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This International Consensus Guideline was developed by experts in the field of small for gestational age (SGA) of 10 pediatric endocrine societies worldwide. A consensus meeting was held and 1300 articles formed the basis for discussions. All experts voted about the strengths of the recommendations. The guideline gives new and clinically relevant insights into the etiology of short stature after SGA birth, including novel knowledge about (epi)genetic causes. Further, it presents long-term consequences of SGA birth and also reviews new treatment options, including treatment with gonadotropin-releasing hormone agonist (GnRHa) in addition to growth hormone (GH) treatment, as well as the metabolic and cardiovascular health of young adults born SGA after cessation of childhood GH treatment in comparison with appropriate control groups. To diagnose SGA, accurate anthropometry and use of national growth charts are recommended. Follow-up in early life is warranted and neurodevelopment evaluation in those at risk. Excessive postnatal weight gain should be avoided, as this is associated with an unfavorable cardiometabolic health profile in adulthood. Children born SGA with persistent short stature < −2.5 SDS at age 2 years or < −2 SDS at 3 to 4 years of age, should be referred for diagnostic workup. In case of dysmorphic features, major malformations, microcephaly, developmental delay, intellectual disability, and/or signs of skeletal dysplasia, genetic testing should be considered. Treatment with 0.033 to 0.067 mg GH/kg/day is recommended in case of persistent short stature at age of 3 to 4 years. Adding GnRHa treatment could be considered when short adult height is expected at pubertal onset. All young adults born SGA require counseling to adopt a healthy lifestyle.

Context The impact of the COVID-19 pandemic on individuals with type 1 diabetes remains poorly defined. Objective We examined United States trends in diabetic ketoacidosis (DKA) among individuals with type 1 diabetes (T1D) during the COVID-19 pandemic at 7 large US medical centers and factors associated with these trends. Methods We compared DKA events among children and adults with T1D during COVID-19 surge 1 (March-May 2020) and COVID-19 surge 2 (August-October 2020) to the same periods in 2019. Analysis was performed using descriptive statistics and chi-square tests. Results We found no difference in the absolute number of T1D patients experiencing DKA in 2019 vs 2020. However, a higher proportion of non-Hispanic Black (NHB) individuals experienced DKA in 2019 than non-Hispanic White (NHW) individuals (44.6% vs 16.0%; P Conclusion DKA frequency increased among T1D patients during COVID-19 surges with highest frequency among NHB patients. DKA was less common among patients using CGM or insulin pumps. These findings highlight the urgent need for improved strategies to prevent DKA among patients with T1D—not only under pandemic conditions, but under all conditions—especially among populations most affected by health inequities.

Two male patients, who presented at 13.5 and 13.9 years of age with growth failure and short stature, were ultimately diagnosed with isolated growth hormone deficiency (GHD). Patient 1 was first evaluated when his height declined from −0.67 SD to −1.3 SD. He had a peak growth hormone (GH) concentration to GH stimulation test (GHST) of 16.9 ng/mL (16.9 μg/L) and remained untreated. As puberty advanced, his height decreased further to −1.65 SD. A second GHST while his serum testosterone was 79 ng/dL (2.74 nmol/L) had a peak GH of 5.4 ng/mL (5.4 μg/L), consistent with GHD. He was treated with GH for 4.8 years and reached adult height of 180.5 cm (0.57 SD), gaining 2.22 SDS. Patient 2, height −2.63 SD, had an unstimulated peak GH concentration of 19 ng/mL (19 μg/L). As puberty advanced, his height decreased further to −2.96 SD. Repeat peak GH concentration was 9.2 ng/mL (9.2 μg/L) when serum testosterone was 83.9 ng/dL (2.91 nmol/L). GH treatment resulted in rapid increase of height velocity from 1.8 cm/year to 11.3 cm/year in 6 months, consistent with GHD. Both patients demonstrate that GHD may develop over time and cannot be excluded by a single GHST. Longitudinal monitoring of children with poor growth as puberty progresses is essential to uncover GHD.

Purpose: This study aimed to evaluate the time interval to menarche after gonadotropin-releasing hormone agonist (GnRHa) treatment in females with central precocious puberty (CPP) and to identify factors contributing to timing of menarche.Methods: We retrospectively reviewed medical records of 39 females with CPP who reached menarche after GnRHa treatment (leuprolide or histrelin). CPP diagnostic criteria were breast development at

Background Diabetes is a risk factor for poor COVID‐19 outcomes, but pediatric patients with type 1 diabetes are poorly represented in current studies. Methods T1D Exchange coordinated a US type 1 diabetes COVID‐19 registry. Forty‐six diabetes centers submitted pediatric cases for patients with laboratory confirmed COVID‐19. Associations between clinical factors and hospitalization were tested with Fisher's Exact Test. Logistic regression was used to calculate odds ratios for hospitalization. Results Data from 266 patients with previously established type 1 diabetes aged, Highlights Outcomes for children with type 1 diabetes who experience COVID‐19 are currently unknown. We report 266 cases from US diabetes clinics of children with type 1 diabetes who had COVID‐19. Diabetic ketoacidosis was the major adverse outcome, and it was associated with higher A1c.

The terms ‘idiopathic short stature’ (ISS) and ‘small for gestational age’ (SGA) were first used in the 1970s and 1980s. ISS described non-syndromic short children with undefined aetiology who did not have growth hormone (GH) deficiency, chromosomal defects, chronic illness, dysmorphic features or low birth weight. Despite originating in the pre-molecular era, ISS is still used as a diagnostic label today. The term ‘SGA’ was adopted by paediatric endocrinologists to describe children born with low birth weight and/or length, some of whom may experience lack of catch-up growth and present with short stature. GH treatment was approved by the FDA for short children born SGA in 2001, and by the EMA in 2003, and for the treatment of ISS in the US, but not Europe, in 2003. These approvals strengthened the terms ‘SGA’ and ‘ISS’ as clinical entities. While clinical and hormonal diagnostic techniques remain important, it is the emergence of genetic investigations that have led to numerous molecular discoveries in both ISS and SGA subjects. The primary message of this article is that the labels ISS and SGA are not definitive diagnoses. We propose that the three disciplines of clinical evaluation, hormonal investigation and genetic sequencing should have equal status in the hierarchy of short stature assessments and should complement each other to identify the true pathogenesis in poorly growing patients.

Introduction X-linked adrenoleukodystrophy (ALD) is caused by mutations in the ABCD1 gene encoding the adrenoleukodystrophy protein that transports very-long-chain fatty acids (VLCFAs) to peroxisomes for degradation. An early manifestation is primary adrenal insufficiency (AI). Our clinic's protocol to screen for AI involves obtaining a morning cortisol and ACTH every 6 months, followed by cosyntropin (ACTH) stimulation testing if screening ACTH >100pg/mL or cortisol Cases Patient 1 is a 6 month old full-term male with ALD detected on New York state (NYS) newborn screen and a hemizygous pathogenic variant, c.1201C>T, p. R401W in the ABCD1 gene. At 6 weeks, ACTH and cortisol levels were acceptable (table 1). After screening ACTH was elevated(175pg/mL) at 5 months, ACTH stimulation testing was performed at 6 months. Baseline cortisol was 11ug/dL and stimulated cortisol was insufficient at 13ug/dL. There was no hyperpigmentation, but were neurological concerns such as inability to roll over, left arm preference, and waning moro response. A brain MRI was recommended. Patient 2 is a 7 month old full-term male with ALD detected on NYS newborn screen and a hemizygous pathogenic variant, c.1661G>A (p. R554H) in the ABCD1 gene. At 6 weeks, ACTH and cortisol levels were acceptable (table 2). At 7 months, ACTH was elevated (120.7pg/mL). ACTH stimulation testing was performed with baseline cortisol of 6.9ug/dL and insufficiently stimulated cortisol of 13.5ug/dL. Neurological evaluation was normal. Because of inadequate rises in cortisol to ACTH stimulation, stress dosing hydrocortisone was recommended for both patients. Discussion These infants with early onset adrenal dysfunction raise the question of whether the peak incidence of AI is earlier than previously thought. This would not be surprising as VLCFAs were found to accumulate in fetal adrenal glands. Our findings further support the need for widespread newborn screening for ALD, followed by routine adrenal screening consistent with published guidelines to avoid adrenal crisis. In a case series of 2 patients with ALD and early onset AI, the reported mutations were p. R660W and p. R401Q. 1 In patient 1, a mutation at position 401 of the ALD protein was also reported, which stresses the importance of registries to correlate genotypes and phenotypes. Early onset adrenal disease has not yet been correlated with early neurologic disease. However, the neurological changes noted in patient 1 raise this concern and highlight the importance of multidisciplinary clinics with endocrinology and neurology. Sources: 1. Eng, L., & Regelmann, M. O. (2019). Early Onset Primary Adrenal Insufficiency in Males with Adrenoleukodystrophy: Case Series and Literature Review. The Journal of pediatrics,211, 211–214. https://doi.org/10.1016/j. jpeds.2019. 04. 021 Presentation: No date and time listed

Background Antifungals act on fungal sterols structurally similar to human cholesterol. Ketoconazole reversibly suppresses steroidogenesis by inhibiting cytochrome P450 enzymes and interferes with dihydrotestosterone (DHT) activity by binding to the androgen receptor. Hypospadias was reported in infants exposed to nystatin in utero. Case presentation A male infant exposed to antepartum nystatin presented with severe under-undervirilization and transient adrenal corticosteroid abnormalities. He was born in USA at 31 weeks gestation to a mother treated with vaginal Polygynax capsules (nystatin-100,000 international units, neomycin sulphate-35,000 international units and polymyxin B-35,000 international units) for vaginal discharge in the Ivory Coast. She used approximately 60 capsules between the first trimester until delivery. The infant was born with micropenis, chordee, perineo-scrotal hypospadias and bifid scrotum with bilaterally palpable gonads. The karyotype was 46,XY. No Mullerian structures were seen on ultrasound. Serum 17-hydroxyprogesterone (17 OHP) on newborn screening was high (304 ng/ml, normal Conclusions We report severe undervirilization in a 46,XY infant born to a mother treated with prolonged and high dose nystatin during pregnancy. This presentation suggests that prolonged antepartum use of high dose nystatin could lead to severe but transient defects in androgen synthesis and/or action possibly by acting as an endocrine disruptor. Further studies are warranted to confirm this finding. Thus, endocrine disruptors should be considered in male newborns with atypical genitalia not explained by common pathologies.

Background Autosomal dominant pseudohypoaldosteronism Type 1 (PHA-1) is a salt-wasting syndrome due to mutation in the renal mineralocorticoid receptor. Here, we report an infant with a novel mutation in NR3C2 causing PHA and associated with transient hypercalcemia. Clinical Case An ex-28 weeks (birth weight 1.35 kg) male infant admitted to the NICU had increased urine output of 6 mL/kg/hr on days of life (DOL) 9-10. Initial laboratory tests showed hyponatremia (121-127 mEq/L), hyperkalemia (5.4-8.4 mEq/L), hypochloremia (89-94 mEq/L), and hypercalcemia (11.2-11.6 mg/dL). Weight had decreased 4% from birth. On exam he was normotensive with no midline defect or hyperpigmentation; he had palpable testes bilaterally and 2 cm penile length. Sodium chloride (NaCl) supplementation 2.5 mEq/day was started on DOL 10. State newborn screen 17-OHP levels were normal. His family history was unremarkable. To further investigate the hyponatremia and hyperkalemia, serum ACTH, cortisol, aldosterone, and renin were obtained. ACTH and cortisol were 33 pg/mL and 11.4 mcg/dL, respectively. While awaiting the results of the aldosterone and renin assays, fludrocortisone was started with minimal improvement in serum sodium and hypercalcemia worsening to 12.0 mg/dL. Laboratory tests obtained to investigate the hypercalcemia included phosphorus 5.5 mg/dL, hypercalciuria (urine calcium to creatinine ratio 0.4), 25-OH vitamin D 21.0 ng/mL (normal 30-100 ng/mL), and PTH 29 pg/mL (normal 10-65 pg/mL). PTH was inappropriately normal, concerning for primary hyperparathyroidism. While awaiting the aldosterone level, it was therefore recommended to decrease fludrocortisone dose. Plasma renin activity resulted at 319 ng/mL/hr (normal 2-37 ng/mL/hr) and aldosterone at 612 ng/dL (normal 5-90 ng/dL), suggesting a diagnosis of PHA. Fludrocortisone was discontinued and NaCl supplementation was increased. A heterozygous pathogenic variant, c.2457C>A (p.Tyr819Ter), was identified in the mineralocorticoid receptor gene, NR3C2, confirming the diagnosis of autosomal dominant PHA-1. This variant has not been previously reported but meets the American College of Medical Genetics and Genomics and the Association for Molecular Pathology's criteria for pathogenicity. At his outpatient follow up at 4 months, sodium was 134 mEq/L and calcium was 10.5 mg/dL. He was continued on 1.5 grams NaCl supplementation. Conclusion We report a patient with a novel mutation in the NR3C2 gene resulting in autosomal dominant PHA-1 and associated with transient hypercalcemia. Further exacerbation of hypercalcemia was seen with addition of fludrocortisone. We suspect the etiology of the transient hypercalcemia to be secondary to excess mineralocorticoids (exogenous or endogenous) that drives PTH to increase serum calcium levels, as previously described by Vaidya et al. (1) Reference (1) Vaidya A, Brown JM, Williams JS. The renin-angiotensin-aldosterone system and calcium-regulatory hormones. J Hum Hypertens. 2015 Sep;29(9): 515-21. Presentation: Monday, June 13, 2022 12:30 p.m. - 2:30 p.m.

Cortisol and growth hormone (GH) deficiencies are causes of neonatal hypoglycemia. When they coexist, a pituitary disorder is suspected. We present an infant with hypoglycemia in whom an ACTH receptor defect was associated with transient GH deficiency. A full-term boy with consanguineous parents presented with hypoglycemia (serum glucose 18 mg/dL) at 4 hours of life with undetectable serum cortisol (

Objective To determine the efficacy of a 4-month school-based health, nutrition and exercise intervention on body fatness and examine possible effects of demographic and anthropometric covariates. Methods Height, weight, waist circumference and body composition were measured in a diverse population of 644 NYC middle school students (mean ± SD age 12.7 ± 0.9 years; 46% male; 38% Hispanic, 17% East Asian, 15% South Asian, 13.5% African American, 8.5% Caucasian, 8% other) during the fall and spring semesters. Year 1 participants (n = 322) were controls. Experimental participants (year 2, n = 469) received a 12-session classroom-based health and nutrition educational programme with an optional exercise intervention. Results Groups were demographically and anthropometrically similar. The intervention resulted in significant reductions in indices of adiposity (ΔBMI z-scores [-0.035 ± 0.014; p = 0.01], Δ% body fat [-0.5 ± 0.2; p

Background/Aims: Studies are lacking regarding the timing of peak growth hormone (PGH) response. We aim to elucidate the timing of PGH response to arginine and levodopa (A-LD) and evaluate the influence of body mass index (BMI) and other metabolic parameters on PGH. Methods: During growth hormone (GH) stimulation testing (ST) with A-LD, serum GH was measured at baseline and every 30 min up to 180 min. The PGH cut-off was defined as Results: In the 315 tested children, stimulated PGH levels occurred at or before 120 min in 97.8% and at 180 min in 2.2%. GH area under the curve (AUC) positively correlated with PGH in all patients and with IGF-1 in pubertal males and females. BMI negatively correlated with PGH in all subjects. GH AUC negatively correlated with HOMA-IR and total cholesterol. Conclusion: We propose termination of the GH ST with A-LD at 120 min since omission of GH measurement at 180 min did not alter the diagnosis of GH deficiency based on a cut-off of < 10 ng/mL. BMI should be considered in the interpretation of GH ST with A-LD. The relationships between GH AUC and metabolic parameters need further study.

Summary We describe a case of an infant who presented with clinical features of hyperthyroidism. The child was found to be tachycardic, hypertensive and diaphoretic, she was noted to have poor weight gain and difficulty in sleeping. The child was admitted to the pediatric intensive care unit for care. She was found to have biochemical evidence of hyperthyroidism with positive thyroid stimulating immunoglobulin. She responded well to methimazole and propranolol and had a remarkable recovery. She is the youngest patient to be diagnosed with Graves disease in the English literature, at 12 months of life. Learning points Hyperthyroidism must always be considered even at very young age, for patient presenting with poor weight gain and hyperdynamic state. Autoimmune diseases are becoming more common in infancy. Craniosynostosis and increased height for age are well-documented consequences of untreated hyperthyroidism in developing children.

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.

Objective We examined whether diabetic ketoacidosis (DKA), a serious complication of type 1 diabetes (T1D) was more prevalent among Non-Hispanic (NH) Black and Hispanic patients with T1D and laboratory-confirmed coronavirus disease 2019 (COVID-19) compared with NH Whites. Method This is a cross-sectional study of patients with T1D and laboratory-confirmed COVID-19 from 52 clinical sites in the United States, data were collected from April to August 2020. We examined the distribution of patient factors and DKA events across NH White, NH Black, and Hispanic race/ethnicity groups. Multivariable logistic regression analysis was performed to examine the odds of DKA among NH Black and Hispanic patients with T1D as compared with NH White patients, adjusting for potential confounders, such as age, sex, insurance, and last glycated hemoglobin A1c (HbA1c) level. Results We included 180 patients with T1D and laboratory-confirmed COVID-19 in the analysis. Forty-four percent (n = 79) were NH White, 31% (n = 55) NH Black, 26% (n = 46) Hispanic. NH Blacks and Hispanics had higher median HbA1c than Whites (%-points [IQR]: 11.7 [4.7], P

Highlights Our multicenter study reports a higher proportion of diabetic ketoacidosis presentation of over 60% in newly diagnosed patients with type 1 diabetes with or without confirmed coronavirus disease 2019 (COVID-19) at diagnosis. This finding is suggestive of delays in seeking care during the COVID-19 pandemic.

Introduction: Deterioration in glycemic control often occurs during adolescence in children with type 1 diabetes (T1D). Shared appointments have been shown to improve quality of life scores and treatment adherence in children with chronic illnesses. Objective: To examine the impact of combined individual visits and shared education appointments in adolescents with T1D on diabetes control, self-management, and diabetes related distress. Methods: Adolescents ages 11-19y with T1D for over 1y and poor control/adherence defined by HbA1C > 9%, 2 or more DKA episodes in the past year or 2 missed appointments were enrolled in a 6 month DKA prevention program consisting of monthly individual visits followed by an hour long shared education visit. HbA1C levels were obtained every 3 mo. Participants completed a diabetes distress score (DDS) and diabetes self-management questionnaire (DMSQ) prior to participation and at the 6th visit. Participants were followed for an additional 6 months after completion of the program. Those who attended 2 or more session were included in the analysis. Results: Ten adolescents (8 female, average age 13.9 y, diabetes duration from 1-11 y, average A1C 10.6% SD 2.0) were enrolled. None of the 10 participants had DKA during the program. There was no statistically significant change in A1C. No changes were noted in the DDS; however there was improvement in dietary control on DMSQ from 4.0 to 5.7 (p value 0.058). Six attended 5 or more of the sessions. Those 6 participants had a decrease in average A1C by 0.3% over 6 mo with no DKA episodes within 6 mo of completion. The 4 participants who attended 2-4 sessions had an increase in average A1C of 0.85% over the same period and 3 had DKA episodes within 6 mo after completion. Conclusions: Shared education visits may be a valuable approach to the care of adolescents with diabetes. No episodes of DKA and no significant changes in glycemic control were noted in 6 mo; however larger long-term studies are needed to explore whether continued shared visits can improve glycemic control. Disclosure M. Wilkes: None. T. Murphy: None. A. Aluf: None. D. Sperber: None. A. Sherry: None. S. Sethuram: None. L. Choleva: None. R. Rapaport: None.

Завантажено з https://academic.oup.cOm/jcem/article-abstract/92/3/804/25968918 ЧЕРВНЯ 2018.НАДРУКОВАНО В СШАTHE JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM 92(3):804 – 810PRINTED IN U.S.A.COPYRIGHT © 2007 BY THE ENDOCRINE SOCIETY DOI: 10.1210/JC.2006-2017Мета: Низька маса тіла залишається основною причиною захворюваності та смертності в ранньому віці та дитинстві. Це пов’язано з підвищеним ризиком виникнення проблем зі здоров’ям пізніше в житті, зокрема ішемічної хвороби серця та інсульту. Булa скликана нарада з метою виявлення основних проблем охорони здоров’я, що стоять перед дитиною, народженою з малою відносно гестаційного віку (МГВ) - small for gestational age (SGA), і як результат запропонувати стратегії ведення таких дітей.Учасники: були обрані 42 учасники на основі їх попередніх досліджень та обстежень в акушерстві, перинатальній та неонатальній медицині, педіатрії, педіатричній та дорослій ендокринології, епідеміології та фармакології.Докази: відбувся обмін письмовими матеріалами, вони були переглянуті, оцінені, а потім відкриті для всіх учасників. Це сформувало дискусійну базу засідання. Якщо опубліковані дані виявлялись недоступними або неадекватними, дискусія грунтувалася в такому разі на думках клінічних експертів.Процес консенсусу: кожна група питань була розглянута усіма учасниками, а потім обговорена на пленарних засіданнях за допомогою консенсусу та визначення невирішених питань. Консенсусну заяву було підготовлено на пленарному засіданні сесії, з подальшим редагуванням групами фахівців, після чого вона стала доступною для ознайомлення всім учасникам засідання.Висновки: Діагноз МГВ повинен грунтуватися на точній антропометрії при народженні, включаючи масу, довжину та об’єм голови. Ми рекомендуємо ранній нагляд у клініці росту для тих, хто не досягає необхідних параметрів. Оцінка раннього нейророзвитку та втручання у дітей ризикового віку. Ендокринні та метаболічні порушення у дитині МГВ визнаються, але рідко. Для 10%, хто не надолужує показників, лікування МГВ може збільшити лінійний ріст. Раннє втручання з GH для тих, хто має серйозну затримку в зростанні (висота за SD шкалою

Background: Papillary thyroid cancer (PTC) is an uncommon pediatric disease with an excellent prognosis. In follow-up surveillance, neck ultrasound (US), basal and thyroid-stimulating hormone-stimulated serum thyroglobulin (Tg) levels, and diagnostic whole-body radioactive iodine scans (DxWBS) have been traditionally used in both adults and children for the detection of recurrence or metastases of PTC. Methods: Two pediatric patients with metastatic PTC were followed after standard ablative treatment with routine neck US and serum Tg levels, as well as periodic DxWBS. Results: Neck US identified recurrent and metastatic PTC which DxWBS failed to detect. Conclusion: Neck US was superior to DxWBS in the detection of recurrent PTC in these 2 pediatric patients. These findings are consistent with the 2015 American Thyroid Association (ATA) Guidelines that neck US is an ideal imaging modality in pediatric patients for the surveillance of PTC local recurrence or lymph node metastases.

Context Weaver syndrome is characterized by tall stature, advanced bone age, characteristic facies, and variable intellectual disability. It is caused by heterozygous mutations in enhancer of zeste homolog 2 (EZH2), a histone methyltransferase responsible for histone H3 at lysine 27 (H3K27) trimethylation. However, no early truncating mutations have been identified, suggesting that null mutations do not cause Weaver syndrome. Objective To test alternative hypotheses that EZH2 variants found in Weaver syndrome cause either a gain of function or a partial loss of function. Design Exome sequencing was performed in a boy with tall stature, advanced bone age, and mild dysmorphic features. Mutant or wild-type EZH2 protein was expressed in mouse growth plate chondrocytes with or without endogenous EZH2, and enzymatic activity was measured. A mouse model was generated, and histone methylation was assessed in heterozygous and homozygous embryos. Results A de novo missense EZH2 mutation [c.1876G>A (p.Val626Met)] was identified in the proband. When expressed in growth plate chondrocytes, the mutant protein showed decreased histone methyltransferase activity. A mouse model carrying this EZH2 mutation was generated using CRISPR/Cas9. Homozygotes showed perinatal lethality, whereas heterozygotes were viable, fertile, and showed mild overgrowth. Both homozygous and heterozygous embryos showed decreased H3K27 methylation. Conclusion We generated a mouse model with the same mutation as our patient, found that it recapitulates the Weaver overgrowth phenotype, and demonstrated that EZH2 mutations found in Weaver syndrome cause a partial loss of function.

Background: Graves disease (GD) is the most common cause of hyperthyroidism worldwide. The usual age of presentation is between 20-30 years, and it is more common in females. Transient hyperthyroidism does occur in infants born to mothers with GD, however, the novo GD in infants is extremely rare. We are aware of only four cases of GD in children under the age of 2 years old previously reported in the literature, with the youngest being of 18 months. Although rare, the complications can be devastating, so identifying and treating GD in infants is vital. We describe an infant who presented at 12 months of life with poor weight gain. Patient Findings: A 12-month old female patient presented with weight loss, tachycardia, diaphoresis and hypertension. She had a palpable thyroid gland without ocular changes. She was found to have an undetectable Thyroid Stimulating Hormone (TSH) with an elevated free T4 of 2.1 ng/dL (normal 0.80 - 1.50 ng/dL). She was stabilized in the intensive care unit with beta-blocker and methimazole. The diagnosis of GD was subsequently confirmed with an extremely elevated elevated Thyroid Stimulating Immunoglobulins (TSI) titer of 263 Iu/L (normal 0.00-0.55 IU/L), her TSH receptor gene was normal. At 34 months of age, her TSI titer is still elevated at 34 IU/L and she still requires methimazole to maintain a euthyroid state. She is growing and developing appropriately. Conclusion: To our knowledge, this report describes the youngest child to be diagnosed with GD in the English literature. Only four patients between the ages of 18 - 24 months have been described. Autoimmune diseases are rare in infants, the reason for which GD developed at such a young age remains unclear. Clinical signs and symptoms of hyperthyroidism in infants can be subtle and easily missed: increased growth velocity, failure to gain weight, autonomic changes, and irritability. Most patients have an enlarged thyroid gland, and some have ocular changes. The major long-term complications of undiagnosed hyperthyroidism include craniosynostosis and permanent neurocognitive damage. A high index of suspicion is needed for the recognition and prompt treatment of GD in infants, leading to better clinical outcome.

Background: Multiple complex interactions exist between growth hormone (GH)-Insulin like growth factor-1 axis and the immune system. We and others have demonstrated GH receptors on the cell surface of peripheral blood mononuclear cells, human IM-9 cultured lymphocytes, thymus, spleen and lymph nodes. Administration of GH to GH deficient (GHD) children has shown a transient decrease in percent B cells and T cell percentages, interleukin-2 receptor levels and lymphocyte mitogenic stimulation response. Data about acute effects of GH on the immune system are lacking. Aim: The aim of this study was to evaluate the acute effect of endogenous GH on the cellular landscape of the immune system. Methods: A prospective study was conducted in pediatric patients being evaluated for short stature who underwent a standard 3-hour growth hormone stimulation test using arginine and glucagon. Exclusion criteria included genetic syndromes, renal failure, recent immunosuppressant or steroid use and small for gestational age. Blood samples for immunologic markers, that included complete blood count (CBC) and time of flight mass flow cytometry (CyTOF), were collected at the beginning (T0) and end (T3) of the test. Differences in patients by time point (T0 and T3) and by GH response to stimulation (growth hormone sufficient {GHS} versus GHD) were calculated using a two-way ANOVA test with repeated measures over time, considering the interaction between time point and GH status. Results: Fifty-four patients (39 boys, 15 girls) aged 5-18 years, were enrolled in the study. Twenty-two participants had peak GH level

Background: Beta thalassemia is characterized by the abnormal synthesis of β hemoglobin chains resulting in hemolytic anemia. Treatment involves frequent blood transfusions, which leads to the deposition of iron in many organs, including endocrine tissue such as the thyroid gland. Iron overload has been associated with various malignancies, most notably liver and hematological. To date, 7 cases of papillary thyroid cancer in patients with beta thalassemia have been reported in the adult literature, but none in pediatrics. Clinical Case: The patient is a 15 year 4 month old female with beta thalassemia requiring chronic red blood cell transfusions since the age of 5 months. She initially presented to us for evaluation of secondary amenorrhea. She underwent a splenectomy at the age of 10 years and received chelating therapy with deferasirox and deferiprone. Her ferritin levels had been stable around 1500ng/mL for the year prior to presentation; however, MRI revealed iron deposition in her pancreas, liver, kidneys, bone marrow and pituitary gland. On exam, her thyroid gland was asymmetric with the right lobe measuring 1cm larger than the left. The gland was firm in consistency with palpable lymph nodes along the right anterior cervical chain. A thyroid ultrasound was completed which revealed an enlarged right lobe containing 3 focal hypoechoic masses with calcific foci. Biopsy obtained via fine needle aspiration was consistent with papillary thyroid carcinoma. She underwent total thyroidectomy and histological examination confirmed the diagnosis. Her postoperative course was uncomplicated and she was started on replacement therapy with levothyroxine. Conclusion: To our knowledge this is the first case of papillary thyroid carcinoma in a pediatric patient with beta thalassemia. The incidence of thyroid cancer in patients with beta thalassemia is currently unknown, however there may be utility in routine surveillance of this patient population.

Introduction: SARS-Cov-2 (severe acute respiratory distress syndrome- coronavirus 2) viral infection has a predilection for pancreatic beta cells causing insulin deficiency. Studies from the SARS-CoV outbreak in 2003 highlighted the relationship between SARS-CoV and ACE-2 (angiotensin-converting enzyme 2) receptors in pancreatic islet cells. We describe a pediatric patient who developed Diabetes Mellitus after exposure to the Sars-CoV-2 virus. Case Report: A previously healthy 13-year-old female of Mexican descent was found to be hyperglycemic at her annual visit. The patient endorsed polyuria and polydipsia for 3 weeks, and weight loss for 3months. 3 months prior to presentation, her mother became ill and tested positive for SARS-CoV-2 by PCR analysis. The patient had no SARS-CoV-2 associated symptoms. Her exam was notable for a BMI was in the 78%ile for age with no acanthosis nigricans. She had no family history of diabetes or autoimmune disease. Initial blood glucose was 729 mg/dL, with bicarbonate of 20.6 mEq/L, pH 7.45, and anion gap of 14 mEq/L. Large ketones were present in the urine. Her concomitant C-peptide level of 1.0 ng/ml was low in the setting of hyperglycemia. Her HbA1c was 14.3%. Diabetes-related autoantibodies, celiac, and thyroid antibodies were negative. Her Sars-CoV-2 antibody titer was positive with a negative PCR. The patient was treated with a basal-bolus regimen of subcutaneous insulin at a maximal total daily dose of 0.7 u/kg/day. 5 weeks later, her insulin requirement and HbA1C were both lower; at 0.5 u/kg/day and 9.3% respectively. Discussion: This patient’s symptoms of hyperglycemia started shortly after her exposure to the SARS-CoV-2 virus. She had no features consistent with Type 2 DM. She similarly had no serological evidence of DM related autoimmunity, thus being different from reports of new-onset Type 1 DM with confirmed autoimmunity presenting during the Sars-CoV-2 pandemic. Although Type 1B DM without evidence of humoral islet autoimmunity and monogenic DM could not be fully excluded, we postulate that the patient developed SARS-CoV-2 associated DM given her time course and documented exposure to SARS –CoV-2 with the presence of SARS-CoV antibodies. One similar case has previously been reported By Holstein et al. 1 While we share the lack of direct evidence of causation, we postulate that more patients with similar presentations will be reported during the current pandemic. Reference: 1.Hollstein, T et al. Autoantibody-negative insulin-dependent diabetes mellitus after SARS-CoV-2 infection: a case report [published online ahead of print, 2020 Sep 2]. Nat Metab. 2020;10.1038/s42255-020-00281-8. doi:10.1038/s42255-020-00281-8