bluuebunny/crossref_metadata_2025_split huggingface dataset:
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

Abstract
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 &lt; 10 mm in diameter) are typical in females and macroadenomas (10–40 mm in diameter) are typical in males. Giant prolactinomas (&gt; 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 &gt;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

Abstract
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&lt;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

Abstract
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 &gt;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.
Growth Patterns in Children With Multiple Endocrine Neoplasia Type 2B: Small Stature in Childhood
Authors: van den Broek Medard F M , van Santen Hanneke M , Valk Gerlof D , Verrijn Stuart Annemarie A 
Published: May 2021

Abstract
Background: Multiple Endocrine Neoplasia 2B (MEN2B) is characterized by medullary thyroid carcinoma (MTC) before the age of one, pheochromocytoma and several non-endocrine manifestations. Marfanoid habitus is considered to be an important related feature, leading to the assumption that children with MEN2B have a tall stature. However, very little is known about actual growth patterns in children with MEN2B and its implication for final height.
Aim: To describe the growth patterns during childhood and adolescence and relate final height to target height (TH) in MEN2B patients.
Methods: Growth during childhood was investigated in eight patients with MEN2B under care in a Dutch MEN expertise center. Growth charts were assessed in relation to parental height, age at diagnosis and at thyroidectomy, body mass index (BMI), pubertal development and extensiveness of disease manifestations.
Results: Four out of eight patients showed longitudinal growth below their TH range. Three others showed prepubertal growth in the lowest margin of their TH range. Small stature was accompanied by delayed bone maturation. Arm span to height ratio was not increased in any of the (six) patients studied. All four patients who reached adulthood attained final height within their TH range, despite small stature during childhood. Small stature in childhood was not associated with age at diagnosis, age at thyroidectomy, extensiveness of MTC, BMI or endocrine deficiencies.
Conclusions: Children with MEN2B did not present with marfanoid features regarding height or arm span. In contrary, short stature may be prevalent, with longitudinal growth beneath the individual TH range. Nevertheless, a normal final height within the TH range may well be reached. Growth patterns seem to be independent of both age at diagnosis and thyroidectomy as well as disease severity.
The Functional Glomerulosa Cells Define the Unicity of the Adult Human Adrenal Cortex
Authors: Camponova Pamela , Duparc Céline , Roy Malanie , Lefebvre Herve , Thomas Michael 
Published: May 2021

Abstract
The zonation of the human adrenal cortex has long been established morphologically and histologically as three distinct layers of cells. The outer zona glomerulosa (ZG) comprises densely packed cells arranged in clusters that produce aldosterone; the zona fasciculata (ZF) is composed of cells with large cytoplasm, containing lipid droplets arranged in radial columns that synthetize cortisol; and the zona reticularis is composed of compact and pigmented cells producing androgens. The main purpose of this work was to study the expression of aldosterone synthase (CYP11B2 which catalyzes the last steps of aldosterone synthesis) and 11β-hydroxylase (CYP11B1 which catalyzes the last step of cortisol synthesis) in normal adrenal glands to address issues regarding the zonation and the fate of the cells constitutive of each zone through the expression of Ki-67 and cleaved Caspase-3. Thirty eight normal human adrenals (16 females, 22 males, ranging in age from 22 to 81 years old with a median age of 52 years old) were obtained from brain-dead organ donors (kindly provided by the Organ Transplant Clinics, University Hospital of Rouen). As early as 22 years old, we found that the histological ZG (h-ZG) does not correspond to the functional ZG (f-ZG) expressing CYP11B2. Moreover, the h-ZG CYP11B2- cells were CYP11B1+ showing that these cells ascribed to the h-ZG are in fact cortisol producing cells. The progressive replacement of CYP11B2+ cells by CYP11B1+ cells in the h-ZG might demonstrate the role of the extracellular matrix in the morphological maintenance of the adrenal cortex. Our analysis also showed that steroidogenic cells were either CYP11B1 or CYP11B2 positive. By immunofluorescence, we observed in many cases isolated or clusters of CYP11B2+ cells located deeply in the h-ZF and sometimes in the vicinity of the central vein. We were able to show that those cells were probably issued from CYP11B2+ cell clusters located in h-ZG which migrated centripetally. Ki-67 immunoreactivity was highly variable and observed throughout the entire cortex. We also found a positive correlation between the steroidogenic and endothelial cells proliferation. It is interesting to note that some Ki-67+ cells located in the h-ZG were CYP11B1+. Cortical cells positive for cleaved Caspase-3 were extremely rare but detected in all zones when present. These findings challenge the classic view of lineage conversion of differentiated ZG cells and show a new pathway where the CYP11B2+ cells migrate without changing their phenotype.
Novel Pathogenic Variants in LHX3, LHX4 and GLI2 Identified in Pediatric Patients With Congenital Hypopituitarism: From Variant Calling To Variant Testing
Authors: Vishnopolska Sebastian , Mercogliano María Florencia , Camilletti Maria Andrea , Mortensen Amanda Helen , Braslavsky Debora Giselle , Keselman Ana Claudia , Bergada Ignacio , Marino Roxana Marcela , Ramirez Pablo , Garrido Natalia Perez , Ciaccio Marta , Di Palma María Isabel , Belgorosky Alicia , Miras Mirta , Nicola Juan Pablo , Marti Marcelo , Kitzman Jacob , Camper Sally Ann , Perez-Millan Maria Ines 
Published: May 2021

Abstract
Congenital hypopituitarism (CH), septo-optic dysplasia (SOD), and holoprosencephaly (HPE) constitute an important group of structural birth defects that cause significant morbidity and life-long consequences for quality of life and care. The genetic causes are highly overlapping. As such, these disorders can be considered as a spectrum of related disorders. Improved insight into genetic causes would be valuable for patients, families, and medical geneticists. Very few systematic genetic screens have been carried out for patients with CH. We implemented genetic screening using single-molecule molecular inversion probes sequencing to identify causative mutations in a set of 67 genes previously reported in CH patients and the spectrum encompassing SOD and HPE. We captured genomic DNA from 170 Argentinean pediatric patients with CH, and 54% of the patients in this cohort have craniofacial, ophthalmologic, and/or central nervous system defects. We found candidate pathogenic, likely pathogenic and variants uncertain significance (VUS) in 23% of the cases. In order to evaluate the functional consequences of VUS in LHX3, LHX4, and GLI2, we performed in-vitro functional assays to study the activity of the mutated proteins. To test LHX3/4 variants we co-transfected HEK293T cells with wild type (WT) or mutated LHX3/4 variant plasmids and luciferase reporter genes driven by the ɑGSU promoter or GH1 promoter and assayed for luciferase activity. For GLI2 functional analysis we used the cell line NIH/3T3-CG, stably transfected to express GFP under the presence of GLI2 activated form. Endogenous Gli2 was knocked out by CRISPR-Cas9 and clones were selected for absence of GFP expression upon activation of the sonic hedgehog pathway. We tested the ability of transfected WT or mutated GLI2 expression plasmids to restore GFP fluorescence. We concluded that variants LHX3:p.Pro187Ser LHX4:p.Arg84His, p.Gln100His and p.Trp204Leu and GLI2:p.1404Lfs impair activation of the reporter gene, while the LHX3:p.Leu220Met and GLI2:p.L761P have WT activity on their respective assays. Identification of disease-causing variants in CH is complicated by phenotypic variation, incomplete penetrance, and VUS. Functional testing of potentially pathogenic variants is critical to arrive at a definitive molecular diagnosis. A full catalogue of variant effects in known causative genes would be invaluable for clinicians in order to simplify the interpretation of novel variants and reduce the diagnostic odyssey that families often experience.
Are Vitamin D Deficiency and VDR Gene Polymorphisms Associated With Higher Blood Pressure Defined by the 2017 ACC/AHA in Postmenopausal Women?
Authors: dos Santos Betânia Rodrigues , Casanova Gislaine , Silva Thaís Rasia , Marchesan Lucas Bandeira , Oppermann Karen , Spritzer Poli Mara 
Published: May 2021

Abstract
Postmenopausal status has been associated with an unfavorable phenotype tied to hormonal and metabolic changes, which collectively could contribute to an increased risk of cardiovascular disease. Vitamin D deficiency is frequent in postmenopausal women and may be linked to this phenotype and especially to an increased risk of developing hypertension. Vitamin D actions are modulated by the vitamin D receptor (VDR), and metabolic abnormalities have been associated with VDR gene variants in different populations. The aims of the present study were to assess the vitamin D levels, prevalence of vitamin D deficiency and genotypes of Fok-I, Bsm-I, Apa-I and Taq-I polymorphisms in the VDR gene and to determine whether vitamin D deficiency and VDR gene variants are associated with blood pressure levels and systemic arterial hypertension by the 2017 ACC/AHA definition in postmenopausal women. We conducted a cross-sectional study of biobanked blood samples from 339 postmenopausal women with no evidence of clinical disease. Blood pressure strata were defined according to the 2017 ACC/AHA cutoffs. Circulating 25(OH)D levels were considered deficient if &lt;20 ng/mL. Genotype analysis was performed by RT-PCR with allelic discrimination assays. Mean serum total 25(OH)D levels were 22.99±8.54 ng/mL, and 40.1% of participants were deficient in vitamin D. Overall, 7.7% had elevated blood pressure, 36.6% had stage 1 and 37.8% had stage 2 hypertension. Mean total (p=0.014) and free 25(OH)D levels (p=0.029) were lower in women with stage 2 hypertension than in those with normal blood pressure. The CC+CT genotypes of Bsm-I and the AA+AG genotypes of Taq-I polymorphisms were more frequent in women with stage 2 hypertension (Bsm-I CC+CT: 85.8% vs. TT: 14.2%, p=0.045; Taq-I AA+AG: 91.3% vs. GG: 8.7%, p=0.021). A higher prevalence ratio of stage 2 hypertension was associated with age (PR 1.058; 95%CI 1.033-1.083; p&lt;0.001), BMI (PR 1.046; 95%CI 1.025-1.068; p&lt;0.001), vitamin D deficiency (PR 1.333; 95%CI 1.016-1.749; p=0.038) and Taq-I polymorphism (PR 1.764; 95%CI 1.030-3.019; p=0.039). Women with vitamin D deficiency and the AA+AG genotype of Taq-I polymorphism were 33% and 76% more likely to have stage 2 hypertension, respectively, but these analyses lost significance when adjusted for age and BMI. In conclusion, the present results suggest that vitamin D deficiency and Taq-I polymorphism are associated with stage 2 hypertension, depending on age and BMI, in postmenopausal women.
Cross-Method Comparison of Serum Androstenedione Measurement Using Three Different Assays: The Siemens Immulite Immunoassay, the Roche Elecsys Immunoassay, and an LC/MS-MS Assay
Authors: Wei Ruhan , Bowers Kathleen , Kroner Grace M , Payto Drew , Franco Jessica Colon 
Published: May 2021

Abstract
Introduction: Androstenedione is a common precursor of male and female sex hormones produced by the adrenal glands and gonads. Serum androstenedione is a helpful biomarker in the diagnostic workup of a subset of patients with polycystic ovary syndrome (PCOS), the investigation of virilizing endocrinopathies, and for monitoring pediatric patients with congenital adrenal hyperplasia. The gold standard for the measurement of androstenedione is LC-MS/MS. A newly developed androstenedione competitive immunoassay is now available in the US, the Roche Elecsys Androstenedione (ASD) immunoassay. Until recently, the Siemens Immulite assay was the only non-radioimmunologic immunoassay available. We characterized the analytical and clinical performance of the ASD across different patient populations and in comparison to the Immulite and an LC-MS/MS assay. Methods and materials: The experiments performed were: linearity and analytical measuring range (AMR), precision (intra- and inter-assay), and accuracy. Androstenedione was measured on de-identified residual serum samples (n=40) using the ASD and Immulite immunoassays and an LC-MS/MS assay. The reference intervals (RIs) provided by Roche for healthy male (0.280-1.52 ng/mL), healthy female (0.490-1.31 ng/mL), postmenopausal women (0.187-1.07 ng/mL), healthy children (&lt;0.519 ng/mL), and patients with PCOS (0.645-3.47 ng/mL) were verified with at least 20 specimens, according to CLSI C28A3. Statistical analysis was performed using EP Evaluator and R program. Results: The ASD had a linear response across the AMR of 0.3 to 10.0 ng/mL. The inter- and intra-assay coefficients of variation were 4.5% and 2.0% or lower, at concentrations 0.5-6.7 ng/mL, respectively. The ASD and LC-MS/MS assays had a mean bias of -0.0542 ng/mL (-2%), Deming regression of y = 1.000 [0.961; 1.039] x - 0.0548 [-0.1806; 0.0709], and r = 0.9930. The Immulite assay had a mean bias of 1.15 ng/mL (44%) and 1.22 ng/mL (32%) compared to the LC-MS/MS and ASD assays, respectively. The recommended RIs from Roche for healthy male, female, and postmenopausal female groups were successfully verified in our patient population. However, the androstenedione concentrations for the healthy children and PCOS groups were outside of the suggested RIs, with concentrations up to 1.41 ng/mL and 0.527-2.24 ng/mL, respectively. Unlike published elsewhere, hormone therapies such as contraceptive pills and steroid treatments did not significantly affect serum androstenedione concentrations in healthy females and patients with PCOS. Conclusion: The ASD is superior to the Immulite immunoassay, and it has excellent comparability with the LC-MS/MS for serum androstenedione measurement. The RIs published by Roche may not be universally transferable; verification is recommended, and establishing RIs for the pediatric population may be necessary.