PLS3 Mutations in X-Linked Osteoporosis: Clinical and Genetic Features in Five New Families.

Childhood-onset osteoporosis is a rare but clinically significant condition. Studies have shown pathogenic variants in more than 20 different genes as causative for childhood-onset primary osteoporosis. The X-chromosomal PLS3, encoding Plastin-3, is one of the more recently identified genes. In this study, we describe five new families from four different European countries with PLS3-related skeletal fragility. The index cases were all hemizygous males presenting with long bone and vertebral body compression fractures. All patients had low lumbar spine bone mineral density (BMD). The age at the first clinical fracture ranged from 1.5 to 13 years old. Three of the identified PLS3 variants were stop-gain variants and two were deletions involving either a part or all exons of the gene. In four families the variant was inherited from the mother. All heterozygous women reported here had normal BMD and no bone fractures. Four patients received bisphosphonate treatment with good results, showing a lumbar spine BMD increment and vertebral body reshaping after 10 months to 2 years of treatment. Our findings expand the genetic spectrum of PLS3-related osteoporosis. Our report also shows that early treatment with bisphosphonates may influence the disease course and reduce the progression of osteoporosis, highlighting the importance of early diagnosis for prompt intervention and appropriate genetic counseling.

No relationship between male pubertal timing and depression - new insights from epidemiology and Mendelian randomization.

BACKGROUND: In males, the relationship between pubertal timing and depression is understudied and less consistent than in females, likely for reasons of unmeasured confounding. To clarify this relationship, a combined epidemiological and genetic approach was chosen to exploit the methodological advantages of both approaches. METHODS: Data from 2026 males from a nationwide, representative study were used to investigate the non-/linear relationship between pubertal timing defined by the age at voice break and depression, considering a multitude of potential confounders and their interactions with pubertal timing. This analysis was complemented by Mendelian randomization (MR), which is robust to inferential problems inherent to epidemiological studies. We used 71 single nucleotide polymorphisms related to pubertal timing in males as instrumental variable to clarify its causal relationship with depression based on data from 807 553 individuals (246 363 cases and 561 190 controls) by univariable and multivariable MR, including BMI as pleiotropic phenotype. RESULTS: Univariable MR indicated a causal effect of pubertal timing on depression risk (inverse-variance weighted: OR 0.93, 95%-CI [0.87-0.99)], p = 0.03). However, this was not confirmed by multivariable MR (inverse-variance weighted: OR 0.95, 95%-CI [0.88-1.02)], p = 0.13), consistent with the epidemiological approach (OR 1.01, 95%-CI [0.81-1.26], p = 0.93). Instead, the multivariable MR study indicated a causal relationship of BMI with depression by two of three methods. CONCLUSIONS: Pubertal timing is not related to MDD risk in males.

No evidence for a causal contribution of bioavailable testosterone to ADHD in sex-combined and sex-specific two-sample Mendelian randomization studies.

The higher prevalence of attention-deficit/hyperactivity disorder (ADHD) in males raises the question of whether testosterone is implicated in ADHD risk. However, cross-sectional studies did not identify an association between ADHD and testosterone levels. Mendelian randomization (MR) studies can overcome limitations inherent to association studies, especially of reverse causation and residual confounding. In the current study, sex-combined and sex-specific two-sample MR analyses were conducted to address whether testosterone has a causal influence on ADHD risk. Sex-combined as well as sex-specific target-genetic variants for bioavailable testosterone were derived from a large genome-wide association study (GWAS) on up to 382,988 adult white European UK Biobank study participants. In our sex-specific analyses for ADHD, including data from 14,154 males and 4,945 females with ADHD (17,948 and 16,246 controls respectively), no association between bioavailable testosterone and ADHD risk was found, neither in males (inverse-variance weighted (IVW): beta = 0.09, 95%-CI [-0.10, 0.27]) nor in females (IVW: beta=-0.01, 95%-CI [-0.20, 0.19]). However, in the sex-combined analysis, including 38,691 cases and 186,843 controls, genetically predicted bioavailable testosterone was associated with ADHD risk (IVW: beta = 0.24, 95%-CI [0.09, 0.39]). The inclusion of birth weight and/or SHBG as additional variables in multivariable MR analyses did not alter this result. However, when correcting for potential BMI-driven pleiotropy by a multivariable MR study, all effect estimates for testosterone showed non-significant results. Taken together, no robust evidence for a causal effect of bioavailable testosterone on the risk for ADHD was found.

Novel Variants of SOX4 in Patients with Intellectual Disability.

SOX4 is a transcription factor with pleiotropic functions required for different developmental processes, such as corticogenesis. As with all SOX proteins, it contains a conserved high mobility group (HMG) and exerts its function via interaction with other transcription factors, such as POU3F2. Recently, pathogenic SOX4 variants have been identified in several patients who had clinical features overlapping with Coffin-Siris syndrome. In this study, we identified three novel variants in unrelated patients with intellectual disability, two of which were de novo (c.79G>T, p.Glu27*; c.182G>A p.Arg61Gln) and one inherited (c.355C>T, p.His119Tyr). All three variants affected the HMG box and were suspected to influence SOX4 function. We investigated the effects of these variants on transcriptional activation by co-expressing either wildtype (wt) or mutant SOX4 with its co-activator POU3F2 and measuring their activity in reporter assays. All variants abolished SOX4 activity. While our experiments provide further support for the pathogenicity of SOX4 loss-of-function (LOF) variants as a cause of syndromic intellectual disability (ID), our results also indicate incomplete penetrance associated with one variant. These findings will improve classification of novel, putatively pathogenic SOX4 variants.

Use of insulin pump therapy is associated with reduced hospital-days in the long-term: a real-world study of 48,756 pediatric patients with type 1 diabetes.

In pediatric diabetes, insulin pump therapy is associated with less acute complications but inpatient pump education may lead to more hospital days. We investigated the number of hospital days associated with pump vs. injection therapy between 2009 and 2018 in 48,756 patients with type 1 diabetes < 20 years of age from the German Diabetes Prospective Follow-up Registry (DPV). Analyses were performed separately for hospitalizations at diagnosis (hierarchical linear models adjusted for sex, age, and migration), and for hospitalizations in the subsequent course of the disease (hierarchical Poisson models stratified by sex, age, migration, and therapy switch). At diagnosis, the length of hospital stay was longer with pump therapy than with injection therapy (mean estimate with 95% CI: 13.6 [13.3-13.9] days vs. 12.8 [12.5-13.1] days, P < 0.0001), whereas during the whole follow-up beyond diagnosis, the number of hospital days per person-year (/PY) was higher with injection therapy than with pump therapy (4.4 [4.1-4.8] vs. 3.9 [3.6-4.2] days/PY), especially for children under 5 years of age (4.9 [4.4-5.6] vs. 3.5 [3.1-3.9] days/PY).Conclusions: Even in countries with hospitalizations at diabetes diagnosis of longer duration, the use of pump therapy is associated with a reduced number of hospital days in the long-term. What is known: • In pediatric diabetes, insulin pump therapy is associated with better glycemic control and less acute complications compared with injection therapy. • However, pump therapy implies more costs and resources for education and management. What is new: • Even in countries where pump education is predominantly given in an inpatient setting, the use of pump therapy is associated with a reduced number of hospital days in the long-term. • Lower rates of hospitalization due to acute complications during the course of the disease counterbalance longer hospitalizations due to initial pump education.

Effect of vitamin D deficiency on depressive symptoms in child and adolescent psychiatric patients: results of a randomized controlled trial.

PURPOSE: While observational studies revealed inverse associations between serum vitamin D levels [25(OH)D] and depression, randomized controlled trials (RCT) in children and adolescents are lacking. This RCT examined the effect of an untreated vitamin D deficiency compared to an immediate vitamin D3 supplementation on depression scores in children and adolescents during standard day and in-patient psychiatric treatment. METHODS: Patients with vitamin D deficiency [25(OH)D ≤ 30 nmol/l] and at least mild depression [Beck Depression Inventory II (BDI-II) > 13] (n = 113) were 1:1 randomized into verum (VG; 2640 IU vitamin D3/d) or placebo group (PG) in a double-blind manner. During the intervention period of 28 days, both groups additionally received treatment as usual. BDI-II scores were assessed as primary outcome, DISYPS-II (Diagnostic System for Mental Disorders in Childhood and Adolescence, Self- and Parent Rating) and serum total 25(OH)D were secondary outcomes. RESULTS: At admission, 49.3% of the screened patients (n = 280) had vitamin D deficiency. Although the intervention led to a higher increase of 25(OH)D levels in the VG than in the PG (treatment difference: + 14 ng/ml; 95% CI 4.86-23.77; p = 0.003), the change in BDI-II scores did not differ (+ 1.3; 95% CI - 2.22 to 4.81; p = 0.466). In contrast, DISYPS parental ratings revealed pronounced improvements of depressive symptoms in the VG (- 0.68; 95% CI - 1.23 to - 0.13; p = 0.016). CONCLUSION: Whereas this study failed to show a vitamin D supplementation effect on self-rated depression in adolescent in- or daycare patients, parents reported less depressive symptoms in VG at the end of our study. Future trials should consider clinician-rated depressive symptoms as primary outcome. TRIAL REGISTRATION: "German Clinical Trials Register" ( https://www.drks.de ), registration number: DRKS00009758.

Effect of an vitamin D deficiency on depressive symptoms in child and adolescent psychiatric patients - a randomized controlled trial: study protocol.

BACKGROUND: Depression is a significant health and economic burden worldwide affecting not only adults but also children and adolescents. Current treatment options for this group are scarce and show moderate effect sizes. There is emerging evidence that dietary patterns and specific nutritional components might play a role in the risk for developing depression. This study protocol focusses on the role of vitamin D which is for long known to be relevant for calcium and phosphorous homeostasis and bone health but might also impact on mental health. However, the assessment of the vitamin D status of depressed juvenile patients, or supplementation of vitamin D is currently not part of routine treatment. Controlled intervention studies are indispensable to prove whether a vitamin D deficiency ameliorates depressive symptoms. METHODS/DESIGN: This double blinded, randomized controlled trial will enroll 200 inpatients from a child and adolescent psychiatric department with a vitamin D deficiency defined by a 25(OH)-vitamin D-level < 30 nmol/l (12 ng/ml) and a Beck Depressions Inventory (BDI-II) score > 13 (indicating at least: mild depression). Upon referral, all patients will be screened, checked for inclusion criteria, and those eligible will be randomized after written consent into a supplementation or placebo group. Both study-arms will receive treatment-as-usual for their psychiatric disorder according to established clinical guidelines. The participants of the vitamin D supplementation group will receive 2640 I.E. vitamin D3 q.d. for 28 days in accordance with best practice in pediatric endocrinology. We hypothesize that delaying supplementation of vitamin D in the placebo arm will affect the treatment success of the depressive symptomatology in comparison to the vitamin D supplementation group. Patients will be enrolled for a period of 28 days based on the mean length of hospitalization of juveniles with depression. DISCUSSION: Randomized controlled trials in children and adolescents with depression are needed to elucidate the role of a vitamin D deficiency for mental disorders and to investigate the relevance of a routine assessment and supplementation of vitamin D deficits. TRIAL REGISTRATION: DRKS00009758, 16/06/2016 (retrospectively registered).

Granulocyte transfusions in critically ill children with prolonged neutropenia: side effects and survival rates from a single-center analysis.

UNLABELLED: Granulocyte transfusions for neutropenic patients have been used for over 40 years, although effectiveness, indications, and both patient and donor safety remain debated. This single-center study assessed the side effects, clinical course, and survival of granulocyte transfusions in critically ill pediatric patients, with underlying hemato-oncological disorders, prolonged neutropenia, and proven or suspected severe infection. Donor-specific side effects and influence of donor-specific characteristics on patient outcome were also investigated. A median of 4.02 × 10(10) cells was collected from 39 healthy donors for 118 granulocyte concentrates. Donors reported no significant side effects. Complications for patients were frequent but mostly minor and included vomiting, hypotension, and dyspnea. In one episode of life-threatening dyspnea, association with the granulocyte transfusion could not be ruled out. Overall survival on day 100 was 61.9 %. Patients received a median of 0.13 × 10(10) cells per kg body weight. Doses above this median were associated with a significantly better survival. Lower patient weight and age-/sex-adjusted weight were also associated with better survival. CONCLUSION: Granulocyte mobilization and collection is a safe practice. Transfusions are well tolerated in critically ill patients. Patient weight and transfused cells per kg bodyweight are major determinants of survival in pediatric patients. WHAT IS KNOWN: • Granulocyte transfusions for neutropenic patients have been used for over 40 years • The effectiveness of the technique remains controversial • Patient and donor safety remain debated • New mobilization protocols generate higher yields of granulocytes What is new: • Granulocyte collection can safely be performed • Granulocytes can safely be administered to patients • Lower patient weight and age-/sex-adjusted weight are associated with better survival rates • Patients receiving above 0.13 × 10 (10) cells per kg body weight had an excellent outcome • Further standardized, prospective studies are warranted.

Pediatric Survivors of Retinoblastoma Are at Risk for Altered Bone Metabolism After Chemotherapy Treatment Early in Life.

Survivors of childhood cancer frequently suffer from endocrine late effects, which are, at least partly, attributed to toxic effects of chemotherapy. Treatment of retinoblastoma typically involves chemotherapy at a very young age. The authors conducted a cross-sectional study to assess bone health in a pediatric cohort of 33 survivors of retinoblastoma (mean age: 4.4 years) who had undergone chemotherapy treatment at an especially young age (mean age: 0.76 years). Of these patients, 14 had unilateral and 19 bilateral retinoblastoma. Polychemotherapy consisted of treatment with cyclophosphamide, etoposide, vincristine, and carboplatin. Ten patients had undergone external beam radiotherapy. Clinical and biochemical parameters of growth, pubertal development, and bone health were obtained. A vitamin D deficiency was found in 51.7% of the patients, and 13.7% of patients displayed severe vitamin D deficiency. Secondary hyperparathyroidism and altered readings for bone formation or resorption markers were present in 15%. Nine percent reported bone pain or experienced fractures of the long bones after primary diagnosis. No difference between children with bilateral and unilateral disease or irradiated versus nonirradiated children was observed. The parameters of thyroid function, growth, and pubertal development were within age-appropriate norms in almost all children. In conclusion, altered parameters of bone health can be present in survivors of retinoblastoma at a young age and warrant regular follow-up in these children. The endocrine hypothalamic-pituitary axes, however, were not impaired at this early age in this group of survivors of retinoblastoma.

New Reference Values for Thyroid Volume by Ultrasound in German Children and Adolescents from a Population-Based Study.

CONTEXT: Reliable reference values for thyroid ultrasound measurements are essential to effectively guide individual diagnostics and direct health care measures at the population level, such as iodine fortification programs. However, the latest reference values for total thyroid volume (Tvol) provided by the WHO in 2004 only apply to the 6 to 12-year-old age group and are limited to countries with a long history of iodine sufficiency, which does not reflect the situation in most European countries, including Germany. OBJECTIVE: The present aims to derive up to date thyroid volume ultrasound reference values in German children and adolescents. DESIGN: Data from the baseline assessment of a nationwide study in German children and adolescents (KiGGS) conducted between 2003 and 2006 were used to determine sex-specific reference values for Tvol in thyroid-healthy participants aged 6 to 17 years by age and body surface area (BSA) according to the Lambda-Mu-Sigma (LMS) method. RESULTS: Data from 5559 participants were available for reference chart construction (girls: 2509 (45.1%)). On average, the 97th percentile is 33.4% and 28.5% higher than the corresponding WHO's reference values for boys and girls, respectively. These findings are consistent with most other studies in German and European children and adolescents at a similar time of investigation. Notably, the sample used for this study was iodine-sufficient according to WHO criteria. CONCLUSIONS: The reference values provided by the WHO are overly conservative for this population and could potentially apply to other European countries with a similar history of iodine supply.

Resource utilization and costs of transitioning from pediatric to adult care for patients with chronic autoinflammatory and autoimmune disorders.

BACKGROUND: A structured transition of adolescents and young adults with chronic autoinflammatory and autoimmune disorders from the pediatric to the adult health care system is important. To date, data on the time, processes, outcome, resources required for the necessary components of the transition process and the associated costs are lacking. METHODS: Evaluation of resource use and costs in a prospective cohort study of 58 adolescents with chronic autoinflammatory and autoimmune disorders, for the key elements of a structured transition pathway including (i) compilation of a summary of patient history, (ii) assessment of patients' disease-related knowledge and needs, (iii) required education and counseling sessions, (iv) and a transfer appointment of the patient with the current pediatric and the future adult rheumatologist. RESULTS: Forty-nine of 58 enrolled patients (84.5%) completed the transition pathway and were transferred to adult care. The mean time from the decision to start the transition process to the final transfer consultation was 315 ± 147 days. Transfer consultations were performed in 49 patients, including 10 patients jointly with the future adult rheumatologist. Most consultations were performed by the multidisciplinary team with a median of three team members and lasted 65.5 ± 21.3 min. The cumulative cost of all consultation and education sessions performed including the transfer appointment was 283 ± 164 Euro per patient. In addition, the cost of coordinating the transition process was 57.3 ± 15.4 Euro. CONCLUSIONS: A structured transition pathway for patients with chronic autoinflammatory and autoimmune disorders is resource and time consuming and should be adequately funded.

Cardiorespiratory fitness in adolescents and young adults with Klinefelter syndrome - a pilot study.

Background: Klinefelter syndrome (KS) may be associated with a wide spectrum of phenotypic changes including endocrine, metabolic, cognitive, psychiatric and cardiorespiratory pathologies in adults. However, in adolescence the clinical phenotype of KS is not well described, especially regarding physical fitness. The present study reports on cardiorespiratory function in adolescents and young adults with KS. Methods: Adolescents and young adults with KS were recruited in a cross-sectional pilot study. Biochemical parameters of fitness including hormonal status, a body impedance analysis, the grip strength, the amount of physical activity at home for 5 days via trackbands and anamnestic parameters were assessed. In addition, participants underwent an incremental symptom-limited cardiopulmonary exercise test (CPET) on a bicycle ergometer. Results: Nineteen participants with KS aged 15.90 ± 4.12 years (range: 9.00 - 25.00) participated in the study. Pubertal status was Tanner 1 (n = 2), Tanner 2 - 4 (n = 7) and Tanner 5 (n = 10). Seven participants received testosterone replacement therapy. Mean BMI z-score was 0.45 ± 1.36 and mean fat mass was 22.93% ± 9.09. Grip strength was age-appropriate or above normal. 18 participants underwent CPET with subnormal results for maximum heart rate (z-score -2.84 ± 2.04); maximum workload (Wattmax; z score -1.28 ± 1.15) and maximum oxygen uptake per minute (z- score -2.25 ± 2.46). Eight participants (42.1%) met the criteria for chronotropic insufficiency (CI). Data from track-bands showed sedentary behavior for 81.15% ± 6.72 of the wear time. Conclusion: A substantial impairment of cardiopulmonary function can be detected in this group of boys to young adults with KS, including chronotropic insufficiency in 40%. The track-band data suggest a predominantly sedentary lifestyle, despite normal muscular strength as assessed via grip strength. Future studies need to investigate the cardiorespiratory system and its adaption to physical stress in a larger cohort and in more detail. It is feasible that the observed impairments contribute to the avoidance of sports in individuals with KS and may contribute to the development of obesity and the unfavorable metabolic phenotype.

Data collection on rare bone and mineral conditions in Europe: The landscape of registries and databases.

BACKGROUND: knowledge on the natural history of rare diseases is necessary to improve outcomes. Disease registries may play a key role in covering these unmet needs in the rare bone and mineral community. OBJECTIVE: to map existing bone and mineral conditions registries in Europe and their characteristics. METHODS: online survey about the use of registries/databases and their characteristics. This survey was disseminated among members of the European Reference Network on Rare Bone Diseases (ERN BOND) and non-ERN experts in the field of bone and mineral conditions as well as patient organisations. RESULTS: sixty-three responses from health care providers (HCPs) and 10 responses from patient groups (PGs) were collected. The response rate for ERN BOND members was 55%. Of 63 HCPs, 37 declared using a registry. Osteogenesis imperfecta (OI) was the most registered condition. We mapped 3 international registries, all were disease-specific. CONCLUSIONS: There is a need for developing a common high-quality platform for registering rare bone and mineral conditions.

Transition for adolescents with a rare disease: results of a nationwide German project.

PURPOSE: The transition process from paediatric/adolescent to adult medical care settings is of utmost importance for the future health of adolescents with chronic diseases and poses even more difficulties in the context of rare diseases (RDs). Paediatric care teams are challenged to deliver adolescent-appropriate information and structures. Here we present a structured transition pathway which is patient-focused and adoptable for different RDs. METHODS: The transition pathway for adolescents 16 years and older was developed and implemented as part of a multi-centre study in 10 university hospitals in Germany. Key elements of the pathway included: assessment of patients' disease-related knowledge and needs, training/educational and counselling sessions, a structured epicrisis and a transfer appointment jointly with the paediatric and adult specialist. Specific care coordinators from the participating university hospitals were in charge of organization and coordination of the transition process. RESULTS: Of a total of 292 patients, 286 completed the pathway. Deficits in disease-specific knowledge were present in more than 90% of participants. A need for genetic or socio-legal counselling was indicated by > 60%. A mean of 2.1 training sessions per patient were provided over a period of almost 1 year, followed by the transfer to adult care in 267 cases. Twelve patients remained in paediatric care as no adult health care specialist could be identified. Targeted training and counselling resulted in improved disease-specific knowledge and contributed to empowering of patients. CONCLUSION: The described transition pathway succeeds to improve health literacy in adolescents with RDs and can be implemented by paediatric care teams in any RD specialty. Patient empowerment was mainly achieved by individualized training and counselling.

Subclinical Hypothyroidism and Incident Depression in Adolescents and Young Adults: Results from a Nationwide Representative Prospective Study.

Background: Although the relationship between subclinical hypothyroidism and major depressive disorder (MDD) has been studied in adults in cross-sectional and prospective population-based studies, this has not yet been done in adolescents. However, since thyroid function and MDD risk are subjected to maturational processes and ramifications of illness duration over the life span, these findings may not readily transfer to adolescents. Methods: The relationship between subclinical hypothyroidism and MDD was studied in a representative subsample of the nationwide KIGGS ("The German Health Interview and Examination Survey for Children and Adolescents") survey. A total of 4118 adolescents were examined over a median period of 6 years, and data were analyzed by a logistic regression approach accounting for important covariates related to thyroid function and/or MDD risk. The same approach was chosen to investigate the relationship between quartiles of thyrotropin (TSH) and free thyroxine (fT4) levels and incident MDD in euthyroid participants to broaden the focus on the relationship between thyroid hormone levels and MDD in a dose-response manner. Results: During the observation period, 121 cases of MDD were reported. There was no association between subclinical hypothyroidism and MDD when comparing 111 adolescents with subclinical hypothyroidism with 4007 euthyroid adolescents, representative of ∼106,000 and 3,610,000 adolescents from the general pediatric population, respectively. This also applied when studying the relationship between quartiles of TSH and fT4 levels and MDD in euthyroid participants. All results were confirmed by sensitivity analyses accounting for thyroid autoimmunity. Conclusions: Consistent with findings in adults, there is no association between subclinical hypothyroidism or quartiles of TSH and fT4 levels in the normal range and MDD in adolescents, despite potential age-related differences regarding thyroid function and MDD risk.

Disorders of the Calcium Sensing Signaling Pathway: From Familial Hypocalciuric Hypercalcemia (FHH) to Life Threatening Conditions in Infancy.

Familial hypocalciuric hypercalcemia (FHH) is a mostly benign condition of elevated calcium and PTH levels based on a hyposensitive calcium sensing receptor (CaSR) in FHH 1 or its downstream regulatory pathway in FHH2 and FHH3. In children, adolescents and young adults with FHH the main challenge is to distinguish the condition from primary hyperparathyroidism and thereby to avoid unnecessary treatments including parathyroidectomy. However, inheritance of FHH may result in neonatal hyperparathyroidism (NHPT) or neonatal severe hyperparathyroidism (NSHPT), conditions with high morbidity, and in the latter even high mortality. This review focuses on the genetic and pathophysiological framework that leads to the severe neonatal form, gives recommendations for counselling and summarizes treatment options.

Causal Effect of Age at Menarche on the Risk for Depression: Results From a Two-Sample Multivariable Mendelian Randomization Study.

A fair number of epidemiological studies suggest that age at menarche (AAM) is associated with depression, but the reported effect sizes are small, and there is evidence of residual confounding. Moreover, previous Mendelian randomization (MR) studies to avoid inferential problems inherent to epidemiological studies have provided mixed findings. To clarify the causal relationship between age at menarche and broadly defined depression risk, we used 360 genome-wide significantly AAM-related single-nucleotide polymorphisms (SNPs) as instrumental variable and data from the latest GWAS for the broadly defined depression risk on 807,553 individuals (246,363 cases and 561,190 controls). Multiple methods to account for heterogeneity of the instrumental variable (penalized weighted median, MR Lasso, and contamination mixture method), systematic and idiosyncratic pleiotropy (MR RAPS), and horizontal pleiotropy (MR PRESSO and multivariable MR using three methods) were used. Body mass index, education attainment, and total white blood count were considered pleiotropic phenotypes in the multivariable MR analysis. In the univariable [inverse-variance weighted (IVW): OR = 0.96, 95% confidence interval = 0.94-0.98, p = 0.0003] and multivariable MR analysis (IVW: OR = 0.96, 95% confidence interval = 0.94-0.99, p = 0.007), there was a significant causal effect of AAM on depression risk. Thus, the present study supports conclusions from previous epidemiological studies implicating AAM in depression without the pitfalls of residual confounding and reverse causation. Considering the adverse consequences of an earlier AAM on mental health, this finding should foster efforts to address risk factors that promote an earlier AAM.

The adrenal steroid profile in adolescent depression: a valuable bio-readout?

There is preliminary evidence that adrenal steroids other than cortisol may be valuable biomarkers for major depressive disorder (MDD). So far, studies have been conducted in adults only, and conclusions are limited, mainly due to small sample sizes. Therefore, the present study assessed whether adrenal steroids serve as biomarkers for adolescent MDD. In 261 depressed adolescents (170 females) treated at a single psychiatric hospital, serum adrenal steroids (progesterone, 17-hydroxyprogesterone, 21-deoxycortisol, 11-deoxycortisol, cortisol, cortisone, deoxycorticosterone, corticosterone) were determined by liquid chromatography-tandem mass spectrometry. Findings were compared to that of an age- and sex-matched reference cohort (N = 255) by nonparametric analysis of variance. Nonparametric receiver operating characteristics (ROC) analyses were conducted to evaluate the diagnostic performance of single steroids and steroid ratios to classify depression status. Sensitivity analyses considered important confounders of adrenal functioning, and ROC results were verified by cross-validation. Compared to the reference cohort, levels of deoxycorticosterone and 21-deoxycortisol were decreased (P < 0.001). All other glucocorticoid- and mineralocorticoid-related steroids were increased (P < 0.001). The corticosterone to deoxycorticosterone ratio evidenced excellent classification characteristics, especially in females (AUC: 0.957; sensitivity: 0.902; specificity: 0.891). The adrenal steroid metabolome qualifies as a bio-readout reflecting adolescent MDD by a distinct steroid pattern that indicates dysfunction of the hypothalamus-pituitary-adrenal axis. Moreover, the corticosterone to deoxycorticosterone ratio may prospectively qualify to contribute to precision medicine in psychiatry by identifying those patients who might benefit from antiglucocorticoid treatment or those at risk for recurrence when adrenal dysfunction has not resolved.

Prevalence of osteopathologies in a single center cohort of survivors of childhood primary brain tumor.

Background: Childhood primary brain tumors (CPBT) are the second largest group of childhood malignancies and associated with a high risk for endocrine late effects. Objective: To assess endocrine late effects and their relevance for the development of osteopathologies in survivors. Methods: This single center cross sectional study investigated data from 102 CPBT survivors with a mean age of 13.0 years and a mean age at diagnosis of 8.7 years. Clinical, biochemical, radiographic, and anamnestic data regarding endocrine and bone health were obtained at study visits. In addition, data regarding tumor stage and therapy was obtained by chart review. An expert opinion was applied to define presence of osteopathologies. Results: Impaired bone health, defined by at least one pathological screening parameter, was present in 65% of patients. 27.5% were found to have overt osteopathologies per expert opinion. 37.8% displayed a severe vitamin D deficiency (25-OH vitamin D < 10 ng/ml) and 11% a secondary hyperparathyroidism. Patients with osteopathologies had lower 25-OH vitamin D levels compared to patients without osteopathologies. Multiple endocrine late effects were present: diabetes insipidus in 10.8%, aberrant pubertal development in 13.7%, central hypocortisolism in 14.9%, thyroid dysfunction in 23.8% and growth hormone deficiency in 21.8%. A total of 31.3% of survivors displayed any endocrinopathy. Tumors located near hypothalamic structures and patients who received irradiation had a higher likelihood of endocrine morbidity. Conclusion: This study indicates that endocrine deficiencies are common in pediatric survivors of CPBTs. Osteopathologies are present in this cohort. A prominent effect of hormonal deficiencies on bone health was not detected, possibly because patients were sufficiently treate for their endocrine conditions or indicating resilience of the childhood bone remodeling process. Vitamin D deficiency is frequent and should be treated as recommended.

Age at menarche relates to depression in adolescent girls: Comparing a clinical sample to the general pediatric population.

CONTEXT: The timing of puberty, physical features of pubertal development, and hormones are closely intertwined but may also individually contribute to the risk for depression and depression severity. Additionally, their effects on mood may depend on depression severity, but previously this has only been studied in mostly subclinical depression. METHODS: In 184 girls from a single psychiatric hospital with significant depressive symptoms (Beck Depression Inventory-II score > 13), the relationship between depression severity and age at menarche (AAM), pubertal status, and gonadal/adrenal hormones (estradiol, progesterone, DHEA-S, androstenedione, testosterone, dihydrotestosterone) was investigated. Moreover, AAM in depressed girls was compared to that from a representative sample of German adolescents without a psychiatric disorder (N = 1674). Androgen levels were compared to those of age- and sex-matched controls (N = 59). RESULTS: AAM but not pubertal stage or biochemical parameters related to depression. Girls with AAM at the lower normative range of pubertal development were 61 % more likely to develop depression and scored 4.9 points higher on the depression scale than girls experiencing menarche at the population average. Androstenedione levels were increased in the psychiatric sample, but neither androgen nor gonadal hormone levels were associated with depression severity. LIMITATIONS: The study is cross-sectional. CONCLUSIONS: These observations confirm previous studies in mostly subclinical depression and highlight the importance of AAM for adolescent depression. Thus, AAM could be considered a prognostic factor for a clinical risk score assessing the probability of adolescent depression. Moreover, these findings suggest fostering efforts that address risk factors that contribute to an earlier AAM.