Background: We have previously demonstrated that short children with Idiopathic Short Stature (ISS), Growth Hormone Deficiency (GHD), and their short siblings have significantly diminished pituitary volumes (PV) compared to normal children. In comparison, patients with Turner syndrome have not been found to manifest this finding. We speculate that pituitary hypoplasia may also contribute to short stature in Noonan syndrome (NS) patients. Objective: To compare pituitary volumes between normal children and children with Noonan syndrome. Patients and Methods: A retrospective chart review for NS patients from 2010-16 between the ages of 3-11.5 yrs who underwent a high resolution post-contrast MRI (1 mm slices) was undertaken. 8 patients were identified. 4 of the patients had the PTPN11 gene mutation and formed the P1 group. The other 4 NS patients lacked confirmed PTPN11 mutations. High resolution post-contrast MRIs (1 mm slices) from years 1999-06 in children aged 3-11.5 yrs with seizures and headaches without major pathologic findings were reviewed. 31 children met these criteria and formed the control group. PV was evaluated using the ellipsoid formula (LxWxH/2). The wilcoxon rank sum test was used to compare means of non-parametric data between 2 groups, and a Kruskall-Wallis was used to compare means of non-parametric data between multiple groups in NCSS12. Results: The mean and median age for NS children was 7.92±3.22 yrs and 8.86 yrs, respectively. The mean and median age for the P1 group was 7.04±3.09 yrs and 6.27 yrs, and the mean and median age for the other NS group was 8.81±3.53 yrs and 10.21 yrs. The mean and median age for controls was 6.88±2.70 yrs and 7.08 yrs, respectively. The difference in age between all groups was not significant (p=0.23). Mean and median PV for the NS children were 205.74±52.81 mm3 and 178 mm3 respectively. The mean and median PV for the controls were 294.71±93.85 mm3 and 276.27 mm3, respectively. Mean and median PV for the P1 group was 182±19.40 mm3 and 175 mm3, and the mean and median PV for the other NS group was 229.49±68.03 mm3 and 228.48 mm3. Differences in PV between controls, P1, and other NS was significant (p=0.02). The difference in PV of controls versus P1 was significant (p=0.01). The difference in PV of controls versus all NS patients was significant (p=0.01). The difference between the PV of controls and other NS patients was not significant (p=0.28). The difference between the PV of P1 and other NS patients was not significant (p=0.56). Conclusion: These data suggest that NS patients have significantly lower PV compared to controls, particularly those with the PTPN11 mutation. Our previous work has demonstrated an association between diminished PV, GHD, and ISS. We hypothesize that the diminished PV may be in part responsible for short stature in NS as well. WE SEEK COLLABORATION WITH OTHER INVESTIGATORS TO FURTHER EXPLORE THIS HYPOTHESIS.

Background: Preliminary studies have demonstrated improvement in metabolic control of patients (PTs) using subcutaneous Continuous Glucose Monitoring systems (CGMs). In this study, we investigated the effect of CGMs on PTs’ glycemic control and compared the change in patient HbA1c levels between sensors. Objective: To determine how CGMs affect metabolic control in PTs and the effect of different sensors on glycemic control. Patients and Methods: 33 PTs with Type 1 diabetes mellitus (DM) who began using a CGM between 2017 and 2019 were selected for inclusion. CGM systems used included DexcomG6™, DexcomG5™, DexcomG4™, Enlite™, Guardian 3™, or Medtronic Sure-T™ sensors. Results: The mean (MN) age of PTs at initial visit was 15.3 ± 5.1 yrs and the MN age at second visit was 15.8 ± 5.1 yrs. The MN time between visits was 5.0 ± 2.4 months (mos). 6 PTs had follow up (F/U) times less than 3 mos, 18 PTs had F/U times between 3 and 6 mos, 6 PTs had F/U times between 6 and 9 mos, and 3 PTs had F/U times greater than 9 mos. The MN and median (MD) HbA1c at the initial visit for all PTs was 8.28% ± 1.48 and 8.10%, respectively. The MN and MD HbA1c at final F/U for all PTs was 7.57% ± 1.11 and 7.50%, respectively. The difference in MN HbA1c was significant (p<0.001). The MN and MD HbA1c at the initial visit for PTs with a F/U time less than 3 mos was 7.55% ± 0.77 and 7.75%, respectively. The MN and MD HbA1c at F/U for these PTs was 7.20% ± 0.79 and 7.20%, respectively. The difference in MN HbA1c was significant (p<0.05). The MN and MD HbA1c at the initial visit for all PTs with a F/U time greater than 3 mos was 8.44% ± 1.53 and 8.10%, respectively. The MN and MD HbA1c at F/U for these PTs was 7.66% ± 1.15 and 7.50%, respectively. The difference in MN HbA1c was significant (p<0.001). The MN change of HbA1c between visits was not significant between PTs who had 3–6 mo, 6–9 mo, and 9+ mo F/U times (p=0.96) 15 PTs had HbA1c levels less than or equal to 8.0%. The MN and MD HbA1c at initial visit for these PTs was 7.20% ± 0.41 and 7.30%, respectively. The MN and MD HbA1c at F/U for these PTs was 6.75% ± 0.47 and 6.80%, respectively. The difference in MN HbA1c was significant (p<0.001). 20 PTs had HbA1c levels greater than 8.0% at initial visit. The MN and MD HbA1c at the initial visit for these PTs was 9.18% ± 1.47 and 8.80%, respectively. The MN and MD HbA1c at F/U for these PTs was 8.26% ± 1.03 and 8.00%, respectively. The difference in MN HbA1c was significant (p<0.001). The MN change in HbA1c between the high HbA1c group (-.92% ± 1.02) and low HbA1c group (-0.45% ± 0.32) was not significant (p>0.05). 25 PTs used a Dexcom™ sensor while 8 PTs used a Medtronic™ sensor. The MN change in HbA1c was not significant between these brands (p>0.05). Conclusion: CGMs improve metabolic control in pediatric PTs with Type 1 DM regardless of initial HbA1c. Further, this improved control is sustained over time. Sensor brands appear to be equally effective at achieving this goal.

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.

Background: Patients with diminished GH secretion are candidates for GH therapy (GHT). The GH stimulation test (GHST) is considered the gold standard for the diagnosis of GH deficiency (GHD), yet the cutoff of 10 ng/mL has not been well validated statistically. Another proposed method to define GHD has been to measure patients’ pituitary volumes (PV), as the size of the gland may correlate with the amount of GH produced. Objective: This study seeks to ascertain whether the GHST or PV is a better predictor of response to GHT, and determine which method can better define true GHD. Patients and Methods: A database at a Pediatric Endocrinology center was queried for patients aged 6-18 yrs who underwent a GHST, MRI, and GHT between 1/2018 - 6/2019. Patients with relevant comorbidities, those with GHST peak ≥ 10.0 ng/mL, and patients that were non-adherent to their GHT were excluded. Clonidine and L-dopa were stimulants for the GHST. 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). 87 patients met these criteria for analysis. PV was converted to standard deviation scores (SDS) based on age and sex using the largest data set of pituitary volumes available in the literature. To account for sex-related growth rate differences by age, heights at the initial and subsequent time points were also converted to SDS based on age and sex using parameters provided by the National Center of Health Statistics. Response to treatment was defined as change in height SDS over the assessed time interval. The initial height was included as a covariate. R statistical software was utilized to analyze the correlation between response to GHT and GHST peak value, as well as response to GHT and PV. The relationship between GHST peak value and PV SDS was analyzed with a Spearman correlation. Results: The GHST peak was not a significant predictor of growth response to treatment in both the first or second intervals (r= -0.01, p= 0.207 and r= 0.00, p= 0.815 respectively). GHST peak and PV SDS were not correlated (r=0.08, 95% CI: -0.14, 0.28). Lower SDS of PV significantly predicted growth response to therapy in the first 1 to 8.7 months of treatment (n= 87, model r2=0.231, b=-0.05, SE=0.02, P=0.012). This association in the second interval between 7.8 and 17.4 months of treatment was neither as strong as the first interval nor was it statistically significant (n=62, model r2=0.145, b=-0.05, SE=0.03, P=0.127). Within-person growth velocity was greater in the first interval (mean = 0.37, SD = 0.17) than in the second interval (mean = 0.20, SD = 0.16). Conclusion: Our data indicates that PV can be a valuable tool in defining GHD and should be considered a criterion for determining eligibility for GHT. To our knowledge this is the first study to determine that PV is a better predictor of growth response to GHT than the GHST.

Background: The sequential follow-up of simple fluid-filled pituitary cysts (PC) has not been fully elucidated. In this study, we further report our follow up of PCs in a cohort of pediatric patients (PTs). Objective: To further analyze the sequential cyst volume (CV) change in short children. Patients and Methods: A pediatric endocrinology and neuroradiology center was queried for the presence of PCs. PTs who underwent multiple high resolution post-contrast MRIs (1mm slices) were subjects of this study. PTs with additional MRI abnormalities were excluded. Pituitary volumes (PV) and CVs were measured using the ellipsoid formula (LxWxH/2). The percentage of the gland occupied by the cyst (POGO) was measured and calculated. A cyst with a POGO ≤15% was defined as a small pituitary cyst (SPC), and a POGO >15% was defined as a large pituitary cyst (LPC). 34 PTs met inclusion criteria, all of whom were diagnosed with short stature (23 growth hormone deficient (GHD) PTs and 11 idiopathic short stature (ISS) PTs). All PTs were receiving GH during data collection. Results: The mean (MN) and median (MD) ages for these subjects were 10.7 yrs ±3.5 and 11.1 yrs, respectively (RSP). Of the 34 PTs, 24 PTs’ (71%) initial MRI demonstrated a SPC and 10 PTs’ (29%) initial MRI demonstrated a LPC. The MN and MD times between first and second MRIs were 1.23 yrs and 0.83 yrs RSP, with a range (RG) of 0.14 to 4.08 yrs. The MN and MD ΔCV for all PTs was 23.33% ±179.17% and -25.94% RSP, with a RG of -100.00% to 763.94%. The MN and MD ΔPOGO by the cyst for all PTs was 48.59% ±313.26% and -36.84% RSP, with a RG of -100.00% to 1734.79%. The MN and MD ΔCV for PTs with a SPC was 10.68% ±2.65% and 11.09% RSP, with a RG of -100.00% to 763.94%. The MN and MD ΔPOGO by the cyst for PTs with a SPC was 78.33% ±369.96% and -31.34% RSP, with a RG of -100.00% to 1734.79%. The MN and MD ΔCV for PTs with a LPC was -24.60% ±51.89% and -26.57% RSP, with a RG of -88.57% to 91.38%. The MN and MD ΔPOGO by the cyst for PTs with a LPC was -22.79% ±44.90% and -40.46% RSP, with a RG of -80.95% to 47.11%. Statistical analysis showed no significant %ΔCV or %ΔPOGO when comparing male vs. female, SPC vs. LPC, GHD vs. ISS, or pre-pubertal vs. pubertal PTs. Analysis of ΔPOGO of the 24 SPC PTs demonstrated that 4 (17%) of them developed into LPCs. Analysis of the 10 LPC PTs showed that 6 (60%) of them shrunk into SPCs, one of which re-enlarged into a LPC, and another of which fluctuated between LPC and SPC over a period of 7.34 yrs and 9 sequential MRIs. None of the PTs experienced significant sequelae related to their PCs. Conclusion: CV can change greatly over time, however few sequelae should be expected. LPCs tend to demonstrate major changes in size and should be tracked for CV change. A minority of SPCs will develop into LPCs. Prediction of change in CV over time requires more sequential data. Change in CV did not appear to be influenced by GH therapy.