bluuebunny/crossref_metadata_2025_split huggingface dataset:
Late Endocrine Effects After HSCT in Children With Nonmalignant Diseases; A Single Center Cohort Analysis
Authors: de Kloet Liselotte C , Bense Joëll E , van der Stoep-Yap Eileen , Louwerens Marloes , von Asmuth Erik G J , Lankester Adriaan C , de Pagter Anne P J , Hannema Sabine E 
Published: May 2021

Abstract
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.
Extracellular Vesicles From SDHB Deficient hPheo1 Cells Activate STAT3 in Wild-Type Cells
Authors: Ghayee Hans K , Patel Sujal , Tuna Kubra M , Liu Lauren , Xu Yiling , Alli Abdel A 
Published: May 2021

Abstract
Pheochromocytomas and paragangliomas (PPGLs) are rare neuroendocrine tumors that originate from the adrenal medulla and extra-adrenal paraganglia, respectively. Inactivating mutations in succinate dehydrogenase (SDHx) genes leads to succinate accumulation, increased HIF1-α levels, and uncontrollable growth of PPGLs. We hypothesized that small extracellular vesicles (EVs) released from progenitor cells derived from pheochromocytoma (hPheo1) with a shRNA mediated knockdown of SDHB are enriched in succinate metabolites that play a key role in the activation of various tyrosine dependent signaling pathways that are involved in turmorigenesis and proliferation. We isolated EVs from the conditioned media of human wild-type hPheo1 cells and hPheo1 cells with shRNA SDHB knockdown. The EVs from three separate preparations of each group were characterized by nanoparticle tracking analysis, transmission electron microscopy, and Western blotting using antibodies against different types of EV and one non-EV marker. Our results show small EVs from the SDHB knockdown hPheo1 cells increased the activation of phosphotyrosine residues in wild-type cells compared to cells treated with control EVs from the same cell type. Additionally, our data show these EVs increase phospho-STAT3 compared to the control EVs (3843.10 +/- 1138.89 vs. 213.65+/- 40.75; p&lt;0.05; n=3) in cultured wild-type hPheo1 cells. Protein tyrosine kinases (PTKs) control various cellular processes including growth, differentiation, and metabolism by activating various signaling pathways including STAT3. The significance of these findings is that in some cancers, elevated succinate from a SDHx mutation has been shown to activate STAT3 which may explain a possible pathway for tumorigenesis. Studies from other investigators have shown that STAT3 expression is elevated in malignant PPGL tissues. Through enriched EV analysis our findings have confirmed the role of STAT3 in SDHB deficient cells. Additional studies are needed to identify other metabolites that are enriched in EVs that regulate phosphorylation of tyrosine residues and STAT3 activation.
Impact of BMI on Growth Hormone Stimulation Tests in Children and Adolescents: A Systematic Review and Meta-Analysis
Authors: Abawi Ozair , Augustijn Dieuwertje , Hoeks Sanne , de Rijke Yolanda B , van den Akker Erica L T 
Published: May 2021

Abstract
Background: Peak stimulated growth hormone (GH) levels are known to decrease with increasing BMI, possibly leading to overdiagnosis of GH deficiency (GHD) in children with overweight and obesity. However, current guidelines do not provide guidance how to interpret peak GH values of these children, nor has this been assessed systematically. The aim of this systematic review and meta-analysis was to study the effect of BMI on stimulated peak GH values in children, and to quantify to which extent peak GH values in children with obesity are decreased. Methods: We searched the Medline, Embase, Cochrane, Web of Science, and Google Scholar databases (13 July 2020) for studies reporting impact of BMI on peak GH in children. Where possible, individual participant data was extracted and/or obtained from the authors. Primary outcome was the association between peak GH values and BMI standard deviation score (SDS). Pooled correlation coefficients were calculated under a random effects model, and exploratory moderator analyses and meta-regression were performed. Study heterogeneity was assessed using the I2 statistic. For studies with available individual participant data, linear mixed-models regression analysis was performed with BMI SDS as predictor and ln(peak GH) as outcome, accounting for used GH stimulation agent (fixed effect) and study (random effect). This systematic review was performed in accordance to the PRISMA guidelines. Results: In total, 56 studies were included, providing data on n=5100 children (1346 with individual participant data). Across all studies, a pooled r of -0.37 (95% CI -0.44 to -0.31, n=2785) was found. Study heterogeneity was large (I2=58%). Pubertal status, sex, presence of syndromic obesity, and mean age and BMI SDS of the population did not significantly moderate the pooled r (all p&gt;0.05). Individual participant data analysis revealed a beta of -0.11 (95% CI -0.08 to -0.15, p&lt;0.001), i.e., per 1 point increase in BMI SDS, peak GH decreases by 11% (95% CI 7 to 14%). In the 8 studies performed in children referred for short stature, obesity was present in 27/893 (3.02%) children without GHD and in 36/615 (5.85%) children with GHD (p=0.0069). This corresponds to a RR of 1.43 (95% CI 1.14 to 1.78, p=0.002) for a diagnosis of GHD in children with short stature with obesity compared to children without obesity. Discussion: To our knowledge, this is the first systematic review and meta-analysis to investigate the impact of BMI on peak GH values in children, showing a significant negative correlation and risk of overdiagnosis of GHD in children with obesity. All in all, with ever-rising prevalence of pediatric obesity, our study highlights the urgent need for BMI (SDS)-specific cut-off values for GH stimulation tests in children.
Impact of IGF-1 Normative Datasets on Indication and Outcome of Growth Hormone Stimulation Testing
Authors: de Bie Prim , Heijboer Annemieke C , Deckers Martine M L 
Published: May 2021

Abstract
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 &lt; 0 SD in case of a high probability and if serum IGF-1 Z-score is &lt; -1 SD in case of low probability. An IGF-1 Z-score &gt; 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 &gt; 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.
Stratifying the Genetic Aetiology in Children Born Small for Gestational Age With Persistent Short Stature (SGA-SS)
Authors: Toni Ledjona , Plachy Lukas , Dusatkova Petra , Elblova Lenka , Amaratunga Shenali Anne , Kolouskova Stanislava , Obermannova Barbora , Snajderova Marta , Sumnik Zdenek , Pruhova Stepanka , Lebl Jan 
Published: May 2021

Abstract
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.
Topline Results of the CARE-PWS Phase 3 Study: Intranasal Carbetocin Improves Hyperphagia and Anxiety and Distress Symptoms in Prader-Willi Syndrome (PWS)
Authors: Ryman Davis , Deal Cheri L 
Published: May 2021

Abstract
Prader-Willi syndrome (PWS) is a complex genetic disorder associated with multiple neuroendocrine abnormalities including significantly decreased hypothalamic oxytocin levels, resulting in symptoms of severe hyperphagia (an unrelenting false sense of starvation) and multiple severe neuropsychiatric and behavioral issues. CARE-PWS, a multi-center, randomized, double-blind, placebo-controlled phase 3 study, has evaluated the efficacy, safety, and tolerability of intranasal carbetocin, a selective oxytocin receptor agonist, in participants with PWS.
Eligible participants aged 7 through 18 with genetically confirmed PWS were randomized in equal proportions to three treatment arms for the 8-week placebo-controlled period of the study: carbetocin 9.6 mg, carbetocin 3.2 mg, or a matching placebo, administered by nasal spray three times a day with meals. The primary endpoint assessed changes from baseline to week 8 in Hyperphagia Questionnaire for Clinical Trials (HQ-CT) or Children’s Yale-Brown Obsessive Compulsive Scale (CY-BOCS) scores for the carbetocin 9.6 mg arm vs placebo, and the first secondary endpoint assessed changes from baseline to week 8 in HQ-CT or CY-BOCS scores for the carbetocin 3.2 mg arm vs placebo. Additional secondary endpoints included changes from baseline to week 8 in PWS Anxiety and Distress Questionnaire (PADQ) scores, and Clinical Global Impression of Change (CGI-C) scores evaluating the overall change in severity of PWS symptoms at week 8.
Due to COVID-19, enrollment was closed early with 119 evaluable participants for the primary analysis. In the carbetocin 9.6 mg arm, trends toward numerically greater improvements in HQ-CT and CGI-C scores relative to placebo were observed but did not reach statistical significance; however, the carbetocin 3.2 mg arm demonstrated a significant improvement in HQ-CT scores (LS mean improvement vs placebo -3.14 points, p=0.016). In the 3.2 mg arm, additional consistent evidence of improvements versus placebo was seen in multiple secondary endpoints, including CGI-C (p=0.027) and PADQ (p=0.027). Numeric trends toward improvement in CY-BOCS scores were observed in each dose arm, but did not reach statistical significance versus placebo. During the subsequent long-term follow-up period of the study, both carbetocin arms have experienced continued numeric improvements from baseline across multiple endpoints. Intranasal carbetocin was generally well-tolerated; the most frequently reported adverse event was flushing, which was generally mild and transient.
In conclusion, results of the CARE-PWS study support that intranasal carbetocin appears to be safe and well tolerated, and reduces hyperphagia and anxiety and distress behaviors in PWS.
6-Year-Old Girl With a Luteinized Follicular Ovarian Cyst and an Estradiol Level &gt; 1,000 PG/ML
Authors: Jacob Marianne , Poppas Dix , Lekarev Oksana 
Published: May 2021

Abstract
Background: Precocious puberty in girls is defined as onset of secondary sexual characteristics, such as breast development, before 8 years of age. To differentiate between central and peripheral precocious puberty, laboratory and imaging evaluation is helpful. When gonadotropins are low but estradiol is elevated, results may suggest a primary ovarian source of estrogen production. Small ovarian cysts are not uncommon, are benign and self-resolve. However, large ovarian cysts are rare, let alone ones requiring surgical removal.
Clinical Case: A 6 year 7 month old girl presented with several days of breast tenderness and palpable bilateral breast tissue noted by her mother. There was no history of vaginal bleeding. There were no reported exposures to estrogen-containing products. Her mother reached menarche at age 14 years. The patient was born full term and was otherwise healthy. On exam, her height was at the 90-95th %ile (mid-parental height at the 95th %ile) and her growth velocity was 10.9 cm/yr. She had Tanner 2 breasts (1 cm breast bud on the left and 1.5 cm on the right), Tanner 1 pubic hair and no axillary hair, body odor, acne or café-au-lait macules. A bone age was read as 6 years at a chronological age of 6 years 7 months. A laboratory evaluation revealed an estradiol of 1,029 pg/mL (&lt;15 pg/mL), LH &lt;0.02 mIU/mL, FSH &lt;0.09 mIU/mL, 17-hydroxyprogesterone (17-OHP) 410 ng/dL (&lt;91 ng/dL), AFP 2.3 ng/mL (&lt;6.1 ng/mL), beta-hCG &lt;2 mIU/mL, TSH 2.41 mIU/L (0.5-3.2 mIU/L), and free T4 0.9 ng/dL (0.9-1.4 ng/dL). Pelvic ultrasound revealed a large unilocular cystic structure measuring 6.5 x 4.1 x 6.1 cm in the left adnexal region with no left ovary visualized. The right ovary appeared prepubertal. The uterus was prepubertal in appearance with endometrial thickness of 2 mm. Abdominal ultrasound showed no evidence of a suprarenal mass. A laparoscopic cyst resection was completed, given the risk of left ovarian torsion. Cytology was negative; pathology revealed a luteinized follicular cyst. Repeat labs in one month showed a prepubertal estradiol level of 6.7 pg/mL with LH 0.02 mIU/mL and FSH 0.38 mIU/mL. 17-OHP normalized to 29 ng/dL. Breast tissue had regressed.
Conclusion: This case describes the rare finding of a large luteinized follicular ovarian cyst that required surgical removal in a 6-year-old girl in the setting of a significantly elevated estradiol level. Luteinized follicular cysts have been described in newborns, though rare. To our knowledge, this is the first described case of a luteinized follicular cyst in this patient’s age group. Laboratory and imaging evaluation should be considered in girls presenting with precocious puberty, despite the extent of thelarche, as the clinical examination does not always correlate with degree of estradiol elevation. This is especially important if clinical changes are acute and other features are consistent with puberty, such as rapid linear growth.
A Case of Severe MIS-C in Pediatric Diabetes: Complications of COVID-19
Authors: Dye Alyssa M , Arnold Sandra R , Finkel Terri H , Kim Ahlee 
Published: May 2021

Abstract
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 &gt;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 &gt;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.