Inter-individual variation in ovarian reserve after gonadotoxic treatment in female childhood cancer survivors - a genome-wide association study: results from PanCareLIFE.

OBJECTIVE: We aimed to discover new variants associated with low ovarian reserve after gonadotoxic treatment among adult female childhood cancer survivors using a genome-wide association study approach. DESIGN: Genome-wide association study. SUBJECTS: A discovery cohort of adult female childhood cancer survivors, from the pan-European PanCareLIFE cohort (n=743; median age: 25.8 years), excluding those who received bilateral ovarian irradiation, bilateral oophorectomy, central nerve system or total body irradiation, or stem cell transplantation. Replication was attempted in the USA-based St. Jude Lifetime Cohort (n=391; median age: 31.3 years). EXPOSURE: Female childhood cancer survivors are at risk of therapy-related gonadal impairment. Alkylating agents are well-established risk factors, and the inter-individual variability in gonadotoxicity may be explained by genetic polymorphisms. Data were collected in real-life conditions and cyclophosphamide equivalent dose was used to quantify alkylation agent exposure. INTERVENTION: No intervention was performed. MAIN OUTCOME MEASURE: Anti-Müllerian hormone (AMH) levels served as a proxy for ovarian function and findings were combined in a meta-analysis. RESULTS: Three genome-wide significant (<5.0x10-8) and 16 genome-wide suggestive (<5.0x10-6) loci were associated with log-transformed AMH levels, adjusted for cyclophosphamide equivalent dose of alkylating agents, age at diagnosis, and age at study in the PanCareLIFE cohort. Based on effect allele frequency (EAF) (>0.01 if not genome-wide significant), p-value (<5.0×10-6), and biological relevance, 15 SNPs were selected for replication. None of the SNPs were statistically significantly associated with AMH levels. A meta-analysis indicated that rs78861946 was associated at borderline genome-wide statistical significance (Reference/effect allele: C/T; EAF: 0.04, Beta (SE): -0.484 (0.091), p-value= 9.39×10-8). CONCLUSION: This study found no genetic variants associated with a lower ovarian reserve after gonadotoxic treatment, as the findings of this GWAS were not statistically significant replicated in the replication cohort. Suggestive evidence for potential importance of one variant is briefly discussed, but the lack of statistical significance calls for larger cohort sizes. As the population of childhood cancer survivors is increasing, large-scale and systematic research is needed to identify genetic variants that could aid predictive risk models of gonadotoxicity and as well as fertility preservation options for childhood cancer survivors.

Predictive factors for radiation-induced pituitary damage in pediatric patients with brain tumors.

BACKGROUND AND PURPOSE: Multiple studies demonstrated hypothalamic-pituitary dysfunction in survivors of pediatric brain tumors. However, few studies investigated the trajectories of pituitary height in these patients and their associations with pituitary function. We aimed to evaluate longitudinal changes of pituitary height in children and adolescents with brain tumors, and their association with endocrine deficiencies. MATERIALS AND METHODS: We conducted a retrospective analysis of 193 pediatric patients (54.9% male) diagnosed with brain tumors from 2002 to 2018, with a minimum of two years of radiological follow-up. Pituitary height was measured using MRI scans at diagnosis and at 2, 5, and 10 years post-diagnosis, with clinical data sourced from patient charts. RESULTS: Average age at diagnosis was 7.6 ± 4.5 years, with a follow-up of 6.1 ± 3.4 years. 52.8% underwent radiotherapy and 37.8% experienced pituitary hormone deficiency. Radiation treatment was a significant predictor of decreased pituitary height at all observed time points (p = 0.016, p < 0.001, p = 0.008, respectively). Additionally, chemotherapy (p = 0.004) or radiotherapy (p = 0.022) history and pituitary height at 10 years (p = 0.047) were predictors of endocrine deficiencies. ANOVA revealed an expected increase in pituitary height over time in pediatric patients, but this growth was significantly impacted by radiation treatment and gender (p for interaction = 0.005 and 0.025, respectively). CONCLUSION: Cranial irradiation in pediatric patients is associated with impairment of the physiologic increase in pituitary size; in turn, decreased pituitary height is associated with endocrine dysfunction. We suggest that pituitary gland should be evaluated on surveillance imaging of pediatric brain tumor survivors, and if small for age, clinical endocrine evaluation should be pursued.

Fracture risk among children and adolescents with celiac disease: a nationwide cohort study.

BACKGROUND: Metabolic bone disease is a common manifestation of celiac disease (CD). We aimed to assess fracture risk among children and adolescents with CD compared with a matched group. METHODS: This registry-based cohort study included 2372 children with CD who were matched 1:5 to 11,860 children without CD. Demographic and clinical data were obtained from the electronic database of Meuhedet, a health maintenance organization. Fracture events at ages 1-18 years were identified by coded diagnoses. RESULTS: The overall fracture incidence rate was 256 per 10,000 patient-years (PY) in the CD group and 165 per 10,000 PY in the comparison group (p < 0.001). The hazard ratio (HR) to have a fracture was 1.57 (95% CI 1.43-1.73, p < 0.001) for the CD group compared to the matched group. The HR for multiple fractures was 1.67 (95% CI 1.38-2.01, p < 0.001). Analysis of the pre- and post-diagnosis periods separately showed that the HR for fractures in the pre-diagnosis period was 1.64 (95% CI 1.42-1.88, p < 0.001) for the CD group compared to the matched group, and 1.52 (95% CI 1.26-1.71, p < 0.001) in the period from diagnosis to the end of the follow-up period. CONCLUSIONS: Children with CD had increased fracture risk both preceding and following the diagnosis of CD. IMPACT: One manifestation of celiac disease (CD) is metabolic bone disease, including osteoporosis and impaired bone mineralization. We found increased fracture risk among children with CD, both preceding the CD diagnosis and during the years following the diagnosis. Recognition of the high risk of fractures in this population may help promote prevention. Further studies are needed to evaluate changes in bone quantity and quality after initiation of a gluten-free diet, and to identify those at risk for persistent metabolic bone disease.

Short Stature and Distinct Growth Characteristics in Angelman Syndrome.

Objectives - Angelman syndrome (AS) is a rare, genetic, neurodevelopmental disorder characterized by severe impairments in speech, cognition and motor skills accompanied by unique behaviors, distinct facial features and high prevalence of epilepsy and sleep problems. Despite some reports of short stature among AS patients, this feature is not included in the clinical criteria defined in 2005. We investigated growth patterns among AS patients with respect to mutation type, growth periods, family history and endocrine abnormalities. Methods - Data was collected from patients' medical files in AS national clinic. Mutation subtypes were divided to deletion and non-deletion. Four growth periods were defined: preschool, childhood, peak-height velocity, and final-height. Results - The cohort included 88 individuals (46 males), with 54 (61.4%) carrying deletion subtype. A median of 3 observations per individual , produced 280 data points. Final-height-SDS was significantly lower compared to general population (-1.23±1.26, p<0.001), and in deletion group vs. non-deletion (-1.67±1.3 vs. -0.65±0.96, p=0.03). Final-height-SDS was significantly lower compared to height-SDS in preschool period (-1.32 vs -0.47, p=0.007). Patient's final-height-SDS was significantly lower than the parents' (∆final-height-SDS=0.94±0.99, p=0.002). IGF1-SDS was significantly decreased compared to general population (-0.55±1.61, p=0.04), with lower values among deletion group (-0.70±1.44, p=0.01) Conclusions - AS patients demonstrate specific growth pattern with deceleration during childhood and adolescence resulting in significantly decreased final height compared to normal population, and even lower among deletion subgroup, which could be attributed to reduced IGF1 levels. We propose adding short stature to the clinical criteria and developing adjusted growth curves for AS population.

Impact of COVID-19 on Lifestyle Habits and Emotional State of Childhood Cancer Survivors and Their Parents.

OBJECTIVE: The COVID-19 pandemic and associated social distancing measures affected the physical and emotional state of children and parents worldwide. Survivors of childhood cancer may be particularly vulnerable to these effects. We aimed to evaluate the lifestyle habits and emotional states of childhood cancer survivors and their parents during the COVID-19 outbreak. METHODS: Lifestyle habits and emotional distress were assessed in 43 childhood cancer survivors (aged 8-21 years) and their parents before and during the COVID-19 lockdown, using the PROMIS anxiety and depression modules and the "Mabat Youth" questionnaire. RESULTS: Most parents (80.5%) reported eating more family meals during home confinement compared to their usual routine. Patients' physical activity levels did not change significantly during confinement, leisure-related screen time nearly doubled (p < 0.001), and sleep duration increased (p = 0.006). Anxiety levels of children (p = 0.045) and parents (p = 0.02) increased during confinement compared to pre-pandemic levels, with no significant changes in depression levels. CONCLUSIONS: Contrary to concerns regarding lifestyle habits during the COVID-19 lockdown, eating behaviors of childhood cancer survivors improved, sleep duration increased, and physical activity remained unchanged. Still, screen time increased significantly. Parents of childhood cancer survivors reported higher anxiety levels for themselves and their children during home confinement. Our findings may assist medical and psycho-social teams in guiding parents of cancer survivors during similar circumstances in the future.

Increased fracture risk among children diagnosed with attention- deficit/hyperactivity disorder: a large matched cohort study.

To analyse the risk of fractures among children with attention-deficit/hyperactivity disorder (ADHD) compared with matched children without ADHD; and to evaluate the impact of pharmacological treatment. This registry-based cohort study included 31,330 children diagnosed with ADHD and a comparison group of 62,660 children matched by age, sex, population sector and socioeconomic status. Demographic and clinical information was extracted from the electronic database of Meuhedet, a health maintenance organization. Fracture events between 2-18 years of age were identified by coded diagnoses. The overall fracture incidence rate was 334 per 10,000 patient-years (PY) in the ADHD group and 284 per 10,000 PY in the comparison group (p < 0.001). Among boys, the fracture incidence rates were 388 per 10,000 PY and 327 per 10,000 PY (p < 0.001), for the respective groups. Among girls, the rates were lower in both groups compared to boys, but higher in the ADHD compared to the matched group (246 vs 203 per 10,000 PY, p < 0.001). Among the children with ADHD, the hazard ratios (HR) to have a fracture were similar in boys (1.18, 95%CI 1.15-1.22, p < 0.001) and girls (1.22, 95%CI 1.16-1.28, p < 0.001). Children with ADHD were also at increased risk for two and three fractures; the hazard ratios (HRs) were 1.32 (95%CI 1.26-1.38, p < 0.001) and 1.35 (95%CI 1.24-1.46, p < 0.001), respectively. In a multivariable model of the children with ADHD, pharmacological treatment was associated with reduced fracture risk (HR 0.90, 95%CI 0.82-0.98, p < 0.001) after adjustment for sex, resident socioeconomic status and population sector.   Conclusion: Children with ADHD had greater fracture risk than a matched group without ADHD. Pharmacological treatment for ADHD may decrease this risk. What is Known: • Children with attention-deficit/hyperactivity disorder (ADHD) may be more prone to injuries and fractures than children without ADHD. What is New: • Children with ADHD were 1.2 times more likely to have a fracture than children with similar characteristics, without ADHD. The increased risk for fractures was even greater for two and three fractures (hazard ratios 1.32 and 1.35, respectively). • Our study suggests a positive effect of pharmacological treatment for ADHD in reducing fracture risk.

Growth hormone treatment and the risk of adolescent scoliosis: A large matched cohort study.

AIM: We aimed to evaluate the risk of developing adolescent scoliosis among recipients of recombinant human growth hormone (rhGH). METHODS: This registry-based cohort study included 1314 individuals who initiated rhGH treatment since 2013, treated during 10-18 years of age for at least 6 months. This group was matched to a comparison group of 6570 individuals not treated with rhGH. Demographic and clinical information was extracted from the electronic database. The results are presented using hazard ratios (HR) and 95% confidence intervals (CI). RESULTS: During a median follow-up of 4.2 years, 59 (4.5%) rhGH recipients and 141 individuals (2.1%) from the comparison group were diagnosed with adolescent scoliosis. The age at diagnosis did not differ between the groups (14.7 versus 14.3 years, p = 0.095). Patients treated with rhGH were more likely diagnosed with scoliosis (HR 2.12, 95% CI 1.55-2.88, p < 0.001). Among males, the risk was about three times greater in the treated versus the comparison group (HR 3.15, 95% CI 2.12-4.68, p < 0.001), while in females the risk was not increased (HR 1.12, 95% CI 0.72-2.04, p = 0.469). CONCLUSIONS: Recombinant human growth hormone treatment was associated with an increased risk to be diagnosed with adolescent scoliosis in males. Scoliosis development should be monitored appropriately in rhGH recipients.

Hypothalamic-pituitary-gonadal function, pubertal development, and fertility outcomes in male and female medulloblastoma survivors: a single-center experience.

BACKGROUND: Endocrine deficiencies, including hypothalamic-pituitary-gonadal axis (HPGA) impairment, are common in survivors of childhood and adolescent medulloblastoma. Still, data regarding pubertal development and fecundity are limited, and few studies assessed HPGA function in males. We aimed to describe HPGA function in a large cohort of patients with medulloblastoma. METHODS: A retrospective study comprising all 62 medulloblastoma patients treated in our center between 1987 and 2021, who were at least 2 years from completion of therapy. HPGA function was assessed based on clinical data, biochemical markers, and questionnaires. RESULTS: Overall, 76% of female patients had clinical or biochemical evidence of HPGA dysfunction. Biochemical evidence of diminished ovarian reserve was seen in all prepubertal girls (n = 4). Among the males, 34% had clinical or biochemical evidence of gonadal dysfunction, 34% had normal function, and 29% were age-appropriately clinically and biochemically prepubertal. The difference between males and females was significant (P = .003). Cyclophosphamide-equivalent dose was significantly associated with HPGA function in females, but not in males. There was no association between HPGA dysfunction and other endocrine deficiencies, length of follow-up, weight status, and radiation treatment protocol. Two female and 2 male patients achieved successful pregnancies, resulting in 6 live births. CONCLUSIONS: HPGA dysfunction is common after treatment for childhood medulloblastoma. This is seen more in females, likely due to damage to the ovaries from spinal radiotherapy. Our findings may assist in counseling patients and their families regarding risk to future fertility and need for fertility preservation.

Decreases in pediatric fractures during the COVID-19 pandemic - a nationwide epidemiological cohort study.

The COVID-19 pandemic led to fundamental changes in daily routines of children. Our aim was to evaluate the incidence and characteristics of fractures among Israeli children during 2020 compared with 2015-2019. Demographic, clinical data, and incidence rates of fractures in individuals aged < 18 years were derived from the electronic database of Meuhedet Health Services, which provides healthcare services to 1.2 million people in Israel. We further subdivided the year to five periods according to government regulations of lockdown and isolation at each period. Fracture sites were determined according to ICD9 definitions. During 2020, 10,701 fractures occurred compared with 12,574 ± 599 fractures per year during 2015-2019 (p-value < 0.001). Fracture rates were lower during all periods in 2020. The largest decline was observed during the first lockdown for both boys (56% decline, 95% confidence interval [CI] 52-60%) and girls (47% decline CI 41-53%). While the fracture rate declined for most age groups, the largest decline was recorded for the age group 11-14 years, with significant reduction rates of 66% (CI 59-71%) for boys and 65% (CI 54-73%) for girls. The most prominent declines were of fractures of the hand bones of both boys and girls (64% and 59%, respectively). Conclusions: Our data showed a significant decrease in fracture rate in 2020 compared to the previous 5 years, as well as differences between periods within that year. What is New: •The COVID-19 pandemic led to fundamental change in daily routines of children with significant decrease in school attendance and sport activities. •Consequent to these public health measures, the incidence rate of pediatric fractures decreased significantly. What is New: •This study demonstrates declines in fracture rates during lockdown periods, with only partial reversing of the trends between the lockdown periods. •The most pronounced decline was observed during the first lockdown period. •The decline was most prominent in children aged 11-14 years; there was no significant change in fracture incidence of children aged <3 years.

Epidemiology of childhood fractures in Israel during 2000-2019.

BACKGROUND: Differences have been reported in incidence rates of fractures in the pediatric population, between countries and over time. The aim of this study was to evaluate the incidence and characteristics of fractures over 20 years among Israeli children. METHODS: Incidence rates of fractures were derived from the electronic database of Meuhedet Health Services, a health maintenance organization providing healthcare services to 1.2 million people in Israel. Demographic and clinical data were extracted of all the fractures in individuals aged <18 years during 2000-2019. Fracture sites were determined according to ICD9 definitions. Fracture data were analyzed by age, sex, season and sector (general Jewish population, ultra-orthodox Jews and Arabs). RESULTS: During the study period 188,283 fractures occurred in 142,049 individuals. The most common were fractures of the upper limb (65%), followed by fractures of the lower limb [20%]. The overall fracture rate was 251 per 10,000 person- years (PY), and was higher for boys than girls (319 vs. 180 per 10,000 PY, p < 0.001). During 20 years, standardized fracture rates decreased significantly in the general Jewish population, among both boys (from 457 to 325 per 10,000 PY, p < 0.001) and girls (from 244 to 196 per 10,000 PY, p < 0.001); increased among ultra-orthodox Jewish boys (from 249 to 285 per 10,000 PY, p = 0.002) and girls (from 147 to 194 per 10,000 PY, p < 0.001); and did not change significantly among Arab boys and girls. The fracture rate peaked among girls aged 10-11 years and among boys aged 12-13 years. Seasonal variation showed a bimodal distribution with peaks during spring and autumn. CONCLUSIONS: The incidence of pediatric fractures is affected by age, gender, sector and season. Recognition of fracture characteristics may help identify specific populations and conditions for targeted prevention strategies.

Changes in trabecular bone score and bone density in female adolescents with anorexia nervosa: a longitudinal study.

Impaired bone health is a common complication of anorexia nervosa (AN). We aimed to assess longitudinal changes in bone mineral density (BMD) and trabecular bone score (TBS), a measure of bone quality, in female adolescents with anorexia nervosa (AN). We conducted a retrospective longitudinal study of 41 female adolescents with AN who underwent two dual-energy X-ray absorptiometry (DXA) scans. Clinical data, including age, weight, height, body mass index (BMI), and DXA measurements were retrieved from the medical charts. Lumbar bone mineral apparent density (BMAD) was calculated to correct for size. Changes (Δ) in BMD, BMAD, and TBS were examined for correlations with clinical characteristics. Mean ages at the time of DXA scans were 14.8±1.9 and 16.8±2.0 years. There was a significant improvement in anthropometric parameters and DXA measurements at the second DXA scan. However, these values were still significantly lower than expected in the general population. The Δlumbar BMD Z-score was 0.3±0.7, the Δlumbar BMAD Z-score was 0.2±0.7 and the ΔTBS Z-score was 0.5±0.7. ΔTBS Z-score was positively correlated with Δheight Z-score, Δweight Z-score and ΔBMI Z-scores, and negatively correlated height Z-score, weight Z-score and TBS Z-scores at the first DXA scan (p<0.05). Δheight Z-score, ΔBMI Z-score and the progression from early to late puberty were identified as significant independent predictors of Δlumbar BMAD Z-score (p<0.05). During two years of treatment, both BMD and TBS increased significantly. Improvement in height and in weight status, and progression in puberty are predictors of improvement in BMD and TBS.

Effect of Genetic Variation in CYP450 on Gonadal Impairment in a European Cohort of Female Childhood Cancer Survivors, Based on a Candidate Gene Approach: Results from the PanCareLIFE Study.

BACKGROUND: Female childhood cancer survivors (CCSs) carry a risk of therapy-related gonadal dysfunction. Alkylating agents (AA) are well-established risk factors, yet inter-individual variability in ovarian function is observed. Polymorphisms in CYP450 enzymes may explain this variability in AA-induced ovarian damage. We aimed to evaluate associations between previously identified genetic polymorphisms in CYP450 enzymes and AA-related ovarian function among adult CCSs. METHODS: Anti-Müllerian hormone (AMH) levels served as a proxy for ovarian function in a discovery cohort of adult female CCSs, from the pan-European PanCareLIFE cohort (n = 743; age (years): median 25.8, interquartile range (IQR) 22.1-30.6). Using two additive genetic models in linear and logistic regression, nine genetic variants in three CYP450 enzymes were analyzed in relation to cyclophosphamide equivalent dose (CED) score and their impact on AMH levels. The main model evaluated the effect of the variant on AMH and the interaction model evaluated the modifying effect of the variant on the impact of CED score on log-transformed AMH levels. Results were validated, and meta-analysis performed, using the USA-based St. Jude Lifetime Cohort (n = 391; age (years): median 31.3, IQR 26.6-37.4). RESULTS: CYP3A4*3 was significantly associated with AMH levels in the discovery and replication cohort. Meta-analysis revealed a significant main deleterious effect (Beta (95% CI): -0.706 (-1.11--0.298), p-value = 7 × 10-4) of CYP3A4*3 (rs4986910) on log-transformed AMH levels. CYP2B6*2 (rs8192709) showed a significant protective interaction effect (Beta (95% CI): 0.527 (0.126-0.928), p-value = 0.01) on log-transformed AMH levels in CCSs receiving more than 8000 mg/m2 CED. CONCLUSIONS: Female CCSs CYP3A4*3 carriers had significantly lower AMH levels, and CYP2B6*2 may have a protective effect on AMH levels. Identification of risk-contributing variants may improve individualized counselling regarding the treatment-related risk of infertility and fertility preservation options.

Dual diagnosis of type 1 diabetes mellitus and attention deficit hyperactivity disorder.

BACKGROUND: Data regarding glycemic control in children and adolescents with a dual diagnosis of type 1 diabetes mellitus (T1DM) and attention-deficit/hyperactivity disorder (ADHD) are limited. OBJECTIVE: To compare various aspects of diabetes control among youth with T1DM, between those with and without ADHD. METHODS: In this cross-sectional study of youth with T1DM, 39 had ADHD (mean age 14.1 ± 2.8 years) and 82 did not (control group, mean age 12.6 ± 3.3 years). Health-related quality of life was assessed by a Diabetes Quality of Life (DQOL) questionnaire submitted to their parents. Glycemic data were downloaded from glucometers, pumps, and continuous glucose monitoring systems. HbA1c levels, hospitalizations, and severe hypoglycemic and diabetes ketoacidosis events were retrieved from the medical files. RESULTS: Compared to the control group mean HbA1c level of the ADHD group was higher: 8.3 ± 1.1% versus 7.7 ± 1.0% (p = 0.005) and the percent of time that glucose level was in the target range (70-180 mg/dl) was lower: 48 ± 17% versus 59 ± 14% (p = 0.006). Mean glucose and glucose variability were higher in the ADHD group. Youth with ADHD who were not pharmacologically treated had worse HbA1c and more hospitalizations than those who were treated. DQOL did not differ between the control group, the treated ADHD group, and the untreated ADHD-Group. CONCLUSIONS: Dual diagnosis of T1DM and ADHD during childhood leads to worse diabetes control, which is more pronounced in the context of untreated ADHD. Healthcare providers should be aware of the difficulties facing youth with T1DM and ADHD in coping with the current intensive treatment of diabetes.

Possible modification of BRSK1 on the risk of alkylating chemotherapy-related reduced ovarian function.

STUDY QUESTION: Do genetic variations in the DNA damage response pathway modify the adverse effect of alkylating agents on ovarian function in female childhood cancer survivors (CCS)? SUMMARY ANSWER: Female CCS carrying a common BR serine/threonine kinase 1 (BRSK1) gene variant appear to be at 2.5-fold increased odds of reduced ovarian function after treatment with high doses of alkylating chemotherapy. WHAT IS KNOWN ALREADY: Female CCS show large inter-individual variability in the impact of DNA-damaging alkylating chemotherapy, given as treatment of childhood cancer, on adult ovarian function. Genetic variants in DNA repair genes affecting ovarian function might explain this variability. STUDY DESIGN, SIZE, DURATION: CCS for the discovery cohort were identified from the Dutch Childhood Oncology Group (DCOG) LATER VEVO-study, a multi-centre retrospective cohort study evaluating fertility, ovarian reserve and risk of premature menopause among adult female 5-year survivors of childhood cancer. Female 5-year CCS, diagnosed with cancer and treated with chemotherapy before the age of 25 years, and aged 18 years or older at time of study were enrolled in the current study. Results from the discovery Dutch DCOG-LATER VEVO cohort (n = 285) were validated in the pan-European PanCareLIFE (n = 465) and the USA-based St. Jude Lifetime Cohort (n = 391). PARTICIPANTS/MATERIALS, SETTING, METHODS: To evaluate ovarian function, anti-Müllerian hormone (AMH) levels were assessed in both the discovery cohort and the replication cohorts. Using additive genetic models in linear and logistic regression, five genetic variants involved in DNA damage response were analysed in relation to cyclophosphamide equivalent dose (CED) score and their impact on ovarian function. Results were then examined using fixed-effect meta-analysis. MAIN RESULTS AND THE ROLE OF CHANCE: Meta-analysis across the three independent cohorts showed a significant interaction effect (P = 3.0 × 10-4) between rs11668344 of BRSK1 (allele frequency = 0.34) among CCS treated with high-dose alkylating agents (CED score ≥8000 mg/m2), resulting in a 2.5-fold increased odds of a reduced ovarian function (lowest AMH tertile) for CCS carrying one G allele compared to CCS without this allele (odds ratio genotype AA: 2.01 vs AG: 5.00). LIMITATIONS, REASONS FOR CAUTION: While low AMH levels can also identify poor responders in assisted reproductive technology, it needs to be emphasized that AMH remains a surrogate marker of ovarian function. WIDER IMPLICATIONS OF THE FINDINGS: Further research, validating our findings and identifying additional risk-contributing genetic variants, may enable individualized counselling regarding treatment-related risks and necessity of fertility preservation procedures in girls with cancer. STUDY FUNDING/COMPETING INTEREST(S): This work was supported by the PanCareLIFE project that has received funding from the European Union's Seventh Framework Programme for research, technological development and demonstration under grant agreement no 602030. In addition, the DCOG-LATER VEVO study was funded by the Dutch Cancer Society (Grant no. VU 2006-3622) and by the Children Cancer Free Foundation (Project no. 20) and the St Jude Lifetime cohort study by NCI U01 CA195547. The authors declare no competing interests. TRIAL REGISTRATION NUMBER: N/A.

Trabecular Bone Score in Children and Adolescents With Inflammatory Bowel Diseases.

INTRODUCTION: Trabecular bone score (TBS) is a textural index that evaluates bone microarchitecture of the lumbar spine. Our aim was to assess TBS in children with inflammatory bowel diseases and to evaluate correlations with clinical, laboratory and densitometric variables. METHODS: A retrospective study of TBS and areal bone mineral density measurements by dual-energy X-ray absorptiometry (DXA) of children with either Crohn's disease (CD) or ulcerative colitis (UC). Bone mineral apparent density was calculated for size adjustment. TBS Z-score for each child were calculated based on data from a healthy population of similar age and gender distribution. Variables significantly associated with TBS were included in stepwise linear regression models to examine independent predictors of TBS. RESULTS: Fifty patients (age at DXA scan 13.8 ± 3.0 years, 29 males) were included. No significant differences were observed between the patients with CD and UC, in age at diagnosis, age at DXA scan and disease duration. The mean TBS of patients with CD (n = 35) was lower than of patients with UC (n = 15): 1.340 ± 0.080 vs 1.395 ± 0.092, p = 0.040. The mean TBS Z-score of patients with CD, -0.443 ± 0.788, was significantly lower than expected in healthy children (p = 0.002), while the mean TBS Z-score of patients with UC, 0.231 ± 0.685, was similar to that of healthy children (p = 0.212). In the stepwise linear regression analysis, BMI Z-score at diagnosis, phosphorus level at diagnosis and age at the time of the DXA scan were significant independent predictors of TBS (r²â€¯= 0.604; ß = 0.037, 95% confidence interval (CI) for ß 0.022-0.051, p < 0.001; ß = 0.045, 95% CI: 0.017-0.073, p = 0.002; and ß = 0.031, 95% CI: 0.005-0.021, p < 0.002, respectively). CONCLUSIONS: TBS is significantly reduced in pediatric patients with CD but not in patients with UC. This finding likely reflects the effect of CD on bone microarchitecture.

Prospective Longitudinal Assessment of Linear Growth and Adult Height in Female Adolescents With Anorexia Nervosa.

CONTEXT: Growth retardation is an established complication of anorexia nervosa (AN); however, findings concerning the adult height of AN patients are inconsistent. OBJECTIVE: The objective of this work was to assess linear growth and adult height in female adolescents with AN. DESIGN AND SETTING: A prospective observational study was conducted in a tertiary university hospital. PARTICIPANTS: Participants included all 255 female adolescent AN patients hospitalized in the pediatric psychosomatic department between January 1, 2000 and May 31, 2015. INTERVENTIONS: Height and weight were assessed at admission and during hospitalization. Patients were subsequently invited for measurement of adult height. Additional data collected included premorbid height data, menstrual history, skeletal age, pertinent laboratory studies, and parental heights. MAIN OUTCOME MEASURE: The main outcome measure of this study was adult height. RESULTS: Mean age at admission was 15.4 ±â€…1.75 years, mean body mass index (BMI) was 15.7 ±â€…1.8 kg/m2 (BMI SDS = -2.3 ±â€…1.45 kg/m2). Premorbid height SD scores (SDS) were not significantly different from those expected in normal adolescents (0.005 ±â€…0.96). However, height SDS at admission (-0.36 ±â€…0.99), discharge (-0.34 ±â€…0.96), and at adult height (-0.29 ±â€…0.95), were significantly (P < .001) lower than expected. Furthermore, adult height was significantly (P = .006) shorter compared to the midparental target height. Stepwise forward linear regression analysis identified age (r = 0.32, P = .002) and bone age (r = -0.29, P = .006) on admission, linear growth during hospitalization (r = 0.47, P < .001), and change in luteinizing hormone during hospitalization (r = -0.265, P = .021) as independent predictors of improvement in height SDS from the time of admission to adult height. CONCLUSIONS: Whereas the premorbid height of female adolescent AN patients is normal, linear growth retardation is a prominent feature of their illness. Weight restoration is associated with catch-up growth, but complete catch-up is often not achieved.

Questioning the Value of Brain Magnetic Resonance Imaging in the Evaluation of Children with Isolated Growth Hormone Deficiency.

BACKGROUND: Isolated growth hormone deficiency (IGHD) is a relatively common disorder. Current diagnostic protocol requires a brain magnetic resonance imaging (MRI) study of the hypothalamus and the hypophysis to determine the cause after establishment of the diagnosis. This study aimed to examine the yield of brain MRI in the evaluation of children with IGHD and to define clinical and laboratory parameters that justify its performance. METHODS: A retrospective chart review of all children (<18 years) diagnosed with IGHD was conducted at 3 pediatric endocrinology units between 2008 and 2018. RESULTS: The study included 192 children (107 boys) with confirmed IGHD. The mean age ± standard deviation (SD) at diagnosis was 8.2 ± 3.7 years (median 8.5 years, range 0.8-15.9). The mean height SD score (SDS) at diagnosis was -2.25 ± 0.73. The mean height deficit SDS (defined as the difference between height SDS at diagnosis and mid-parental height SDS) was -1.7 ± 0.9. Fifteen children (7.8%) had pathological MRI findings. No space-occupying lesion was detected. Children with pathological MRIs had greater height deficit SDS and lower peak growth hormone levels on provocative tests compared to children with normal MRIs: -2.3 ± 1.2 vs. -1.6 ± 0.8 (p = 0.02) and 4.4 ± 1.9 vs. 5.7 ± 1.3 (p = 0.01), respectively. CONCLUSION: Our preliminary data indicate that most brain MRIs performed for routine evaluation of children with IGHD are not essential for determining cause. Further studies with larger cohorts are needed in order to validate this proposed revision of current protocols.

Resting energy expenditure in acutely ill and stabilized patients with anorexia nervosa and bulimia nervosa.

OBJECTIVE: Determining resting energy expenditure (REE) may be important in the nutritional assessment of adolescents with eating disorders (EDs). Calculated equations assessing REE, developed according to data from healthy people, may under- or overestimate REE in EDs. We have sought to compare the REE measured in clinical settings to that calculated using equations in actively ill adolescents with anorexia nervosa (AN) and bulimia nervosa (BN), and following stabilization of weight and disordered eating. METHODS: Thirty-five female adolescents with AN and 25 with BN were assessed at admission to inpatient treatment and at discharge. REE was measured using indirect calorimetry (DELTATRAC Metabolic Monitor). Expected REE was calculated using the Harris-Benedict equation. RESULTS: An overestimation of expected versus measured REE was found for both patients with AN and BN, both at admission and discharge. Second, the differences between expected and measured REE were significantly less robust in BN versus AN. Third, REE before renourishing was lower in inpatients with AN versus BN. Fourth, the REE of patients with AN (both measured and expected) increased from admission to discharge, to a greater extent than expected solely from the increase in weight. The difference between admission and discharge expected and measured REE was significant also in patients with BN. DISCUSSION: Our findings suggest that predicted and measured REE are different in both AN and BN, and that both expected and measured REE are not useful in the planning of renourishing programs in patients with AN.

Primary Ovarian Insufficiency Nationwide Incidence Rate and Etiology Among Israeli Adolescents.

PURPOSE: The aim of the study was to estimate the current incidence and the distribution of etiologies of primary ovarian insufficiency (POI) in a nationwide study. The prevalence of POI in young adult women has recently increased, but the data cited for adolescents are more than three decades old. METHODS: Data regarding females aged <21 years diagnosed with POI during the years 2000-2016 were collected from all the pediatric endocrinology units in Israel. POI was defined by at least 4 months of amenorrhea in association with menopausal levels of follicle-stimulating hormone. Iatrogenic cases were excluded. RESULTS: For the 130 females aged <21 years included in the study, the distribution of POI etiologies was Turner syndrome/mosaicism in 56 (43%), idiopathic in 35 (27%), and other (developmental, genetic, metabolic, adrenal, and autoimmune) in 39 (30%) females. During the years 2009-2016, compared with 2000-2008, the incidence rate of new POI diagnoses per 100,000 person-years doubled (4.5 vs. 2.0; p value <.0001), and incidence rates of idiopathic and other etiologies increased by 2.6 (p value = .008) and 3.0 (p value = .002), respectively. In contrast, the incidence of Turner syndrome was constant (p value = .2). In the age group of 15-21 years, the current incidence of non-Turner POI in adolescents is one per 100,000 person-years. CONCLUSIONS: In this nationwide study, the incidence rate of POI in youth aged <21 years was one tenth of the rate that is commonly cited. A significant increase in the rate of POI in non-Turner females was observed over the last decade. Contributions of environmental and epigenetic factors should be studied.