDS in 13% children, between −0.5; 0.5 SDS, in 50% and ≤−0.5 in the remainder. Seventy-eight percent of the children who had baseline LSBMCSDS >−0.5, and 35% of the children with poor baseline (LSBMCSDSConclusions:Bone mineral content as assessed by DXA is sub-optimal and decreases with time in most children with CF and this study has highlighted parameters that can be addressed to improve bone health.

Background\ud To explore the current models of practice in centres delivering specialist care for children with disorders of sex development (DSD), an international survey of 124 clinicians, identified through DSDnet and the I-DSD Registry, was performed in the last quarter of 2014.\ud \ud Results\ud A total of 78 (63 %) clinicians, in 75 centres, from 38 countries responded to the survey. A formal national network for managing DSD was reported to exist in 12 (32 %) countries. The paediatric specialists routinely involved in the initial evaluation of a newborn included: endocrinologist (99 %), surgeon/urologist (95 %), radiologist (93 %), neonatologist (91 %), clinical geneticist (81 %) and clinical psychologist (69 %). A team consisting of paediatric specialists in endocrinology, surgery/urology, clinical psychology, and nursing was only possible in 31 (41 %) centres. Of the 75 centres, 26 (35 %) kept only a local DSD registry and 40 (53 %) shared their data in a multicentre DSD registry. Attendance in local, national and international DSD-related educational programs was reported by 69, 78 and 84 % clinicians, respectively. Participation in audits/quality improvement exercises in DSD care was reported by 14 (19 %) centres. In addition to complex biochemistry and molecular genetic investigations, 40 clinicians (51 %) also had access to next generation sequencing. A genetic test was reported to be more preferable than biochemical tests for diagnosing 5-alpha reductase deficiency and 17-beta hydroxysteroid dehydrogenase 3 deficiency by 50 and 55 % clinicians, respectively.\ud \ud Conclusion:\ud DSD centres report a high level of interaction at an international level, have access to specialist staff and are increasingly relying on molecular genetics for routine diagnostics. The quality of care provided by these centres locally requires further exploration.

Measurement of urinary LH (uLH) and FSH (uFSH) may facilitate non-invasive pubertal assessment but there is a need for further validation by studying children and adolescents with disorders of puberty.65 cases (Male: 25) with a median age of 12 years (2.9-18.1) supplied at least one non-timed urine sample for uLH and uFSH measurement by immunoassay and corrected for creatinine excretion. 25 cases were receiving GnRH-agonist (GnRH-a) at the time of sample collection. In 41 cases, urine samples were collected prior to a LHRH test and in 12 cases matched serum samples for basal LH (sLH) and FSH (sFSH) were also available.There was a significant correlation between sLH and uLH:uCr (r=0.82; p-value0.001) and sFSH and uFSH:uCr (r=0.93; p-value0.001). Based on receiver operator characteristics analysis, a uLH:uCr value of 0.05 IU/mmol as a cut-off would detect a LH peak5U I/L with a sensitivity of 86% and a specificity of 72% with a positive predictive value of 93%. In pubertal boys (6) and girls (22) with a sLH peak5UI/L, median uLH:uCr was 0.27 IU/mmol (0.27-0.28) and 0.17 IU/mmol (0.09-0.43), respectively. The median uFSH:uCr was 0.51 IU/mmol (0.41-0.60) for boys and 1.1 IU/mmol (0.21-2.44) for girls. In the 25 cases on GnRH-a, the median uLH:uCr for boys and girls was 0.02 IU/mmol (0.01-0.02) and 0.02 IU/mmol (0.004-0.07), respectively, and the median uFSH:uCr was 0.07 IU/mmol (0.05-0.09) and 0.27 IU/mmol (0.09-0.54), respectively.Urinary gonadotrophins reflect serum gonadotrophin concentration and may represent a reliable non-invasive method of assessing pubertal progress.

Background: 5α steroid reductase deficiency (5αSRD) is an autosomal recessive enzymatic deficiency and mutations in the 5α steroid reductase type 2 gene (SRD5A2) result in male pseudohermaphrodism caused by decreased dihydrotestosterone (DHT) synthesis. Aim: To identify the specific mutations of the SRD5A2 gene in Cypriot patients with 5αSRD. Subjects and methods: Five unrelated patients with 46,XY karyotype were examined. Four of them were born with ambiguous genitalia and 1 patient, who was raised as girl, presented with primary amenorrhea. The hCG test was informative (elevated testosterone/DHT) of 5αSRD in 3 out of 4 subjects. Sequencing of the SRD5A2 gene was completed for all patients. Genomic DNA was also isolated from a total of 204 healthy unrelated Cypriot subjects. Screening for the IVS1-2A>G mutation was performed by using direct sequencing and restriction enzyme analysis. Results: The IVS1-2A>G was identified in homozygosity in 3 patients and in a compound heterozygote state in the other 2 patients, in combination with p.P181L and p.R171S in exon 3, respectively. The carrier frequency in the Cypriot population for the IVS1-2A>G mutation was estimated to be 0.98% or 2 in 204. Conclusions: The same IVS1-2A>G mutation in the SRD5A2 gene seems to characterize all Cypriot patients with 5αSRD diagnosed so far. Furthermore this relatively rare genetic defect, which has only been reported previously in a single case in the Eastern Mediterranean region, is very likely to be the result of a founder effect.

Background/Aim: To determine the mutations in the CYP21A2 gene in Greek-Cypriots with congenital adrenal hyperplasia (CAH) and attempt a genotype-phenotype correlation. Subjects and Methods: Molecular analysis was performed by multiplex ligation-dependent probe amplification and direct sequencing of PCR products of the CYP21A2 gene in 32 CAH patients. Results: The most frequent genetic defect in the classic salt-wasting and simple virilizing forms was the IVS2-13A/C>G (55%) mutation, followed by Large lesion (20%) and in the non-classical form, the p.V281L (79.5%). Genotypes were categorized in 4 mutation groups (null, A, B and C). All 3 patients in the null group manifested the salt-wasting form and all 6 patients in mutation group A presented with the classical form. One patient in group B had the simple virilizing form and 22 patients in group C exhibited the non-classical form. Conclusion: The spectrum of mutations of the CYP21A2 gene in our population is comparable to the most common reported in similar ethnic groups. The knowledge of the ethnic specificity of the CYP21A2 mutations represents a valuable diagnostic tool for all forms of CAH.

Summary Introduction Anogenital distance (AGD) is a recognised marker of in utero androgen action. Objective This study aimed to evaluate the relationship between severity of hypospadias and AGD. Study design Boys undergoing hypospadias repair in a single tertiary centre between May 2012 and February 16 were included in the study. Anogenital distance was measured from the centre of the anus to the base of the penis, and anoscrotal distance (ASD) from the centre of the anus to the junction between the smooth perineal skin and scrotal skin. Trained paediatric urologists made all measurements using digital callipers. Results Fifty-nine boys with hypospadias and 31 age-matched controls undergoing circumcision (median age 1.37 years, range 1.01–1.96) had AGD and ASD measured under anaesthetic. The patients were divided into two groups, according to hypospadias severity: group 1 – distal penile/subcoronal/glandular (n = 40); and group 2 – perineal/penoscrotal/midshaft (n = 19). The median AGD for controls was 74.0 mm (range 53.2–87.8) and for hypospadias it was 72.3 mm (range 50.7–90.0) (P = 0.816). The median ASD for controls was 42.3 mm (range 31.0–56.1) and for hypospadias it was 39.4 mm (range 20.7–77.0) (P = 0.224). Considering severity of hypospadias, the median AGD for group 1 and group 2 was 73.7 mm (range 50.7–90.0) and 63.3 mm (range 53.6–77.0), respectively (P Discussion This study showed that more severe forms of hypospadias are associated with shorter AGD and ASD. These findings agree with two previous studies that identified reduced AGD in boys with hypospadias. However, these studies did not investigate an association with severity of hypospadias. As hypospadias is multifactorial, only a small proportion of cases are thought to be associated with impaired in utero androgen exposure. The shorter AGD in boys with severe hypospadias compared with mild hypospadias would indicate that AGD is a marker of the severity of androgen production. This may also suggest that less severe forms of hypospadias have a different aetiology involving a later stage of development, and that they are not the result of reduced androgen exposure in the male programming window between the 8–14 weeks gestation. Conclusion This study identified that boys with more severe hypospadias are more likely to have a shorter AGD and ASD than boys with mild hypospadias. This may indicate that there is a more profound impairment of in utero androgen action in severe hypospadias. Download : Download high-res image (104KB) Download : Download full-size image Summary Fig. . Anogenital and anoscrotal distances according to hypospadias severity. AGD, anogenital distance; ASD, anoscrotal distance. Mild = glandular, coronal or distal penile hypospadias; Severe = mid-shaft, penoscrotal or perineal hypospadias. *Severely shorter compared with mild, P