bluuebunny/crossref_metadata_2025 huggingface dataset:
Single Nucleus Transcriptome and Chromatin Accessibility Landscapes of Human Pituitaries
Authors: Ruf-Zamojski Frederique Murielle , Zhang Zidong , Zamojski Michel , Smith Gregory R , Yianni Val , Willis Thea L , Mendelev Natalia , Pincas Hanna , Seenarine Nitish , Amper Mary Anne S , Vasoya Mital , Zhou Xiang , Gambino Luisina Ongaro , Schang Gauthier , Mofsowitz Sagie , Nair Venugopalan D , Welt Corrine Kolka , Troyanskaya Olga G , Turgeon Judith L , Bernard Daniel J , Andoniadou Cynthia Lilian , Sealfon Stuart C
Published: May 2021

The pituitary gland regulates key physiological functions, including growth, sexual maturation, reproduction, and lactation. Here, we present a paired single-nuclei (sn) transcriptome and chromatin accessibility characterization of six post-mortem human pituitaries. These samples were from juvenile, adult, and elderly male and female subjects. Well-correlated snRNAseq and snATACseq datasets facilitated robust identification of the major pituitary cell types in each sample. Using latent variable pathway analysis, we uncovered previously unreported coordinated gene expression modules and chromatin accessibility programs for each major cell type as well as an age-specific program across all the endocrine cell types. These largely appear to be congruent between human and mouse datasets. Given the importance of murine models in the study of human pituitary disorders and pituitary physiology, we next sought to compare expression profiles of pituitary cell types in mouse vs. human. Murine and human cell types were well correlated, exemplified by coordinated gene expression programs, especially for undifferentiated stem cells (SCs). In both species, we identified clusters corresponding to naive and committing SCs. All human SC clusters expressed the established SC markers SOX2 and SOX9, as well as genes involved in SC regulatory pathways (WWTR1, YAP1 andPITX2). Additional markers previously reported in murine pituitary SCs were also found in human SC, including WIF1, LGR5, FOS, CDH1, EGFR, LGR4, and WLS. Remarkably, in human, the main naive SC cluster was roughly divided into a high-JUN and a low-JUN expressing subgroup, whereas Jun expression was less pronounced in the murine SC cluster. In both species, committing SC clusters expressed the endocrine markers for POU1F1, TSHB, or POMC, while SCs committing to an intermediate lobe/melanotrope cell identity were distinguishable based on PAX7 expression. In addition, in the human datasets we identify a population of cells as originating from the pars tuberalis. We offer a range of markers that can be utilized for in vivo validation of these cells. Overall, the characterization of the murine and human pituitary SCs strongly suggests the co-existence of subpopulations with different lineage commitments in addition to a single uncommitted SC population. This sn atlas of the human pituitary is a valuable resource that will be made web-accessible.
Doppler Assessment of the Uterine Arteries for the Definition of Pubertal Onset in Girls
Authors: Cheuiche Amanda Veiga , da Silveira Letícia Guimarães , Lucena Iara Regina Siqueira , Puñales Marcia , Costenaro Fabiola , Kopacek Cristiane , Silveiro Sandra Pinho , de Paula Leila Pedroso
Published: May 2021

Pelvic ultrasonography (US) is a quick, non-invasive and low-cost method, and doppler analysis facilitates assessment of flow impedance measurement in the uterine vascular tree. The pulsatility index (PI) reflects blood flow impedance in the vessel distal to the sampling point and has been suggested as a parameter to define pubertal development. In order to evaluate the PI and US measurements of uterus and ovaries in girls with different pubertal stages, we performed a cross-sectional study in girls with normal pubertal development. US and Doppler assessed PI of the uterine arteries (defined as the difference between the peak systolic flow and end-diastolic flow divided by the mean maximum flow velocity), endometrial thickness, uterine and ovarian volumes were evaluated. All the US exams were performed with the same equipment by the same radiologist. Clinical data such as the age of menarche, pubarche and thelarche were recorded. Statistical analyses were performed in SPSS, with ANOVA test, Spearman correlation and ROC curve with Youden. One hundred and sixty-nine girls aged 5-16 years (mean 11.3 ± 1.8) who performed two hundred and two pelvic US were included (Tanner 1=20%, Tanner 2=22%, Tanner 3=23%, Tanner 4=17%, Tanner 5=17%). Mean age of thelarche, pubarche and menarche were 11.1 ± 1.8, 10.2 ± 1.2 and 12.2 ± 1.1 years respectively. Prepubertal girls (Tanner 1) had mean PI significantly higher than girls in initial puberty (Tanner 2 and 3 grouped) and in late puberty (Tanner 4 and 5 grouped), respectively 6.5 ± 2.27 vs. 4.15 ± 1.55 vs. 2.82 ± 1.06, p<0.001 for all the comparisons. ROC curve analysis demonstrated that the PI is able to identify the onset of puberty with an area under the curve of 0.80 ± 0.04, P<0.001, and a cutoff point of IP=5.05 presented a sensitivity of 0.77 and a specificity of 0.80 to identify the onset of puberty. When we combined the cutoffs of IP <5.05 plus uterine volume >3.75 cm³, we found a sensitivity of 0.72 and specificity of 0.90 to detect puberty. We identified a strong negative correlation between PI and uterine volume (rs=-0.72, p<0.001) and a moderate negative correlation with endometrial thickness (rs=-0.68, p<0.001) and right (rs=-0.60, p<0.001) and left (rs=-0.59, p<0.001) ovarian volumes. In conclusion, we found a significant reduction of the PI during pubertal development, reflecting a progressive increase in blood flow to the uterus, which can be a valuable non-invasive and highly specific tool to confirm the onset of puberty.
Effects of L-3,4-dihydroxyphenylalanine (L-Dopa) Treatment in the Neuroendocrine Response to Stress
Authors: Orrillo Santiago Jordi , Imsen Mercedes , Lizarraga Alfonsina , Romero Ana Clara , De Fino Fernanda , Zanoni Milagros Peña , Machado Alejandra Inés Abeledo , Zarate Sandra Cristina , Ferraris Jimena , Diaz Graciela Susana , Pisera Daniel
Published: May 2021

Stressful stimuli evoke a complex response mediated by two systems: the Sympathetic-Adreno-Medullar (SAM) axis and the Hypothalamus-Pituitary-Adrenal (HPA) axis. Among the factors involved in stress, glucocorticoids and catecholamines secreted from the adrenal glands and sympathetic nerves are the main effectors of the physiological adaptations to stressors. Besides these, prolactin (PRL) is another hormone secreted under stress conditions. Catecholamines are synthesized from the hydroxylated precursor L-Dopa. This agent is commonly used for the treatment of Parkinson’s disease and it would act as a neurotransmitter per se. On the other hand, it has been suggested that HPA axis dysregulation is a potential risk factor for the development of depression. In line with this, several studies reported that L-Dopa treatment may alter the serum levels of ACTH, PRL, and glucocorticoids in parkinsonian patients and Parkinson’s disease animal models. In the present study, we determined whether the chronic treatment with L-Dopa altered the stress response inducing depressive-like behaviours. Adult male Wistar rats were treated orally during 24 days with LEBOCAR® - commercial formulation of L-Dopa (75 mg/day) and Carbidopa (7.5 mg/day) - in drinking water. Animals were stressed by immobilization during the last 9 days of treatment and depressive-like behaviours were assessed by the sucrose intake and forced swimming tests. Behavioural tests showed no signs of depressive-like behaviours in the LEBOCAR®-treated and/or stressed rats. We next explored the SAM axis reactivity. Circulating noradrenaline and adrenaline increased in rats treated with LEBOCAR® (p<0.05; HPLC). Also, the adrenals from stressed animals showed higher content of adrenaline (p<0.05). Then, we studied the HPA axis activity. Chronically stressed rats displayed a lower ACTH secretion (ELISA) and a downregulation of POMC expression (qPCR) in the anterior pituitary (p<0.05). In addition, LEBOCAR® treatment induced a reduction in serum ACTH and POMC levels (p<0.05). As expected, serum corticosterone (ELISA) enhanced under chronic stress, an effect that was inhibited by treatment with LEBOCAR® (p<0.05). Finally, pituitary PRL gene expression (qPCR) was downregulated by LEBOCAR® treatment with a more pronounced effect when rats were also stressed (p<0.05). Our results suggest that L-Dopa alters the neuroendocrine stress response enhancing SAM axis reactivity and reducing HPA axis activity and PRL expression.
Infigratinib in Children With Achondroplasia (ACH): Design of PROPEL2 - A Phase 2, Open-Label, Dose-Escalation and Dose-Expansion Study
Authors: Savarirayan Ravi , Kannu Peter , Dambkowski Carl L , Rogoff Daniela , Irving Melita
Published: May 2021

Background: ACH, the most common non-lethal form of skeletal dysplasia, is characterized by defective endochondral ossification resulting from gain-of-function mutations in the fibroblast growth factor receptor 3 (FGFR3) gene, a negative regulator of endochondral bone formation. Current treatment options are non-targeted, ineffective, or painful interventions aimed at preventing or treating complications. Infigratinib is an orally bioavailable and selective FGFR1-3 tyrosine kinase inhibitor in development for FGFR-related conditions. In vitro data with infigratinib showed inhibition of FGFR1-3 activity with reversal of established growth arrest in chondrocytes. In vivo studies revealed dose-dependent improvements in foramen magnum and long bone length in Fgfr3Y367C/+ mice following treatment with infigratinib. Methods: PROPEL2 is a prospective, phase 2, open-label study of infigratinib in children with ACH. Children 3-11 years of age with ACH who have completed at least 6 months of observation in the observational PROPEL study are eligible to participate. PROPEL2 consists of dose escalation with an extended treatment phase, designed as dose finding, followed by a dose-expansion phase to confirm the selected dose and to provide evidence of efficacy. The primary endpoints of the dose-escalation/extended treatment phase are treatment-emergent adverse events and change from baseline in annualized growth velocity. Subjects (n=40) will be enrolled in ascending dose cohorts of approximately 10 subjects/cohort (4 cohorts planned) and treated for 6 months at their assigned dose, continuing for an additional 12 months with dose modifications as required. Up to 20 new subjects will be enrolled in the dose-expansion phase and receive infigratinib (mini-tablets, administered orally once daily) for 12 months. Secondary objectives include: safety/tolerability of infigratinib; changes from baseline in anthropometric parameters, including body proportions; and the pharmacokinetic/pharmacodynamic profile of infigratinib. An exploratory objective is evaluation of changes in ACH disease burden. Current Status: PROPEL2 is currently enrolling - the first subject was entered in July 2020. The planned total enrollment is 60 children with ACH (n=40 in the dose-escalation/extended treatment phase; n=20 in the dose-expansion phase). Following completion of PROPEL2, subjects have the opportunity to enroll in an open-label long-term extension study to assess the safety and efficacy of long-term administration of infigratinib in children with ACH.
Role of Genetic Analysis for the Differential Diagnosis of Delayed Puberty from the UK Puberty Cohort
Authors: Saengkaew Tansit , Dunkel Leo , Howard Sasha R
Published: May 2021

Distinction between self-limited delayed puberty (DP) and idiopathic hypogonadotropic hypogonadism (IHH) is challenging. Several biochemical tests have been applied to differentiate these conditions; however, all have limitations resulting in some patients undergoing inappropriate investigations and treatment. This study investigated whether the identification of a genetic defect in patients presenting with pubertal delay in adolescence through whole exome sequencing (WES) can help in distinguishing these two conditions. The WES data of 47 pubertal delay patients from Paediatric Endocrinology and Paediatric services around the UK were analysed. The variants were filtered for rare, predicted deleterious variants in genes from a virtual panel reported in IHH (n= 36), both IHH and self-limited (n=6), and self-limited DP (n= 4) that segregated with trait. Pathogenic variants were verified by Sanger sequencing, computational bioinformatics, and review of inheritance pattern as compared to previous reported mutations in this gene, and assigned a genotypic diagnosis as self-limited DP, IHH or overlapping. Full clinical history, physical examination and basic laboratory and hormonal investigations were used to determine the clinical diagnosis. Clinically, 38% of patients had self-limited DP and 26% had IHH and the rest of uncertain diagnosis as they were still undergoing a period of follow up under the age of 18 years. Twenty-four variants in 17 genes, accounting for 43% of the tested cohort, were identified to be potentially pathogenic variants, with most inherited in a heterozygous manner. We found a good correlation between genotypic diagnosis and phenotype diagnosis with Cohen’s kappa (k) = 0.235 (95% IC, 0.031 to 0.429). Thus, patients who carry variants reported only in self-limited DP with heterozygous inheritance were likely to have a clinical diagnosis of definite self-limited DP. On the other hand, patients carrying homozygous or loss of function variants in genes reported with heterozygous mutations in IHH will be very likely to have IHH. In addition, we identified variants in patients with clinical self-limited DP to have variants, which had been previously reported only in IHH, including DMXL2, CHD7, OTUD4, and SEMA3E. In summary, this study shows that there is a good genotype-phenotype correlation in patients presenting with pubertal delay. Therefore, genetic investigation may help to distinguish these two conditions, resulting in more accurate diagnosis and appropriate treatment modalities. In addition, new genes, previously implicated only in IHH, have been identified in self-limited DP, which indicate that these two conditions share similar disease mechanisms.
A Machine Learning Approach for Identifying Children at Risk of Suboptimal Adherence to Growth Hormone Therapy
Authors: Spataru Amalia , van Dommelen Paula , Arnaud Lilian , Masne Quentin Le , Quarteroni Silvia , Koledova Ekaterina B
Published: May 2021

Background: Suboptimal adherence to recombinant human growth hormone (r-hGH) treatment can lead to suboptimal clinical outcomes. Being able to identify children who are at risk of suboptimal adherence in the near future, and take adequate measures to support adherence, may maximize clinical outcomes. Our aim was to develop a model based on data from the first 3 months of treatment to identify potential indicators of suboptimal adherence and predict adherence over the following 9 months using a machine learning approach.

Methods: We assessed adherence to r-hGH treatment in children with growth disorders in their first 12 months of treatment using a connected autoinjector and e-device (easypod™), which automatically transmits adherence data via an online portal (easypod™ connect). We selected children who started the use of the device before 18 years of age and who transmitted their injection data for at least 12 months. Adherence (mg injected/mg prescribed) between 4-12 months (outcome) was categorized as optimal (≥85%) versus suboptimal (<85%). In addition to adherence over the first 3 months, comfort settings (needle speed, injection depth, injection speed, injection time), number of transmissions, number of dose changes, age at start and sex were used as potential indicators of suboptimal adherence. Several machine learning models were optimized on a class-balanced training dataset using a 5-fold cross-validation scheme. On the best performing model, machine learning interpretation techniques and chi-squared statistical tests were applied to extract the statistically significant indicators of suboptimal and optimal adherence. Results: Anonymized data were available for 10,943 children. The optimal prediction performances were achieved with the random forest algorithm. The mean adherence and the adherence standard deviation over the first 3 months were the two most important features for predicting adherence in the following 9 months. Not using the system’s features (e.g. not transmitting data often and not changing some of the comfort settings, such as the needle speed setting), as well as starting treatment at an older age were significantly associated with an increased risk of suboptimal adherence (p<0.001). When tested on first-time seen data following the same class distribution as the original data, the model achieved a sensitivity of 80% and a specificity of 81%.

Conclusions: We developed a model predicting whether a child’s adherence in the following 9 months will be below or above the optimal threshold (85%) based on early data from the first 3 months of treatment and we identified the indicators of suboptimal adherence. These results can be used to identify children needing additional medical or other support to reach optimal adherence and therefore optimal clinical outcomes.
Comparison of Quality of Life Responses From Caregiver and Children Aged ≥7 Years Using the Quality of Life in Short Stature Youth (QoLISSY) Questionnaire, Following 12 Months of Growth Hormone Treatment With Either a Weekly Somatrogon or a Daily Genotropin Injection Schedule
Authors: Loftus Jane , Quitmann Julia , Valluri Srinivas , Pastrak Aleksandra , Reiter Lawrence , Roland Carl
Published: May 2021

Objective: Paediatric growth hormone deficiency (pGHD) affects 1/4,000 children. Treatment with daily sub-cutaneous injections of recombinant human growth hormone (r-hGH) increase height velocity and quality of life (QoL). A recent randomised controlled clinical trial (NCT02968004) evaluated the efficacy/safety of weekly Somatrogon (hGH-CTP) and daily Genotropin in pGHD. QoL (an exploratory endpoint) was evaluated using the validated Quality of Life in Short Stature Youth (QoLISSY) questionnaire, which includes three subscales (physical, social, emotional) and total score.

Methods: The QoLISSY core module was administered to patients (aged 3-11 years [girls], 3-12 years [boys]) and parents in US, UK, Australia, New Zealand, Belarus, Russia, Ukraine and Spain, at Baseline (BL) and 12 months after treatment start. The QoLISSY-CHILD was completed by children aged ≥7 years; QoLISSY-PARENT was completed by the Caregiver for children <7 years, and for some children aged ≥7 years. We report here only the QoLISSY results for children aged ≥7 years (reported from either child or parent).

Results: For Total QoLISSY-PARENT, for children aged ≥7 years in the Somatrogon group (N=26), mean scores are 53.65 (BL) and 65.52 (month 12) with mean change of 13.01 (95% Confidence Interval [CI]: 3.99, 22.02). In the Genotropin group (N=28), mean scores are 55.89 (BL) and 63.66 (month 12) with mean change of 6.60 (CI:-0.21, 13.40). For Total QoLISSY-CHILD in the Somatrogon group (N=35), mean scores are 61.48 (BL) and 74.69 (month 12) with mean change of 13.00 (CI: 5.81, 20.19). In the Genotropin group (N=35), these scores are 60.96 (BL) and 69.03 (Month 12) with mean change of 7.84 (CI: 2.71, 12.97). Scores of >70 indicate a good QoL.

Conclusions: QoL in children aged ≥7 years improved, following 12 months of either treatment, whether this was reported by caregiver or child. However, these data show that the baseline scores and 12 month scores from the QoLISSY-PARENT in both treatment groups were numerically lower than those reported by the child. This is consistent with the literature¹, in which the caregivers generally report lower QoL scores on behalf of the child.

¹Explaining parent-child (dis)agreement in generic and short stature-specific health-related quality of life reports: do family and social relationships matter? Quitmann et al Health and Quality of Life Outcomes 2016 vol 14, Article 150
Factors Driving Patient Preferences for Growth Hormone Treatment in Japanese Children With Growth Hormone Deficiency
Authors: Tanaka Toshiaki , Sato Takahiro , Yuasa Akira , Akiyama Takeshi , Tawseef Adeeb
Published: May 2021

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.
Long-Term Effect of Aromatase Inhibition in Aromatase Excess Syndrome
Authors: Binder Gerhard , Nakamura Akie , Schweizer Roland , Ogata Tsutomu , Fukami Maki , Nagasaki Keisuke
Published: May 2021

Aromatase excess syndrome (AEXS) is a very rare disorder characterized by prepubertal gynecomastia, bone age acceleration and early growth arrest. Heterozygote submicroscopic rearrangements within the promotor of CYP19A1 result in overexpression of aromatase and enhanced aromatization of androgens. Long-term treatment effects of aromatase inhibitors are unknown. Retrospectively we collected data from file records of 7 boys (three sibling pairs and one sporadic case) with AEXS. Genetic analysis revealed upstream of CYP19A1 a 165,901 bp deletion in 4 German cousins, a 198,662 bp deletion in 2 Japanese brothers and a 387,622 bp tandem duplication in a Japanese boy. All boys developed prepubertal gynecomastia, at 9.0 yr of age (median; range: 7.0 - 11.0). Height was +1.20 SDS (-0.24 - +1.98); predicted adult height was -1.29 (-3.29 - +1.09 SDS). Four boys were treated with anastrozole 1.0 mg daily, while three reached adult height untreated. Treatment with anastrozole was stopped after 5.6 yr (4.0 - 6.8). Three treated boys exceeded height prognosis by 2.4, 6.9 and 8.1 cm; while one untreated fell below prognosis by 8.6 cm. One treated with a low dose and two untreated reached their prognosis. Adult heights were -0.91 SDS with anastrozole (-2.86 - -0.29) and -0.15 SDS without (-2.31 - -0.03). Distance to target height was -0.22 SDS with anastrozole (-1.72 - +0.52) and +0.54 SDS without treatment (+0.23 - +1.30). Spontaneous growth in AEXS varied, even in the same family. Our data suggest that early started, long-term inhibition by aromatase inhibitor anastrozole (1 mg daily) promotes adult height in boys with AEXS.
Sub-Optimal Adherence With Daily Growth Hormones Increases With Each Year of Treatment in a US Commercial Claims Database
Authors: Loftus Jane , Chen Yong , Alvir Jose Ma J , Chi Lei , Dasgupta Shibasish , Gupta Anu , Wajnrajch Michael P
Published: May 2021

Introduction and Objective: Pediatric growth hormone deficiency (pGHD) occurs in approximately 1 in 4,000 children. The main manifestation is short stature managed with daily injections of somatropin, a recombinant human growth hormone (r-hGH). Prior research has shown that children with good adherence with r-hGH have significantly greater linear growth compared to those with sub-optimal adherence. While previous studies have found sub-optimal adherence with daily r-hGH injectables among children with pGHD, to date, r-hGH adherence has not been studied among large, usual-care populations using validated measurements of adherence. We describe adherence to somatropin treatment over 4 years in a population-based study.

Materials and Methods: A retrospective cohort analysis of commercially insured patients ≥3 and <16 years, diagnosed with pGHD, newly treated with somatropin from 01 January 2002 through 31 December 2019 (study time period) was conducted using Optum De-identified Clinformatics Data Mart database. Index date was defined as the first prescription for somatropin between 01 July 2002 to 30 September 2019. Four patient cohorts were identified (12, 24, 36, and 48 months of post-index continuous enrollment). The demographic and clinical profiles of children with pGHD treated with daily injections of somatropin who have good adherence and those with sub-optimal adherence were characterized. Good adherence was defined as medication possession ratio (MPR) of ≥ 80%, sub-optimal adherence as MPR <80%. Logistic regression models will evaluate the relationship between demographic characteristics (age, gender, race/ethnicity) and adherence (good vs. sub-optimal).

Results: Patient characteristics were similar across each cohort; in the 12-month cohort (n=3091), mean age was 11.34 ±2.89 years, 75.9% were male, 70.9% white, 9.4% Hispanic, 3.6% Asian, and 3.1% black. At 48 months, 1193 (38.6%) of the 12-month cohort remained for follow-up. At 12 months, 80.1% had good adherence and mean (95% CI) MPR was 0.89 (0.88-0.89) while mean (95% CI) MPR at 48 months was 0.82 (0.81-0.83). The proportion with good adherence at months 24, 36, and 48 were 70.2%, 65.6%, and 64.0%, respectively. Adherence was not associated with age or gender. Blacks and Hispanics consistently exhibited lower adherence. At 12 months, good adherence was observed among 85.7% of Asians, 80.0% of whites, 77.2% of Hispanics, and 76.0% of blacks; at 48 months, good adherence was observed among 73.9% of Asians, 65.4% of whites, 56.8% of blacks, and 55.2% of Hispanics. Logistic regression model results will be provided.

Conclusion: Although the majority of children with pGHD demonstrated good adherence with a daily r-hGH regimen, sub-optimal adherence increases with treatment duration and is higher among black and Hispanic children. Strategies that facilitate good adherence to r-hGH may support improved clinical outcomes.
Case Report: Primary Hypothyroidism Caused by Autoimmune Thyroiditis in Infancy Requires Early Intervention
Authors: McSweeney Zina C , Chang Christopher , Nemery Robin Lynne
Published: May 2021

Background: Primary hypothyroidism due to autoimmune thyroiditis is extremely rare in infants, especially under the age of 3 years. For infants, hypothyroidism is most commonly congenital, originating from thyroid dysgenesis with an absent, ectopic, or hypoplastic thyroid gland (1 in 4,000 live births). If left untreated, it can lead to permanent neurodevelopmental deficits. In this report, we describe a male infant who was diagnosed with Hashimoto thyroiditis at 18 months of life, providing a learning example to aid in recognition of this rare disease and enable timely intervention.

Clinical Case:Patient was a 2,765 gram, appropriate for gestational age, male born at term with hypospadias of the penis (surgical correction at 11 months). Patient passed meconium in the first 24 hours of life. During the first few months of life, patient developed constipation. Patient had amblyopia necessitating eye patching and began to wear eye glasses at 18 months of life. Patient’s linear and weight growth were within normal limits. Patient had normal motor development, however had language development delay. No known family history of thyroid disease. Screening labs performed at 17-months of age showed abnormal thyroid function: elevated TSH at 14.86 µIU/mL (ref: 0.45 - 4.50 µIU/mL) and normal free T4 level at 1.24 ng/dL (ref: 0.85-1.75 ng/dL). Repeat testing at 18 months of age continued to show elevated TSH at 6.18 µIU/mL (ref: 0.64 - 4.00 µIU/mL), normal free T4 at 1.07 ng/dL (ref: 0.88 - 2.03 ng/dL), and elevated thyroid peroxidase (TPO) antibodies at 163 IU/ml (ref: <35 IU/ml). At 21 months of age, patient was initiated on L-thyroxine therapy for elevation of TSH (9.570 µIU/mL; ref: 0.64 - 4.00 µIU/mL) and free T4 was normal (1.03ng/dL; ref: 0.88 - 2.03 ng/dL). Notably, the newborn screen for hypothyroidism was within normal limits, suggesting chronic autoimmune thyroiditis instead of congenital thyroid dysgenesis.

Conclusions: This case report provides insights into autoimmune thyroiditis in infancy, which, although especially rare under age 3 years, should be considered in infants who present with autoimmunity or abnormal thyroid testing. In the neonatal period, infants’ immune systems are learning to discriminate requirements for self-tolerance versus protection against pathogens and may be more prone to infections. Although autoimmunity in this stage of development is uncommon, there can be breakthroughs in tolerance, as seen in this case. In addition to this patient, two other infants were seen with elevated TPO antibodies, diagnosed at 17 and 31 months old, with similar clinical trends. There remains a need for additional studies providing further insights into autoimmunity in infancy. Importantly, this case illustrates that, when infants have abnormal thyroid levels (with or without other autoimmune conditions), consideration should be made for anti-thyroid antibody testing.
Cortisol and Aldosterone Adrenocortical Mass in a Previously Healthy Pediatric Patient
Authors: Burdea Liliana , Jo Inha , Boucher-Berry Claudia Cheryl
Published: May 2021

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 (<6), and elevated aldosterone to renin ratio of 92. The morning cortisol level of 7.7 ug/dL (6.7-22.6), with a 24-urine cortisol level elevated at 70.2 ug/d (<56.0). Low dose and high dose Dexamethasone suppression tests were performed, and the morning cortisol was not suppressed, pointing more towards hypercortisolism from the adrenal gland. ACTH levels were found to be suppressed as well. Due to concerns of possible adrenal crisis during or after surgery, the patient was started on stress dose steroids and then tapered off after several weeks. Patient underwent laparoscopic removal of the mass and right adrenal gland with uncomplicated postsurgey period. Pathology showed an adrenal cortical tumor 6 cm/68gm, indeterminate for malignancy versus benign. Extensive genetic studies revealed that patient was heterozygous for the p.N560(c/1679A>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.
Multiple Concomitant Episodes of Diabetic Ketoacidosis and Acute Pancreatitis in a Pediatric Patient With Type 1 Diabetes
Authors: Patel Aashka , Larsen Nicole , Burdea Liliana , Mantis Stelios , Minutti Carla
Published: May 2021

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.
Novel Heterozygous Calcium Sensing Receptor (CASR) Genetic Variant in Child with Unique Phenotype: Hypocalcemia, Mandibular Hypoplasia, Renal Cysts and Type E Brachydactyly
Authors: Legro Nicole , Kees-Folts Deborah , Ladda Roger , Huerta-Saenz Lina
Published: May 2021

Background: There are over 230 disease-causing variants in the calcium-sensing receptor gene (CaSR). Gain-of-function missense mutations in CaSR cause Autosomal Dominant Hypocalcemia (ADH) characterized by hypocalcemia (hCa), hypoparathyroidism (hPTH), and hypercalciuria. Patients with ADH are sensitive to fluctuations in serum calcium (Ca); and supplementation with Ca and vitamin D can cause inappropriate renal calcium retention leading to hypercalcemic events and long-term renal complications. Clinical Case: A 15-year-old adopted (at age 18 months) Korean female was initially diagnosed with hPTH and chronic hCa after presenting with hCa seizures. Laboratory values showed hCa (7.7 mg/dL), hyperphosphatemia (7.6 mg/dL) and hPTH (< 3 pg/mL.) Initially, she was treated with Ca supplementation (20 mg/kg/day elemental Ca), and calcitriol (0.01 mcg/kg/day). She presented at age 4 with hematuria and was found to have obstructive nephrolithiasis requiring operative intervention. Renal ultrasound (US) showed bilateral medullary nephrocalcinosis. She continued treatment with Ca and calcitriol. At age 6, a thiazide diuretic and potassium citrate supplement were added due to hypercalciuria. She had recurrent nephrolithiasis and persistent nephrocalcinosis. Follow-up renal US also showed bilateral renal cysts. Biweekly laboratory evaluation demonstrated an exuberant response to calcium supplementation. Serum Ca levels oscillated between 7.0 -10 mg/dL, but she showed minimal symptoms of hCa. At age 14, she was also recognized to have submandibular hypoplasia and brachydactyly of the 4th and 5th metacarpals and metatarsals bilaterally and genetic testing for CaSR gene mutation was requested. Sshe developed acute kidney injury and hypercalcemia, possibly precipitated by viral illness. However, 3 weeks before, calcitriol dose was increased to 1.25 mcg twice a day (0.07 mcg/kg/day). At admission, serum Ca was 12.7 mg/dL, iPTH 5.2 mg/dL, phosphorus 4.5 mg/dL, BUN 36 mg/dL, creatinine 1.85 mg/dL. Symptoms included headache, muscle spasm and throat spasm. She received intravenous fluids and recovered, but had an extended hospital stay. Targeted genetic analysis of the CaSR gene was completed, and identified a heterozygous variant (c.2506G>T, p.V836L) which is predicted to be likely pathogenic and cause ADH. After CaSR gene mutation identification, the calcitriol and also elemental Ca dosing were decreased to achieve a low Ca level (~7 mg/dL) with normal urine Ca/creatinine ratio. Patient remains asymptomatic. Conclusion: This is the first case of a novel mutation in the CaSR (c.2506G>T, p.V836L) associated with ADH, brachydactyly, renal cysts, and mandibular hypoplasia. Timely genetic testing for ADH in patients with newly diagnosed hPTH can lead to changes in therapy and improved prognosis.
Pediatric Giant Prolactinoma Presenting With Acute Obstructive Hydrocephalus and Intracranial Hypertension
Authors: Hendrix Grace , Benjamin Robert , MacIver Nancie J , Barboriak Daniel P , Balikcioglu Pinar Gumus
Published: May 2021

Background: Pediatric prolactinomas (PP) are rare but represent 50% of all pediatric pituitary adenomas. Girls are affected more frequently than boys, although PP tend to be larger and more aggressive (earlier age, larger mass, and higher prolactin levels) in boys. Thus, microadenomas (tumors < 10 mm in diameter) are typical in females and macroadenomas (10–40 mm in diameter) are typical in males. Giant prolactinomas (> 40 mm in maximum diameter), an unusual subset of macroprolactinomas, are also commonly found in boys. In a large case series, the largest tumor volume reported was 93.5 cm3. Here we report a giant prolactinoma in a female requiring V/P shunt for decompression. Clinical Case: A 16-year old female presented with 2 weeks of intractable headache, nausea and vomiting, vision impairment, and changes in balance described as running into stationary household objects. Historical review revealed primary amenorrhea and short stature. On initial exam, the patient had a right eye afferent pupillary defect, concern for loss of color vision, and bilateral optic nerve edema with blurred disc margins. Brain MRI showed a large lobulated mass centered in the suprasellar cistern, measuring approximately 6.4 x 5.8 x 5.7 cm with a tumor volume of 105 cm3. There was extension superiorly, anteriorly, and laterally, with homogeneously enhancing and cystic components, and mass effect resulting in obstructive hydrocephalus. Differential diagnoses included craniopharyngioma, germinoma, and adenoma. Initial tests demonstrated prolactin of >2,000 ng/mL, with diluted result of 17,811.16 ng/mL. Morning fasting labs confirmed multiple anterior pituitary hormone deficiencies including central hypothyroidism, ACTH deficiency, GH deficiency, and hypogonadotropic hypogonadism. The patient was started on hydrocortisone and levothyroxine. Due to obstructive hydrocephalus and vision impairment, she underwent VP shunt placement for decompression. She was started on cabergoline for medical treatment of the tumor and did not require surgical resection. Repeat prolactin measurements have shown striking improvement (to 2,350 ng/ml, 824 ng/ml, and 152 ng/ml at 1 week, 1-month, and 2-month-follow-up, respectively) with central vision improved in both eyes, papilledema resolved, and resolution of headaches. Conclusion: Giant prolactinomas presenting with hydrocephalus and intracranial hypertension are very rare in pediatrics, especially in girls, and can vary greatly in mass characteristics and resulting hormone deficiencies. Our patient is unique with her large tumor volume and the extent of pituitary hormone deficiencies. Prolactin levels should be measured with all sellar masses, as this may prevent unnecessary invasive intervention and possibly provide prompt response to medical management.
Clinical Features and Remission Rate of Pediatric Graves’ Hyperthyroidism Treated With Antithyroid Drug
Authors: You Kyusang , Kim Goo Lyeon , Yu Jeesuk
Published: May 2021

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<0.05). There was no significant difference in the presence of goiter or exophthalmos between two groups (goiter 95.5% vs 96.3%; exophthalmos 18% vs. 30%). Incidence rate of hypothyroidism during treatment was also not statistically different between the groups (36% vs. 19%). Age at onset, recent age, initial levels of T3, free T4 or TSH, and the presence of anti-thyroglobulin antibody or anti-thyroid peroxidase antibody were not significantly different between the groups. In contrast, initial levels of TSH receptor antibody was significantly lower in the group with remission (15.6±9.7 IU/L vs. 26.2±14.7 IU/L, p=0.004). Conclusion: This study showed that the remission rate was 45% during the treatment duration of 5 years. Initial titer of TSH receptor antibody was the most important factor associated with the remission in the pediatric Graves’ hyperthyroidism.
Efficacy of Levothyroxine on the Frequency and Severity of Migraine in Children with Subclinical Hypothyroidism
Authors: Hayes Dorado Juan Pablo
Published: May 2021

Introduction: Migraine is the most frequent primary intermittent headache in children. Hypothyroidism can exacerbate primary headaches and be a risk factor for persistent headache. Subclinical hypothyroidism is diagnosed when the level of TSH is high and the plasma concentration of free T4 is normal. Objective: To evaluate the efficacy of levothyroxine in the frequency and severity of migraine in children with subclinical hypothyroidism. Materials and methods:Prospective, observational and analytical study. Pediatric patients with a diagnosis of migraine and subclinical hypothyroidism (TSH >4.5 mU/L and normal concentration of free T4). Exclusion criteria: Hemiplegic migraine, basilar, retinal migraine, periodic childhood syndromes, epilepsy, asthma, diabetes mellitus, nephropathy, liver disease, previously diagnosed thyroid disease. Evaluation (for six months) of the frequency (monthly) and severity (severity score) of migraine in children with subclinical hypothyroidism treated with levothyroxine, during three months. Results: Patients attended: 31; excluded: 14; studied: 17 (9 girls). Age: 11.2 + - 1.89 years. The monthly frequency of migraine before treatment with levothyroxine was 14.75 + - 4.1 and after therapy, 5.39 + - 2.1 (p = 0.001); migraine severity score before treatment was 7.2 + - 1.2 and after therapy, 4.05 + - 1.31 (p = 0.001). Conclusions:Levothyroxine therapy in children with migraine and subclinical hypothyroidism was effective in decreasing the frequency and intensity of migraine in patients.