bluuebunny/crossref_metadata_2025_split huggingface dataset:
Steroid Cell NOS in a Child: A Rare Case Report
Authors: Paladugu Sridevi 
Published: May 2021

Abstract
Introduction: Steroid cell tumors are rare sex chord tumours of the ovary with malignant potential. Here we report a case of steroid cell NOS in a 12-year-old girl & similarity of the clinical presentation with non-classic congenital adrenal hyperplasia.
Clinical Case: 12-yr girl came with complaints of hirsutism since many years and a recent change in voice. There was no past history suggestive of adrenal crisis. On examination she had muscular body habitus, moderate hirsutism (FG score 19), acne. SMR B1, P4, A3. Karyotype 46 XX. BA 13yrs. DHEAS- 144, serum cortisol 8am-14ug/dl. Testosterone-8.35ng/ml (normal 0.1-0.9ng/ml). serum 17 (OH) Progesterone basal-16.37 ng/ml(N-0.2-1.3ng/ml). Post synacthen 17OHP &gt;35ng/ml, LH- &lt;0.1, FSH- 0.2(prepubertal range). U/S-adrenals normal, right ovary was enlarged in size, 4x3cm cystic lesion. A CECT ABDOMEN showed Rt ovary -homogenously enhancing fairly well-defined solid lesion. Differential diagnosis was: NC/SVCAH with ovarian rest tumours vs ovarian virilising tumour. Since there was no non-invasive way of confirming between both the diagnosis, we gave a trial with hydrocortisone to see if her 17OHP reduces. After 1 month of therapy with hydrocortisone,17 OHP was still elevated -17.08ng/ml. Since there was no response, she underwent ovarian biopsy/excision. Right ovarian cystectomy was done. HPE showed -consider1. Steroid cell tumour NOS 2. Adrenal rest tumour. Note that these 2 tumours have identical morphology & IHC features. Followup:2 mon post-surgery: B5 P4 A3, mild facial hair,17 OHP - 1.53 ng/ml, Testosterone 2.5 ng/dl.12 months post-surgery child attained menarche had regular menstrual cycles, Serum 17OHP- 0.41 ng/ml, testosterone-11ng/dl.
Conclusion: The usual differential diagnosis in 46 XX female children presenting with signs of androgen excess is CAH, it is not uncommon to find SVCAH presenting in childhood with symptoms & signs of virilisation. Clinically both SV CAH and Steroid cell tumours can present with hyperandrogenic features in the childhood. Amongst steroid cell tumours, 3 subtypes are seen, they include 1. stromal luteoma 2. Leydig cell tumour 3. steroid cell tumour NOS. The steroid cell tumours of the ovary secrete androstenedione, alpha hydroxy progesterone & testosterone .17OHP is raised in both the conditions. The HPE of both adrenal rest tumours & steroid cell NOS is similar & a clear-cut differentiation cannot be made. They are similar in clinical presentation, biochemistry & HPE. It is important to recognise that steroid cell tumour NOS is a differential to SVCAH in childhood. Since these tumours can occur at any age, clues to differentiate both conditions are-raised 17OHP but normal DHEAS & on imaging- normal adrenals with enlarged ovaries with or without solid cystic lesions in steroid cell NOS of the ovary.
Thyroid Hormone Resistance Syndrome Presenting as Exercise Induced Asthma
Authors: Umscheid Joshua D , Mitre Naim , Muhaisen Fadi Jamil Odeh Al 
Published: May 2021

Abstract
Background: Pathogenic variants in the thyroid hormone receptor (THRB) gene are associated with thyroid hormone resistance. Over 85% of the genetic mutations are in the beta TR gene. The disorder is characterized mainly by elevated thyroid hormone levels, unsuppressed levels of TSH, and goiter.
Clinical case: An 11-year-old male initially seen at the PCP office for tachycardia and chest discomfort, especially during school exercise. He reported shortness of breath. His symptoms will resolve at rest. He was diagnosed initially with asthma and was put on Singular, Pulmicort, and albuterol as needed. His symptoms did not improve with this treatment, and he reported symptoms worsened with albuterol. He had a normal Echocardiogram and chest X-ray. A mild goiter was noted on his physical exam. Thyroid ultrasound showed an enlarged thyroid gland. An ovoid echogenic focus in the inferior thyroid lobe measuring 4 X 7 X 8mm was identified. The nodule was wider than tall, with a solid appearance with no internal color flow. Evaluation in our clinic showed normal TSH at 1.624mcIU/mL (0.35-5.5). FT4 was high at 1.54ng/dL (0.82-1.40), and FT3 elevated at 6.3pg/mL (3.3-4.8). Thyroid antibodies and thyroid-stimulating immunoglobulin (TSI) were normal. A 24 hour I-123 thyroid uptake was approximately 55% (10-30%) with no focal increased or decreased uptake. Given his elevated thyroid hormone levels with unsuppressed TSH in the context of goiter and tachycardia, genetic testing for the Thyroid receptor gene was done. He was found to be heterozygous for a pathogenic variant in THRB, c.1286G&gt;A (p.Arg429Gln). This genotype is consistent with a diagnosis of autosomal dominant Thyroid hormone resistance. The patient was started on Atenolol, given his elevated heart rate, and he reported improvement in his symptoms during exercise.
Conclusion: Thyroid hormone resistance was first described as a clinical entity in 1967. The phenotype can vary among individuals. It is characterized by a reduced responsiveness of target tissue to thyroid hormone and binding affinity. The disease can present with goiter, behavioral issues, abnormal growth, and tachycardia. Affected individuals may have attention deficit-hyperactivity disorders (ADHD) and language difficulties. Thyroid hormone resistance can be misdiagnosed, as in our patient. He was diagnosed with asthma and was put on unnecessary medications that worsened his symptoms. Thyroid hormone resistance can also be misdiagnosed with Graves’ disease, given the elevated thyroid hormone. It is essential to highlight the importance of genetic testing in these cases, as an accurate diagnosis will prevent unnecessary treatments with potentially serious side effects.
Variable Clinical Presentation of Children With Hereditary Hypophosphatemic Rickets With Hypercalciuria: A Case Series
Authors: Christensen Stephanie , Tebben Peter J , Sas David , Creo Ana 
Published: May 2021

Abstract
Background: Hereditary Hypophosphatemic Rickets with Hypercalciuria (HHRH) is a rare condition of phosphate wasting due to variants in the SLC34A3 gene, encoding the sodium-phosphate cotransporter 2c (NaPi2c) at the brush border of proximal renal tubular cells (1). While labs are characterized by low serum phosphorus, high 1,25 dihydroxyvitamin D and inappropriately high levels of urine phosphate and calcium, the presenting symptoms can vary widely. Little remains known about specific phenotype-genotype correlations, especially in children. Clinical Cases: We report three new cases of HHRH in an unrelated 12 year-old male, 9 year-old female and 14 year-old male. All three patients were found to have low serum phosphorus for age (2.9-3.2 mg/dL), normocalcemia (9.4-9.9 mg/dL), low to low-normal parathyroid hormone (7-15 pg/mL), elevated 1,25 dihydroxyvitamin D (91-178 pg/mL), and hypercalciuria (4.5-7.6 mg/kg/day). Urine phosphorus was inappropriately elevated given the degree of their hypophosphatemia. Despite having similar lab findings, however, their clinical presentations were varied. The 12 year-old male presented with lower extremity pain, which was previously ascribed to patellofemoral pain syndrome. He had no history of renal symptoms, though a renal ultrasound later identified stones bilaterally. Conversely, the 9 year-old female and 14 year-old male presented with recurrent urinary stones and no bone symptoms. Genetic analyses identified 4 novel SLC34A3 gene mutations. Of interest, the 12 year-old male and 9 year-old female each shared a variant (c.575C-T (p.Ser192Leu)) despite having disparate symptoms. All three patients were treated with phosphorus supplementation and were advised to discontinue Vitamin D, if this had previously been prescribed. Conclusion: These three cases highlight the variability of presenting signs and symptoms among individuals with HHRH. Obtaining an accurate diagnosis is critical, as the addition of Vitamin D can seriously worsen symptoms in HHRH though it is a commonly used treatment for other disorders of phosphate wasting and bone demineralization. To aid in clinical decision making, we present a stepwise approach to the diagnosis of hypophosphatemic diseases. References: (1) Lorenz-Depiereux, B., Benet-Pages, A., Eckstein, G., Tenenbaum-Rakover, Y., Wagenstaller, J., Tiosano, D., Gershoni-Baruch, R., Albers, N., Lichtner, P., Schnabel, D., Hochberg, Z., Strom, T. Hereditary Hypophosphatemic Rickets with Hypercalciuria is caused by mutations in the sodium-phosphate cotransporter gene SLC34A3. Am. J. Hum. Genetic. 2006;78:193-201.
Brain Tumours Involving the Areas of the Circadian System Result in Disturbances in Melatonin Secretion, Fatigue and Poor Quality of Life
Authors: Pickering Line , Main Katharina M , Sehested Astrid , Mathiasen René , Feldt-Rasmussen Ulla , Klose Marianne C , Jennum Poul 
Published: May 2021

Abstract
Background: Sleep disturbances, circadian abnormalities and poor health are often reported in children with brain tumours. The objective of this study was to examine circadian function, sleep pattern, fatigue and mental health in these children. We hypothesized that children with tumours involving the areas of the circadian system have altered melatonin secretion.
Design: Cross-sectional study.
Methods: 309 children diagnosed with a tumour in the brain or cervical medulla and aged ≤18 years were identified, 174 met the inclusion criteria, and 68 consented to participate. They were divided according to their tumour location into 1) location involving the areas of the circadian system, i.e. diencephalon, pineal gland, brain stem and cervical medulla and 2) other areas. Sleep-wake patterns were assessed by two weeks of sleep diary recordings and actigraphy in 66 and 61 children, respectively. Diurnal saliva-melatonin levels were measured in 51 children. Sleep quality, fatigue and mental health were assessed in 65 children by Children’s Sleep Habits Questionnaire, Strengths and Difficulties Questionnaire and Pediatric Quality of Life Inventory, Multidimensional Fatigue Scale and Generic Core Scale.
Results: All children had normal sleep-wake patterns without significant between-group differences. The children with tumours involving the areas of the circadian system had lower melatonin peak levels (p=0.03) and a tendency of lower levels at 00 h and 04 h (all p=0.06). Three patterns of diurnal melatonin profiles were observed: Normal, low peak and phase-shifted peak. In comparison of the two patient groups, more children with tumours involving the areas of the circadian system had melatonin profiles with low peak values (29% vs 13%) and one had phase-shifted peak (3% vs 0%), although not significant. These children were more affected by mental problems (p&lt;0.01), more cognitive fatigued (p=0.03) and had poorer quality of life (p=0.01) than children with tumours located elsewhere.
Conclusion: Children with tumours affecting the areas of the circadian system including the diencephalon, pineal gland, brain stem and cervical medulla have altered melatonin secretion, are fatigued, have poor mental health and poor quality of life. Circadian disturbances may adversely affect health and have negative psychological impact.
Design of the ACcomplisH Trial: A Phase 2, Multicenter, Placebo-Controlled, Dose Escalation Trial Evaluating Safety, Efficacy, and Pharmacokinetics of Weekly TransCon CNP in Children With Achondroplasia
Authors: Savririyan Ravi , Zarate Yuri , Legare Janet M , Decker Carl , Giwa Adebola , Zhang Ying , Charlton R William , Beckert Michael 
Published: May 2021

Abstract
Background: Achondroplasia (ACH) is the most common skeletal dysplasia and the most frequent form of dwarfism. ACH is caused by a gain-of-function mutation in the fibroblast growth factor receptor 3 (FGFR3) gene and results in impairment of the endochondral ossification processes. C-type natriuretic peptide (CNP) promotes chondrocyte development through inhibition of the FGFR3 pathway, specifically through activation of NPRB. CNP is a desirable target as it is known to increase chondrocyte development without off-target effects (Bocciardi, 2007).
TransCon CNP is a long-acting prodrug of CNP designed to optimize safety and efficacy with a once-weekly dose. The Phase 1 clinical trial with TransCon CNP demonstrated that doses up to 150 μg CNP/kg were well-tolerated in healthy adult male volunteers, with no clinically significant trends observed in clinical laboratory assessments, vital sign measurements, ECG parameters, or physical examination findings.
Methods: The phase 2 ACcomplisH trial will be conducted at over 35 sites worldwide. The primary objective of the trial will be to evaluate the safety and efficacy of once-weekly TransCon CNP compared to placebo at 12 months in prepubertal children, aged 2-10 years old, with ACH. Approximately 60 subjects will be randomized 3:1 to receive either weekly TransCon CNP or placebo. Following screening and verification of clinical ACH with genetic confirmation, subjects will remain within the dose cohort for 52 weeks of treatment. TransCon CNP will be dosed 6 to 100 μg CNP/kg/week across 4 cohorts, with an optional 5th cohort at up to 200 μg CNP/kg/week. An independent Data Monitoring Committee will review safety data prior to initiation of a higher dose cohort.
The primary endpoint will evaluate annualized height velocity at 52 weeks of TransCon CNP or placebo. Key secondary endpoints will examine change in upper to lower body segment ratio at week 52, safety, pharmacokinetics (PK), and quality of life associated with weekly TransCon CNP.
Conclusion: CNP is targeted specifically to the underlying pathology of ACH through inhibition FGFR3. No effective medicinal product is currently available for the treatment of ACH. TransCon CNP is designed to provide sustained exposure of CNP. This ongoing Phase 2 ACcomplisH trial is designed to assess the efficacy, safety, and PK of TransCon CNP by weekly administration compared to placebo.
Evaluation of Methods That Estimate Glomerular Filtration Rate in Patients With Prader-Willi Syndrome
Authors: Ko Paul Jihoon , Ballal Shaila , Hirano Patricia , Cowen Neil 
Published: May 2021

Abstract
Background: Prader-Willi syndrome (PWS) is a rare, complex, multisystem disorder caused by the loss of multiple paternally expressed genes on chromosome 15q11-13 and is present in 1/15,000-30,000 individuals. Characteristics of PWS include low muscle mass and hypotonia, accumulation of excess body fat, short stature, hyperphagia, behavioral problems, cognitive disabilities, developmental delays, and hypogonadism. In these patients, serum creatinine (SCr)-based methods to calculate estimated glomerular filtration rate (eGFR) can lead to inaccurate results. eGFR is reported to be negatively correlated to muscle mass and PWS-associated low lean body mass may contribute to low SCr levels. Therefore, eGFR calculations may not accurately reflect PWS patient’s renal function. A more accurate, non-invasive, inexpensive means to monitor renal function for this patient population is desirable. Objective: To assess methods of estimating renal function in pediatric PWS patients and summarize the relationship between eGFR and patient-specific factors. Methods: The pre-treatment data of patients ≥4 years old with genetically confirmed PWS participating in an investigational study of DCCR (diazoxide choline) were evaluated. Lean body mass was measured using dual X-ray absorptiometry. Lean body mass and age were correlated to eGFR/creatinine clearance (CrCl) values calculated using four different equations: Bedside Schwartz (BS), Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI), Modification of Diet in Renal Disease (MDRD), and Cockcroft-Gault (C-G). Results: Of the 124 patients enrolled in the study, 99 were &lt;18 years old and 103 were taking growth hormone (GH). Mean SCr was below normal range at 0.52 mg/dL, with only two subjects (1.6%) having SCr in the normal range (0.84 to 1.21 mg/dL). eGFR calculated using BS was 120±22 mL/min/1.73m2; CKD-EPI 154±23 mL/min/1.73m2; MDRD 211±77 mL/min/1.73m2; and CrCl by C-G 191±80 mL/min. Among the three eGFR equations, CKD-EPI presented with the most reasonable eGFR values &lt;200 mL/min/1.73m2. When stratified by different age groups, SCr increased with age while eGFR decreased (and surprisingly CrCl by C-G increased). When correlating the eGFR values to various parameters, lean mass and age showed significant negative correlations with eGFR for BS, CKD-EPI, and MDRD. In contrast, for C-G there were significant positive correlations between CrCl and both lean mass and age. Conclusion: In PWS, the combination of low SCr and excess accumulation of body fat results in eGFR values that likely overestimate actual renal function in PWS patients. The inconsistent trends in correlation values between eGFR or CrCl by C-G and both lean mass and age indicate current SCr-based methods to estimate renal function in PWS may be inadequate. The use of CKD-EPI or other non-SCr-based methods to monitor renal function should be considered in PWS.
Prevalence Trends of Metabolic Syndrome Among Korean Children and Adolescents From 2007 to 2018
Authors: Kim Jihyun , Lim Jungsub 
Published: May 2021

Abstract
Background: The prevalence of metabolic syndrome (MetS) in adults is increasing worldwide. The change of cardiovascular structure associated with metabolic syndrome appears from childhood, it is crucial to detect MetS early, and control associated risk factors to protect future health. Methods: We used data of children and adolescents (8,718 subjects aged 10-18) from the National Health and Nutrition Survey IV-VII (KNHANES 2007-2018) to estimate the recent prevalence of MetS, and identify related nutritional factors. The definition of MetS used modified NCEP-ATP III and IDF criteria. Results: The prevalence of MetS among Korean adolescents in 2007-2018 was 4.6% using the modified NCEP-ATP III criteria, and the trend of MetS increased significantly (P trend=0.02). In the overweight and obese groups, the risk of MetS increased 7.079 (95% CI, 5.188-9.793) and 27.131 (95% CI, 20.896-35.240) compared to the normal-weight group. During KNHANES IV-VII, overall caloric intake increased, carbohydrate and sodium intake decreased, but fat intake increased (KNHANE-IV; 21.3% to VII; 24.0%, P &lt;0.001). These fat intakes were significantly correlated with an increase in systolic blood pressure, fasting blood glucose, and waist circumference. Conclusion: The prevalence of MetS is also increasing in Korean adolescents, and changes in dietary habits are related. In the future, it is also necessary to study the relationship with lifestyle.
The Effects of Conditioning Regimen on Thyroid Function After Hematopoietic Stem Cell Transplantation in Children: 2-Year Short Term Follow Up
Authors: Lee Nayeong , Kim Sungeun , Kim Seulki , Ahn Moon Bae , Kim Shin-Hee , Won-Kyoung Cho , Jung Min-Ho , Suh Byung-Kyu 
Published: May 2021

Abstract
Background: Long term effect of conditioning regimen such as Total body irradiation (TBI) and chemotherapy has been studied. However short term effect of conditioning regimen on endocrinologic system was not well known. Purpose. Our study aimed to evaluate the effect of conditioning regimen on thyroid function in children who had HSCT after 2 years. Methods:. Date was obtained from retrospective review of medical records who treated malignant hematologic disease and transplanted hematopoietic stem cell in Seoul St. Mary’s hospital from January 1, 2010 to August 31, 2018. Among 563 patients who underwent HSCT for about 9 years, we studied 150 patients who conforming to inclusion criteria of this study. Thyroid function was tested before HSCT and follow 12 and 24 months. Anthropometric date, duration of chemotherapy, history of relapse, graft versus host disease (GVHD) were also analyzed. Results: In patient’s characteristics, median age at HSCT was 10.49 (0.89 - 19.29) years. Out of 150 patients, male was 92 and female was 58. Acute lymphoid leukemia (ALL) was 74, acute myeloid leukemia (AML) was 76. Among them, busulfan based conditioning was done in 53 patients, TBI based conditioning regimen used in 72 and 25 patients had done TBI with busulfan based conditioning regimen. Fifteen patients (12.5%) had thyroid dysfunction after 2 years of HSCT (4 euthyroid sick syndrome, 11 subclinical hypothyroidism and 1 high T4 syndrome). Incidence of thyroid dysfunction by conditioning regimen was different at 2 years after HSCT, higher in TBI with busulfan based group (p = 0.033). In univariate regression analysis, using conditioning regimen, by TBI with busulfan was risk factor of thyroid dysfunction at 2 years after HSCT. Conclusions: TBI with busulfan based group showed higher incidence of thyroid dysfunction and conditioning regimen was risk factor of thyroid dysfunction at 2 years after HSCT.
Peripubertal Anti-Mullerian Hormone Levels Are Associated With Hyperandrogenemia During Adolescence: The Avon Longitudinal Study of Parents and Children
Authors: Dieguez Abigayil , Yeh Chen , Rasmussen-Torvik Laura , Torchen Laura Christine 
Published: May 2021

Abstract
Polycystic ovary syndrome (PCOS) is among the most common endocrine disorders in women and is associated with negative reproductive and metabolic outcomes including subfertility, pregnancy complications, metabolic syndrome, and type 2 diabetes. The diagnosis of PCOS cannot be made until reproductive maturity, when the diagnostic criteria of hyperandrogenemia and oligomenorrhea develop. However, studies have described early metabolic and reproductive characteristics of the disorder in girls at increased risk, suggesting the pathogenesis starts much earlier. Indeed, studies in animal models suggest that exposure to excessive androgen or anti-Mullerian hormone (AMH) levels during critical developmental periods can program the offspring to develop the metabolic and reproductive features of PCOS during reproductive maturity.
We investigated early maternal or peripubertal factors associated with hyperandrogenemia during adolescence using data from the Avon Longitudinal Study of Parents and Children (ALSPAC), a United Kingdom birth cohort which has been ongoing since 1991. We performed linear regression to test for an association of testosterone levels at 15 years with peripubertal reproductive and metabolic phenotypes and with maternal measures of insulin sensitivity. Peripubertal phenotypes included AMH levels at 7, 9, and 11 years, and androstenedione, DHEAS, SHBG, IGF-1, fasting insulin, QUICKI, post-glucose insulin, leptin and adiponectin at age 8 years. Maternal phenotypes included fasting insulin levels and QUICKI at a post-partum visit. Unadjusted and adjusted analyses including the covariates pubertal stage, ethnicity, maternal and daughter BMI were performed.
Testosterone levels at age 15 years were significantly positively associated with AMH levels at ages 7(N=299), 9(N=295), and 11(N=300) years in both the adjusted and unadjusted models (Age 7 unadjusted P&lt;0.0001, adjusted P=0.01; Age 9 unadjusted P&lt;0.0001, adjusted P=0.003; Age 11 unadjusted P&lt;0.0001, adjusted P=0.02). Testosterone at age 15 years was also associated with DHEAS at age 8 years using the unadjusted (P&lt;0.0001) but not the adjusted model. There was no significant association between any of the other peripubertal metabolic and reproductive phenotypes or the maternal metabolic phenotypes of fasting insulin and QUICKI with testosterone level at age 15 years.
We have found a persistent and significant positive association of AMH levels at pre- or peri-pubertal ages with testosterone levels during adolescence, a developmental stage at which a clinical diagnosis of PCOS can be made. It remains unclear if this early elevation in AMH contributes to the pathogenesis of hyperandrogenemia or is an early marker of PCOS. Nonetheless, these findings suggest there are early differences in the reproductive phenotype in girls with hyperandrogenemia, even before the onset of puberty.