bluuebunny/crossref_metadata_2025 huggingface dataset:
Testing of Adrenal Axis Function in Patients With Combined Pituitary Hormone Deficiency Caused by PROP1 Mutation
Authors: Gilis-Januszewska Aleksandra , Rogoziński Damian , Nowak Andrzej Jerzy , Piwońska-Solska Beata , Zygmunt-Górska Agata , Wójcik Małgorzata , Starzyk Jerzy , Hubalewska-Dydejczyk Alicja
Published: May 2021

Background: The mechanism of adrenal axis deterioration in PROP1 mutation remains uncertain and challenging. Aim: The aim of the project was to investigate the adrenal axis function in patients with combined pituitary function deficiency and PROP1 mutation. Methods: We performed the corticotrophin (CRH) stimulation test in 15 patients ((8W/7M) with confirmed CPHD due to the PROP1 mutation. 9/15 were familial cases from four families. Time of observation (ToO) was calculated since the first pituitary axis/ACTH insufficiency has occurred. The results were reported in the group with confirmed Adrenal Insufficiency (AI) and without AI defined as cortisol >18 ug/dl at any point during CRH test. ACTH is reported in pg/ml and cortisol in ug/dl, time of test is given in minutes (0‘, 15’,30’,45’,60’,120’). Results: The mean age of the group was 40,6 ± 12,1 years with mean 34,7 ± 10,3 years of CPHD observation (range 18 – 54 years). The In 5/15 the cortisol response met the criteria excluding AI. Among siblings there were patients both with/without AI. Both subgroups had similar ToO (without AI 35,6 ± 10,0 years vs 34,2 ± 10,3 years with AI). Mean time of AI duration was 15,0 ± 9,3 years. In the group of 5 patients without AI the mean morning cortisol was 12,48 ± 4,31 and ACTH was 31,26 ± 5,43. The mean maximal concentration of cortisol and ACTH were 24,94 ± 3,6 and 123,6 ± 39,9 respectively; Mean increase of cortisol was 12,46 ±4,04 and 92,34±34,48 for ACTH. In 10 patients with AI the mean morning cortisol was 3,33±1,39 and ACTH 22,71±6,75. The mean maximal concentration of cortisol and ACTH were 10,15±4,47 and 97,05 ± 59,15 respectively; Mean increase of cortisol was 6,83 ± 3,41 and 74,35 ± 53,72 for ACTH. For two patients high ACTH increase from 36,7 to 260 and from 28,65 to 112,0 was observed. Analysis of cortisol and ACTH response in both groups revealed that in group without AI the time of peak of ACTH was observed in 15’ (2/5) and 30’ (3/5) vs. in 15’(3/10), 30’(6/10) and 45’ in group with AI. The peak cortisol was observed in 30’, 45’ and 60’ (3/5) in group without AI vs 60’(6/10) or 120’ (4/10) in AI group. The mean maximal increase of ACTH was by 4,09±1,46 and 4,12±1,58 in AI group vs no AI group respectively. Conclusions: In patients with PROP1 mutation the adrenal axis can deteriorate long after other axis insufficiencies, however there are patients with no adrenal insufficiency even during lifelong observation. There is no specific order of deterioration even among affected siblings. In the vast majority of patients independently of cortisol increase there is ACTH response after CRH. Further studies on the pituitary function deterioration in patients with PROP1 mutation should be carried out to understand better the underlying mechanism and to set up the diagnostic timing and procedures.
Vertebral Fractures Occur Regardless of Acromegaly Activity and Are Best Predicted by Proximal Femur Cortical Volumetric Bone Mineral Density
Authors: Kuzma Martin , Vanuga Peter , Sagova Ivana , Pavai Dusan , Jackuliak Peter , Killinger Zdenko , Binkley Neil , Winzenrieth Renaud , Genant Harry K , Payer Juraj
Published: May 2021

Introduction: Vertebral fractures (VFs) in patients with acromegaly are not associated with bone mineral density (BMD) decrease. Previous studies showed impaired trabecular bone parameters among acromegaly patients. However, recent studies suggest that cortical bone could also play a role in VF development. Objective: Evaluate the utility of dual energy x-ray absorptiometry (DXA) BMD and bone structural parameters to determine VF risk among acromegaly patients. Patients and Methods: A single-center two years prospective follow up of acromegaly patients regardless of age, gender, disease activity or associated treatments was conducted. Pituitary hormones, glucose metabolism and bone turnover markers in all subjects were assessed. Each subject had L1-4 spine, femoral neck (FN) and total hip (TH) BMD measured using DXA, and TBS measurement performed ± 7 days from blood sampling. 3D Shaper was used to assess proximal femur trabecular and cortical volumetric (v) BMD, cortical surface (s) BMD and cortical thickness (Cth). VF assessment was performed using the lateral spine imaging IVA™ mode with a Hologic Horizon® densitometer using semi-quantitative approach. Study outcomes were assessed at two time points - baseline and month 24. Results: Seventy subjects (34 M/36F), mean age 55.1 years, including 26 with active disease were studied. After two years a significant decrease in IGF-1 (-30%), osteocalcin (-18%) and TH cortical vBMD (-3%; all p≤0.05) was observed. During follow-up, 13 patients nine of them with controlled disease, developed VF; these patients had greater increase in CTx and decrease in TBS, sBMD, cortical and trabecular vBMD at TH and neck. Multivariate analysis of fracture prediction showed cortical vBMD at TH and neck as best parameters for fracture prediction with AUC 0.766 and 0.774; respectively. TBS was negatively associated with fasting plasma glucose (FPG), HBA1c at each time period. Conclusions: Decrease in cortical vBMD was the most sensitive and specific predictor of incident VF suggesting that cortical bone is involved in fracture development among acromegaly patients. In addition, TBS was strongly negatively associated with glucose metabolism, suggesting glucose intolerance could lead to trabecular bone impairment.
GH Receptor Exon 3 Genotype and Echocardiographic Abnormalities in Patients With Active Acromegaly
Authors: Serrano Karla , Espinosa Etual , Marrero-Rodríguez Daniel , Almeida Eduardo , Silva-Roman Gloria , Peña-Martinez Eduardo , Sosa Ernesto , Mercado Moises
Published: May 2021

Background: The GH receptor (GHR) exon 3 polymorphism occurs at a genomic level. Approximately 50-60% of the population is homozygous for the exon-3 containing genotype (+3/+3), 30-40% are heterozygous (+3/-3) and 10-20% are homozygous for the exon-3 lacking genotype (-3/-3). Some studies suggest that children homo- and heterozygous for the GHR exon 3 lacking genotype (-more efficient 3/-3 and +3/-3, respectively) respond better to treatment with exogenous rhGH and there is also in vitro evidence showing a more efficient signal transduction through this exon 3 deleted isoform. Some studies have found that patients with acromegaly harboring the exon 3-deleted genotype may have a higher prevalence of diabetes and hypertension. Hypothesis and Objective: Patients with active acromegaly harboring the exon 3-lacking GHR genotype may have more echocardiographic abnormalities than those who are homozygous for the exon 3 containing genotype. Patients and Methods: This is a cross-sectional study of patients with active acromegaly, defined by an IGF-1 level > 1.3 times the upper limit of normal (x ULN), who underwent transthoracic echocardiography. Exon-3 GHR genotype was determined by PCR using previously described sense and antisense primers. Results: The cohort consisted of 28 patients, 54% female, with a mean age of 51 ± 12 years. Mean disease duration at the time of echocardiographic examination was 4.48 ± 4.7 years; median basal GH and IGF-1 were 12 ± 26 ng/mL and 2.4 ± 1.04 x ULN. The prevalence of hypertension and diabetes were 43% and 36%, respectively. Fifty three percent of the patients were homozygous for the exon 3-containaing genotype (+3/+3), 18% were homozygous for the exon 3-lacking genotype (-3/-3) and 29% were heterozygous (+3/-3). Clinical and biochemical features did not differ between patients with the different GHR genotypes, except for hypertension that was more prevalent in the +3/+3 genotype group (60% vs 23%, p= 0.04). The frequency of the different echocardiographic parameters was similar among groups (left ventricular hypertrophy 33% vs 15%, p= 0.27; diastolic dysfunction 47% vs 31%, p= 0.39; subclinical systolic dysfunction 42% vs 54%, p= 0.54; left ventricular ejection fraction 59±10% vs 60±16%, p= 0.83); aortic valve abnormalities 19% vs 15%, p=0.63; mitral valve abnormalities 46% vs 15%, p=0.07). Conclusions: Echocardiographic abnormalities in patients with active acromegaly do not differ among patients with the different GHR exon 3 genotypes. The clinical spectrum of acromegaly varies considerably. Although such variability is usually related to the severity of the hypersomatotropinemia, in many patients this is not the case.
USP8 Somatic Mutations in Cushing’s Disease and Silent Corticotropinomas
Authors: Lamback Elisa Baranski , Lima Carlos Henrique de Azeredo , Miranda Renan Lyra , Guterres Alexandro , Andreiuolo Felipe , Wildemberg Luiz Eduardo Armondi , Gadelha Monica Roberto
Published: May 2021

Background: Somatic mutations in the ubiquitin-specific peptidase 8 (USP8) gene have been described in Cushing’s disease (CD). These mutations increase proopiomelanocortin transcription resulting in ACTH production and seem to correlate with somatostatin receptor type 5 (SST5) expression. Aims: Screen USP8 in patients with corticotropinomas and correlate USP8 mutational status with SST5 expression in CD. Methods: Tumor DNA was extracted and then exon 14 amplified by PCR. SST5 was assessed by immunohistochemistry (clone UMB4) and quantified multiplying the percentage of positive cells (0,0%; <10%,1;10-50%, 2; 51-80%, 3; >80%, 4) and intensity (mild, 1; moderate, 2; intense, 3), giving a score (IRS) from 0-12 with ≥ 6 considered high. Results: Among 59 patients, 38 had CD and 21 silent corticotropinomas. In CD, 13 (34.2%) patients had pathogenic mutations (6 had p.Ser719del; 5 had p.Pro720Arg and 2 had p.Pro720Gln). In the mutated CD group, all were women and had median age of 34.5 years (20-46). Median ACTH was 64.7pg/mL [(34.8-330.0), normal <46], urinary free cortisol (UFC) 435.0μg/24h [(87.0-1386.0), normal <100], cortisol after overnight 1mg dexamethasone suppression test (ODST) 17.4μg/dL [(5.0-48.7), normal <1.8], salivary cortisol (SC) 8.1μg/dL [(1.0-15.5), normal <0.35]. Median largest tumor size was 0.9 cm (0-1.9), ki-67 1.7 (0.2-10.0) and IRS 12 (1-12). In wild-type CD group, 19 (76.0%) were women and had median age was 35.0 years old (14-62). Median ACTH was 59.7 (39.0-137.0), UFC 305.8 (77.0-1302.0), cortisol after ODST 23.6 (10.0-33.3), SC 0.67 (0.27-1.28). Median largest tumor diameter 0.7cm (0-3.3), ki-67 1.8 (0.2-10) and IRS 4 (0-12). SC was higher in mutated group compared to wild-type (p=0.001) as well as IRS (p=0.009). In silent corticotropinomas, 2 (9.5%) had pathogenic mutations (1 p.Ser718Pro and 1 p.Pro720Arg): male, 36 years old, 3.2 cm tumor, Ki-67 4%, IRS 6; and female, 52 years old, 3.4 cm tumor, Ki-67 2.5%, IRS 12, respectively. One tumor had a variant not reported as pathogenic (p.Thr739Ala): male, 46 years old, 3.7 cm tumor, Ki-67 0.5%, IRS 0. USP8-wild-type silent corticotropinomas had IRS 0-2. Conclusion: One third of CD patients presented with somatic USP8 mutation. Similar to another study, about 10% of silent corticotropinomas also presented somatic USP8 mutation. Expression of SST5 was high in USP8-mutated CD and higher than wild-type group.
Impact of Covid-19 on the Rate of Diabetic Ketoacidosis in Pediatric New-Onset Type 1 Diabetes
Authors: Bogale Kaleb T , Urban Valerie , Schaefer Eric , Krishna Kanthi Bangalore
Published: May 2021

Introduction: Several demographic and clinical characteristics, including age, low socioeconomic status, and misdiagnosis at initial clinical presentation were previously associated with increased risk of diabetic ketoacidosis (DKA) at diagnosis of type 1 diabetes (T1D) in the pediatric population. However, it is unclear whether the coronavirus (COVID-19) pandemic and subsequent lockdown influenced the rate of DKA in children newly diagnosed with T1D. We undertook this study to identify the impact of the COVID-19 pandemic on the rate of DKA in children newly diagnosed with T1D in a single tertiary care referral center in central Pennsylvania. Methods: We performed an extension of a retrospective analysis of all pediatric patients (age ≤18) newly diagnosed with T1D within a tertiary care referral center between 01/01/2017-09/14/2020. Demographics, insurance coverage, and all clinical documents 30 days before their T1D diagnosis were abstracted to assess for symptoms at diagnosis (polyuria, polydipsia, nocturia, weight loss, nausea, vomiting, altered mental status, infection, vision changes, and autism spectrum disorder), lab values (blood glucose, HbA1c, venous pH, and bicarbonate), and any healthcare encounters within 30 days of their diagnosis of T1D. We performed descriptive statistics and univariate analyses [evaluating children diagnosed with T1D during the pre-COVID-19 era (diagnosed between 1/1/2017-2/28/2020) and post-COVID-19 era (diagnosed between 03/01/2020-09/14/2020) associated with the incidence of DKA], followed by logistic regression analysis (incorporating key clinical factors previously associated with DKA and the pre- or post- COVID-19 era classification). Results: 412 pediatric patients with T1D [171 F:241 M; 370 pre-COVID-19 era:42 post-COVID-19 era] were included. The percentages of DKA diagnoses at admission were very similar between the pre-COVID-19 and post-COVID-19 groups (47% vs. 48%), as were the severity (13% vs. 14% mild DKA; 33% vs. 31% moderate or severe DKA). There were no temporal associations with the rate of DKA in respect to COVID-19, however, age (0-3 and 9-13 years), misdiagnosis during a preceding healthcare encounter, presenting to the emergency department directly, elevated HbA1c (>10.0%/13.4mmol/L), and altered mental status were associated with increased risk of DKA on multivariable analysis. Conclusion: There were no fluctuations in the rate of DKA among pediatric patients newly diagnosed with T1D throughout the COVID-19 pandemic in central Pennsylvania. Interestingly, some geographic locations observed an increased frequency of DKA in children newly diagnosed with T1D, while others noted a decreased rate. Regardless, our findings suggest previously described predictors of DKA in the pediatric population persist, even in the setting of the COVID-19 pandemic.
Defects in the GnRH Neuronal Migration factor, CCDC141, Lead to Self-Limited Delayed Puberty
Authors: Saengkaew Tansit , Mancini Alessandra , Ruiz-Babot Gerard , Cabrera Claudia P , Barnes Michael R , Dunkel Leo , Guasti Leonardo , Howard Sasha
Published: May 2021

GnRH neuronal biology has been identified as a critical element in the pathogenesis of self-limited DP, previously implicated exclusively in the pathophysiology of idiopathic hypogonadotropic hypogonadism (IHH). We hypothesise that this condition may be inherited via genetic variants discoverable through whole-exome sequencing (WES), by focusing on genes involved in GnRH neuron development and function, and genes reported in IHH. We analysed WES data from large Finnish cohort with familial self-limited DP, focusing on genes recently reported in IHH. WES data of 100 DP families have been analysed with a total of 193 individuals: 100 probands, 158 affected and 35 unaffected family members. Potentially pathogenic rare variants segregating within cohort families were identified using a virtual panel of recently reported IHH genes (n=13). This analysis identified 6 rare potentially pathogenic variants in CCDC141 in 25 individuals of 8 families which account for almost 10% of self-limited DP cases in this cohort, without variants identified in cohort control cases. Previous studies reported that homozygous or compound heterozygous mutations of CCDC141 cause Kallmann syndrome and IHH, due to impaired GnRH neuronal migration. In this study, all 6 CCDC141 variants were heterozygous missense variants predicted to be deleterious by in silico prediction tools. Most probands were male (n=7) with typical features of self-limited DP, with absence of secondary sexual characteristics, delayed bone age, and low gonadotropins and sex steroids at first presentation and spontaneous entry into puberty later than age of 14 years without treatment. The majority of pedigrees displayed good segregation of variants with the DP trait, following an autosomal dominant inheritance pattern. However, in two families, there was a complex inheritance pattern with compound heterozygosity (p.Ser55Cys and p.Asp767Asn) and possible incomplete penetrance. In vitro study showed that the overexpression of four key CCDC141 variants in HEK293 cells delayed cell migration, 72% in p.Ser55Cys (p=0.04), 66% in p.Gln507His (p=0.04), 65% in p.Asp767Asn (p=0.02), and 83% in p.Ala1073Thr (p=0.01), when compared to WT (100%). Moreover, WT-overexpressed cells increased the rate of cell migration when compared to non-transfected cells (100% vs 65%, p=0.005), reaffirming that CCDC141 has a role in cell migration. In conclusion, heterozygous deficiency of CCDC141, previously reported to cause IHH, can cause self-limited DP due to abnormal GnRH migration during foetal development.
Growth Outcome and Metabolic Profile of PWS Patients Treated With GH and Differences Between AGA and SGA Group
Authors: Yoon Ju Young , Cheon Chong Kun , Yoo Seok Dong
Published: May 2021

Objective: Prader-Willi syndrome (PWS) is a complex genetic disease associated with growth impairment, severe obesity and metabolic dysfunctions. High proportion of PWS patients are born small for gestational age (SGA), which also increase the risk of growth impairment and metabolic dysfunction. The aim of this study was to describe growth outcome and and metabolic profiles in GH treated PWS patients. We also investigated the differences in clinical outcomes between AGA and SGA group Methods: Data of 55 children and adults with genetically verified PWS aged more than 2 years old (32 male and 23 female, age 2-18.8 years) from single center were studied. Only patients who were treated with GH were included. The clinical characteristics and laboratory findings were reviewed retrospectively. Results: Among 55 subjects, 39 had 15q11-13 deletion and 16 had uniparental disomy (UPD). Twenty (36.3%) were born SGA. All patients received GH treatment, and 11 (20%) discontinued GH treatemnt. Mean age at GH treatment initiation was 2.5 (range 0.3-12.4) years, and mean duration of treatment was 6.3 (range 1.0-11.3) years. Current height-SDS (-0.36 vs -0.16) and BMI-SDS (1.44 vs 1.33) did not differ between AGA and SGA group. Two patients in SGA group, but none in AGA group had diabetes mellitus. Mean glucose level was also higher in SGA group (100.1 vs 114.4 mg/dL) Conclusions: Our report gives an overview of growth profile and metabolic dysfunctions recorded in GH treated PWS patients. Growth profile did not differ between AGA and SGA group. Glucose level was higher in SGA group, so more careful monitoring and prevention for DM will be required in SGA group.
Pituitary Hypoplasia Is the Best MRI Predictor of the Severity and Type of Growth Hormone Deficiency in Children With Congenital Growth Hormone Deficiency
Authors: Sharma Himanshu , Kumar Anshul , Purwar Naincy , Mathur Nitish , Sharma Balram , Mathur Sandeep Kumar
Published: May 2021

Background and Objectives: Congenital idiopathic growth hormone deficiency(GHD) is associated with various MRI abnormalities, including both sellar anomalies such as pituitary hypoplasia, ectopic pituitary, empty sella and abnormalities of the pituitary stalk and extrasellar abnormalities such as Arnold Chiari malformation, corpus callosum agenesis, arachnoid cyst, septum pellucidum agenesis, enlarged ventricles, vermis dysplasia, and sphenoid cyst. However, it remains contentious whether MRI brain findings could provide an additional avenue for precisely predicting the differentiation of GHD based on severity(severe or partial) and type(isolated GHD or multiple pituitary hormone deficiency MPHD). This study aimed to ascertain the abnormality that is the best predictor of severe GHD and type of GHD amongst the different MRI findings. Methods: This was an analytical cross-sectional study conducted from 2018-2020. During the study period, we included a total of 100 subjects diagnosed to have idiopathic GHD after the exclusion of syndromic causes, system illness, presence of pituitary mass, and those with h/o cranial irradiation. Patients were divided into severe GHD and partial GHD based on peak stimulated GH of <5 ng/dl and ≥ 5 ng/dl respectively and into groups based on isolated GHD and MPHD. Patients were further divided into groups based on the presence of pituitary hypoplasia,extrasellar brain abnormalities (EBA), and presence of ectopic posterior pituitary and/or pituitary stalk abnormalities(EPP/PSA), respectively. Analyses were performed using SPSS version 24.0 software. Results: Amongst 100 subjects with idiopathic congenital GHD, 66 (66%) subjects had Isolated GHD while the remaining 34 (34%) had MPHD. 71 had severe GHD, and 29 had partial GHD. Amongst the MRI findings, pituitary hypoplasia was the most common finding observed in 53% of patients, while 23(23%) had EBA, and 25(25%) had EPP/PSA. Pituitary hypoplasia was observed to be the best predictor of severity of GHD with an odds ratio(OR) of 10.8 (95% CI 3.38-29.6) followed by ectopic posterior pituitary /pituitary stalk abnormalities (OR =2.8, 95% CI 1.5-9.5) while the presence of extrasellar abnormalities was the weakest predictor (OR =1.8, 95% CI 1.05-3.2). Pituitary hypoplasia was the only finding to significantly predict MPHD (OR=9.2). On ROC analysis, a Pituitary height SDS of -2.03 had a 73.2 % sensitivity and specificity of 79.3%(AUC =0.787,95% CI 0.7-0.873) for severe GHD and a sensitivity of 88.2 % and specificity of 66.7% (AUC =0.745, 95% CI 0.68-0.877) for MPHD. Conclusion: We observed Pituitary hypoplasia to be not only the most frequent MRI abnormality but also the best predictor of severe GHD and MPHD amongst various sellar and extrasellar abnormalities.
A Novel Variant in the CASR Gene c.368T>Cp.(Leu123Ser) in a Case of Hypocalcemia Refractory to Standard Medical Therapy
Authors: da Silva Diana Festas , Lages Adriana De Sousa , Caetano Joana Serra , Cardoso Rita , Dinis Isabel , Gomes Leonor , Paiva Isabel , Mirante Alice
Published: May 2021

Introduction: Hypoparathyroidism is characterized by low or inappropriately normal PTH production, hypocalcemia and hyperphosphatemia. Autosomal dominant hypocalcemia (ADH) type 1 is one of the genetic etiologies of this, caused by heterozygous activating mutations in the CASR gene. Some individuals fail to meet treatment goals despite standard therapy. Clinical Case: A 13-year-old male patient was admitted in the emergency department due to syncope during physical activity. There was no reference to seizures or other complaints. Standard screening for metabolic diseases revealed no changes at the 7th day of life and family history was unremarkable. There was a history of febrile seizures up to 5 years of age with several hospitalizations for diagnosis investigation that were inconclusive. Physical examination showed a positive Chvostek signal, without other changes. A basic workup revealed hypocalcemia 1.67mmol/L (NR: 2.19-2.66), hyperphosphatemia 3.06mmol/L (NR: 0.95-1.75), hypomagnesemia 0.62mmol/L (NR: 0.7-1.0), low 25Hydroxyvitamin D 8.7ng/mL (NR: >30ng/mL) and inappropriately low PTH 4.0pg/mL (NR: 16.0-87.0). Cranial computed tomography scan showed bilateral calcifications of the basal ganglia. Dual-energy x-ray absorptiometry revealed bone mineral density z-scores increased 15% in spine lumbar and decreased 7% in left femur. Cardiac ultrasound and electrocardiography were normal. The patient started therapy with intravenous calcium gluconate. During this treatment, he developed significant calcification of the peripheral veins at the site of administration, leading to intravenous therapy suspension. The dose of oral calcium, calcitriol and magnesium was gradually increased and sevelamer started to control hyperphosphatemia. Despite the optimization, the patient maintained hypocalcemia refractory to standard therapy. As a last resource strategy in therapeutic optimization, the patient started on rhPTH (1-34). Ever since, the patient has been clinically asymptomatic with biochemical stability and with a reasonable quality of life. At age 18, renal ultrasound revealed diffuse medullary nephrocalcinosis.

The genetic testing revealed a novel variant c.368T>C p.(Leu123Ser) likely pathogenic in heterozygosity in the CASR gene, suggesting the diagnosis of ADH type 1. The patient′s mother did not give her consent for genetic study and patient’s father had already died with a diagnosis of acute leukemia. Conclusion: This case can be explained by the presence of a likely pathogenic variant in heterozygosity in the CASR gene that has been described in the medical literature that has not been identified in gnomAD population database, suggesting the diagnosis of ADH type 1. rhPTH (1-34) may be a treatment option for those individuals who are not well controlled on standard therapy, but long-term follow-up studies are needed to reinforce its safety.
A Rare Variant of Turner Syndrome With Isodicentric X Chromosome Resulting in Trisomy: A Case Report
Authors: Chan Jacqueline T , Cabanas Ma Cristine C
Published: May 2021

Introduction: Turner syndrome is a genetic disorder caused by the loss of an X-chromosome affecting approximately 1 in every 2,500 females. A constitutional karyotype of 45, X accounts for nearly 50% of patients, while mosaicism and other chromosomal structural abnormalities such as deletions, duplications, ring, isodicentric chromosomes, inversions and translocations, have been reported. Isodicentric X chromosomes are formed presumably by end-to-end fusion of chromatids after a break, with subsequent loss of an acentric fragment. These chromosomes in general have phenotypes characteristic of the resultant X deletions. We present a case of a 14-year-old female diagnosed with Turner syndrome and with 2 abnormal cell lines. Case Presentation: This is a case of a 14-year-old female referred to pediatric endocrinology for concerns of short stature and delayed puberty. She denied any food intolerance, bloating and diarrhea. She is otherwise healthy with unremarkable past medical history. Her weight was normal at 15th percentile. Her height was 137cm or 0.01 percentile with a Z score of –3.6. Work up revealed hypothyroidism with TSH 16.3 mcIU/mL (0.4-4.7 mcIU/mL), positive thyroid peroxidase antibody >900 IU/ml and thyroglobulin antibody 14 IU/mL (< 1.8IUm/mL) and celiac disease (tissue transglutaminase IgA > 100 U/mL) both without associated symptoms. Estradiol level was undetectable, and LH and FSH were 9.89 mIU/ml and 52.69 mIU/ml respectively. The rest of her labs including growth factors were normal. Bone age was normal at 13 years for chronological age of 14 years old. Chromosomal microarray revealed 2 abnormal cell lines: one with monosomy X, the other with a normal X chromosome and an isodicentric X chromosome involving the Xp11.22-q28 region resulting in trisomy of the latter cell line.

Levothyroxine was started. Plan is to start growth hormone therapy and initiate puberty after. Patient referred to necessary subspecialties for hearing evaluation as well as cardiac evaluation Conclusion

Turner syndrome usually presents as females with short stature, gonadal dysgenesis and 45,X cell line that is either singly or in combination with another

mosaic cell line. Our patient presented with short stature and absence of puberty. Initial investigation revealed hypothyroidism and highly positive celiac antibodies, but unable to attribute her short stature to both diagnoses given the lack of other symptoms. This case emphasizes the importance of checking the karyotype in females presenting with short stature and more importantly delayed puberty as part of the diagnostic algorithm. In addition, checking thyroid and celiac panel are also imperative as treatment of these are treatable etiologies of short stature.
Factors Affecting Thyroid Hormone Changes Over 1 Month After Birth in Preterm Newborns
Authors: Kim Seulki , Kim Sung Eon , Lee Na Yeong , Ahn Moon Bae , Kim Shin Hee , Cho Won Kyung , Cho Kyung Soon , Jung Min Ho , Suh Byung-Kyu
Published: May 2021

Purpose: To analyze factors affecting thyroid hormone changes over 1 month after birth in preterm newborns. Methods: Thyroid hormones, including free thyroxine (fT4) and thyroid stimulating hormone (TSH) of 216 preterm newborns (mean gestational age [GA] 33.6±2.6 weeks), were retrospectively reviewed at the 1st and 4th weeks after birth. Preterm newborns were classified into three groups according to the GA (< 28 weeks, group A; 28-32 weeks, group B; 32-36 weeks, group C). The association between thyroid hormone changes and clinical factors was analyzed. Results: Preterm newborns with older GA had higher concentrations of fT4 (group A, 0.9±0.2 ng/dL; group B, 1.2±0.2 ng/dL; group C, 1.5±0.3 ng/dL) and TSH (group A, 2.7±3.2 mIU/L; group B, 4.5±3.3 mIU/L; group C, 6.0±3.8 mIU/L), both at the 1st week after birth. fT4 and TSH at the 1st week after birth were positively correlated with the GA (r=0.52, P=0.0001; r=0.30, P=0.0001) and Apgar score at 5 minutes (r=0.31, P=0.0001; r=0.28, P=0.0001). TSH concentration at the 1st week after birth was significantly lower in the abnormal brain sonogram group than in the normal brain sonogram group (4.4±3.7 vs 6.1±3.4 mIU/L, P=0.001); there were no differences at the 4th week after birth between these groups (4.2±2.6 vs 3.4±2.4 mIU/L, P=0.485). Multiple linear regression analysis revealed that GA was positively correlated with fT4 and TSH at the 1st week, and fT4 at 4th week after birth (B=0.08, SE=0.12, P=0.0001; B=0.34, SE=0.15, P=0.029; B=0.02, SE=0.01, P=0.013). Conclusion: Thyroid hormone levels in preterm newborns are mostly within the normal reference value of full-term newborns within 4 weeks of life, and are mainly affected by GA and brain ultrasound abnormalities.
Impact of Male Hypogonadism on Bone Mineral Density in Childhood Hemato-Oncologic Disease
Authors: Kim Sungeun , Lee Nayeong , Kim Seulki , Ahn Moon Bae , Kim Shin-Hee , Won-Kyoung Cho , Cho Kyoung Soon , Jung Min-Ho , Suh Byung-Kyu
Published: May 2021

Introduction: Patients with childhood hemato-oncologic diseases have many medical problems, not only due to disease itself, but also adverse effects of specific treatment that patients had. Osteoporosis, one of the most common side effects of the treatment, decreases quality of life when the disease progresses. Our study investigated the impact of male hypogonadism on secondary osteoporosis in childhood hemato-oncologic patients, using association between male sex hormone and bone mineral density (BMD) measured by dual energy X-ray absorptiometry (DXA). Methods: This study collected BMD score (T-score) of 52 male subjects who were diagnosed with hemato-oncologic diseases in the past (average age of 22.3 years at DXA examination). All subjects measured serum testosterone and we divided them into two subgroups according to gonadal status. The first group, called hypogondal group, was a group of subjects with serum testosterone level less than 3.5 ng/ml. The other group was classified into eugonadal group, with serum testosterone level equal or more than 3.5 ng/ml. Mean BMD score of spine and hip were presented and compared between the two groups. Furthermore, relativity with other risk factors for osteoporosis was calculated using multiple regression analysis. Results: Overall, spine BMD in the hypogondal group did not significantly differ from the eugonadal group. However, hip BMD was significantly lower in the hypogonadal group (mean difference; 0.8, p = 0.023). Furthermore, testosterone level itself showed linear correlation with BMD score in hip (p = 0.013). When other risk factors for osteoporosis were taken into account, hemato-oncologic patients treated with total body irradiation also had significantly lower hip BMD (p = 0.007) compared with non-irradiation group. Hypogonadism still remained a significant factor for decreased bone mineral density in hip (p = 0.022). Conclusions: Hemato-oncologic patients with hypogonadism or previously treated with total body irradiation are at increased risk of decreased bone mineral density in both hips. Hypogonadism alone remains independent risk factor for osteoporosis in hip. Attention of these male patient should be paid to prevent the incidence of secondary osteoporosis.
Estrogen Supplementation Is Associated With Higher Quality of Life Scores in Women With Cystic Fibrosis
Authors: Wu Malinda , Arora Neha , Sueblinvong Viranuj , Hunt William R , Tangpricha Vin
Published: May 2021

Purpose: With rapid advancements in therapeutic options for patients with cystic fibrosis (CF), the median predicted survival has increased to 47 years along with the prevalence of non-pulmonary complications for patients with CF. Women with CF suffer irregular menses, sexual dysfunction and low bone mineral density. With increasing pregnancies among women with CF, they may consider contraception. Estrogen supplementation may modulate these outcomes and others. The purpose of this study was to explore the effects of supplemental estrogen use on quality of life (QOL) in CF.

Methods: Women with CF ages 16-50 years were administered a validated CF-specific QOL survey (CFQ-R) during a routine CF clinic visit through an IRB-approved cross-sectional study. The QOL domain scores of subjects taking and not taking estrogen were compared pairwise by Kruskal Wallis tests and overall by Wilcoxon signed rank test.

Results: The estrogen exposed and estrogen unexposed subjects with CF had similar age, BMI, FEV1, race, CF mutation, pancreatic insufficiency, diabetes and relationship status. The estrogen exposed subjects were taking 20-30 mcg of ethinyl estradiol in oral contraceptive pills. The estrogen exposed subjects had consistently higher QOL scores than the estrogen unexposed subjects (p=0.001). The estrogen exposed subjects had significantly higher scores in 7 of the 12 CFQ-R categories: physical, vitality, treatment burden and role domains and weight, respiratory and digestion symptom scales (p<0.05). When correcting for multiple comparisons, the estrogen-supplemented women had higher role domain scores than women not taking estrogen supplement (p=0.03).

Conclusions: Estrogen supplementation was associated with improved quality of life in women with CF. This cross-sectional study highlights the need for further investigation into the potential benefits of estrogen supplementation. The dose, route, formulation and timing of estrogen therapy may modulate the beneficial effects for women with CF.

Support: This work was supported by the National Center for Advancing Translational Sciences of the National Institutes of Health under award TL1TR002382 and UL1TR002378, and Cystic Fibrosis Foundation award WU20D0. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH or CFF.
Gonadotropin Response to Insulin and Lipid Infusion Reproduces the Reprometabolic Syndrome of Obesity in Lean Women
Authors: Santoro Nanette F , Santoro Nanette F
Published: May 2021

Introduction: The reprometabolic syndrome of obesity is associated with reduced gonadotropins and impaired LH and FSH response to gonadotropin releasing hormone (GnRH). We sought to reproductive the reprometabolic syndrome in normal weight, eumenorrheic women by infusing a combination of insulin and lipid. Materials and Methods: 15 women, mean age 32 (IQR 26,36) and BMI 21.9 (20.2, 22.9) were recruited with intent to perform early follicular phase, 6-hour infusions of insulin (20-40mg/mU/m2/min) and lipid (Intralipid) or saline infusion (controls); 12 women completed both intended studies and an additional 3 women completed only one of the two studies. The first 4 hours of each study assessed endogenous gonadotropins; at 4hrs, a 75 ng/kg GnRH bolus was administered and sampling continued until 6hrs. Linear mixed model analysis was used to determine differences between Intralipid versus saline on endogenous LH pulse amplitude (primary outcomes), mean FSH, and area under the curve (AUC) response to GnRH (secondary outcomes). Results: LH pulse amplitude, mean FSH, and both AUC responses to GnRH were all reduced by Intralipid/insulin; mean FSH (P=0.03) and AUC for LH (P=0.05) were at or near statistical significance. LH pulse amplitude and response to GnRH were significantly reduced (P=0.04 and 0.02) when one participant with very high LH and AMH levels was excluded. Discussion: Acute infusion of insulin/lipid to eumenorrheic, normal weight women recapitulated the reprometabolic syndrome of obesity. These findings imply that specific circulating factors in obese women contribute to their sub fertility and thus may be amenable to discovery and treatment.
PCOCheck AMH ELISA: A Clinical Case Report to Resolve Miss-Matched Antral Follicle Counts (AFC) to Serum AMH
Authors: Kumar Ajay , Kalra Bhanu , Alpadi Kannan , Green Katherine , Wittmaack Frank
Published: May 2021

Introduction: At times clinicians wonder why a subject’s Anti-Mullerian Hormone (AMH) does not correlate to the antral follicle count (AFC). AMH is secreted as a full-length protein and undergoes proteolytic cleavage at amino acid 451 to become biologically active. Additional proteolytic processing takes place at aa229. This processing, which may differ between individuals with different clinical conditions, exposes new antigenic sites which affect AMH measurements. Moreover, AMH epitopes might be masked by protein interaction in the circulation.

Clinical Case: A 24-year-old woman gravida 0 presented with metrorrhagia for several months. The bleeding pattern was unresponsive to a trial of oral contraceptive pills, and they were discontinued. The patient’s history is remarkable for a microprolactinoma, managed with dopamine agonist. She has facial acne, but no hirsutism. Her BMI is 24 kg/m2. Laboratory studies revealed normal testosterone (27 ng/mL) and DHEAS (64 mcg/dL). Her prolactin was 1.1 ng/mL Thyroid function tests were in the normal range. hCG was negative. A random progesterone was 12 ng/mL, consistent with an ovulatory cycle. Her ovarian assessment showed FSH of 6.6 IU/L, LH of 6.7 IU/L, estradiol of 51 pg/mL, Inhibin B of 139 pg/mL, all in the normal range. Transvaginal pelvic ultrasound determined the ovarian volumes to be 8 and 6 mL, respectively, with a basal antral follicle count of 15 per side. This would have predicted a normal AMH level in this patient. However, AMH levels were repeatedly found to be low (0.05 to 0.1 ng/mL) using the pro-Mature AMH assay. As this patient was interested in future fertility, additional studies to further investigate her AMH production were carried out.

AMH Measurement: Novel AMH ELISAs with antibody epitopes specific to Pro-Mature, Mature-Mature and Pro-Pro were used to analyze the sample. The observed AMH concentration by Pro-AMH ELISA, Mature-Mature ELISA and PCOCheck ELISAs were 0.1 ng/mL, 0.14 ng/mL, and 4.99 ng/mL, respectively. AMH Pro-Pro assay (PCOCheck) uses a linear epitope two-sided antibody that is not impacted by post-translational modifications, known AMH mutations or conformational changes due to thermal instability.

Conclusions: The AMH measurements indicate that the patient’s serum may not contain pro-mature associated form of AMH or the C-fragmented AMH in circulation. This may be due to mutated AMH in the C-terminus and can result in C-truncation. This subject’s AMH is mostly fragmented and contains enriched pro-region AMH, which was measured by PCOCheck ELISA.

The Teaching: Tests such as PCOCheck ELISA, targeted to specific regions of AMH will provide clinicians better tools for patient management. Such tests will also help resolve the observed AMH discrepancies with AFC using legacy AMH tests. PCOCheck ELISA can be a valuable tool for assessment of ovarian reserve or polycystic ovary syndrome (PCOS).
Early Treatment of Hypothalamic Hypogonadism With LH-RH Analog Improved the Long-Term Prognosis of Hypogonadism of Adult-Onset Craniopharyngioma
Authors: Iwabuchi Masayasu
Published: May 2021

Object: Craniopharyngiomas frequently grow on the cisternal surface of the hypothalamic region. The survival rate for childhood craniopharyngioma has been improving with more long-term survivors. Long-term survivors of childhood craniopharyngioma suffer a number of impairments, which include visual loss, endocrinopathy, hypothalamic dysfunction, cerebrovascular problems, neurologic and neurocognitive dysfunction. GnRH neurons in hypothalamus that send axons to portal blood system in median eminence fire in coordinated, repetitive, episodic manner, producing distinct pulses of GnRH in the portal blood system. In 2001, we experienced the case of hypothalamic hypogonadism after the radical surgery of craniopharyngioma located in the right basal ganglia and hypothalamus. During the operation, pituitary gland and stalk were preserved. The patient had developed panhypopituitarism and hypothalamic hypogonadism after transcranial surgery. The diagnosis of oligospermia and asthenospermia was made. We hypothesized that the hypogonadism was due to the lack of distinct pulses of GnRH after the surgery. The aim of this program was to demonstrate the efficacy of the pulsatile subcutaneous LH-RH therapy for the recovery of gonadal function from hypothalamic hypogonadism and to observe the long-term prognosis after recovery.

Method: After a diagnosis of hypothalamic hypogonadism, low dose LH-RH treatment was given to a 29-year-old male with small portable automatically-timed infusion pump, connected to a subcutaneous (s.c.) catheter. Gonadorelin acetate was prepared to the concentration of 0.8mg/ml. Sixteen micrograms of LH-RH s.c. was given every 120 min. Serum levels of gonadotropin and testosterone were monitored. The treatment was continued until his gonadal function normalized. Long-term follow up was continued after low dose LH-RH treatment.

Result: After the six months of pulsatile LH-RH treatment, serum level of testosterone turned normal. Then the treatment was paused in 2003. His wife became pregnant with in-vitro fertilization (IVF) in 2007 and gave birth in 2008. Moreover, his wife became pregnant naturally without IVF in 2009 and gave birth in 2010, suggesting the recovery from oligospermia and asthenospermia of her husband. Early recovery from hypothalamic hypogonadism maintained normal gonadal function in 2020.

Clinical Lessons: We demonstrated a case of successful treatment of the hypothalamic hypogonadism after the surgery of craniopharyngioma. The pulsatile subcutaneous LH-RH therapy is efficacious for the case with the lack of the distinct pulses of GnRH after radical surgery of craniopharyngioma. Early treatment of hypothalamic hypogonadism with LH-RH analog improved the long-term prognosis of hypogonadism of adult-onset craniopharyngioma.
Ectopic Cushing’s From Metastatic Prostate Cancer
Authors: Bloomer Zachary , Teague Jennifer , Vietor Nicole
Published: May 2021

Objective: Ectopic ACTH production from malignancy is a rare etiology of Cushing’s syndrome. The most common tumors associated with this syndrome include small cell lung cancer, pancreatic neuroendocrine tumors, pheochromoctoma, thymic carcinoma, and bronchial carcinoma. Metastatic prostate cancer does not commonly produce ACTH. Here, we present a rare case of Cushing’s syndrome due to metastatic prostate cancer.

Case Report: Patient is a 64 year old man with a 2 year history of castrate-resistant prostate cancer who was admitted for the 2nd time in 1 month for profound weakness and new onset hypokalemia. Initial analysis revealed hypertension with systolic blood pressure in the 150s, potassium in the mid 2s, an ACTH level of >1000pg/mL, and a 24-hr urine cortisol of almost 10,000mcg/24hrs. This was confirmed on repeat analysis. Metyrapone was initiated for treatment of hypercortisolemia and systemic chemotherapy with Cisplatin/Irinotecan was started to treat metastatic prostate cancer. ACTH and 24-hr urine cortisol levels returned to normal within a few weeks of therapy. The patient was able to discontinue Metyrapone following systemic chemotherapy treatment. Subsequent labs following discontinuation of metyrapone confirmed ongoing resolution of hypercortisolemia.

Conclusion: This case represents an extremely rare cause of Cushing’s syndrome. Metastatic prostate cancer can rarely produce ACTH and cause clinical Cushing’s syndrome. Ectopic Cushing’s syndrome is often due to very aggressive tumors and is associated with a poor prognosis. Rapid recognition and treatment of this condition can be lifesaving.
Involvement of NR5A1 and NR5A2 in the Regulation of Steroidogenesis by Clock Gene and BMPs by Human Granulosa Cells
Authors: Suyama Atsuhito , Iwata Nahoko , Soejima Yoshiaki , Nakano Yasuhiro , Yamamoto Koichiro , Nada Takahiro , Otsuka Fumio
Published: May 2021

We previously reported that the expression levels of Clock gene are linked to the expression levels of steroidogenetic enzymes in human granulosa cells (EJ 2019). However, the downstream molecules of the Clock gene actions in the regulation of ovarian steroidogenesis have yet to be elucidated. In the present study, we investigated the roles of the transcription factors, NR5A1 (also known as SF-1) and NR5A2 (LRH-1), which play key roles in the reproductive function as well as steroidogenesis by focusing on the functional link between Clock gene and bone morphogenetic protein (BMP) signaling using human granulosa KGN cells. First of all, we examined the effects of BMPs/growth differentiation factor (GDF) on forskolin (FSK)-induced steroidogenesis. As a result, FSK-induced mRNA levels of StAR and P450scc, but not P450arom, were potently suppressed by treatments with BMP-6, -9, -15 and GDF-9. The expression levels of NR5A1 and NR5A2 mRNA were also upregulated by FSK treatment, while the BMP-target gene Id-1 mRNA levels were stimulated by the treatment with BMPs. Of interest, treatments with BMPs/GDF increased FSK-induced NR5A1 mRNA levels but suppressed FSK-induced NR5A2 mRNA levels by granulosa cells. The expression levels of NR5A1 mRNA were positively correlated with the changes of P450arom and 3βHSD mRNA, whereas the expression levels of NR5A2 mRNA were correlated with that of StAR and P450scc mRNA. In addition, the expression levels of NR5A1 and NR5A2 mRNAs were positively correlated with the levels of Clock mRNA. In particular, Clock mRNA levels showed highly positive correlation with the levels of NR5A2 mRNA compared with NR5A1 mRNA. Of note, Id-1 mRNA levels were positively correlated with the levels of NR5A1 mRNA, but negatively correlated with that of NR5A2 mRNA. Furthermore, the inhibition of Clock gene expression by siRNA attenuated the expression levels of NR5A1 and NR5A2 mRNA, resulting in decreased mRNA levels of StAR and P450arom in the presence of FSK. Thus, the present results suggested a novel mechanism by which Clock expression is functionally linked to the expression of NR5A1 and NR5A2, the latter of which is further regulated by BMP signaling by granulosa cells. The interaction among Clock, NR5A1/NR5A2 and BMPs may be involved in the fine tuning of steroidogenesis by ovarian follicles.