bluuebunny/crossref_metadata_2025_split huggingface dataset:
ODP648 MEN1 vs MEN4: when we cannot find a mutation
Authors: Correa Ricardo , Sheth Grishma 
Published: November 2022

Abstract

MEN1 is an autosomal dominant syndrome characterized by involvement of several endocrine and non-endocrine organs. The most common endocrine organs that are affected include pituitary, parathyroid, and/or pancreas. In 10-30% of patients, no germline mutations in the menin gene are identified, presenting a diagnostic challenge. This case raises the question of possible MEN4 syndrome, which shares a similar phenotype to MEN 1 with germline mutation in CDKN1B. Clinical case 59 y/o female with PMH HTN, obesity, hypothyroidism initially presented to our clinic in 2018 for evaluation of hypercalcemia. She prior was seen in 2005 for evaluation of prolactinoma by outside endocrinologist but was lost to follow up. Per history, she had a pituitary MRI in 1991 for work up of amenorrhea and found to have prolactinoma. She was placed on bromocriptine at that time; after repeat pituitary MRI and prolactin levels were found to be normal, bromocriptine was discontinued in 2019 but then restarted a few months later due to uptrending prolactin level. During the visit with us, work up for her hypercalcemia included calcium of 11. 0 mg/dL and PTH level of 93 pg/mL with normal albumin, vitamin D, and renal function. Patient had a negative sestamibi scan but was found to have a 10 mm×5 mm×12 mm enhancing nodule along the left thyroid gland and along left lateral margin of esophagus, suggesting parathyroid adenoma. She subsequently underwent successful left inferior parathyroidectomy in July 2019 with normalization of calcium and PTH levels. No other parathyroid was found to be enlarged. Given her pituitary and parathyroid adenoma, she was sent for genetic testing; she was evaluated for 7 gene variants and all were found negative including MEN1, CDKN1B, GNA11, AP2S1, CASR, CDC73, and RET. Of note, she has no family history of MEN1 or any endocrine tumors. However, further testing was still performed to evaluate for a pancreatic neuroendocrine tumor including CT abdomen, gastrin, C peptide, chromogranin-A, glucagon, VIP, and 5-HIAA. Her initial testing came back normal including normal CT abdomen in 2020. However, her most recently lab results in 2021 revealed an elevated gastrin level of 124 pg/mL and uptrending chromogranin A of 262 ng/mL (&lt;=93), the diagnosis of gastrinoma was confirmed and PPIs were started.

Discussion
This case highlights the importance of continued surveillance in patients with multiple endocrine organ involvement or neoplasia despite negative genetic testing; it also supports the likelihood of unidentified mutations given the improbable chance this patient has 3 independent endocrine tumors. Possibilities including missed germline mutations on testing or phenocopies. This patient likely has an upstream mutation that was not identified and could represent either MEN1 vs MEN4
Presentation: No date and time listed
PSAT181 Amyloidosis as a Possible Cause of Hypoparathyroidism
Authors: Anderson Thea Lee , Bendaram Snigdha Reddy , Madhavan Parvathy 
Published: November 2022

Abstract

Background
Hypoparathyroidism is a relatively uncommon metabolic disorder with an estimated prevalence of 37 per 100,000 person-years in the United States. Postsurgical hypoparathyroidism is the most common etiology and accounts for 75% of the cases. Nonsurgical cases are frequently the result of autoimmune or genetic disorders. Rarely parathyroid gland infiltration, external radiation treatment is also known cause hypoparathyroidism. We present a rare case of hypoparathyroidism associated with amyloidosis.

Case
61-year-old female presented for evaluation of hypothyroidism and hypoparathyroidism and significant fatigue. Patient was already treated with levothyroxine as well as calcitriol at the time of presentation for management of these issues without improvement in her fatigue. Further review of prior records showed progressive decline in kidney function and albumin, hypothyroidism in addition to worsening hypocalcemia evidenced on ionized calcium levels over a two year period. This also coincided with the duration of the onset of fatigue. Past medical history was also significant for parathyroid surgery for primary hyperparathyroidism 12 years prior to the onset of symptoms. Patient did not develop hypoparathyroidism after surgery but maintained normal calcium levels until onset of symptoms 2 years ago.Physical exam did not reveal any abnormalities. Labs (when patient was receiving calcitriol) revealed a calcium of 9.5mg/dL (8.4-10.2mg/dL), with albumin 2.3g/dL(3.8-5.3g/dL), ionized calcium 1.27mmol/L(1.14-1.33mmol/L), 25-hydroxy Vitamin D 14ng/mL(&gt;/=30ng/mL), PTH 7pg/mL(15-88pg/mL), Phosphorus 3.4mg/dL(2.4-4.8 mg/dL), Magnesium 2.6mg/dL(1.8-3.0 mg/dL), Creatinine 2.45mg/dL(0.40-0.99 mg/dL), eGFR 21 mL/min/1.73m2. She was trialled off calcitriol to assess for improvement of her PTH, however was noted to have inappropriately normal PTH despite hypocalcemia and was restarted on calcitriol. TPO antibody and 21 hydroxylase antibody levels were not elevated. Due to CKD, She underwent kidney biopsy that revealed lambda light chain amyloidosis. Patient is currently receiving daratumumab and Cyclophosphamide-Bortezomib-Dexamethasone and plans to undergo stem cell transplant in future.

Conclusion
Notably, the occurrence of amyloidosis with hypothyroidism and infiltrative amyloid goiter is well documented. Although prior case studies have detailed the co-occurrence of hyperparathyroidism and amyloidosis, little is known about the relationship of parathyroid disease and amyloidosis. Due to the temporal association of amyloidosis, hypoparathyroidism, and hypothyroidism, we hypothesize that infiltration of these endocrine glands by amyloid has contributed to the dysfunction. The patient will be monitored for improvement in her parathyroid function as the amyloidosis is treated. Further studies are needed to assess the interplay between the parathyroid and amyloidosis.
Presentation: Saturday, June 11, 2022 1:00 p.m. - 3:00 p.m.
PSUN160 Transfusion Related Endocrinopathies and Thalassemia (TREAT) Study
Authors: Erkin-Cakmak Ayca , Ahmad Tariq , Rishon Anne , Weyhmiller Marcela , Fung Ellen , Lodish Maya , Lal Ashutosh 
Published: November 2022

Abstract
Thalassemia (Thal), the most common form of inherited anemia worldwide, may require regular blood transfusions and life-long medical care. The introduction of oral chelators and imaging methods to monitor iron overload transformed Thal from a rapidly fatal disease of childhood to a chronic illness compatible with prolonged life expectancy. Regular blood transfusions resulting in tissue iron overload and oxidative stress may lead to liver disease and polyendocrinopathy. In this observational descriptive study, we described the patient characteristics and prevalence of endocrinopathies (growth failure, hypothyroidism, hypogonadism, low bone mass, and impaired glucose intolerance) in a contemporary group of transfusion dependent Thal patients cared for our tertiary care center since 2000. A total of 253 transfusion dependent Thal patients were identified. Of those patients, 51.8% were female; 22% (n=56) were adopted, mainly from China. The following ethnicities were represented: Chinese 19.9%, Indian 12.6%, Laotian 7.8%, Asian 7.8%, Italian 7.8%, Vietnamese 3.9%, Afgani 3.4%, Pakistani 3.4%, Thai 2.9%, Greek 2.4%, Cambodian 2.4%, Filipino, Caucasian, Iranian 1.9% each. Majority of the diagnoses were Beta Thal Major (69.9%), followed by E Beta 0 Thal (14.6%). The median age at first visit was 10.6 years (IQR1-IQR3: 2.2-25), last visit was 27 years (IQR1-IQR3: 12.1–39.4) with 33.5% of the patients ≤18 years of age. Median follow-up time was 10 years. Median final adult height (height z-score) for females was 159.5 cm (-0.53) (IQR1-IQR3: 152.4,160.3cm; height z-score: -1.68, -0.47) and for males 167.5cm (-1.3) (IQR1-IQR3: 161.5, 171cm; height z-score: -2.13, -0.81). Only, 16.5% (n=14) of children were on growth hormone treatment due to low-normal growth hormone surrogates or peak growth hormone &lt;10ng/ml in growth hormone stimulation test. Hypothyroidism was diagnosed in 9.9% (n=25) of the patients and 5 patients had central hypothyroidism. Hypogonadism was diagnosed in 32.4% of adult female (n=24), and 44.6% of adult male (n=29) patients who were subsequently prescribed sex steroid replacement. Low bone mass in those with z-scores ≤2.0 was noted in 22.9% (n=43) female and 26% (n=49) males. The mean bone mineral density z-score for spine was -2.1±1.1 for females and -2.5±1.3 for males. Either impaired glucose tolerance or insulin-dependent DM was observed in 29% of the patients (n=54). Endocrinopathies are common and continue to be a significant morbidity in transfusion dependent Thal patients despite improved chelation agent availability and tissue iron monitoring. Future long-term longitudinal and intervention studies elucidating and mitigating potential effects of iron overload on developing children's developing endocrine organs are needed.
Presentation: Sunday, June 12, 2022 12:30 p.m. - 2:30 p.m.
RF22 | PMON09 BPA and BPF, but not BPS, alter pro- and anti-apoptotic transcript levels in granulosa cells, affecting cell viability.
Authors: Favetta Laura , Kourmaeva Emilia , Sabry Reem 
Published: November 2022

Abstract
Endocrine-disrupting compounds (EDCs) elicit adverse responses in the body, including the disruption of female reproductive functions. A common EDC is Bisphenol A (BPA), which is a frequently used plasticizer. Due to the negative effects of BPA on human health, production of BPA-free products using analogs, such as BPS and BPF, has increased; yet their effects are still largely unknown. Adequate oocyte maturation requires proper functioning of the surrounding environment, consisting of granulosa cells that impact oocyte competency. Granulosa cells are also susceptible to BPA disruption, affecting oocyte maturation and, ultimately, fertility.
In our lab, we showed that BPA and BPS significantly increased apoptosis in bovine embryos through increased DNA fragmentation (Saleh et al., 2021). However, the apoptotic pathway used is not fully characterized. Thus, the aim of this study is to investigate how bisphenols affect granulosa cell viability and through which apoptotic pathway. In vitro cultured granulosa cells were exposed for 12 or 48 hrs to six treatment groups: control, vehicle, estradiol, BPA, BPS and BPF at a low dose (0.005 mg/mL) and at the BPA Lowest Observed Adverse Effect Level (LOAEL-0.05 mg/mL). Live cells were counted using trypan exclusion. A significant decrease in the number of live cells after BPA treatment at the LOAEL dose for 12 hrs was observed (P=0.02, n=9).
mRNA expression of three proapoptotic (BAX, BAD, Casp9) and two antiapoptotic (HSP70 and BCl-2) genes was quantified by qPCR. A significant increase in BAX transcript levels after 12 hrs of exposure to BPA and BPF at the LOAEL dose (P=0.046, P= 0.033, n=6) as well as in BAD (P= 0.049, n=3) and Casp9 (P=0.049, n=4) levels after BPA exposure at the LOAEL dose was detected. Interestingly, at the 48 hr timepoint, a significant increase in BAD (P= 0.018, n= 9), BAX (P=0.002, n=10), and Casp9 (P=0.015, n=5) transcript levels was observed only following BPF treatment at the LOAEL dose. Despite expecting a decrease, both anti-apoptotic transcripts, at 12 and 48 hrs, showed increased levels following exposure to BPA and/or BPF at the LOAEL dose. This suggests an early first line of defense or shock response. Future protein analysis will help in further understanding these unexpected findings.
To quantify apoptosis levels, flow cytometry together with Annexin V/PI staining was used. Results indicate that after 48 hrs of treatment, BPA at the LOAEL dose significantly increases late apoptosis (P=0.004, n=5) and necrosis (P=0.0014, n=5), while showing a significant decrease in the number of healthy cells (P=0.0007, n=5). Preliminary data also show a similar pattern after BPA treatment for 12 hrs. This research aims to further our knowledge of the mechanisms by which bisphenols affect oocyte competency and suggests that BPF might have equivalent potency and effects to BPA.
Presentation: Monday, June 13, 2022 12:30 p.m. - 2:30 p.m.
ODP282 Liver Dysfunction Monitoring in Patients With Turner Syndrome Followed at The Endocrinology Unit of a Tertiary Hospital in The Federal District (Brazil)
Authors: Siqueira Hiloma , Faria Erika , Furtado Adriana , Oliveira Pedro Philippo , Neto Nicãcio , Oliveira Alana , Cunha Jessica , Milward Marina , Rosa Isabella , Lima Cristiane , Carvalho-Louro Daniela Marino 
Published: November 2022

Abstract

Introduction
Liver involvement is common in patients with Turner syndrome. Most patients are asymptomatic and the pathogenesis of these findings remains unclear.

Objectives
The aim of this study is to correlate the main clinical, anthropometric and laboratory characteristics with the findings of hepatic elastography in patients with Turner syndrome.

Methods
We performed an observational cross-sectional study of adult patients diagnosed with Turner syndrome, confirmed by karyotype, without signs/symptoms of acute or chronic liver disease. Anthropometric and laboratory tests were done, including liver enzymes, lipid, and glycemic profile. Patients underwent liver health assessment using transient liver elastography at a tertiary hospital. Continuous variables were compared by Student's t-test and Mann-Whitney test as appropriate, while categorical variables were compared by Chi-square and Fisher exact test as appropriate.

Results
Twenty-three patients were enrolled and completed the study, with valid results from parameters of hepatic elastography. Patients who presented hepatic fibrosis risk on elastography, showed a higher concentration of triglycerides (p=0,046) and ALT/TGP (p=0. 028). The group with fatty liver showed higher concentrations of triglycerides (p=0. 033) and GGT (p=0. 046). Nine patients (34,8%) demonstrated intermediate risk of fibrosis and only one patient (4,8%) had a value suggestive of advanced fibrosis on liver elastography by kPa measurement. On the other hand, the CAP (Controlled Attenuation Parameter) identified steatosis grade I (S1) in 1/23 patients (4.3%), grade II (S2) in 1/23 patients (4.3%), and grade III (S3) in 7/23 patients (30.4%). Hepatic fibrosis and steatosis were not associated with the use of rhGH in childhood (p=0.190), neither with karyotype (p=0.675).

Conclusions
Our data showed a mild relationship among findings of elastography and comorbidities/kariotype. We demonstrate the importance of elastography as a non-invasive method for assessing liver involvement in Turner's syndrome, identifying degrees of fibrosis and steatosis in this population. Thus, fibroscan, with the measures of LSM (liver stiffness measurement) and CAP, emerges as a promising technique in the routine assessment of liver health in patients with Turner syndrome.
Presentation: No date and time listed
OR08-6 A Novel Nonsense Mutation in Delta-Like Non-Canonical Notch Ligand 1 Gene (DLK1) in a French Girl With Central Precocious Puberty
Authors: Latronico Ana Claudia , McElreavey Ken , Brito Nahime Vinicius , Pinheiro Machado Canton Ana , Raja Brauner , Rezende Tinano Flavia , Ribeiro Piovesan Maiara , Montenegro Luciana 
Published: November 2022

Abstract

Background
Central precocious puberty (CPP) results from early reactivation of the hypothalamic-pituitary-gonadal (HPG) axis. Four monogenic causes of CPP have been described (KISS, KISS1R MKRN3 and DLK1). Rare loss-of-function mutations of DLK1, a maternally imprinted gene located on chromosome 14q32.2, were identified in families with CPP. Both inherited or de novo DLK1 mutations were described in these affected families.

Objective
To investigate genetic abnormalities in the DLK1 in a French cohort of patients with idiopathic CPP.
Patients: Genomic DNA was obtained from 122 patients (99 girls and 23 boys) with sporadic or familial CPP. Automatic sequencing of the coding regions of DLK1 gene (5 exons, using Sanger method) was performed in all cases, including 91 familial and 31 sporadic cases.

Results
A pathogenic heterozygous variant in the DLK1 gene (c.372C&gt;A p.Cys124Ter (rs749564412) was identified in a girl with sporadic CPP associated with overweight. This nonsense mutation was considered rare (gnomAD total population 1/251,082) and it was located in the third EGF-like repeat domain in the extracellular region. The affected girl had progressive breast development at 4.5 years and accelerated growth velocity. She had breast development Tanner stage 4 at 5.5 years and bone age (BA) was 6 yr. Her height was 114.5 cm and BMI 18.16 (BMI Z-score = 2.48). Basal LH and FSH was 0.6 IU/L and 5.7 IU/L, respectively. GnRH-stimulated LH and FSH peaks were 14 IU/L and 18 IU/L, respectively, with LH: FSH ratio of 0.77. Other hormonal results were normal (estradiol: 11 pg/mL; ACTH: 11 pg/mL; IGF-1: 235 ng/mL; cortisol: 77 ng/mL). Brain MRI was normal. Pelvic ultrasound revealed uterus length: 49 mm, mucosal thickness of 4 mm, ovaries 20 and 25 mm with follicles less than 10 mm. She was treated with a depot GnRH analog (triptorelin). The DLK1 variant was inherited from her asymptomatic father who had a height of 181 cm. Familial history of CPP history was denied.

Conclusion
DLK1 loss-of-function are rare genetic cause of familial or sporadic CPP. Novel genetic findings in this factor reinforce its role in the physiopathology of the premature HPG axis reactivation and precocious sexual development in humans.
Presentation: Saturday, June 11, 2022 12:45 p.m. - 1:00 p.m.
OR16-3 Analysis of Testis-Enriched Genes in Estrogen-Dependent Genome Regulation in Breast Cancer
Authors: Choudhari Ramesh , Diva Kimberly , Ramos Enrique , Sedano Melina , Yang Barbara , Gadad Shrikanth 
Published: November 2022

Abstract
Emerging studies show that testis-enriched genes play critical roles in several biological processes. The expression of these genes is tightly regulated and limited to immune-privileged organs; however, many of them escape regulation and are aberrantly expressed in several diseases such as cancer. Intriguingly, our genomic analysis revealed that many of them are transcribed from previously considered gene deserts. We also found that a significant number of them are robustly regulated by estrogen and other peptide hormones such as Tumor Necrosis Factor-alpha (TNF alpha). However, their direct role in estrogen-dependent transcriptional regulation and biological outcomes remains unstudied. In this regard, our integrated genomic approach, including RNA with 4-thiouridine (4sU) coupled with RNA-sequencing and CRISPR-based genetic screening, has identified key estrogen-regulated testis-enriched genes that may modulate estrogen-signaling. Through a series of molecular and phenotypic assays, we selected a potential but understudied transcript, which is predominantly localized to the nucleus. Furthermore, in the current study, we have interrogated the functional mechanisms by which selected transcript controls estrogen-dependent gene regulation in estrogen receptor-positive (ER+) breast cancer. We found that the transcript controls estrogen-dependent cell and tumor growth. Additionally, we have manipulated the levels of the transcript in estrogen-receptor-positive (ER+) breast cancer cells employing gain- and loss-of-function studies and performed 4sU-RNA-seq. Interestingly, the transcript modulates the expression of estrogen-driven transcripts that are transcribed from ER-alpha (ERa) binding sites. Mechanistically, the transcript is localized in the nucleus and interacts with chromatin-associated proteins. In addition, our integrated genomic analyses comprising 'Assay for Transposase-Accessible Chromatin using sequencing (ATAC-seq)' and 'chromatin immunoprecipitation (ChIP) with massively parallel DNA sequencing ChIP-seq' (H3K27ac, H3K27me3) identified a critical role for the transcript in controlling the epigenetic landscape at target gene promoters and enhancers in ER+ breast cancer. Collectively, our data support a functional role for testis-enriched genes in enhancer transcription and chromatin organization. This study sheds light on the molecular functions of testis-enriched genes and presents an opportunity to identify new diagnostic and develop treatment strategies in ER+ breast cancer.
S.S.G. is supported by a grant from the Cancer Prevention and Research Institute of Texas (CPRIT; RR170020). S.S.G. is also supported by a grant from Lizanell and Colbert Coldwell foundation.
Presentation: Sunday, June 12, 2022 11:30 a.m. - 11:45 a.m.
OR16-4 Genomic Interrogation of the Phytoestrogen Genistein in Ovarian Cancer Cells
Authors: Kraus W Lee , Hou Tim 
Published: November 2022

Abstract
Although studies have shown beneficial effects of the phytoestrogen genistein on reducing ovarian cancer risk, little is known at the molecular level regarding how genistein inhibits ovarian cancer growth, with estrogen receptor beta (ERb), a hormone-regulated transcription factor, receiving the bulk of the attention. When endogenous and exogenous ligands engage ERb, the receptor binds to regulatory regions in the genome known as enhancers, where it associates with coregulatory proteins, increases histone modifications associated with active enhancers, promotes chromatin looping, stimulates enhancer transcription and the production of enhancer RNAs, and ultimately regulates target gene transcription. Since signaling pathways converge at the transcriptome level, an unbiased approach is needed to examine how genistein acts to suppress ovarian cancer growth beyond ERb. We have previously used global run-on sequencing (GRO-seq), a high-throughput method that identifies the location and orientation of all transcriptionally active RNA polymerases across the genome, to identify active enhancers based on enhancer transcription and enrichment of the aforementioned genomic features. To determine the genomic responses upon genistein treatment in ovarian cancer cells, we have used PRO-seq to characterize the enhancer landscape in OVCAR3 and OVCAR4 ovarian cancer cell lines treated with genistein. The advantage of this method is the lack of a priori assumptions needed to determine which signaling pathways are regulated by genistein, since PRO-seq allows pathway determination based on the universe of active enhancers. Ultimately, this approach will allow us to uncover signaling pathways beyond ERb and determine how genistein acts as a signaling ligand to change the transcriptome in ovarian cancer cells.
Presentation: Sunday, June 12, 2022 11:45 a.m. - 12:00 p.m.