Study Tanner staging of β- thalassemic patients attending thalassemic Center in Ibn Al-Atheer Teaching Pediatric Hospital

Purpose: determine any relationship between tanner staging of the patients and transfusion program, iron overload and chelation therapy and study tanner staging of β- thalassemic patients attending Thalassemic Center in Ibn Al-Atheer Teaching Pediatric Hospital. Patients and Methods: A descriptive-analytic study (case series study) was done on β- thalassemic patients attending Thalassemia Center in Ibn Al- Atheer Teaching Hospital in Mosul, during the period from the 1st of January to the 30th of June 2019.Sixty patients with β- thalassemia, 45 of them are β- thalassemia major cases and 15 are β- thalassemia intermedia cases. The patients of the major type were sub-classified into 3 groups according to their ages: Group 1, Patients from the age of ≥ 13 years; Group 2, Patients from the age of 14 years to 16 years and Group 3, Patients from the age of more than 17 years. Results: current study showed male (77.78, 66.67) % more than female (22.22; 33.33) % in both types of thalassemia (Major and Intermedia) respectively.so the most of the patients in this study live in urban areas (58.33%) and (41.67%) in rural areas, mean age at diagnosis of thalassemia major was 7.16 months, Delayed tanner staging was found in 64.44% of patients with thalassemia major, while in thalassemia intermedia only 33.33% were considered to be on a delayed stage. as well as 4(80%) of Tanner Stage (II) for pateints in age group (≥ 13) years compare to 20% for stage (III), so 50% for both stage (II and III) respectively in age group (14-16) years. Conclusion: Two-third of the patients with thalassemia major had delayed puberty (64.44%), while one- third of the patients with thalassemia intermedia had delayed pubertal development (33.33%).

Determining the timing of pubertal onset via a multicohort analysis of growth

Objective Growth-based determination of pubertal onset timing would be cheap and practical. We aimed to determine this timing based on pubertal growth markers. Secondary aims were to estimate the differences in growth between cohorts and identify the role of overweight in onset timing. Design This multicohort study includes data from three Finnish cohorts—the Type 1 Diabetes Prediction and Prevention (DIPP, N = 2,825) Study, the Special Turku Coronary Risk Factor Intervention Project (STRIP, N = 711), and the Boy cohort (N = 66). Children were monitored for growth and Tanner staging (except in DIPP). Methods The growth data were analyzed using a Super-Imposition by Translation And Rotation growth curve model, and pubertal onset analyses were run using a time-to-pubertal onset model. Results The time-to-pubertal onset model used age at peak height velocity (aPHV), peak height velocity (PHV), and overweight status as covariates, with interaction between aPHV and overweight status for girls, and succeeded in determining the onset timing. Cross-validation showed a good agreement (71.0% for girls, 77.0% for boys) between the observed and predicted onset timings. Children in STRIP were taller overall (girls: 1.7 [95% CI: 0.9, 2.5] cm, boys: 1.0 [0.3, 2.2] cm) and had higher PHV values (girls: 0.13 [0.02, 0.25] cm/year, boys: 0.35 [0.21, 0.49] cm/year) than those in DIPP. Boys in the Boy cohort were taller (2.3 [0.3, 4.2] cm) compared with DIPP. Overweight girls showed pubertal onset at 1.0 [0.7, 1.4] year earlier compared with other girls. In boys, there was no such difference. Conclusions The novel modeling approach provides an opportunity to evaluate the Tanner breast/genital stage–based pubertal onset timing in cohort studies including longitudinal data on growth but lacking pubertal follow-up.

Urinary and salivary endocrine measurements to complement Tanner staging in studies of pubertal development

Background Many studies investigating pubertal development use Tanner staging to assess maturation. Endocrine markers in urine and saliva may provide an objective, sensitive, and non-invasive method for assessing development. Objective Our objective was to examine whether changes in endocrine levels can indicate the onset of pubertal development prior to changes in self-rated Tanner stage. Methods Thirty-five girls and 42 boys aged 7 to 15 years were enrolled in the Growth and Puberty (GAP) study, a longitudinal pilot study conducted from 2007–2009 involving children of women enrolled in the Agricultural Health Study (AHS) in Iowa. We collected saliva and urine samples and assessed pubertal development by self-rated Tanner staging (pubic hair, breast development (girls), genital development (boys)) at three visits over six months. We measured dehydroepiandrosterone (DHEA) in saliva and creatinine-adjusted luteinizing hormone (LH), testosterone, follicle stimulating hormone (FSH), estrone 3-glucuronide (E13G) and pregnanediol 3-glucuronide (Pd3G) concentrations in first morning urine. We evaluated the relationships over time between Tanner stage and each biomarker using repeated measures analysis. Results Among girls still reporting Tanner breast stage 1 at the final visit, FSH levels increased over the 6-month follow-up period and were no longer lower than higher stage girls at the end of follow-up. We observed a similar pattern for testosterone in boys. By visit 3, boys still reporting Tanner genital stage 1 or pubic hair stage 1 had attained DHEA levels that were comparable to those among boys reporting Tanner stages 2 or 3. Conclusions Increasing concentrations of FSH in girls and DHEA and testosterone in boys over a 6-month period revealed the start of the pubertal process prior to changes in self-rated Tanner stage. Repeated, non-invasive endocrine measures may complement the more subjective assessment of physical markers in studies determining pubertal onset.

Pituitary Volume Cutoffs as Another Tool for Determining Growth Hormone Treatment Eligibility

Background: The GH stimulation test (GHST) is the gold standard for the diagnosis of GH deficiency (GHD), yet a significant number of short children fail to be diagnosed as GHD. We have speculated that pituitary volume (PV) could be used in conjunction with results from the GHST to diagnose GHD; however, cutoff values for low PVs need to be further explored. Objective: To define a diagnostic cutoff value of PV for determining GH treatment eligibility for patients (PTs) with short stature. Patients and Methods: The database of GHST results at a Pediatric Endocrinology center was queried for PTs aged 6-18 yrs who underwent a GHST, MRI, and blood work between 1/2018 - 6/2019. PTs with relevant comorbidities were excluded. Clonidine and L-dopa were used to induce GH secretion during the GHST. GHD was defined as a peak GH ≤ 10 ng/mL. MRIs were acquired on a Philips 1.5 or 3.0 T scanner (1mm slices) and PV was calculated using the ellipsoid formula (LxWxH/2). 144 PTs were the subjects of this study. ROC curve analysis was utilized to generate cutoff values. PV was used to predict GHD in prepubertal (age < 11 yrs) and pubertal (age > 11 yrs) children. The value with the greatest Youden index (J) was selected as the definitive cutoff. Results: The mean (MN) and median (MD) ages of PTs were 12.2 ± 2.2 and 12.3, respectively. The MN and MD ages of prepubertal PTs (n=43) were 9.4 ± 1.1 and 9.7, respectively. The MN and MD ages of pubertal PTs (n=103) were 13.4 ± 1.4 and 13.2, respectively. Initially, 10 ng/mL was utilized as the cutoff for GHD. For predicting GHD from PV in prepubertal PTs, sensitivity was 89.47% and specificity was 66.67%. The distance to corner was 0.3488, and the highest J was 0.5641, corresponding to a PV of 240.00 mm3. The Area Under the Curve (AUC) was 0.6581 with a standard error (SE) of 0.2429 (p>0.05). For predicting GHD from PV in pubertal PTs, sensitivity was 72.94% and specificity was 81.25%. The distance to corner was 0.3292, and the highest J was 0.5419, corresponding to a PV of 275.00 mm3. The AUC was 0.7901 with a SE of 0.0687 (p<0.05). Further analysis was done to explore the use of 7 ng/mL as the cutoff for GHD. For predicting GHD from PV in prepubertal PTs, sensitivity was 25.00% and specificity was 90.91%. The distance to corner was 0.7555, and the highest J was 0.1591, corresponding to a PV of 133.66 mm3. The AUC was 0.4989 with a SE of 0.0931 (p>0.05). For predicting GHD from PV in pubertal PTs, sensitivity was 57.89% and specificity was 63.64%. The distance to corner was 0.5563, and the highest J was 0.2153, corresponding to a PV of 240.00 mm3. The AUC was 0.6112 with a SE of 0.0584 (p<0.05). Conclusion: PVs ≤ 275.00 mm3 in pubertal PTs should be considered low; however, cutoffs for prepubertal PVs were not significant in this study. To our knowledge, we present the first study to generate a PV cutoff based on the GHST. Future studies including more PTs and tanner staging will further improve the accuracy of PV cutoffs for GHT eligibility.

6-Month Subcutaneous Leuprolide Acetate Effectively Suppresses Clinical Signs of Puberty in Children With Central Precocious Puberty

Objective: Gonadotropin-releasing hormone (GnRH) agonists, such as intramuscular leuprolide acetate, triptorelin and the subcutaneous histrelin implant, are standard treatment for central precocious puberty (CPP). Implants require surgery and sometimes anesthesia, while frequent intramuscular injections can be painful. A shift to longer acting-formulations and subcutaneous injections has been proposed for the treatment of CPP. Therapies with convenient administration, prolonged duration of action and favorable safety profile may be beneficial, improving patient adherence. 87% of subjects achieved stimulated LH suppression to <4 IU/L by Week (W) 24 in a Phase III trial evaluating the efficacy and safety of the first6-month subcutaneous injectable in situ gel leuprolide acetate for CPP. We present secondary analyses of bone age (BA) advancement, weight, BMI, and pubertal maturation from this trial. Methods: 62 children (60 girls, 2 boys) with CPP (naïve to treatment) received 2 doses of 45 mg subcutaneous leuprolide acetate at 24-week intervals, constituting the intent-to-treat population. Radiographs of the left hand and wrist were used to determine BA using the Greulich and Pyle method. BA was assessed by a blinded central reader. Rate of BA advancement was determined by the ratio of BA to chronological age (CA, BA/CA). Pubertal maturation was categorized with the Tanner staging system using breast development, external genitalia, and pubic hair. Safety outcomes were measured. Results: Mean age at onset of treatment was 7.5 ± 0.9 (SD) (range 4-9) years. BA/CA consistently declined throughout treatment, from 1.4 ± 0.2 at baseline, to 1.3 ± 0.1 at W24 and 1.3 ± 0.1 at W48. Although mean weight increased 8.7% from screening to W24 (34.8 kg vs 37.7 kg) and 16.9% from screening to W48 (40.4 kg), mean BMI remained stable throughout the study. The proportion of girls with early breast Tanner stage development (stage 1 and 2) increased from 9% at baseline to 37% at W48. The proportion of girls with late breast Tanner stage development (stage 4 and 5) decreased from 18% at baseline to 5% at W48. Both boys regressed from Tanner stage 3 to stage 2 for external genitalia development by W48. Tanner staging for pubic hair development remained stable for approximately 80% and decreased for 7% of children by W48. 52/53 treatment emergent adverse events were mild or moderate. Conclusions: 6-month 45 mg subcutaneous leuprolide acetate is a promising treatment for CPP. It effectively suppressed LH, suppressed clinical signs of pubertal maturation and demonstrated a good safety profile. It also has the beneficial features of subcutaneous administration, small injection volumeand twice a year dosing. This may be a welcome addition to the armamentarium given the proposed shift in CPP therapies towards longer-acting formulations and subcutaneous injections.

Sexual maturity assessment in Indian children—a study from western India

Objectives Pubertal assessment is crucial as puberty is the transition from childhood to adulthood. Pubertal assessment, growth, and secular trend in puberty need to be explored further in India. The objectives were to assess Sexual Maturity Rating (SMR) among children and establish normative data of puberty from western India. We also compared age of attainment of various stages of puberty with BMI and secular trend in menarche. Methods A cross-sectional observational study was undertaken at a tertiary care pediatric center. The study population were healthy girls and boys between 6 and 18 years. Demographic data was noted. Anthropometry and SMR assessment (Tanner staging) were performed. The age of menarche was noted among the girls and their mothers. Data were analyzed using SPSS 21. Results In girls, median age of thelarche, pubarche, and menarche was 9.37 (8.5–10.2), 10.18 (9.87–10.49), and 12.55 years (12.41–12.75) respectively. There was an early appearance of thelarche but menarche was delayed in overweight-obese girls (statistically not significant). Age of menarche showed a shift to left in girls as compared to their mothers (p=0.036). In boys, median age of testicular stage 2 and pubarche was 10.7 (9.9–11.8) and 11.6 years (11.1–12.1) respectively. In overweight-obese boys the pubertal milestones were achieved earlier (statistically not significant). Conclusions Normative data on pubertal assessment from western India is presented. Age of menarche shows a shift to left in girls as compared to their mothers. Pubertal milestones were observed at a younger age in overweight obese children which was not significant.

TuberOus SClerosis registry to increAse disease awareness (TOSCA) Post-Authorisation Safety Study of Everolimus in Patients With Tuberous Sclerosis Complex

This non-interventional post-authorisation safety study (PASS) assessed the long-term safety of everolimus in patients with tuberous sclerosis complex (TSC) who participated in the TuberOus SClerosis registry to increase disease Awareness (TOSCA) clinical study and received everolimus for the licensed indications in the European Union. The rate of adverse events (AEs), AEs that led to dose adjustments or treatment discontinuation, AEs of potential clinical interest, treatment-related AEs (TRAEs), serious AEs (SAEs), and deaths were documented. One hundred seventy-nine patients were included in the first 5 years of observation; 118 of 179 patients had an AE of any grade, with the most common AEs being stomatitis (7.8%) and headache (7.3%). AEs caused dose adjustments in 56 patients (31.3%) and treatment discontinuation in nine patients (5%). AEs appeared to be more frequent and severe in children. On Tanner staging, all patients displayed signs of age-appropriate sexual maturation. Twenty-two of 106 female (20.8%) patients had menstrual cycle disorders. The most frequent TRAEs were stomatitis (6.7%) and aphthous mouth ulcer (5.6%). SAEs were reported in 54 patients (30.2%); the most frequent SAE was pneumonia (>3% patients; grade 2, 1.1%, and grade 3, 2.8%). Three deaths were reported, all in patients who had discontinued everolimus for more than 28 days, and none were thought to be related to everolimus according to the treating physicians. The PASS sub-study reflects the safety and tolerability of everolimus in the management of TSC in real-world routine clinical practice.

103 Pediatric resident knowledge and comfort in providing care to transgender youth: A single centre needs assessment

Background Transgender youth experience high rates of health disparities and inequities. There is currently no formal curriculum for transgender health within our centre’s pediatric residency program. This gap in training is similar to other programs across the country. With the drastic rise in trans youth patients seeking care, general pediatricians will be the first point of contact for many. Pediatricians therefore need to be equipped with the proper knowledge and skill to provide care to these patients. Objectives We conducted a needs assessment to assess pediatric residents’ comfort with the health care needs of transgender patients, and to assess knowledge about the medical management of transgender youth. The goal was to identify learning gaps within our centre’s residency program to guide future curriculum. Design/Methods A survey with Likert scale and case-based questions, based on literature review, identified key components of trans care. The study was granted an exemption from ethics review. Results We achieved a 50% response rate (24/58) from pediatric residents, and 50% of these residents were in their senior years (PGY3 and PGY4). All residents felt it was important to have trans specific training during residency. While the majority of senior residents received training during their residency, the total duration was estimated to be ≤ 5 hours. Despite the training received, only 50% [95% CI: 30, 70] of residents felt comfortable asking patients about their gender identity, and only 8% [0, 19] and 33% [14, 52] of residents were comfortable diagnosing gender dysphoria in children and teens, respectively. Most residents felt uncomfortable addressing trans specific health care needs, and 83% [62, 100] of senior residents were uncomfortable counselling patients on available gender affirming pharmacologic agents. Similarly, 92% [77, 100] of senior residents felt uncomfortable prescribing either GnRH analogs or hormonal therapy for trans youth. Lastly, only 58% [30, 86] of senior residents felt comfortable performing Tanner staging in trans patients. Conclusion In order to help narrow the gap in care for trans patients, we need to better educate pediatric residents on trans specific health care. Future curriculum should focus on discussing gender identity, identifying gender dysphoria, performing Tanner staging, and counselling patients on gender affirming pharmacologic therapies. These skills are critical for general pediatricians to adequately provide care to trans youth.