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Introduction GNAS mutations have been reported in both McCune-Albright syndrome (MAS) and juvenile granulosa cell tumors (JGCT) but have never been reported simultaneously in the same patient. Case Presentation A 15-year-old girl developed secondary oligomenorrhea. Laboratory studies revealed suppressed gonadotropin levels with markedly elevated estradiol and inhibin B levels. Pelvic ultrasound showed a 12-cm heterogeneous right adnexal mass; pelvic magnetic resonance imaging to further characterize the mass displayed heterogeneous bilateral femoral bone lesions initially concerning for metastatic disease. Positron emission tomography/computed tomography showed minimal 18F-fluorodeoxyglucose (FDG) uptake in the pelvic mass but unexpectedly revealed FDG uptake throughout the skeleton, concerning for polyostotic fibrous dysplasia in the context of MAS. The adnexal mass was excised and pathology confirmed a JGCT. The patient’s affected bone and JGCT tissue revealed the same pathogenic GNAS p.R201C mutation, while her peripheral blood contained wild-type arginine at codon 201. Conclusion This mutation has been previously reported in cases of MAS and JGCT but never simultaneously in the same patient. This demonstration of a GNAS mutation underlying both JGCT and MAS in the same patient raises questions about appropriate surveillance for patients with these conditions.

Context Clinical management of congenital hypogonadotropic hypogonadism (CHH) remains a challenge in pediatric endocrinology. Objective To investigate whether daily subcutaneous injections of the recombinant human LH/FSH preparation could mimic the physiological male mini-puberty. Design and Setting The REMAP (REplacement of MAle mini-Puberty) study with up to 10 years of follow-up. Patients and Intervention Ten neonates or infants, all with bilateral cryptorchidism in intra-abdominal/inguinal position and micropenis with the absence of neonatal male mini-puberty, received daily subcutaneous injections of Pergoveris® (LH/FSH 75/150 IU) for 3 months. Main Outcome Measures Restoration of bilateral cryptorchidism/micropenis and the Leydig/Sertoli cells function. Results At the end of treatment, median LH and FSH, both undetectable before treatment, reached high normal levels of 4.45 IU/L and supranormal levels 83 IU/L, respectively; median inhibin-b and anti-Mullerian hormone levels increased from subnormal (27.8 and 1.54 ng/mL, respectively) to normal levels (365 and 150 ng/mL, respectively); median testosterone increased from just detectable (0.02 ng/mL) to normal levels (3.3 ng/mL). Stretched penile length increased from a median of 2 to 3.8 cm. During therapy, all testes descended to the scrotal position (by the end of the first month in three patients, the second month in four patients, and the third month in three patients), measuring 1.5 mL and appearing normal in ultrasonography. Three infants received additional treatment with testosterone enanthate. In two infants, one of two testes regressed in the low inguinal area; both infants were successfully treated surgically. After 1 to 10 years of follow-up, all testes are still in scrotal position and have slightly regressed in size. Conclusions The proposed regimen mimics neonatal male mini-puberty and successfully treats infants with micropenis and cryptorchidism in CHH.

Context We hypothesize, based on the degree of residual hypothalamic-pituitary function, that some, but not all, children with growth hormone deficiency (GHD) may have beneficial growth responses to the orally administered growth hormone (GH) secretagogue LUM-201. Objective To determine if pretreatment testing can identify predictive enrichment markers (PEM) for subjects with adequate residual function who are responsive to LUM-201. Methods We performed an analysis of a completed, randomized, placebo-controlled trial of LUM-201, a GH secretagogue receptor agonist, in which all randomized subjects had pretreatment testing. This international multicenter study conducted in pediatric endocrinology clinics included 68 naïve-to-treatment, prepubertal children with established diagnoses of GHD. Outcome measures included the sensitivity, specificity, and predictive accuracy of potential markers to predict 6-month growth responses to oral LUM-201 and daily rhGH. Results Two PEM were identified for use in defining PEM-positive status: (1) baseline insulin-like growth factor I (IGF-I) concentration >30 ng/mL and (2) peak GH response of ≥5 ng/mL upon administration of single-dose LUM-201. PEM-positive status enriches a population for better growth responses to LUM-201. PEM-negative status enriches a population for better growth responses to rhGH. Conclusion Combined, the peak GH response to single-dose LUM-201 and the baseline IGF-I concentration are effective PEMs for 6-month growth responses to LUM-201 and rhGH in prepubertal children with GHD.

Background: Prolactinomas are rare in children, with an incidence of 1: 10.000.000 cases, representing less than 2% of all intracranial tumors in this age group (1). Indeed, only a few cases are reported in prepubertal children. Clinical Case: Eight-year old female prepubertal child, previously healthy, presented a progressive loss of the visual acuity in the last 5 months and was admitted to the emergency department with an intensive headache associated with nauseas, started 48 hours before the admission. At the physical examination, the patient was eutrophic, with an infantile genitalia and no breast development or galactorrhea. No focal neurologic deficits were detected and presented normal pupils reflex and preserved extrinsic eye movements. The Campimetry evidenced bitemporal heteronymous hemianopsia and the nuclear magnetic resonance of the central nervous system identified a suprasellar and intrasellar expansive lesion measuring 3.2 x 2.6 x 2.3 cm, with bleeding signs and compression of the optic chiasm. The hormonal evaluation showed: free T4 0.55 ng/dL (normal value: 0.93-1.70ng/dL), total T4 4.8ng/dL (5.1-14.1ng/dL), TSH 4.06µUI/mL (0.6-5.4µUI/mL), morning serum cortisol 1.80mcg/dL (6.2-2mcg/dL), ACTH 7.0pg/mL ( Reference: (1) Yang, A., Cho, S. Y., Park, H., Kim, M. S., Kong, D.S., Shin, H.J., & Jin, D.K. (2020). Clinical, Hormonal, and Neuroradiological Characteristics and Therapeutic Outcomes of Prolactinomas in Children and Adolescents at a Single Center. Frontiers in Endocrinology. 2020; 11:527.

Background: Previously we reported impairment in quality of life (QoL) measures in children with Cushing disease (CD) by parent proxy; however, little is known about QoL measures from the affected child’s perspective. Method: Prospective study of 48 (26 females, Age:11.5±3.0 yr.) children diagnosed with CD. Prior to treatment, the Child Health Questionnaire (CHQ) was used to assess QoL by parent (proxy) and child report. Results: In children with active CD, there was a discrepancy between parent and child responses for mental health and self-esteem subscales. Child responses were significantly lower than parent responses (lower scores indicate poorer function) for mental health (56 ± 2 vs. 67 ± 2, p&lt0.001) and self-esteem (32.8 ±3 vs. 60.5 ±3, p&lt0.001). No significant differences were found between parent vs.child report for other subscale scores of the CHQ. Conclusion: This is the first study to compare child vs. parent report of health-related quality of life children with active CD. Parent reports underestimated the impact of CD on quality of life measures for mental health and self-esteem. It is important for clinicians to obtain information about health-related quality of life from the child’s perspective in order to guide management and take precautionary measures to alleviate negative outcomes.

Background: Spexin is a novel peptide implicated in food intake and obesity. The primary aim of this study was to analyze whether serum spexin levels, along with total leptin and active ghrelin levels were different in prepubertal children born small for gestational age(SGA) and appropriate for gestational(AGA). Secondary aims were to analyze whether serum spexin, leptin and active ghrelin levels correlated with metabolic syndrome(MS)antecedents according to the Dietary and lifestyle-induced health effects in children and infants (IDEFICS)study. Subjects and Methods: We conducted a cross-sectional study on prepubertal37SGA- (median:5.6yr)and50prepubertalAGA-born children(median:5.9yr). Anthropometric data, homeostasis model assessment of insulin resistance(HOMAIR),plasma lipids, serum spexin, total leptin and active ghrelin levels were analyzed. Associations of serum spexin levels with MS antecedents according to the IDEFICS study were investigated. Results: Children bornSGA had higher body mass index and waist circumference than AGA-born peers(p 0.05). Children bornSGA had higher MS risk scores than AGA-born peers(p Conclusions: Serum spexin levels were not different inSGA- and AGA-born children. Serum spexin levels were reduced in children with MS antecedents independent of size at birth.

Background: We have shown that gene expression (GE) data have promise as a novel tool to aid in the diagnosis of childhood growth hormone deficiency (GHD)1. Our previous study compared GE data in children with GHD to healthy control children of normal stature. The aim of this study was to assess the utility of GE data in the diagnosis of GHD in childhood and adolescence using non-GHD short stature children as a control group. Methods: GE data were obtained from patients undergoing growth hormone stimulation testing via a sample of blood taken at the start of the test. Arginine and glucagon stimulation tests with a cut-off for peak GH of Results: Twenty-four patients were recruited to the study, with eight subsequently diagnosed with GHD. Of the eight patients diagnosed with GHD, three had two stimulation tests and five had one stimulation test with anterior pituitary hypoplasia (in addition one patient had an arachnoid cyst and another a thin stalk). Median (range) peak GH was 2.5 (0.1 - 5) mcg/L in the GHD group and 11.0 (7.4 - 31) mcg/L in the non-GHD group. There were no significant differences in gender, age, auxology (height SDS, weight SDS, BMI SDS) or biochemistry (IGF-I or IGFBP-3 SDS) between the GHD and non-GHD subjects. 82 of the 271 genes used in our previous study were above the threshold of detection for RNA-seq in this study. A random forest algorithm using these 82 genes gave an AUC of 0.97 (95% CI 0.93 - 1.0) for the diagnosis of GHD. Boruta was able to identify 65/82 genes with predictive capacity greater than permuted data within the dataset. Using a gene ontology approach the top fifty biological processes generated 16 clusters by affinity propagation which included regulation of TORC1 signalling and inositol phosphate metabolism. Conclusion: This study demonstrates highly accurate diagnosis of childhood GHD using a combination of GE data and random forest analysis and validates the findings of our original study. 1Murray etal (2018) JCI Insight 3(7): e93247

Congenital hypopituitarism (CH), septo-optic dysplasia (SOD), and holoprosencephaly (HPE) constitute an important group of structural birth defects that cause significant morbidity and life-long consequences for quality of life and care. The genetic causes are highly overlapping. As such, these disorders can be considered as a spectrum of related disorders. Improved insight into genetic causes would be valuable for patients, families, and medical geneticists. Very few systematic genetic screens have been carried out for patients with CH. We implemented genetic screening using single-molecule molecular inversion probes sequencing to identify causative mutations in a set of 67 genes previously reported in CH patients and the spectrum encompassing SOD and HPE. We captured genomic DNA from 170 Argentinean pediatric patients with CH, and 54% of the patients in this cohort have craniofacial, ophthalmologic, and/or central nervous system defects. We found candidate pathogenic, likely pathogenic and variants uncertain significance (VUS) in 23% of the cases. In order to evaluate the functional consequences of VUS in LHX3, LHX4, and GLI2, we performed in-vitro functional assays to study the activity of the mutated proteins. To test LHX3/4 variants we co-transfected HEK293T cells with wild type (WT) or mutated LHX3/4 variant plasmids and luciferase reporter genes driven by the ɑGSU promoter or GH1 promoter and assayed for luciferase activity. For GLI2 functional analysis we used the cell line NIH/3T3-CG, stably transfected to express GFP under the presence of GLI2 activated form. Endogenous Gli2 was knocked out by CRISPR-Cas9 and clones were selected for absence of GFP expression upon activation of the sonic hedgehog pathway. We tested the ability of transfected WT or mutated GLI2 expression plasmids to restore GFP fluorescence. We concluded that variants LHX3:p.Pro187Ser LHX4:p.Arg84His, p.Gln100His and p.Trp204Leu and GLI2:p.1404Lfs impair activation of the reporter gene, while the LHX3:p.Leu220Met and GLI2:p.L761P have WT activity on their respective assays. Identification of disease-causing variants in CH is complicated by phenotypic variation, incomplete penetrance, and VUS. Functional testing of potentially pathogenic variants is critical to arrive at a definitive molecular diagnosis. A full catalogue of variant effects in known causative genes would be invaluable for clinicians in order to simplify the interpretation of novel variants and reduce the diagnostic odyssey that families often experience.

Background: We investigated iodine status and its association with thyroid function among preschool children residing in iodine-sufficient area. Methods: From the Environment and Development of Children study, 477 children were evaluated for thyroid function and urine iodine concentration (UIC) at age 6 during 2015-2017. After excluding children born with multiple birth and with congenital hypothyroidism or Hashimoto thyroiditis, 439 (231 boys) were included. Subclinical hypothyroidism (SCH) was defined as thyroid stimulating hormone (TSH) levels between 4.9-10 μIU/mL with normal free T4 levels. Iodine status was evaluated by UIC and children were categorized into 4 groups: iodine deficient (UIC < 100 μg/L), adequate (UIC, 100-299 μg/L), mild excessive (UIC, 300-999 μg/L), severe excessive (UIC ≥ 1000 μg/L). Results: Goiter was palpated in 64 (14.6%) with female predominance (26.0% vs. 4.3%, P < 0.001). Serum level of free T4 and T3 was 1.2 ± 0.1 ng/dL and 148.1 ± 18.5 ng/dL, respectively. The median TSH level was 2.3 (0.53-8.59) μIU/mL and the prevalence of SCH was 4.3% without sex-difference. The median UIC level was 606.2 (19.9-16409.7) μg/L, higher in boys (684 vs. 545 μg/L, P = 0.021) than in girls. Iodine was deficient in 19 (4.3%), adequate in 96 (21.9%), mild excessive in 170 (38.7%), and severe excessive in 145 (35.1%). After excluding 19 iodine deficient children, the relationship between iodine status and thyroid function was evaluated by multiple regression analysis after adjusting for age, sex, birth weight, gestational age, body mass index Z-score, and family history. As iodine status increased from adequate, mild excessive to severe excessive group, T3 levels decreased, and TSH levels increased with marginal significance (P for trend < 0.1 for T3 and TSH). When stratified by sex, similar association was found in only girls (P for trend = 0.043 for T3, and 0.062 for TSH) but not in boys, and mild excessive group showed lower free T4 levels (β = -0.05, P = 0.013) and severe excessive group had lower T3 levels (β = -7.04, P = 0.035) than iodine adequate group in only girls, but not in boys. Conclusion: Iodine was deficient in 4.3%, adequate in 21.9%, and excessive in 73.8% among preschool children residing in South Korea. As iodine status increased from adequate to excessive group, TSH levels increased with decreasing free T4 and T3 levels in girls.

Children with cardiomyopathy are a vulnerable population and understanding the factors that contribute to cardiac dysfunction are of great importance. At the biochemical level, energy utilization by cardiomyocytes during stress may provide insight into the progression of cardiomyopathy. There is a large body of literature that describes insulin resistance in adults with cardiomyopathy (1,2). Extensive literature on the topic in adult individuals exists however investigation in the pediatric population is sparse. The pathophysiology of disease in children and adolescents is unique. To study the role of insulin resistance in pediatric cardiomyopathy, we measured the homeostasis model assessment-estimated insulin resistance (HOMA-IR) at baseline in pre-pubertal patients (age 13-18 years old; mean 16 years old; n = 8) with either hypertrophic cardiomyopathy (HCM) or dilated cardiomyopathy (DCM). In patients with HCM, greater insulin resistance was positively correlated with greater left ventricular (LV) septal thickness (r = 0.55; p = 0.33; n = 5) and LV posterior wall thickness (r = 0.7; p = 0.19; n = 5) during diastole. As expected, insulin resistance was strongly correlated with BMI (r = 0.84; p = 0.08; n = 5) though greater BMI was not as strongly associated with LV septal thickness (r = 0.59; p = 0.3; n = 5) or posterior wall thickness (r = 0.59; p = 0.3; n = 5). In patients with DCM, insulin resistance was positively correlated with LV end diastolic volume (r = 0.59; p = 0.59; n = 3). Interestingly, there was an observed inverse association between insulin resistance and BMI in DCM (r = -0.85; p = 0.34; n =3). Though our sample population is limited, thus affecting statistical significance, results showed that there was a trend towards greater insulin resistance in patients with poorer cardiac measurements. These findings are consistent with adult literature and the proposition that cardiac dysfunction is an insulin resistant state. References: (1) Riehle C, Abel ED. Insulin Signaling and Heart Failure. Circulation research. 2016;118(7):1151-1169. (2) Shah A, Shannon RP. Insulin resistance in dilated cardiomyopathy. Reviews in cardiovascular medicine. 2003;4 Suppl 6:S50-57

Introduction: Abdominal pain is a common presenting symptom in diabetic ketoacidosis (DKA). Correction of the acidosis usually leads to resolution of the abdominal pain. In some instances, the pain may persist due to additional etiologies presenting alongside DKA. Though uncommon, there has been shown to be an association between DKA and acute pancreatitis (AP). In these rare cases, AP was secondary to the hypertriglyceridemia (HTG) state induced by DKA. We report a 13-year-old female known with type 1 diabetes (T1D) who presented with multiple concomitant episodes of DKA and AP and normal triglyceride levels. Case Presentation: The patient is a 13-year-old female with T1D who presented with two days of hyperglycemia, nausea, and diffuse abdominal pain. Initial laboratory evaluation was remarkable for point-of-care glucose of >500 mg/dL (60-99), venous pH of 7.006 (7.330-7.430), bicarbonate of < 5 mmol/L (20-28), beta-hydroxybutyrate of 5.6 mmol/L (0.0-0.8); consistent with severe DKA. She received normal saline bolus fluids and then started on the DKA protocol with improvement of acidosis, though with the persistence of abdominal pain. Due to concern for other causes of her abdominal pain, additional workup was done, notable for elevated lipase of 624 U/L (10-52), amylase of 434 U/L (25-100), and triglyceride of 121 mg/dL (30-149). An abdominal ultrasound showed findings consistent with AP, lipase levels peaked at 1753 U/L before down-trending to 959 U/L, and amylase decreased to 389 U/L. After several days abdominal pain resolved, and the patient was discharged home. The patient was readmitted six weeks and again one year later for laboratory and symptoms, including abdominal pain consistent with DKA. Both lipase and amylase were elevated during both admissions with normal triglyceride levels. Magnetic resonance cholangiopancreatography was significant for findings compatible with acute pancreatitis with no evidence of cholelithiasis or choledocholithiasis. The patient underwent genetic testing, including normal PRSS1, SPINK1, CFTR, CPA1, and CTRC. A variant of unknown clinical significance was identified in the CTRC gene (c.550G>A), which was not thought to be the cause of her recurrent pancreatitis. Interestingly, since her hemoglobin A1c has been in a better range for the past year, she did not have any recurrent episodes of pancreatitis. Conclusion: The insulin-deficient state associated with DKA can lead to moderate to severe HTG, which in turn can cause AP. Even though abdominal pain is a common symptom in patients presenting in DKA, one should think about other causes when the abdominal discomfort is out of proportion or not improving as acidosis resolves. Our patient had recurrent pancreatitis for unknown etiology; however, she has not had any pancreatitis episodes in the last year since her diabetes has been under better control.

Background: Youth with congenital adrenal hyperplasia (CAH) have a higher prevalence of obesity, early adiposity rebound, and increased fat mass. Unsuccessful dietary self-control could contribute to obesity, and understanding food-seeking behavior could therefore guide prevention. Dietary decision-making involves key brain regions such as the limbic system and the prefrontal cortex, which are associated with choice and reward. These regions (i.e., prefrontal cortex, amygdala, hippocampus) can be smaller in volume in CAH patients. However, little is known about dietary decision-making in CAH. We hypothesized that CAH youth would exhibit differences in dietary decision-making and aimed to study food choices in CAH youth compared to controls. Methods: 37 CAH youth (12.2 ± 3.1 y, 60% male, BMIz 1.6 ± 0.8) and 100 controls (11.7 ± 2.4 y, 57% male, BMIz 0.9 ± 1.2) completed a behavioral computer-based food choice task. They rated 30 high- and 30 low-calorie food cues for tastiness, healthiness, and liking. Food pairs discordant for taste and health ratings were generated, and youth were asked to choose the item they wanted to eat. Cursor-trajectory analyses measured area under the curve (AUC) and maximum deviation time (MDT), with successful choice trials evident when the healthier food was chosen. Based on individual ratings for food cues, β-coefficients for ratings predicting food preference were generated. Results: CAH youth and controls did not show differences in food ratings (P > 0.30 for all) or in the percentage of successful trials of total choice trials (P = 0.16). However, CAH youth showed larger mean AUCs compared to controls [T(135) = 2.15; P = 0.03] suggesting that they may experience more conflict and exert more cognitive effort in decision-making. CAH youth also had longer mean MDTs [T(102.3) = 2.59; P = 0.01] in successful choice trials, indicating a later time at which a final decision was made. β-health and β-taste predicting food preference did not differ between groups, and β-health was correlated with successful choice trials in both CAH (r = 0.38, P = 0.02) and controls (r = 0.48, P < 0.01). However, β-taste was negatively correlated with successful choice trials in controls only (r = -0.42, P < 0.01; CAH r = -0.22, P = 0.18). Conclusion: Although youth with and without CAH had similar perceptions of food, CAH youth may exert greater cognitive effort and experience more conflict in dietary decision-making. This could suggest that factors inherent to CAH such as abnormal neural pathways, or disease treatment, could affect the cognitive control of food choices in CAH youth.

Type 1 diabetes (T1D) is a common illness of childhood, requiring lifelong, daily complex management to prevent acute and chronic complications. Studies have shown that use of insulin pumps and continuous glucose monitors (CGM) offers benefit for glycemic control. However, such device use is not universal in adolescents. We aimed to compare baseline socio-demographic and diabetes characteristics associated with diabetes technology (pump and CGM) uptake and continued use in 13-17 year old teens with T1D. Data were derived from a multicenter clinical trial aimed at optimizing self-care and glycemic control in teens with T1D. Socio-demographic and diabetes data were collected quarterly by parent-youth interview and electronic medical record review prospectively over 18 months. Chi-square and t-tests compared characteristics of device and non-device users (pump vs no pump; CGM vs no CGM). The study sample comprised 301 teens (41% male) with mean±SD age 15.0±1.3 years, T1D duration 6.5±3.7 years, and A1c 8.5±1.1%. Most (65%) used a pump at entry or initiated pump therapy during the study; 35% used injection therapy at entry or stopped pump therapy. In contrast, 27% used a CGM at entry or started a CGM during the study, while 73% never used or stopped using CGM. Device users at entry and those who began use had similar characteristics, as did those who never used and those who discontinued device use. Pump users were more likely to use CGM than non-pump users (36% vs 10%, p

Introduction: Adrenocortical tumors (ACTs) are rare in the pediatric population compared to the adults, with an incidence of 0.3-0.5 cases per million child-years. Most ACTs are sporadic, but some occur as a component of hereditary cancer syndrome. We report a case of a 16 year old male with single unilateral adrenocortical tumor that was found to secrete cortisol and aldosterone. Case Presentation: 16-year-old male previously healthy, presented to nephrology for elevated blood pressure (BP) and microscopic hematuria evaluation. He was otherwise asymptomatic. Manual BP was noted to be 156/84 mmHg and physical exam was within normal limits. Laboratory evaluation revealed a normal comprehensive metabolic panel. Echocardiography was notable for moderate left ventricular hypertrophy, and a renal ultrasound revealed a heterogeneous solid right adrenal mass which measured 5.6 x 4.5 cm. Adrenal MRI showed a well-defined round 5.7 x 5.0 x 5.2 cm right adrenal mass with heterogeneously T1 isointense and T2 hyperintensity, with no evidence of vascular invasion. The left adrenal gland was normal. Additional workup was notable for an aldosterone level of 18.4 ng/dL (4.0-31.0 ng/dL), plasma renin activity 0.2 ng/ml/h (T) variant of unknown significance in the MSH2 gene. His blood pressure continued to remain elevated after surgery, and he was started on lisinopril with minimal improvement. The patient is currently doing well, and his blood pressure is better controlled now with amlodipine. He is undergoing surveillance with laboratory evaluation and imagining every 3-6 months. Discussion: ACTs are extremely rare in pediatric patients. Their presentation might be variable, and even when they are found incidentally, it is crucial to assess for hormonal secretion. Although our patient had no signs of hypercortisolism on physical exam, his ACT was secreting both cortisol and aldosterone. In this case report, we demonstrated a rare case of unilateral ACT causing hyperaldosteronism and hypercortisolism with persistent hypertension following adrenalectomy.

Background: Prader-Willi syndrome (PWS) is a rare, complex, multisystem disorder caused by the loss of multiple paternally expressed genes on chromosome 15q11-13 and is present in 1/15,000-30,000 individuals. Characteristics of PWS include low muscle mass and hypotonia, accumulation of excess body fat, short stature, hyperphagia, behavioral problems, cognitive disabilities, developmental delays, and hypogonadism. In these patients, serum creatinine (SCr)-based methods to calculate estimated glomerular filtration rate (eGFR) can lead to inaccurate results. eGFR is reported to be negatively correlated to muscle mass and PWS-associated low lean body mass may contribute to low SCr levels. Therefore, eGFR calculations may not accurately reflect PWS patient’s renal function. A more accurate, non-invasive, inexpensive means to monitor renal function for this patient population is desirable. Objective: To assess methods of estimating renal function in pediatric PWS patients and summarize the relationship between eGFR and patient-specific factors. Methods: The pre-treatment data of patients ≥4 years old with genetically confirmed PWS participating in an investigational study of DCCR (diazoxide choline) were evaluated. Lean body mass was measured using dual X-ray absorptiometry. Lean body mass and age were correlated to eGFR/creatinine clearance (CrCl) values calculated using four different equations: Bedside Schwartz (BS), Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI), Modification of Diet in Renal Disease (MDRD), and Cockcroft-Gault (C-G). Results: Of the 124 patients enrolled in the study, 99 were

Introduction: Monogenic diabetes results from a mutation in single gene, predominantly inherited and typically affects the young. DNAJC3 acts in attenuating endoplasmic reticulum stress and is found in abundance in pancreatic tissue. Clinical Case: We report a homozygous DNAJC3 mutation in two siblings of a consanguineous Saudi family. A 3-year boy presented with short stature and thyroid nodule; lab findings confirmed hypothyroidism, with TSH 27.8 and FT4 6.7 (n: TSH:0.35-4.94 mIU/L, FT4:9.0-19 pmol/L). Subsequently, L-thyroxine was started. GH stimulation test was normal. He was severely short; 80.5 cm (< 1 percentile, -3.79 SD). The patient developed sensorineural hearing loss (SNHL) at 6 years. He had low intellectual function and weak school performance. GH treatment was postponed to age 9 due to strong family history of DM. At that point, the patient developed progressive ataxic gait, for which he had muscle biopsy that excluded mitochondrial disease and workup for multiple sclerosis, which was excluded. Brain and spine MRI showed prominent neurodegeneration in subcortical white matter. At age 11, the patient developed DM, 4 years after GH treatment initiation. DM autoimmune markers were negative on multiple occasions. Lifestyle modification was initiated but soon required basal and bolus insulin therapy. Whole exome sequencing revealed homozygous DNAJC3 mutation, which explained his clinical presentation. At age of 17, adult height was 141 cm (Z-score: -5.87). His older brother had similar history discovered retrospectively but did not develop neurodegeneration or ataxia from the same DNAJC3 mutation. Literature Review: Literature review revealed six individuals with homozygous DNAJC3 mutation. All patients developed DM, with onset ranging from 11 to 19 years, highly suggestive of MODY. Other endocrine manifestations included short stature, and hypothyroidism due to primary etiology; in view of elevated TSH levels, vs. being secondary, as suggested by the authors. All patients had mitochondrial disease workups and was excluded. Variable neurodegeneration degrees are described; SNHL, progressive ataxia, sensorimotor neuropathy, and cognitive deficits. MRI findings showed atrophy of cerebellum, brainstem, cervical spinal cord, and hyperintense T2 lesions typical of neurodegeneration. Conclusion: Homozygous DNAJC3 gene mutation fits MODY criteria, we propose recognizing it as one of the known MODY gene mutations. Hypothyroidism is due to primary etiology, evident by TSH spikes. Physicians evaluating mitochondrial disease in patients with a constellation of SNHL, DM, hypothyroidism, neurodegeneration, and short stature should suspect DNAJC3 as one differential diagnosis. GH treatment must be initiated cautiously, with close monitoring due to its known diabetogenic effect, especially in DNAJC3 mutations, defective endoplasmic stress attenuation mechanism.

Introduction: Several demographic and clinical characteristics, including age, low socioeconomic status, and misdiagnosis at initial clinical presentation were previously associated with increased risk of diabetic ketoacidosis (DKA) at diagnosis of type 1 diabetes (T1D) in the pediatric population. However, it is unclear whether the coronavirus (COVID-19) pandemic and subsequent lockdown influenced the rate of DKA in children newly diagnosed with T1D. We undertook this study to identify the impact of the COVID-19 pandemic on the rate of DKA in children newly diagnosed with T1D in a single tertiary care referral center in central Pennsylvania. Methods: We performed an extension of a retrospective analysis of all pediatric patients (age ≤18) newly diagnosed with T1D within a tertiary care referral center between 01/01/2017-09/14/2020. Demographics, insurance coverage, and all clinical documents 30 days before their T1D diagnosis were abstracted to assess for symptoms at diagnosis (polyuria, polydipsia, nocturia, weight loss, nausea, vomiting, altered mental status, infection, vision changes, and autism spectrum disorder), lab values (blood glucose, HbA1c, venous pH, and bicarbonate), and any healthcare encounters within 30 days of their diagnosis of T1D. We performed descriptive statistics and univariate analyses [evaluating children diagnosed with T1D during the pre-COVID-19 era (diagnosed between 1/1/2017-2/28/2020) and post-COVID-19 era (diagnosed between 03/01/2020-09/14/2020) associated with the incidence of DKA], followed by logistic regression analysis (incorporating key clinical factors previously associated with DKA and the pre- or post- COVID-19 era classification). Results: 412 pediatric patients with T1D [171 F:241 M; 370 pre-COVID-19 era:42 post-COVID-19 era] were included. The percentages of DKA diagnoses at admission were very similar between the pre-COVID-19 and post-COVID-19 groups (47% vs. 48%), as were the severity (13% vs. 14% mild DKA; 33% vs. 31% moderate or severe DKA). There were no temporal associations with the rate of DKA in respect to COVID-19, however, age (0-3 and 9-13 years), misdiagnosis during a preceding healthcare encounter, presenting to the emergency department directly, elevated HbA1c (>10.0%/13.4mmol/L), and altered mental status were associated with increased risk of DKA on multivariable analysis. Conclusion: There were no fluctuations in the rate of DKA among pediatric patients newly diagnosed with T1D throughout the COVID-19 pandemic in central Pennsylvania. Interestingly, some geographic locations observed an increased frequency of DKA in children newly diagnosed with T1D, while others noted a decreased rate. Regardless, our findings suggest previously described predictors of DKA in the pediatric population persist, even in the setting of the COVID-19 pandemic.

GnRH neuronal biology has been identified as a critical element in the pathogenesis of self-limited DP, previously implicated exclusively in the pathophysiology of idiopathic hypogonadotropic hypogonadism (IHH). We hypothesise that this condition may be inherited via genetic variants discoverable through whole-exome sequencing (WES), by focusing on genes involved in GnRH neuron development and function, and genes reported in IHH. We analysed WES data from large Finnish cohort with familial self-limited DP, focusing on genes recently reported in IHH. WES data of 100 DP families have been analysed with a total of 193 individuals: 100 probands, 158 affected and 35 unaffected family members. Potentially pathogenic rare variants segregating within cohort families were identified using a virtual panel of recently reported IHH genes (n=13). This analysis identified 6 rare potentially pathogenic variants in CCDC141 in 25 individuals of 8 families which account for almost 10% of self-limited DP cases in this cohort, without variants identified in cohort control cases. Previous studies reported that homozygous or compound heterozygous mutations of CCDC141 cause Kallmann syndrome and IHH, due to impaired GnRH neuronal migration. In this study, all 6 CCDC141 variants were heterozygous missense variants predicted to be deleterious by in silico prediction tools. Most probands were male (n=7) with typical features of self-limited DP, with absence of secondary sexual characteristics, delayed bone age, and low gonadotropins and sex steroids at first presentation and spontaneous entry into puberty later than age of 14 years without treatment. The majority of pedigrees displayed good segregation of variants with the DP trait, following an autosomal dominant inheritance pattern. However, in two families, there was a complex inheritance pattern with compound heterozygosity (p.Ser55Cys and p.Asp767Asn) and possible incomplete penetrance. In vitro study showed that the overexpression of four key CCDC141 variants in HEK293 cells delayed cell migration, 72% in p.Ser55Cys (p=0.04), 66% in p.Gln507His (p=0.04), 65% in p.Asp767Asn (p=0.02), and 83% in p.Ala1073Thr (p=0.01), when compared to WT (100%). Moreover, WT-overexpressed cells increased the rate of cell migration when compared to non-transfected cells (100% vs 65%, p=0.005), reaffirming that CCDC141 has a role in cell migration. In conclusion, heterozygous deficiency of CCDC141, previously reported to cause IHH, can cause self-limited DP due to abnormal GnRH migration during foetal development.

Background: Multisystem inflammatory syndrome in children (MIS-C) is a serious inflammatory response to a prior coronavirus disease of 2019 (COVID-19), characterized by fever, inflammation, and multiorgan dysfunction. Current literature does not indicate a relationship between pediatric diabetes and risk of developing MIS-C. Here, we report a case of pediatric type 2 diabetes (T2D) with diabetic ketoacidosis (DKA) and severe multi-organ dysfunction with SARS-CoV-2 serology positivity. Clinical Case: A 13-year-old African American female with obesity (Body Mass Index >99th %) and poorly controlled T2D (HbA1c 12.8%) presented to the emergency department for one week of sore throat, headache, and abdominal pain. SARS-CoV-2 positivity was confirmed by PCR. The next day, she was found unconscious at home. She was diagnosed with DKA and was directly admitted to the pediatric intensive care unit. IV insulin and aggressive fluid resuscitation were initiated and her DKA resolved over the next 72 hrs. However, she exhibited continued altered mental status with slurred speech and significant respiratory distress requiring respiratory support. Due to the severe presentation and multi-organ involvement, a multi-disciplinary care team was formed. Further workup confirmed acute respiratory distress syndrome with pneumonia; severe acute kidney injury (AKI, creatinine of 4.56 mg/dL); presumed myocarditis (ST elevation on EKG, troponin 4.47 ng/mL, BNP 129.8 pg/mL); punctuate intraparenchymal hemorrhage in the splenium of the corpus callosum; transaminitis (AST 188 u/L, ALT 100 u/L); pancreatitis (amylase 651 u/L, lipase >9500 u/L); thrombocytopenia with consumptive coagulopathy (platelet 81 X 103/µL, d-dimer 5.91 mcg FEU/mL), increased inflammatory markers (ESR 53 mm/hr, ferritin 127 ng/mL), and positive SARS-CoV-2 serology. A presumed diagnosis of MIS-C was made per the Centers for Disease Control and Prevention definition and she was started on dexamethasone and intravenous immunoglobulin (IVIG). While consideration was given to the possibility of acute COVID-19 infection in combination with DKA, she was not a candidate for remdesivir due to AKI. On day 12, she developed new dysarthria, dyspraxia and behavioral changes. Encephalopathy workup was negative (CSF Encephalopathy autoimmune panel negative, NMDA receptor negative) and she was restarted on dexamethasone and IVIG. She was discharged on day 28. Conclusion: There is a paucity of literature of MIS-C associated with COVID-19 in the pediatric diabetes. Our case highlights several novel aspects of MIS-C with concurrent poorly controlled diabetes and DKA, including severe central nervous system manifestations and prolonged hospitalization. Further studies are warranted to elucidate an association between pediatric diabetes and MIS-C and to develop guidelines for management of MIS-C in poorly controlled pediatric diabetes.

Background: Studies comparing the timing and pace of puberty in overweight/obese girls (OW/OB) vs normal weight girls (NW) have produced conflicting results; some suggest earlier activation of the central components of the reproductive axis in OB while others are more consistent with a peripheral source of estrogen (e.g. adipose tissue) driving puberty in OB. Importantly, there have been no longitudinal assessments of both clinical and biochemical pubertal markers in OB vs. NW. Methods: 90 healthy pre-menarchal girls (26 OW/OB, 54 NW) from the community, aged 8.2-14.7 years, completed 2.8 ± 1.7 (mean, SD) study visits over the course of 4 years. Visits included dual-energy x-ray absorptiometry to calculate percent total body fat (TBF), Tanner staging, breast ultrasound for morphological staging (BMORPH; stages A-E), pelvic ultrasound, hand x-ray (bone age, BA), blood tests for reproductive hormones, and urine collection to determine a vaginal maturation index (VMI), an index of estrogen exposure in urogenital epithelial cells. Menarchal status was determined at each visit and via follow-up questionnaires. The effect of TBF on hormones and markers of estrogen action, the pace of breast maturation, and age at menarche were determined using a mixed, multi-state, or Cox proportional hazards model, respectively. Mixed and Cox models controlled for BMORPH at visit 1 (V1) and race. Results: NW girls were older than OW/OB (11.3 vs. 10.2 yrs, p

Introduction : In the United States, non-Hispanic white (NHW) children are disproportionately over-represented relative to children of racial and ethnic minorities in pediatric growth hormone (GH) treatment registries. This study sought to determine if this racial inequity is due to differences in GH stimulation testing and/or GH prescribing patterns in children referred for endocrine evaluation of short stature. Methods : Retrospective chart review was performed including children aged 2-16 years, with height z-score ≤ -1.5, and of NHW, non-Hispanic black (NHB) or Hispanic race/ethnicity, referred for endocrine growth evaluation between January 1, 2012 and December 31, 2019. Age, sex, anthropometry, GH stimulation test results and GH treatment data were extracted. Comparisons between NHB, NHW and Hispanic children were performed using analysis of variance, chi-squared tests, Mann Whitney U and logistic regression tests. Results : This study included 7,425 patients (5,905 NHW, 800 NHB, and 720 Hispanic). GH stimulation testing was performed in 992, and 576 were prescribed GH. NHW children were 1.4 (95% CI 1.04 - 1.8) times more likely than NHB children and 1.7 (95% CI 1.2 - 2.2) times more likely than Hispanic children to undergo GH stimulation testing. NHB children treated with GH had: 1) lower median peak GH concentration when compared with NHW (p=0.02) and Hispanic (p=0.08) children (NHB 4.7 [1.2, 8.3] ng/ml, NHW 7.2 [4.9, 9.7] ng/ml, Hispanic 7.1 [4.3, 11.9] ng/ml); 2) lower median height z-scores than NHW (p=0.01) but not Hispanic children (p=0.5); and 3) a greater height deficit from mid-parental height when compared with NHW (p=0.01) and Hispanic (p=0.002) children Discussion: Racial and ethnic disparities are present in the evaluation and treatment of children with disordered growth. This likely results from both over-investigation of NHW children as well as under-investigation and under-treatment of children from minority communities. The evaluation and treatment of children with short stature should be determined by clinical concern alone, but this is unfortunately not current practice.

In the Netherlands, the diagnosis of growth hormone deficiency in children follows the Dutch national guidelines for Triage and Diagnosis of Growth Disorders in Children. Initial biochemical evaluation includes an IGF-1 measurement as screening parameter for growth hormone deficiency. Based on the clinical probability of growth hormone deficiency and the IGF-1 Z-score, a growth hormone stimulation test is performed if serum IGF-1 Z-score is < 0 SD in case of a high probability and if serum IGF-1 Z-score is < -1 SD in case of low probability. An IGF-1 Z-score > 0 SD virtually excludes a growth hormone deficiency disorder. The interpretation of growth hormone stimulation testing is dependent on both the peak growth hormone concentration, but also on the baseline IGF-1 Z-score, particularly in cases of partial deficiency. Although, nation wide, Dutch laboratories have harmonized their measurement for IGF-1 (as was previously done for growth hormone), a Dutch harmonized normative data set has not been widely adopted. Moreover a clinical evaluation of the implementation of this dataset based on dynamic testing has not been published. To assess the impact of choice of a particular normative dataset on the diagnosis of growth hormone deficiency we recalculated Z-scores of IGF-1 measurements between 2016 and 2019, using our home reference values based on de normative dataset by Elmlinger (E)1, and using the normative datasets defined by Bidlingmaier (B)2 and by the Dutch IGF-1 harmonization program (NL). Based on these three Z-scores, the outcomes of growth hormone stimulation tests performed in this period (n=86) were reassessed according to the interpretation described in the Dutch guideline. Using all three normative datasets the same 4 patients were identified as likely to have a growth hormone deficiency, whereas 10(E), 10(B), or 8(NL) patients were identified as possible partial growth hormone deficiency. In 70(E), 66(B) or 72(NL) patients the growth hormone stimulation test was unaffected. Using normative dataset B, 6 patients displayed a pattern associated with a possible growth hormone resistance, or of bio-inactive growth hormone syndromes, which based on its incidence would be unlikely for a secondary care setting. A striking observation was however, that of all patients with a normal stimulation test 9 (E)/16 (B) or 30 (NL) had a IGF-1 Z-score of > 0 SD. This implies that, for the diagnosis of growth hormone deficiency, it is safe to implement the Dutch harmonized dataset, which in addition could result in a reduction in the number of growth hormone stimulation tests that have to be performed. References: 1. Elmlinger MW et al. Clin Chem Lab Med. 2004;42(6):654-64. 2. Bidlingmaier M et al. J Clin Endocrinol Metab. 2014 May;99(5):1712-21.

Background: Pediatric bone diseases due to osteoclast overactivity have limited therapeutic options. Denosumab, a human monoclonal antibody against RANK-ligand, has been used in the treatment of these conditions despite limited pediatric safety data. Rebound hypercalcemia after denosumab cessation is a rare and potentially serious complication in children with an unpredictable course (1). We present the first report of a child with cherubism who experienced acute symptomatic hypercalcemia five months after denosumab cessation. Clinical Case: An 11 year old male presented to our emergency department (ED) with 2 weeks of nausea, vomiting, abdominal pain, and bilateral leg pain. He was diagnosed with cherubism at age 3 years with progressive painless bilateral jaw swelling, teeth crowding, and proptosis. His bilateral maxilla and left mandible were debulked between ages 5-8 years due to tumors causing dyspnea. The resected tumors showed RANK-ligand expression. Thus, he started a 1-year course of denosumab 80 mg monthly subcutaneous injections for additional lesions not amenable to surgery with marked clinical and radiographic improvement. He had mild hypocalcemia during denosumab therapy, for which he received cholecalciferol 2000 IU and calcium citrate total 1500 mg per day. Calcium citrate was stopped with corrected serum calcium (Ca) 10.1 mg/dL (8.8-10.8 mg/dL) three months prior to ED visit. His presentation to ED five months after denosumab revealed marked hypercalcemia (corrected Ca 13.9 mg/dL), iPTH 5.4 pg/mL (7.5-53.5 pg/mL), 25-OH vitamin D 19 ng/mL (30-100 ng/mL), and hypercalciuria (urine Ca/creatinine ratio 0.58 mg/mg, normal Reference: (1)Upfill-Brown A, Bukata S, Bernthal NM, Felsenfeld AL, Nelson SD, Singh A, Wesseling-Perry K, Eilber FC, Federman NC. Use of Denosumab in Children With Osteoclast Bone Dysplasias: Report of Three Cases. JBMR Plus. 2019 Aug 22;3(10):e10210

Presentation Type: OralScience Type and Topic: Clinical Trial Introduction: LUM-201 (ibutamoren, formerly MK-0677) is an orally administered GH-secretagogue that stimulates the GH secretagogue receptor (GHSR1a) in the hypothalamus and pituitary. LUM-201 is in development for long-term use in a subset of PGHD patients with moderate growth deficiencies. A diagnosis of PGHD is confirmed by low GH responses to standard GH secretagogues (clonidine, arginine, L-dopa, glucagon, insulin) so it is somewhat counter-intuitive to suggest that children who cannot respond to one GH secretagogue might have favorable responses to LUM-201. Objective: To determine if LUM-201 stimulates GH responses differently than standard GH secretagogues. Methods: 68 naïve-to-treatment, prepubertal children with GHD received two standard GH stimulation tests and a test with a single 0.8 mg/kg dose of LUM-201. The 68 subjects included 20 girls and 48 boys. The median (interquartile range) age was 9.2 years (7.2,10.8), bone age 6.0 years (4.5, 7.9), height SDS -3.3 (-4.5, -2.5), pretreatment height velocity 4.0 cm/y (3.2, 4.6), and baseline IGF-1 51 ng/mL (24,111). Results: The median (interquartile range) of maximal GH response to single dose LUM-201 was 15.0 ng/mL (3.5, 49) and to various pairs of standard stimuli was 5.4 ng/mL (1.8-7.6) (p< 0.00001). The median (IQR) for the difference between GH responses to LUM-201 and standard stimuli was 9.6 ng/ml (1.9, 42). In a multivariate analysis (r2 =0.73) differential GH increased with higher values of baseline IGF-I (p < 0.00001) and standard GH stimulation test (p = 0.047) but was not influenced by age (p = 0.16), sex (p = 0.28), baseline HV (p = 0.24), age-bone age differences (p = 0.33) or height-SDS (p = 0.75). Conclusion: In GHD children, the GH response to single dose LUM-201 greatly exceeds that observed with standard GH testing agents. The difference is greatest among patients with higher baseline values of IGF-I and higher GH responses to standard stimuli. The synergistic actions of LUM-201 on the physiological mechanisms regulating GH release explain why GH responses are greater in response to LUM-201 compared to traditional tests used to diagnose PGHD. Key words: LUM-201, GH deficiency, GH secretagogues, pediatrics, stimulation tests, short stature, pituitary, hypothalamus

Introduction: Pediatric Graves’ hyperthyroidism needs long-term therapy and there is no specific guideline. Antithyroid medication is used as the first line of treatment, among antithyroid medication, radioiodine therapy, and surgery. The study was designed to investigate the clinical features and remission rate and the factors associated with the remission of Graves’ hyperthyroidism treated with antithyroid drug in children and adolescents. Methods: Initially, 114 children and adolescents who have been managed with thyrotoxicosis in a single tertiary center were included in the study. Retrospective review of medical records was performed on the demographic data, clinical information, and laboratory results. Ten patients with Hashitoxicosis, 36 patients who were followed less than 1 year, and 19 patients with no available initial results of thyroid function test were excluded from the study. We analyzed the clinical features and remission rate between the group with remission and the group without remission. Chi-square, Fisher’s exact test, and t-test were used for statistics. Results: A total of 49 patients were included in the study (M:F 11:38). Mean age at diagnosis was 12.6±3.7 years old and the follow up duration was 4.9±2.5 years. Goiter was visible in 47 patients (96%) and exophthalmos was found in 12 patients (24%). Thirteen patients (27%) showed treatment-related hypothyroidism during follow up. Twenty-seven patients (55%) could discontinue the medication for more than 1 month. Among those, eleven patients showed recurrence and 6 out of 11 patients reached remission again. As a result, 22 patients (45%, male 7) maintained the remission state. Average time till remission was 4.2±2.4 years. Remission rate was 2%, 8%, 12%, 35%, and 45% during the treatment of 1, 2, 3, 4, and 5 years, respectively. Mean follow up duration was significantly longer in the group with remission (5.7±2.2 years), compared with the group without remission (4.3±2.6 years) (p

Endocrine complications are amongst the most frequent late effects after pediatric hematopoietic stem cell transplantation (HSCT) for malignant diseases. Little is known about the prevalence and risk factors of endocrine complications in children transplanted for nonmalignant diseases. This retrospective study included 134 males and 63 females transplanted for a non-malignant disease between 1997 and 2018 with at least 2 years of follow up. Endocrine late effects and growth were evaluated. Gonadal dysfunction was defined as transient or permanent elevation of gonadotropins or hypogonadotropic hypogonadism. Median age at HSCT was 5.7 years (IQR 2.8-11.3) and median follow-up was 6.2 years (IQR 3.0-10.4). Underlying diseases were inborn errors of immunity (n=74), hemoglobinopathies (n=66) and bone marrow failure (n=57). The majority of patients had received busulfan-based conditioning (46%) or treosulfan-based conditioning (34%). Gonadal dysfunction occurred in 24/44 (post)pubertal female patients (55%) and was permanent in 19/44 (43%). 22/44 received hormonal substitution, which could be discontinued in 7. In females who received busulfan-based conditioning 16/17 (94%) developed gonadal dysfunction compared to 5/15 (33%) patients with treosulfan-based conditioning; the odds ratio for permanent gonadal dysfunction was 18.7 (3.61-135, p=0.001). Gonadal dysfunction occurred in 28/66 (post)pubertal male patients (42%) and was permanent in 23/66 (35%). 6/66 received hormonal substitution, which could be discontinued in 1. Gonadal dysfunction was more common in males (post)pubertal at HSCT, 14/21 (67%), compared to those prepubertal at HSCT, 14/45 (31%), p=0.014. 3/15 treated with a treosulfan-based regimen (20%) developed gonadal dysfunction, all transient, versus 19/39 with a busulfan-based regimen (49%), with 2 transient. 29/187 patients developed hypothyroidism (16%), 7 patients received thyroxine treatment (4%). All patients with persistent primary hypothyroidism (n=6) had positive TPO-antibodies. 17 patients received growth hormone treatment and were excluded from analysis. In patients without growth hormone treatment near adult height (NAH) was -1.2 SDS (median, IQR -2.0- -0.3) below mean parental height (MPH) in males and -0.4 SDS (median, IQR -1.6-0.3) in females. NAH below -2 SDS was seen in 13/43 males (30%) and 2/36 females (6%). The majority of these patients already had a height below -2 SDS before HSCT (73%). In conclusion, this study on late endocrine effects after HSCT in children with nonmalignant diseases indicates frequent gonadal dysfunction, present in 55% of females and 42% of males. In this cohort, risk of gonadal dysfunction in females was higher after busulfan-based conditioning than treosulfan-based conditioning. Careful long-term endocrine follow-up is indicated.

Background: Growth hormone (GH) is indicated for the treatment of short stature in children born small for gestational age (SGA) who fail to show catch-up growth. In pilot studies, early initiation of GH has been associated with favorable growth responses in short SGA children. However, few studies have examined the short- and long-term effects of initiating GH in children born SGA who are Methods: The NordiNet IOS (NCT00960128) and ANSWER (NCT01009905) programs are complementary, non-interventional, multicenter studies that evaluated the long-term effectiveness and safety of Norditropin (somatropin; Novo Nordisk A/S, Denmark) as prescribed in real-life clinical practice. In this analysis, children born SGA who were prepubertal at GH initiation were grouped according to age at GH start: Results: Overall, 3351 SGA patients were included in the effectiveness set (age at GH start: Conclusions: This analysis of real-world data confirms the effectiveness and safety of GH in children born SGA, irrespective of patient age at treatment initiation.

Background: The 46,XX testicular disorder of sex development (DSD), also known as 46,XX male reversal, is a rare form of DSD and clinical phenotype shows complete sex reversal from female to male. The sex-determining region Y (SRY) gene can be identified in most 46,XX testicular DSD patients; however, approximately 20% are SRY-negative. Here we present a 2 week old with discrepant prenatal karyotype and infant phenotype. Case: This 2-week-old had dysmorphic features (bitemporal narrowing, broad and flat nasal bridge, bilateral epicanthal folds) and multiple congenital anomalies; IUGR, hypertelorism, cleft lip and palate, ASD, small kidneys, sacral dimple. Physical exam revealed palpable inguinal masses and microphallus without hypospadias. Postnatal karyotype showed a 46,XX chromosome complement with duplication of 22q13-qter. He was negative for SRY gene by FISH. Microarray analysis confirmed the duplication encompassing the SOX10 gene. Lab evaluation showed LH 10.81 mIU/ml, FSH 3.21 mIU/ml and total testosterone 241 ng/dl. These values are consistent with activation of the hypothalamic–pituitary–gonadal axis during the neonatal period in males. Conclusion: Our case along with previous cases supports the existence of a gene on chromosome 22q that can trigger testis determination in the absence of SRY. Potential mechanisms responsible for ovotesticular disorder in the XX (SRY−) individual could involve activation of testis specifying genes in the absence of SRY and/or inadequate expression of pro-ovary/anti-testis genes such as SOX 8 and SOX9. SOX10, a gene closely related to SOX9 and SOX8, and its overexpression has been suggested as a candidate for 46,XX DSD. Over-expression of SOX10 in mice resulted in the XX DSD. The spectrum of sex reversal phenotypes and gonadal asymmetry seen in the Sox10 transgenic mice closely mirrors the range of gonadal and reproductive tract anomalies seen in cases of partial duplication of human chromosome 22q13. Although SRY-negative 46,XX testicular DSD is a rare condition, an effort to make an accurate diagnosis is important for the provision of proper genetic counseling and for guiding patients in their long-term management.

Type 1 diabetes (T1D) is an autoimmune disease characterized by destruction of the pancreatic β-cells. T1D pathogenesis has a strong genetic basis. However, in recent decades, the prevalence of high-risk HLA haplotypes among new diagnoses has declined, the age of onset has decreased, and T1D incidence has increased. These changes are consistent with increased environmental pressure and coincide with introduction of the Western diet, widespread antibiotic use and reduced breast feeding. These factors are thought to drive intestinal dysbiosis, increased gut permeability and systemic inflammation. Notably, our studies of T1D families and the BioBreeding (BB) rat have identified a peripheral inflammatory state associated with diabetes susceptibility that is consistent with microbial antigen exposure and pattern recognition receptor ligation. Lactobacillus plantarum 299v (Lp299v), a probiotic strain, is reported to increase plasma and stool levels of anti-inflammatory short chain fatty acids (SCFA) and promote IL-10 signaling in colonic derived macrophages and T-cells. Here we investigated the effect of Lp299v supplement on T1D progression and inflammatory phenotypes in diabetes prone BB DRlyp/lyp rats. Rats were weaned at 21 days onto a normal cereal diet (ND) or a gluten-free hydrolyzed casein diet (HCD), with and without daily Lp299v supplementation. All DRlyp/lyp ND rats developed T1D by day 83 (mean time to onset of 62.8+/-7.9 days). DRlyp/lyp ND+Lp299v rats exhibited an insignificant delay in T1D onset (62.6+/-6.5 days), however 8% remained diabetes-free to day 130. Providing DRlyp/lyp rats HCD prevented T1D in 17% of rats (to age 130 days) and significantly delayed onset (mean time to onset 72.8+/-7.3 days, p

Background: SARS-CoV-2 uses the angiotensin-converting enzyme 2 (ACE2) receptor to enter human cells. This receptor is avidly expressed in the pancreatic islets, suggesting the virus may target β-cell function. 17% of adults with COVID-19 have evidence of pancreatic injury. There is a direct relation between insulin resistance and COVID-19 severity and mortality with patients with higher insulin resistance presenting with higher inflammatory response. Fulminant type 1 diabetes (fT1D) has abrupt onset of symptoms with insulinopenia without evidence of autoimmunity, usually preceded by viral illness. Clinical case: A 12-year-old Hispanic male presented with a week history of polyuria, polydipsia, headache, and fatigue but no weight loss, fever, cough, anosmia, or diarrhea. Laboratory testing revealed new onset diabetes with DKA with HbA1C 11.3%, blood pH 7.04, glucose 381 mg/dL, C-peptide 0.6 ng/mL, β-hydroxybutyrate 8.2 mmol/L, and a positive nasopharyngeal PCR for SARS-CoV-2 but no elevation of inflammatory markers (CRP, ESR and ferritin). There was evidence of mild pancreatic injury (lipase 179 U/L, n:15-110 U/L), and all autoantibodies for autoimmune diabetes were negative. He was pubertal (Tanner 3), non-obese (BMI Z score -0.3) and without acanthosis nigricans. Past medical and family history were non-contributory. He was treated with IV insulin at 0.1 u/kg/h until DKA resolved within 24 h then transitioned to subcutaneous insulin at 1 u/kg/day. He did not have signs of systemic inflammatory response, need for respiratory support, or glucocorticoids but had persistent hyperglycemia prompting an increase of insulin dosing and resumption of IV insulin. His insulin requirements continued to increase up to 4 u/kg/d with sustained hyperglycemia indicative of an exceptional state of insulin resistance. On Day 6 of admission metformin was initiated, on Day 9 insulin requirements declined and he was discharged on an insulin regimen close to 1.5 u/kg/d. Eventually metformin was discontinued on Day 20 after diagnosis without rebound in insulin requirements. On Day 28 he had improved glycemic control (HbA1c 8.8%) at insulin doses more appropriate for his age and pubertal status (0.9 u/kg/d). Clinical lessons: We report a case of autoantibody negative diabetes with pancreatic injury and marked insulin resistance unrelated to systemic inflammatory response associated with COVID-19. The clinical presentation was reminiscent of fT1D with the exception of exceptional insulin resistance. This is perhaps a novel form of diabetes mellitus not otherwise classified. Although the pathophysiology remains obscure, it is plausible that it is mediated by direct islet injury. Notably, there was a discordance between the severity of illness and insulin resistance suggesting an intrinsic effect of SARS-CoV-2 on glucose hemostasis.

Introduction: The genetic basis of human growth regulation has only been partly elucidated thus far. Therefore, finding causative genes in patients with short stature help in understanding precise pathophysiological mechanisms, establishing genotype-phenotype relationships and optimizing treatment. In order to extend our knowledge about the genes involved in short stature, we studied a unique cohort of consanguineous families with children with short stature from Sulaymani in Kurdistan, Iraq. Patients and Methods: Fifty-five consanguineous families, with children shorter than -2.3SDS at the time of examination (median height -3.3SDS, range -2.3 to -15SDS), who were examined at the endocrine outpatient clinic of the Department of Pediatrics, Sulaymani University College of Medicine between January 2018 and February 2020, were included in the study. In families with more than one child with short stature, the shorter sibling was selected as the proband (median age 8 years, range 1 - 15 years). Three probands were subsequently excluded due to the diagnosis of Turner’s syndrome and Edward’s syndrome Consent was obtained from all families and probands’ DNA was analyzed by Whole Exome Sequencing (WES) methods. The data were processed by a bioinformatic pipeline and detected variants were filtered using variant analysis software. Selected potentially pathogenic variants were confirmed using Sanger sequencing methods and evaluated by the American College of Medical Genetics (ACMG) standards and guidelines. Results: A monogenic cause of short stature, which explained the patient phenotype, was elucidated in 13 of 26 families who were analyzed thus far. Seven families had multiple affected children making a total of 22 patients with a positive genetic diagnosis. Pathogenic or likely pathogenic variants (according to the ACMG standards) were found in genes involved in the GH-IGF-1 axis (GHR), in the extracellular matrix of the growth plate (COL1A2, MMP13, LTBP3, and ADAMTS17), in the regulation of chondrocytes (NPR2 and CTSK), transporter coding genes (SLC34A3), and other genes (PTCH1, GALNS, DNACJ21, ZSWIM6, GNPTG). Among them, there are 9 novel variants and 10 homozygous variants including variants in genes causing syndromic short stature. Unexpectedly, we successfully identified three cases of autosomal dominant short stature (variants in genes NPR2, COL1A2, PTCH1) as well. The remaining probands from 26 families are still being analyzed. Conclusion: With the help of NGS methods, we have successfully elucidated the genetic cause of short stature in nearly 50% of patients who were analyzed thus far. These results further strength the concept that genes affecting the growth plate (chondrocytes and the extracellular matrix) play a crucial role in growth regulation. Acknowledgements: The study was co-funded by grants AZV 18-07-00283 and GAUK 340420.

Introduction: Steroid cell tumors are rare sex chord tumours of the ovary with malignant potential. Here we report a case of steroid cell NOS in a 12-year-old girl & similarity of the clinical presentation with non-classic congenital adrenal hyperplasia. Clinical Case: 12-yr girl came with complaints of hirsutism since many years and a recent change in voice. There was no past history suggestive of adrenal crisis. On examination she had muscular body habitus, moderate hirsutism (FG score 19), acne. SMR B1, P4, A3. Karyotype 46 XX. BA 13yrs. DHEAS- 144, serum cortisol 8am-14ug/dl. Testosterone-8.35ng/ml (normal 0.1-0.9ng/ml). serum 17 (OH) Progesterone basal-16.37 ng/ml(N-0.2-1.3ng/ml). Post synacthen 17OHP >35ng/ml, LH- Conclusion: The usual differential diagnosis in 46 XX female children presenting with signs of androgen excess is CAH, it is not uncommon to find SVCAH presenting in childhood with symptoms & signs of virilisation. Clinically both SV CAH and Steroid cell tumours can present with hyperandrogenic features in the childhood. Amongst steroid cell tumours, 3 subtypes are seen, they include 1. stromal luteoma 2. Leydig cell tumour 3. steroid cell tumour NOS. The steroid cell tumours of the ovary secrete androstenedione, alpha hydroxy progesterone & testosterone .17OHP is raised in both the conditions. The HPE of both adrenal rest tumours & steroid cell NOS is similar & a clear-cut differentiation cannot be made. They are similar in clinical presentation, biochemistry & HPE. It is important to recognise that steroid cell tumour NOS is a differential to SVCAH in childhood. Since these tumours can occur at any age, clues to differentiate both conditions are-raised 17OHP but normal DHEAS & on imaging- normal adrenals with enlarged ovaries with or without solid cystic lesions in steroid cell NOS of the ovary.

Background: Being born small for gestational age (SGA) is linked with higher systolic blood pressure (SBP). Fetuses with growth restriction (FGR) may be either SGA or appropriate size for gestational age at birth. However, it is not known which factors contributing to size at birth influence the relationship with SBP. Aim. To determine whether antenatal markers of FGR can predict the upper quartile of childhood SBP. Methods: Brachial SBP was measured for 75 children aged 3-6 years from the Manchester BabyGRO Study, using a Tensiomed®Arteriograph with a child-sized cuff. SBP quartiles were generated. Participants were born to mothers who had attended a specialised clinic, following identification of higher FGR risk based on abnormal maternal serology (pregnancy associated plasma protein-A, β-human chorionic gonadotrophin, α-fetoprotein, Inhibin-A). Antenatal ultrasound data at 23 weeks gestation were obtained. Uterine artery Doppler (UtAD) notching was assigned a rank (0=absent, 1=unilateral, 2=bilateral). Random forest (RF) is a machine learning approach that generates many independent, uncorrelated decision trees based on multiple variables. This was used to determine the relative importance of antenatal variables in prediction of upper quartile of childhood SBP. Variables included in the model were maternal body mass index (BMI), parity, ethnicity (black/white/asian/mixed), maternal SBP and diastolic BP (DBP), maternal serology relating to FGR risk, UtAD pulsatility index, resistance index and notching rank (all measures of uteroplacental blood flow resistance), placental size measurements, 23 week estimated fetal weight (EFW) centile, ∆23w EFW-birthweight centile and birthweight SDS. A receiver operating characteristic (ROC) curve was generated, providing an area under the curve (AUC). A variable of importance (VIP) score was calculated for each marker that was significant in the model. All analyses were conducted in R (version 3.6). Results: RF analysis demonstrated antenatal markers relating to FGR risk predict the upper quartile of childhood SBP with an AUC 0.97. The top five ranked variables were maternal DBP (VIP score 14.0), birthweight SDS (11.5), parity (9.9), notching rank (9.5) and ∆23w EFW-birthweight centile (9.1). Conclusion: Maternal and antenatal markers, as well as birthweight SDS are linked with the upper quartile of SBP at 3-6 years. Antenatal markers were within the top five ranked and could help identify those babies at risk of higher SBP in childhood.

Background: Ten percent of children born small for gestational age with a birth weight and/or length of below -2 SD for their gestational age fail to catch-up and remain short during childhood (SGA-SS). The etiology of SGA-SS is heterogeneous: some children have specific phenotypic features that allow targeted genetic testing; in others, elucidating genetic or environmental background is more challenging. Aim: To decipher genetic etiologies among a large single-center cohort of SGA-SS children and to stratify them according to molecular mechanisms leading to pre- and postnatal growth failure. Patients/Methods: In our center 447 children (223 females) fulfilled the criteria of SGA-SS. Of these 182 families agreed to take part and offered the child’s and both parents’ DNA for genetic testing by a panel of 399 growth-related genes, or by Whole Exome Sequencing (WES). The results were processed by a bioinformatic pipeline and detected variants were filtered using variant analysis software. Pathogenic or likely pathogenic variants (according to ACMG standards and guidelines) were confirmed by Sanger sequencing. Results: The genetic etiology was elucidated in 73/182 (40%) children so far. We confirmed (likely) pathogenic gene variants affecting pituitary development and/or the GH-IGF-1 axis in 10/73 (14%) patients (PTCH1, HGMA2 [in two], OTX2, LHX4, GHSR, STAT3, IGFALS, IGF1R [in two]), abnormal components of cartilaginous matrix in 17/73 (23%) (ACAN [in two], FLNB [in three], FBLN5, COL11A1[in four], COL1A2, COL2A1[in five], MATN3), impaired paracrine regulation of chondrocytes in 4/73 (6%) (NPR2 [in three], FGFR3), SHOX gene defects in 12/73 (16%), gene variants affecting other components of intracellular regulation and signaling in 9/73 (12%) (CDC42, KMT2A, KMT2D, NSD1, SRCAP, PRG4, PTPN11, SON, LMNA), Silver-Russell syndrome (11p15 [in seven] or UPD7) in 11/73 (15%), and miscellaneous single-gene or chromosomal conditions (TRPS1, TRHR, RAI1, chromosomal microdeletions and/or translocations) in an additional ten (14%) children. Conclusions: In our study we showed that by using current genetic techniques we were able to elucidate the genetic cause in a significant number of patients born SGA-SS. The genetic etiology spectrum of SGA-SS reflects the complex system of growth regulation, with a significant role of growth plate genes that are causative in 33/73 (45%) cases clarified thus far. Acknowledgements: The study was co-funded by grants AZV NV18-07-00283 and GAUK 408120.

Introduction: The association between Helicobacter pylori infection and hyperinsulinemia and insulin resistance has been described. Objective: To investigate the frequency of hyperinsulinemia and insulin resistance in adolescents with Helicobacter pylori infection. Materials and Methods: Prospective, observational and analytical study. Adolescents with Helicobacter pylori infection; July 2019 - June 2020 period. Exclusion criteria: Obesity, hypothyroidism, hepatopathy, nephropathy, collagen disease, corticotherapy, use of proton pump inhibitors and H2 antihistamines. Variables: Antibodies against Helicobacter pylori; fasting plasma glucose and insulinemia, 2-hour plasma glucose and insulinemia after oral glucose tolerance test (OGTT); determination of the insulin resistance index by the Homeostasis Model Assessment (HOMA-IR). Two groups of patients: Those with Helicobacter pylori infection and the other of uninfected adolescents. Results: Patients attended: 34; studied: 19; excluded: 15. Group of non-infected: 20. The HOMA-IR value was 2.5 + -0.8 in adolescents with Helicobacter pylori infection and 1.8 + -0.6 (p = 0.02) in uninfected patients. Conclusions:The values of insulinemia and HOMA-IR were higher in the group of adolescents with Helicobacter pylori infection, compared to those evidenced in the group of uninfected.

Background: There are no any clear evidence to date has evaluating patients and caregiver preferences for r-hGH (recombinant-human growth hormone) injection in children in Japan. This study quantitatively evaluated the factors driving preferences for daily r-hGH injection among Japanese children with Growth Hormone Deficiency (GHD) or their respective caregivers to determine the relative importance of treatment delivery attributes. This study was performed amongst Japanese children with GHD or their caregivers who visited a specialized clinic in Japan as part of their routine care between June and July 2020. Methods: The participants were asked to complete a web-based discrete choice experiment (DCE) questionnaire using a handheld tablet device during a routine clinical visit. DCE is a quantitative method widely used in healthcare to elicit preferences from participants in the absence of revealed preference data. Choice-based conjoint analysis was used to evaluate the relative importance of attributes as choice predictors and determine utilities for each attribute. Of the 47 respondents who participated in this study, 41 were caregivers who responded on behalf of the patients, and the remaining 6 were patients who completed the DCE themselves. All participants were screened by a clinician to ensure they met all eligibility criteria. Results: The injection schedule was found to be the most important attribute for both patients and caregivers (Relative importance: 43.6%); a once-weekly injection schedule was preferred over a daily injection schedule. For maintenance of injection devices, patients had a stronger preference for reusable pens which can be used by replacing cartridges, while caregivers preferred disposable pen devices. The storage and preparation attribute was deemed more important to patients than it was to caregivers, with patients preferring storage in room temperature even if it needed an additional mixing(reconstitution) step. Both patients and caregivers showed a clear preference for devices that offered a dose setting memory. Conclusion: The results of this study showed that patients prefer a once-weekly injection schedule over a daily injection schedule. A less frequent injection schedule should enhance adherence and compliance to r-hGH treatment over the long term and will also improve QoL in children with GHD. The benefits of a less frequent injection schedule can be further explored using real-world studies.

Objective: Prader-Willi syndrome (PWS) is a complex genetic disease associated with growth impairment, severe obesity and metabolic dysfunctions. High proportion of PWS patients are born small for gestational age (SGA), which also increase the risk of growth impairment and metabolic dysfunction. The aim of this study was to describe growth outcome and and metabolic profiles in GH treated PWS patients. We also investigated the differences in clinical outcomes between AGA and SGA group Methods: Data of 55 children and adults with genetically verified PWS aged more than 2 years old (32 male and 23 female, age 2-18.8 years) from single center were studied. Only patients who were treated with GH were included. The clinical characteristics and laboratory findings were reviewed retrospectively. Results: Among 55 subjects, 39 had 15q11-13 deletion and 16 had uniparental disomy (UPD). Twenty (36.3%) were born SGA. All patients received GH treatment, and 11 (20%) discontinued GH treatemnt. Mean age at GH treatment initiation was 2.5 (range 0.3-12.4) years, and mean duration of treatment was 6.3 (range 1.0-11.3) years. Current height-SDS (-0.36 vs -0.16) and BMI-SDS (1.44 vs 1.33) did not differ between AGA and SGA group. Two patients in SGA group, but none in AGA group had diabetes mellitus. Mean glucose level was also higher in SGA group (100.1 vs 114.4 mg/dL) Conclusions: Our report gives an overview of growth profile and metabolic dysfunctions recorded in GH treated PWS patients. Growth profile did not differ between AGA and SGA group. Glucose level was higher in SGA group, so more careful monitoring and prevention for DM will be required in SGA group.

Background: Long term effect of conditioning regimen such as Total body irradiation (TBI) and chemotherapy has been studied. However short term effect of conditioning regimen on endocrinologic system was not well known. Purpose. Our study aimed to evaluate the effect of conditioning regimen on thyroid function in children who had HSCT after 2 years. Methods:. Date was obtained from retrospective review of medical records who treated malignant hematologic disease and transplanted hematopoietic stem cell in Seoul St. Mary’s hospital from January 1, 2010 to August 31, 2018. Among 563 patients who underwent HSCT for about 9 years, we studied 150 patients who conforming to inclusion criteria of this study. Thyroid function was tested before HSCT and follow 12 and 24 months. Anthropometric date, duration of chemotherapy, history of relapse, graft versus host disease (GVHD) were also analyzed. Results: In patient’s characteristics, median age at HSCT was 10.49 (0.89 - 19.29) years. Out of 150 patients, male was 92 and female was 58. Acute lymphoid leukemia (ALL) was 74, acute myeloid leukemia (AML) was 76. Among them, busulfan based conditioning was done in 53 patients, TBI based conditioning regimen used in 72 and 25 patients had done TBI with busulfan based conditioning regimen. Fifteen patients (12.5%) had thyroid dysfunction after 2 years of HSCT (4 euthyroid sick syndrome, 11 subclinical hypothyroidism and 1 high T4 syndrome). Incidence of thyroid dysfunction by conditioning regimen was different at 2 years after HSCT, higher in TBI with busulfan based group (p = 0.033). In univariate regression analysis, using conditioning regimen, by TBI with busulfan was risk factor of thyroid dysfunction at 2 years after HSCT. Conclusions: TBI with busulfan based group showed higher incidence of thyroid dysfunction and conditioning regimen was risk factor of thyroid dysfunction at 2 years after HSCT.

Background: Pathogenic variants in the thyroid hormone receptor (THRB) gene are associated with thyroid hormone resistance. Over 85% of the genetic mutations are in the beta TR gene. The disorder is characterized mainly by elevated thyroid hormone levels, unsuppressed levels of TSH, and goiter. Clinical case: An 11-year-old male initially seen at the PCP office for tachycardia and chest discomfort, especially during school exercise. He reported shortness of breath. His symptoms will resolve at rest. He was diagnosed initially with asthma and was put on Singular, Pulmicort, and albuterol as needed. His symptoms did not improve with this treatment, and he reported symptoms worsened with albuterol. He had a normal Echocardiogram and chest X-ray. A mild goiter was noted on his physical exam. Thyroid ultrasound showed an enlarged thyroid gland. An ovoid echogenic focus in the inferior thyroid lobe measuring 4 X 7 X 8mm was identified. The nodule was wider than tall, with a solid appearance with no internal color flow. Evaluation in our clinic showed normal TSH at 1.624mcIU/mL (0.35-5.5). FT4 was high at 1.54ng/dL (0.82-1.40), and FT3 elevated at 6.3pg/mL (3.3-4.8). Thyroid antibodies and thyroid-stimulating immunoglobulin (TSI) were normal. A 24 hour I-123 thyroid uptake was approximately 55% (10-30%) with no focal increased or decreased uptake. Given his elevated thyroid hormone levels with unsuppressed TSH in the context of goiter and tachycardia, genetic testing for the Thyroid receptor gene was done. He was found to be heterozygous for a pathogenic variant in THRB, c.1286G>A (p.Arg429Gln). This genotype is consistent with a diagnosis of autosomal dominant Thyroid hormone resistance. The patient was started on Atenolol, given his elevated heart rate, and he reported improvement in his symptoms during exercise. Conclusion: Thyroid hormone resistance was first described as a clinical entity in 1967. The phenotype can vary among individuals. It is characterized by a reduced responsiveness of target tissue to thyroid hormone and binding affinity. The disease can present with goiter, behavioral issues, abnormal growth, and tachycardia. Affected individuals may have attention deficit-hyperactivity disorders (ADHD) and language difficulties. Thyroid hormone resistance can be misdiagnosed, as in our patient. He was diagnosed with asthma and was put on unnecessary medications that worsened his symptoms. Thyroid hormone resistance can also be misdiagnosed with Graves’ disease, given the elevated thyroid hormone. It is essential to highlight the importance of genetic testing in these cases, as an accurate diagnosis will prevent unnecessary treatments with potentially serious side effects.

Obesity appears to have a negative impact on pediatric bone health, and insulin resistance may mediate this relationship. It is unclear if cardiorespiratory fitness (CRF) has a protective effect on bone in obese children. We tested the hypothesis that CRF attenuates the negative effect of obesity and insulin resistance on skeletal health in a large cohort of Hispanic youth. We studied 413 (193 males and 220 females) children and adolescents from the Viva la Familia Study. They were all pubertal; mean age (SD) 13.4 ± 2.3 years; 27% were normal weight (NW), 19% overweight (OW) and 54% obese (OB). They underwent measurement of body composition, total body bone mineral content (BMC) and density (BMD) by DXA scan; VO2peak using the ramp protocol on a treadmill for CRF; fasting glucose and insulin. The homeostasis model assessment of insulin resistance (HOMA-IR) was calculated. BMC increased from NW to OW to OB (mean 1.35 ± 0.4, 1.41 ± 0.4, and 1.49 ± 0.4 kg, respectively, p=.005). Peak VO2 decreased from NW to OW to OB (41.3 ± 9.7, 35.5 ± 7.7, 28.9. ± 5.5 mL/kg per min, respectively, p In conclusion, lean body mass is the major determinant of BMC and BMD in Hispanic youth. Adiposity associated insulin resistance has a negative effect on BMC and BMD. CRF contributes positively to the variance in BMC and BMD. This suggests that CRF and higher lean mass attenuate the adverse effects of insulin resistance on bone health in children.

Background: Congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency (21OHD) is a rare, autosomal recessive disease of the adrenal cortex leading to a lack of cortisol production and compensatory ACTH secretion, which drives excess androgen production. The chronic exposure to excess androgen, coupled with supraphysiologic glucocorticoid doses, can lead to advanced skeletal maturation with reduced growth in puberty, premature epiphyseal closure, and shorter final adult height. The I-CAH Registry, launched in 2007, currently has >1500 cases of CAH from 26 countries. Aim of the current study was to identify growth-related characteristics of children and adolescents with 21OHD CAH registered in the I-CAH registry and who were based in Europe. Methods: The I-CAH registry was queried on 8-Oct-2019 using the following criteria: CYP21A enzyme deficiency; European site, male or female, age 1 subgroup. Analyses included standard deviation scores (SDS) for patients’ height for chronological age (CA), weight for CA, and height for bone age (BA) using World Health Organization growth chart data for reference values. Results: Of 232 patients in 10 European countries, 126 (54%) were female and most were from Germany (25%), United Kingdom (23%), Netherlands (14%), and Italy (11%). The 232 patients had a total of 2042 visits, with 44% (900 visits) in the 0-2yr group, 42% (860 visits) in the 2-11yr group, and 14% (282 visits) in the 12-17yr group. No discernible pattern by age group was found for height for CA based on mean/median SDS scores. For weight for CA, mean/median SDS scores showed an increasing trend in older patients: 0-2yr (0.22/-0.06 [896 visits]); 2-11yr (0.47/0.55 [855 visits]); and 12-17yr (0.55/0.66 [278 visits]). Mean/median SDS scores for height for BA decreased with age: 0-2yr (0.31/0.05 [36 visits]); 2-11yr (-0.32/-0.23 [172 visits]); and 12-17yr (-0.49/-0.26 [44 visits]). Paired BA and CA values from 259 patient visits showed a trend towards bone age being greater than CA, starting at approximately 48 months of age and leveling out around 120-130 months. Mean BA was advanced by 9.7 months compared to CA (SD: 21.2 months, 95%; CI: 7.1 to 12.3 months, [p

The Case: An 8 days old male, born at 40 wks, 2.8 kg (SGA) presented to local ED with lethargy, decreased PO intake and urine output, respiratory distress. No fever, URI sx, vomiting/diarrhea. His dad had URI symptoms and fever a week prior. He was found to have T=95.5F, glucose Discussion/Conclusion: There is a dearth of information on SARS-CoV-2 infection in newborns. The few studies available show favorable outcomes in this population, with typical mild-moderate respiratory symptoms and fever, while some newborns are asymptomatic. Our patient required oxygen tx and developed HH requiring Diazoxide therapy. To our knowledge, this is the first reported case of HH in the newborn with SARS-CoV-2 infection. Hyerperinsulinism is the most common cause of hypoglycemia in infants. These newborns are at risk of developing significant neurologic morbidity, which can be dose dependent. Prompt diagnosis and aggressive management are important to reduce such risk. Perinatal stress is likely the underlying mechanism leading to HH in newborns with SARS-CoV-2 infection. Patient is also SGA. Both perinatal stress and SGA can lead to inappropriately elevated insulin levels and resultant hypoglycemia. HH in both of these conditions is effectively managed by Diazoxide. Our case illustrates that although most newborns do well with SARS-CoV-2 infection, a high index of suspicion for HH should be maintained in such newborns, particularly in those with at least one other risk factor for HH such as SGA. More studies are needed to elucidate underlying pathology and tease out actual incidence of hypoglycemia in neonates with SARS-CoV-2 infection.

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 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.

Background: he obesity epidemic has led to an increase in the incidence of type 1 diabetes mellitus (T1DM) on the background of overweight. The combination of T1DM and obesity can lead to an erroneous diagnosis of type 2 diabetes (T2DM). Methods: The study included 35 adolescents with T1DM. Inclusion criteria were obesity at onset, high titer of diabetes-associated autoantibodies, and insulin requirement less than 0.5 U/kg with a diabetes duration of more than 6 months. We assessed the level of HbA1c, fasting level of insulin and c-peptide, and level during the Mixed-Meal Tolerance Test, the immunological status of GADA, IA-2, ZnT8, ICA. Results: The age of onset was 12.7 years [10.6; 14.5], the tanner stage of puberty was 4 [3; 5]. Sex distribution: boys (n = 25) - 71.5%, girls (n = 10) - 28.5%. HbA1c at the time of onset equaled 8,9% [7.4; 10.45]. Ketosis/diabetic ketoacidosis was registered in 47.8%. The duration of the diabetes was 1.7 years at the moment of examination [0.7; 2.9]. The fasting level of C-peptide - 1.37 mμg/ml [1.0.9; 2.19], insulin level (n = 26) - 13.93 uU/ml [9.57; 19.77]. The maximum level of stimulated secretion of C-peptide (n = 21) - 5.13 mμg/ml [3.05; 6.07], of insulin secretion (n = 21) - 58.59 uU/ml [31.02; 79.74]. Higher HOMA of insulin resistance (n = 25) was detected in 72% of the examined patients. In the study of pancreatic autoantibodies, an increase in ICA was detected in 57% (median of titer 1.68 [0.28;11.7]), IA-2 - 67% (192.8 ME/ml [65; 310.1]), GAD - 59% (90.25 ME/ml [32.27; 214.6]), ZnT8 - 82% (350.5 [90.4; 506.05]). The presence of 2 or more autoantibodies is found in 94% of cases. Dyslipidemia was observed in 34.8%, arterial hypertension was identified in 23% of patients. Received therapy: insulin 82%; metformin 0.02%; metformin + insulin 5.7%. Median daily dose per patient was 0.3 U/kg [0.2; 0.5]. Conclusion: T1DM in adolescents with obesity and overweight has a similar clinical picture both with T1DM (insulin dependence, high titer of autoantibodies, ketosis) and T2DM (slow progression of the disease, low insulin requirement, preserved secretion of c-peptide, and insulin for more than 1.5 years). We hypothesize that obesity and insulin resistance may contribute to DM onset at an earlier date, even if a satisfactory function of pancreatic beta-cells is still preserved. Given that the onset of the disease in our group falls on adolescence it seems that pubertal insulin resistance also contributes to the features of the course of the disease. Understanding the role of obesity in the progression of disorders of carbohydrate metabolism will allow postponing the acute manifestation of the disease and initiation of insulin therapy through lifestyle modifications in patients at risk. A long period of preserved insulin secretion opens up the possibility of new personalized therapies.