bluuebunny/crossref_metadata_2025_split huggingface dataset:
A Case Series of Four Preterm Intrauterine Growth Restricted Babies With Transient Hyper-Insulinemic Hypoglycemia and Cholestasis
Authors: Rana Pratibha , Rodrigues Megan , Mahajan Chaitali N , Nyp Michael F , Vishal Pandey 
Published: May 2021

Abstract
Background: Premature infants with intrauterine growth restriction (IUGR) are predisposed to stress related hyper Insulinemic hypoglycemia (HIH). These babies are at risk for other prematurity related complications including direct hyperbilirubinemia. However, association of HIH with this has not been described, and transient cholestasis in HIH infants has not been reported. We present 4 such infants with perinatal stress related HIH who had cholestasis that resolved with time. Case series: In our retrospective review of these preemies with IUGR who had developed HIH, we found that 4 infants developed direct hyperbilirubinemia. Their gestational ages at birth ranged between 26 to 27 weeks, with birth weights between 527 to 642 grams. These infants had received total parenteral nutrition (TPN) for durations ranging between 12 to 19 days of life (DOL). HIH was established in them at variable ages between 55 to 75 DOL, based on an exaggerated glycemic response to glucagon. Of these, 1 baby was not started on Diazoxide due to underlying fluid overload. His HIH resolved by DOL 182. Two babies responded to therapy and while one remained on this till its resolution at 9 months age, another had the Diazoxide discontinued due to acute respiratory worsening leading to readmission. HIH in the latter resolved by 109 DOL. Fasting The last baby developed fluid overload early in therapy leading to its discontinuation without establishing response. Hypoglycemia in these infants resolved by ages between 4 to 9 months of life. Interestingly direct hyperbilirubinemia was noted by age 16 to 59 DOL. In all infants, the diagnosis of HIH was established after the onset of cholestasis. Extensive work up for hyperbilirubinemia ruled out any organic pathology. This transient cholestasis was noted to have resolved by ages 80 to 115 DOL. Conclusion: It appears from our experience in these premature infants, cholestasis may be associated with HIH. Its diagnosis preceded the establishment of HIH. We noted that HIH diagnosis was delayed by around 30 days after the onset of intermittent hypoglycemia. Both the cholestasis and HIH were transient. Whether the cholestasis may prognosticate the development of HIH or is indicative of transient HIH needs to be investigated. Any association between the two needs to be studied to address a common causality. IUGR babies with conjugated hyperbilirubinemia develop a mild and transient HI state which is self-resolving. Due to transient nature of this HIH in these IUGR babies with cholestasis, a genetic work up for HIH may be deferred.
Involvement of JAK-STAT-SOCS3 Pathway in the Regression of Mice X-Zone of Adrenal Cortex
Authors: Auricino Thais Barabba , Bento Eduarda Correa , Pacicco Lotfi Claudimara Ferini 
Published: May 2021

Abstract
Previously, we showed that the histological markers of the mice X-zone of adrenal cortex were still present in adult male and female postpartum SF1/SOCS3KO mice. Abnormal distribution of lipid droplets along the adrenal cortex and reduced ACTH-induced corticosterone secretion were observed in SF1/SOCS3KO mice (1). Here we have examined the adrenals of the SF1/SOCS3KO male and virgin female at 3, 8, 15 and 30 weeks through morphological and molecular analysis. Hematoxylin-eosin stains showed X-zone retention in the SF1/SOCS3KO mice adrenals regardless of the postnatal age analyzed. CYP17A1-positive cells were immunolocalized in the X-zone of SF1/SOCS3KO mice that were confirmed by immunoblotting. A fetal adrenal enhancer (FAdE) and Pik3c2g and 20αHSD genes expression were analyzed by RT-PCR, and these genes were present in the male SF1/SOCS3KO mice up to the age of 8 and 15 weeks, but not in the control mice. Therefore, we showed retention of X-zone in the adrenal cortex of SOCS3KO mice up to the age of 30 week, which suggest the involvement of JAK/STAT/SOCS3 signaling pathway in the differentiation process of adrenal cortex. Reference: (1) Pedroso et al., J Endocrinol.2017 Dec;235(3):207–222.
Challenges in the Diagnosis and Consequential Management of Patients 46, XY DSD
Authors: Berrezueta Paula Espinoza , Ejaz Sehar , Bakhsh Ismaeel 
Published: May 2021

Abstract
Background: Disorders of sex development (DSD) are clinical conditions that cause an incongruity between the chromosomal and phenotypic sex of an individual. A high variable group of congenital disorders can arise depending upon the timing and location of defect involved in sex determination and differentiation. 46, XY DSD occurs in 1:20,0000 male births; with external genitalia ranging from ambiguous to normal female. Such conditions can be psychologically stressful for patients and their families and have been historically difficult to diagnose, especially at genetic level. Failure to diagnose exact mutation may make the therapeutic approach, genetic counseling and risk assessment even more challenging. Clinical case: Full term baby is born to non -consanguineous parents after an uneventful pregnancy. Mother denied any history of acne/hirsutism, hormone or substance use during pregnancy. At birth, external genitalia showed non-rugated labia majora with posterior fusion, absence of labia minora and vaginal opening. Enlarged clitoris/ Penile like structure measuring 1.5 cm with palpable corpora and hypospadias was present. No palpable gonads were appreciated. No other dysmorphic features were present and rest of the physical exam was unremarkable. Cosyntropin stim test on day 4 of life showed appropriate adrenal response. Pelvic ultrasound and MRI showed an elongated structure posterior to the bladder presumably uterus with no identifiable gonads. Chromosome analysis revealed an XY karyotype. FISH for SRY and microarray were unremarkable. Further testing at 4 weeks of life showed sub optimal elevation of Gonadotropins and Testosterone. Female gender was assigned due to parents’ preference and endocrine/ Urology recommendations. The 46,XY DSD genetic panel including testing for non-syndromic DSD, steroid abnormalities, skeletal dysplasia syndromes, and multiple malformation syndromes was unremarkable. Conclusion: Although a number of cytogenetic or single-gene defects have been associated with DSD, the true incidence of pathogenic variants has not been established. Many cases of 46, XY DSD remain unexplained likely due to an unidentified pathogenic variant of genes not routinely included in the panel or not yet identified to be associated with DSD. Without a clear diagnosis, genetic counseling and risk assessment is difficult. Parents should be informed about future options regarding sexual development, hormonal therapy and surgical treatments available. The determination of social sex must be made in consideration of underlying possible etiology, phenotypic sex, ethnic traditions, sexual identity and the acceptance of the assigned social sex by the parents. The affected child and his/her family must be followed throughout life to determine the patient’s adjustment to his/her social sex.
Mutational Profile of Metastatic Pheochromocytoma and Paraganglioma
Authors: Choi Yun Mi , Lim Jinyeong , Jeon Min Ji , Lee Yu-Mi , Sung Tae-Yon , Hong Eun-Gyoung , Lee Ji-Young , Jang Se Jin , Kim Won Gu , Song Dong Eun , Chun Sung-Min 
Published: May 2021

Abstract
Background: In pheochromocytoma and paraganglioma (PPGL), germline and somatic mutations in one of the known susceptibility genes are present in about 60% of tumors. However, the genetic events that drive the malignant progression of the disease are yet poorly understood. We aimed to evaluate the mutational profiles of metastatic PPGLs by targeted next-generation sequencing (NGS) to characterize the genetic events in metastatic PPGLs. Methods: Among the previously reported metastatic PPGL series from Asan Medical Center (AMC), Seoul, Korea, fifteen patients with available formalin-fixed, paraffin embedded (FFPE) archival samples for targeted exome sequencing were enrolled in this study. We also analyzed accessible data of aggressive PPGLs from The Cancer Genome Atlas (TCGA) and compared with findings of AMC samples. Results: A total of 115 germline and 34 somatic variants were identified in AMC cohort. Tumors of AMC cohort had median 0.58 per megabase tumor mutation burden. Most frequently mutated mutations were SDHB germline mutation (27%), and SETD2, NF1, HRAS somatic mutations (13%). Genes are subtyped into pseudohypoxia group (n=5), kinase group (n=5) and unknown (n=5) group. In unknown subgroup, two samples showed ATRX mutations and one accompanied SETD2 mutation. In copy number variation analysis, the most frequently observed pattern was deletion of 1p arm where SDHB is present. In survival analysis, SDHB mutation and pseudohypoxia subtype was significantly associated with poor prognosis. Conclusion: The analysis of NGS from patients with metastatic PPGLs demonstrated rare genetic events as well as well-known mutations. The pseudohypoxia subtype presented poor prognosis than kinase or unknown subtypes. Subjects who had no deletion in 1p arm showed favorable treatment response. Further studies to discover driver events and markers of metastasis are warranted.
Mitotane in the Treatment of Adrenocortical Carcinoma: Metabolic and Endocrine Disruption
Authors: Cortez Samuel , Sprague Jennifer Eryn , McNerney Kyle 
Published: May 2021

Abstract
Background: Mitotane is a well-known adrenocytolitic agent resulting in adrenal insufficiency. However, little is known about its multiple and complex metabolic and endocrine effects.
Clinical Case: Patient is a 6 year 9 month old female who presented with acne, pubic hair and rapid weight gain. Initial evaluation showed elevated testosterone (64 ng/dL), 17-OH-progesterone (236 ng/dL), DHEA-S (922 mcg/dL), and random cortisol (30.9 mcg/dL) with suppressed ACTH (&lt;2.0 pg/mL). She had an inappropriate lack of suppression after a 1 mg overnight dexamethasone suppression test (cortisol 49 mcg/dL, nl &lt;2 mcg/dL). Abdominal CT showed large necrotic-appearing right adrenal mass (10.7x8.8x15 cm) with no metastasis. Surgical excision was complicated by intraoperative rupture. Pathology confirmed stage III right adrenal cortical carcinoma. Patient was started on etoposide, cisplatin, doxorubicin, and mitotane as adjuvant therapy. 6 days after surgery, her DHEA-S and cortisol levels were undetectable. She was started on glucocorticoid replacement therapy with hydrocortisone at 18 mg/m2/day. Due to severe nausea, she was switched to dexamethasone 5 mg/m2/day (245 mg/m2/day dose equivalent to hydrocortisone). However, the patient developed hypotension, increased nausea and emesis and was switched back to hydrocortisone. The patient’s clinical course was complicated by hyperlipidemia with total cholesterol 215 mg/dL, HDL 48 mg/dL and LDL 150 mg/dL, as well as central hypothyroidism with low FT4 (0.8 ng/dL) and an inappropriately low normal TSH (0.31 mcIU/mL). She was started on levothyroxine with a final dose of 2.6mcg/kg/day to achieve euthyroid state. Mineralocorticoid deficiency has been reported in a small number of case reports of mitotane use. Our patient continues to demonstrate adequate mineralocorticoid function based on her normal electrolytes, aldosterone and plasma renin activity level.
Conclusion: Mitotane exerts multiple clinically relevant metabolic and endocrine effects. Patients treated with mitotane should be monitored for complications including mineralocorticoid deficiency, central hypothyroidism, and hyperlipidemia. Dexamethasone must be avoided because of the rapid inactivation by CYP4503A4 leading to adrenal crisis. Typical glucocorticoid replacement dose must be doubled due to induction of CYP3A4 activity that leads to glucocorticoid inactivation.
Successful Use of Intragastric Dextrose in a Unique Presentation of Congenital Hyperinsulinism
Authors: Gurnurkar Shilpa , Patel Unnati , Lord Katherine , Vyas Neha 
Published: May 2021

Abstract
Introduction: Congenital hyperinsulinism (HI) is the most common cause of persistent hypoglycemia in infants and can pose challenges if unresponsive to diazoxide. HI can be caused by monogenic mutations or can be associated with genetic syndromes. Macrocephaly Capillary malformation (MCAP) is a rare overgrowth syndrome, caused by heterozygous variants in the PIK3CA gene. A small number of pathologic variants in this gene have been reported to cause HI.
Clinical Case: A 4-month-old boy presented with a hypoglycemic seizure while fasting for an MRI. His history was notable for being born LGA and having macrocephaly, segmental infantile hemangioma, and ventriculomegaly requiring VP shunt. Critical labs were consistent with HI: plasma glucose (PG) of 23 mg/dL (54-117), inappropriately detectable insulin (2.7 mIU/mL) and c-peptide (1.6 ng/mL), low beta hydroxybutyrate (0.1 mmol/L) and low free fatty acids (0.16 mmol/L), and a positive glucagon stimulation test (increase in PG from 48 to 101 mg/dL in 30 minutes). Diazoxide was started at 5 mg/kg/day and titrated to 15 mg/kg/day, but he was unable to maintain PG &gt;70 mg/dL. He was deemed unresponsive and the diazoxide was discontinued. His intravenous glucose infusion rate (GIR) was 14.4 mg/kg/min. An octreotide trial (8 mcg/kg/day) revealed a robust response: PG 64 mg/dL before initial dose, 105 mg/dL 3 hours later. However, he developed tachyphylaxis to the octreotide and it was discontinued. To further evaluate the etiology of his HI, he underwent an 18F-DOPA PET scan, which showed diffuse uptake. Genetic sequencing for the 9 known HI genes was negative. At 6-months-old, he was evaluated by genetics who based on his clinical features diagnosed him with MCAP.
After failure of diazoxide and octreotide therapies, he was slowly transitioned from IV dextrose to continuous intragastric dextrose (IGD) using D20W. He was managed with a GIR of 10 mg/kg/min during the day (while receiving bolus feeds) and 5 mg/kg/min while on continuous feeds overnight. The continuous IGD allowed him to maintain euglycemia and develop his oral feeding skills. By 17-months-old, feeds by mouth improved and GIR had decreased to 6.5 mg/kg/min during the day and 2.5 mg/kg/min overnight. Genetic analysis eventually revealed a heterozygous p.Glu365Lys (c.1093 G&gt;A) variant in the PIK3CA gene as the likely cause of the HI.
Conclusion: Genetic syndromes should be considered in infants with persistent hyperinsulinism and multiple congenital anomalies. Clinical work-up may provide important clues to the diagnosis. Diazoxide unresponsive HI can be treated with continuous IGD to prevent hypoglycemia-induced brain damage. Continuous IGD likely leads to better oral skills and decreased oral aversion compared to using continuous formula feeds.
The “Eyes” Have It. Ophthalmological Findings of Bilateral Cataract in a Boy with Hypoparathyroidism
Authors: Ruan Juejue , Zhang Lei , Yang Jun , Feldt Matthew M , Yan Yun 
Published: May 2021

Abstract
Background: Hypoparathyroidism is a relatively rare pediatric endocrine disorder in which parathyroid hormone (PTH) production is low or absent, resulting in low serum calcium and high phosphorus. In children, hypoparathyroidism is either congenital or acquired and is often associated with a genetic syndrome. Clinical manifestations include neuromuscular hyperexcitability, tetany, cardiac arrhythmias, and seizure. Radiographic findings include basal ganglia calcifications. In adult literature, ophthalmological findings of lenticular opacities and cataract have also been reported in hypoparathyroidism. Due to the rarity of this condition, there is a paucity of ophthalmological findings in children. We report a pediatric case with severe hypocalcemia, recurrent generalize seizures, intracranial calcifications and bilaterally cataracts secondary to hypoparathyroidism. Case: A 7-year-old boy, from a remote area in China, presented to a local hospital with one-year history of paresthesia in hands and feet. Initial lab evaluation revealed hypocalcemia with serum calcium of 1.76 mmol/L (2.03-2.68). Oral calcium supplement was started but symptoms progressively worsened. He was transferred to a tertiary hospital for further evaluation. On admission, physical exam was significant for positive Chvostek and Trousseau signs and lab evaluation showed serum calcium: 1.28 mmol/L (2.15-2.57), phosphorus: 4.2 mmol/L (0.95-1.75), magnesium: 0.97 mmol/L (0.73-1.06), PTH: 2.2 pg/mL (8.7-79), and 25(OH)Vit D: 97.1 mmol/L (36-126). Multiple symmetrical calcifications were found in the frontal lobe and basal ganglia. Ophthalmology consultation revealed bilateral cataracts with impaired vision. Trio whole exome sequencing with copy number variation testing reveled no pathogenic or likely pathogenic copy number and sequence level variants. He was diagnosed with idiopathic acquired hypoparathyroidism. The seizure disorder, intracranial calcification, and bilateral cataracts were attributed to severe and prolonged hypocalcemia secondary to hypoparathyroidism. He had a second episode of seizure after he was admitted, and seizure resolved after treated with midazolam and IV calcium gluconate. He was started on 1,25 (OH)2 vitamin D. Clinical symptoms resolved and he became biochemically eucalcemic with titrated therapy. Summary: Although lenticular changes have been observed in adults with hypoparathyroidism since the 1950’s, hypoparathyroidism and resulting cataract formations are relatively rare. Proposed mechanism of cataract formation in hypoparathyroidism is prolonged hypocalcemia resulting in membrane damage in the aqueous humor and subsequent sodium content increase in the lens. To our knowledge there are no prior pediatric reports of cataracts associated with hypoparathyroidism and signifies the importance of ophthalmologic referral and evaluation.
Antenatal Markers Related to Fetal Growth Restriction Can Predict Childhood Systolic Blood Pressure
Authors: Perchard Reena , Garner Terence , Whatmore Andrew James , Stevens Adam , Higgins Lucy , Johnstone Edward , Clayton Peter Ellis 
Published: May 2021

Abstract
Background: Being born small for gestational age (SGA) is linked with higher systolic blood pressure (SBP). Fetuses with growth restriction (FGR) may be either SGA or appropriate size for gestational age at birth. However, it is not known which factors contributing to size at birth influence the relationship with SBP. Aim. To determine whether antenatal markers of FGR can predict the upper quartile of childhood SBP. Methods: Brachial SBP was measured for 75 children aged 3-6 years from the Manchester BabyGRO Study, using a Tensiomed®Arteriograph with a child-sized cuff. SBP quartiles were generated. Participants were born to mothers who had attended a specialised clinic, following identification of higher FGR risk based on abnormal maternal serology (pregnancy associated plasma protein-A, β-human chorionic gonadotrophin, α-fetoprotein, Inhibin-A). Antenatal ultrasound data at 23 weeks gestation were obtained. Uterine artery Doppler (UtAD) notching was assigned a rank (0=absent, 1=unilateral, 2=bilateral). Random forest (RF) is a machine learning approach that generates many independent, uncorrelated decision trees based on multiple variables. This was used to determine the relative importance of antenatal variables in prediction of upper quartile of childhood SBP. Variables included in the model were maternal body mass index (BMI), parity, ethnicity (black/white/asian/mixed), maternal SBP and diastolic BP (DBP), maternal serology relating to FGR risk, UtAD pulsatility index, resistance index and notching rank (all measures of uteroplacental blood flow resistance), placental size measurements, 23 week estimated fetal weight (EFW) centile, ∆23w EFW-birthweight centile and birthweight SDS. A receiver operating characteristic (ROC) curve was generated, providing an area under the curve (AUC). A variable of importance (VIP) score was calculated for each marker that was significant in the model. All analyses were conducted in R (version 3.6). Results: RF analysis demonstrated antenatal markers relating to FGR risk predict the upper quartile of childhood SBP with an AUC 0.97. The top five ranked variables were maternal DBP (VIP score 14.0), birthweight SDS (11.5), parity (9.9), notching rank (9.5) and ∆23w EFW-birthweight centile (9.1). Conclusion: Maternal and antenatal markers, as well as birthweight SDS are linked with the upper quartile of SBP at 3-6 years. Antenatal markers were within the top five ranked and could help identify those babies at risk of higher SBP in childhood.
Design and Baseline Demographics of a Five-Year, Multi-National Observational Cohort Study of Children With Achondroplasia (ACHieve Study)
Authors: Ward Leanne M , de Bergua Josep Maria , Robinson Marie-Eve , Zhang Ying , Decker Carl , Giwa Adebola , Charlton R William 
Published: May 2021

Abstract
Background: Achondroplasia (ACH) is the most common form of dwarfism occurring in 1 in 22,000 births (95% CI 18,500 to 26,000). This skeletal dysplasia is caused by a gain-of-function mutation in the fibroblast growth factor receptor 3 (FGFR3) gene located on chromosome 4p16.3 and results in sustained activation of the FGFR3 pathway leading to impaired chondrogenesis and endochondral bone formation. Both typical childhood growth patterns and the impaired linear growth of ACH are modulated by the delicate balance between growth-inhibiting FGFR3/mitogen-activated phosphokinase and growth-promoting c-type natriuretic peptide/natriuretic peptide receptor B.
Individuals with ACH frequently develop clinically significant comorbidities, many with onset during childhood. Currently, there are no therapies addressing the underlying pathology. Most available treatments are surgical with goals to alleviate the symptoms from specific comorbidities (i.e. foramen magnum and spinal stenosis or recurrent otitis media). Since the available therapies do not address the underlying etiology, individuals with ACH often undergo multiple surgeries and myriad other forms of supportive care throughout their lives. The precise timing of comorbidity onset and the natural history of many of the skeletal dysplasia features are incompletely defined. This information is needed to inform the design and conduct of pathology-targeted intervention studies.
Aim: The purpose of this study is to gather information about the precise timing of comorbidity onset, the longitudinal growth trajectory, and the evolution of body proportionality in children with ACH.
Methods and Future Results: The ACHieve study (NCT03875534) is a multi-center, longitudinal, observational cohort study in children with ACH from birth up to 8 years at enrollment. In this non-therapeutic study, children are evaluated every six months for up to 5 years in 25 centers from North America, Europe and Oceania. The first patient was enrolled in 2019 and a total of 84 children have been enrolled to date. At each assessment, children undergo comprehensive anthropometric studies, (including body proportionality measurements and recumbent or standing height) and information on the timing and nature of ACH-related comorbidities and their treatments are collected. Additional information about the baseline demographics, including sex, age distribution, race/ethnicity, and height standard deviation scores will be presented at the time of conference.
Conclusions: The ACHieve study will provide additional insight into the natural history of growth, body proportionality, and comorbidities in children with ACH. These observations will serve as a benchmark for future intervention trials targeting the pathology of the underlying skeletal dysplasia.