bluuebunny/crossref_metadata_2025_split huggingface dataset:
8368 Functional Evaluation Of Novel CYP21A2 Variants: Expanding The Genetic Basis Of Non-classic CAH
Authors: Matveeva Anna , Xu Yingtong , Tardy-Guidollet Véronique , Pandey Amit V 
Published: October 2024

Abstract
Disclosure: A. Matveeva: None. Y. Xu: None. V. Tardy-Guidollet: None. A.V. Pandey: None.
Introduction: Congenital adrenal hyperplasia (CAH) comprises a group of autosomal recessive genetic disorders affecting the production of glucocorticoids, mineralocorticoids, and gonadocorticoids. In approximately 95% of cases, CAH results from a deficiency in CYP21A2. A Non-Classic form of CAH (NC-CAH) arises when CYP21A2 activity decreases to 20-50% of the normal level, occurring at an estimated frequency of 1 in 200 - 1000 individuals. The clinical picture is characterized by the accumulation of androgen precursors, causing hirsutism, acne, metabolic syndrome, menstrual irregularities, infertility in females, and androgenic alopecia, oligospermia in males. Methods: We selected mutations from CYP21A2 sequence data of patients with NC-CAH symptoms admitted to CHU Lyon, France (L49V, A81T, R125G, I161T, L199F, L289H, L289F, V306D, L462P). Additional variants were selected from the SNP databases (dbSNP, gnomAD, ClinVar) based on a high frequency in humans (H393Q, P387L, T201A, S203G S274Y, S494N, R76K, Leu10del). All variants underwent in silico assessment considering evolutionary, structural, and functional aspects (ConSurf, Predict SNP2, CADD, DANN, FATHMM, FunSeq2, GWAVA, PANTHER, SNPs&GO, PhD-SNP, SIFT, SNAP, Meta-SNP, Polyphen2, HDIV, DUET). The CYP21A2 proteins carrying the mutations were overexpressed in HEK 293T cells. We evaluated CYP21A2 enzyme activities by measuring the conversion of 14C-Progesterone into 11-deoxycortisol by thin layer chromatography and autoradiography. Samples were tested in duplicates, using the activity of WT CYP21A2 as a control. Results: Computational analysis revealed that A81T, R125G, I161T, and L289H substitutions significantly impair protein structure, while other variants showed moderate effects. Except for L199F, all patient-derived variants exhibited reduced 21-hydroxylase (CYP21A2) activity associated with NC-CAH phenotypes. Variants from databases did not demonstrate a significant loss of function related to CAH. Conclusion: In this study we investigate the pathogenicity of uncharacterized CYP21A2 variants in relation to non-classic congenital adrenal hyperplasia (NC-CAH), contributing to a better understanding of associated phenotypes. The findings, particularly the identification of novel mutations and the assessment of their impact on CYP21A2 activity, hold promise for improving diagnosis and treatment strategies aimed at mitigating severe outcomes of NC-CAH, such as miscarriages or irreversible alopecia. It also raises awareness among heterozygous carriers, assisting in family planning and medical decisions.
Presentation: 6/1/2024
7812 Community Practice Setting Experience in Evaluation of Incidental Thyroid Nodules
Authors: Abate N , Rhodes H , Horlavadi M , Adams-Huet B , Chandalia M 
Published: October 2024

Abstract
Disclosure: N. Abate: None. H. Rhodes: None. M. Horlavadi: None. B. Adams-Huet: None. M. Chandalia: Advisory Board Member; Self; Boehringer Ingelheim. Speaker; Self; Boehringer Ingelheim, Eli Lilly & Company, Novo Nordisk.
Background: There is a significant increase in detection of incidental thyroid nodules due to increase in routine screening ultrasounds at church, workplace, and health fairs, increase in routine ultrasound in primary care clinics and incidental finding of thyroid nodule during carotid artery ultrasound. These patients are then referred for thyroid nodule fine needle aspiration biopsy. Aim of this study was to evaluate real world data in frequency of thyroid cancer in patients referred for incidental thyroid nodule to a nonacademic Endocrinology clinic utilizing centralized collection of cytology and molecular analysis. Method: Medical records were reviewed for consecutive FNA of incidental thyroid nodule in an Endocrinology clinic in greater Houston from 2021 to 2023. FNA was performed in patients selected based on ACR TI-RADS classification. Patients with Bethesda score of 3 or more had molecular testing with Thyroseq performed. Patients with intermediate or high probability of cancer on Thyroseq as well as Patients with Bethesda 4 and 5 on cytopathology were referred for surgery. Surgical pathology was obtained in patients who underwent surgery. Data was tabulated and analyzed using SAS. Results: A total of 304 subjects, 267 Female and 37 males, age 57 ± 13, nodule size 2.69 ± 1.4 (mean ± SD), had thyroid nodule FNA between 2021 and 2023. Of these FNA, 23 (7.5%) sample collections were insufficient, 233 (77.3%) were benign (Bethesda 2), 46 (15%) were Atypia of undetermined significance or Suspicious for malignancy. Of those subjects with Bethesda 3 or higher, 36 patients had molecular testing by Thyroseq Method. Fifteen patients had intermediate and high risk finding on Thyroseq. Thirty-four subjects had surgery and 8 patients had malignancy on surgical pathology. One patient was identified as Medullary Thyroid cancer on Thyroseq, confirmed by surgery. Frequency of malignancy in incidentally detected thyroid nodule in the whole group was 2.6%, those with Bethesda 3 and more was 17.4% and those with Thyroseq intermediate or high risk was 27%. Conclusion: Availability of centralized cytopathology and reflex molecular testing to Community practice settings helps reducing unnecessary thyroid surgeries in patients with incidental thyroid nodules.
Presentation: 6/1/2024
8534 Comorbid Autoimmune Thyroid Disease in a Parent-Child Pair with Resistance to Thyroid Hormone Beta
Authors: Smith A H , Grethen E 
Published: October 2024

Abstract
Disclosure: A.H. Smith: None. E. Grethen: None.
Resistance to Thyroid Hormone Beta (RTHβ) is an inherited disorder caused by mutations in the gene encoding the thyroid hormone receptor beta protein, resulting in decreased binding affinity to triiodothyronine in certain tissues. An asymptomatic individual with RTHβ may demonstrate abnormalities in serologic evaluation of thyroid hormone markers. When other thyroid pathologies present with RTHβ, however, the diagnosis and management can quickly become complex. Below we discuss two cases, a parent-child pair, with different presentations of presumably the same RTHβ gene. Patient 1 is a 61-year-old male with a history of autoimmune thyroiditis several years ago, presenting for continuation of care; he has had levothyroxine doses gradually uptitrated to over 3 mcg/kg to normalize TSH despite persistently high free T4 levels. He also has a family history notable for six out of seven siblings with autoimmune thyroid disease. Patient 2 is a 44-year-old male who was evaluated for hypothyroidism and difficulty with levothyroxine titration. Prior to consultation, he underwent radioactive iodine ablation for presumed Grave’s disease, followed by total thyroidectomy due to persistent symptoms. Post-operatively, he required high doses of levothyroxine to maintain normal TSH levels; however T4 and T3 levels remained high. Both patients confirmed proper levothyroxine supplementation. Further analysis of both patients demonstrated mildly elevated TBG and normal alpha subunit. Patient 2 pursued genetic testing while patient 1 declined, revealing a heterozygous R320S mutation in the TR-beta protein. Further testing and genetic counseling were offered to other family members. Propranolol and levothyroxine supplementation were titrated accordingly; triiodothyronine administration was attempted but did not alleviate symptoms. These two cases demonstrate the increased risk of autoimmune thyroid disorders in patients with RTHβ and the unique challenges they pose in accurate diagnosis. Autoimmune thyroiditis in RTHβ, with goiter, elevated T4 and elevated T3 levels, can be easily confused with Grave’s disease, especially when TSH is suppressed during active thyroiditis. Timely diagnosis can aid in targeted management of sequelae, prevent ineffective treatments for comorbid conditions which may mimic other diseases, and provide anticipatory/preventive guidance for family members to help with screening.
Presentation: 6/1/2024
6502 Comparing TBII vs TSI Assays at University Hospital; A Quality Improvement Project
Authors: Chozet Luis Edmundo , Le Guillaume , Vasco Maria Adelaida Escobar , Bruder Jan 
Published: October 2024

Abstract
Disclosure: L.E. Chozet: None. G. Le: None. M.A. Escobar Vasco: None.
Radionuclide uptake and scan in the setting of thyrotoxicosis is considered the gold standard test to diagnose Graves' disease (GD). However, TSH-receptor antibodies (TRAB) tests are now being used as optional first-line tests given their widespread availability and cost-effectiveness. Thyrotropin-binding inhibitory immunoglobulin (TBII) and thyroid-stimulating immunoglobulin (TSI) assays are commonly obtained in patients admitted with thyrotoxicosis. Both assays are readily available at our institution. Our project aimed to further review and compare these two assays. To determine turnaround times of these assays at our institution, as well as cost-effectiveness of ordering both TBII and TSI assays vs only ordering one assay. We did a retrospective evaluation of 27 patients with lab evidence of thyrotoxicosis at University Hospital between April 2022, and May 2023 who were tested with both TBII, TSI assays simultaneously during their hospital stay to compare their concordance. We then compared turnaround times in days for laboratory results to be available. TBII, TSI assays are not done in-house. They are instead sent to an outside laboratory. Our hospital pathology services provided us with information regarding lab costs. We investigated which assay is more cost-effective. Based on our data, TBII and TSI were concordant in almost all patients evaluated (26 out of 27). Ordering TBII as the first initial test for GD is more cost-effective than ordering both TSI, TBII simultaneously. Our findings are consistent with previous studies, which suggest that ordering both assays (TBII and TSI) could be reserved for patients where the diagnosis of GD is not clear.
Presentation: 6/3/2024
6431 Comparison of Diagnostic Scoring Systems for Myxedema Coma
Authors: Wei K S , Joyo A , Lim A N , Angell T E 
Published: October 2024

Abstract
Disclosure: K.S. Wei: None. A. Joyo: None. A.N. Lim: None. T.E. Angell: None.
Introduction: Myxedema coma (MC) is a rare condition of severe hypothyroidism with high mortality. Diagnostic scoring systems exist, such as criteria by Popoveniuc et al. (2014) and Chiong et al. (2015), which both include categories of: “highly likely MC” (hlMC), “suggestive of MC” (sMC), and “unlikely MC” (uMC). Because few data support their clinical utility, we performed an analysis comparing these diagnostic criteria and associations with mortality and hospital measures. Methods: Patients with MC were included from a retrospective cohort of hospitalized adult patients with TSH greater than or equal to 10 mIU/L and free thyroxine (fT4) below the lower reference limit. Initial clinical diagnosis of MC was generally based on: hypothyroidism, precipitating illness, hypothermia, and altered mentation. Data collection included patient characteristics, mortality, ICU admission, and hospital length of stay (LOS). Patients were post-hoc categorized based on criteria of Popoveniuc and Chiong. Results: Of 386 initial patients, 25 patients had a clinical diagnosis of MC (median age = 60.1 years [IQR: 53.6-70.0]; 10/25 [40%] female). Median TSH was 58 mIU/L (IQR: 33.8-93.3) and median fT4 was 0.48 ng/dL (IQR: 0.16-0.68). All patients received IV levothyroxine and supportive care. Using Popoveniuc, 20/25 (80%) patients were hlMC and 5/25 (20%) were sMC. In contrast, using Chiong, 11/25 (44%) were hlMC, while 14/25 (56%) were sMC. No patient was considered uMC by either system. 10/25 (40%) patients were hlMC in both systems. 10/25 (40%) were hlMC in Popoveniuc but not Chiong, while only 1/25 (4%) was hlMC in Chiong but not Popoveniuc. Finally, 4/25 (16%) were not hlMC in either system. Mortality occurred in 3/25 (12%) patients, 2 of which were hlMC in Popoveniuc but not Chiong. There was a trend toward longer median hospital LOS in patients identified as hlMC vs not hlMC using Popoveniuc (11 days [IQR: 5.3-37.0] vs. 3.0 days [IQR: 2.0-17.5], p=0.07) but no statistically significant differences in hospital LOS were noted. There were no significant differences in ICU admission or LOS. Conclusion: Existing diagnostic scoring criteria of MC identified most patients but differed in their categorizations. Some cases of clinically diagnosed MC were not identified as hlMC by either scoring criteria. Criteria by Popoveniuc et al. appears to better capture patients most at risk for mortality and prolonged hospitalization.
Presentation: 6/2/2024
7876 Complex Complications of Thionamide Therapy in One Patient: Methimazole-Induced Agranulocytosis and PTU-Induced ANCA-Vasculitis
Authors: Zweibach Eugenia , Chang Amy 
Published: October 2024

Abstract
Disclosure: E. Zweibach: None. A. Chang: None.
Introduction: Thionamides, including methimazole and propylthiouracil (PTU), are essential for treating Graves' disease but can cause serious side effects such as agranulocytosis and ANCA-vasculitis. Although agranulocytosis itself is quite uncommon, the incidence of ANCA vasculitis is even more infrequent, making combination of conditions particularly exceptional. We present a unique case of a Graves' disease patient who suffered both complications: agranulocytosis due to methimazole and ANCA vasculitis from PTU, with successful resolution of both the clinical signs and laboratory findings following drug discontinuation. Case: 61-year-old female with a history of Graves' disease previously managed with methimazole but discontinued due to agranulocytosis, presented with lower extremity swelling, atrial fibrillation with RVR, and high output cardiac failure. Laboratory tests showed hyperthyroidism (TSH 0.008, Free T4 3.07), leading to a diagnosis of thyroid storm. Patient was started on PTU inpatient and discharged with this medication to home. Eight months later, the patient developed alarming signs including gross hematuria, oral ulcers, widespread muscle pain, found to have AKI with Cr of 2.79 and hospitalized for further eval. While hospitalized, the patient was found to have a range of complications including leukopenia with normal granulocyte count, anemia, AKI, proteinuria, and microscopic hematuria. Rheumatological evaluation showed +ANA and a high ANCA titer &gt;1:1280, along with elevated levels of MPO and PR-3, and reduced complement levels. These symptoms and laboratory findings led to a diagnosis of ANCA vasculitis induced by PTU, resulting in the cessation of this medication. Following the discontinuation of PTU there was a notable improvement with normalization of serum Cr and resolution of proteinuria within 1.5 months. Concurrently, MPO and PR-3 levels began to decrease, and her hematological abnormalities resolved. During this period, her Free T4 levels gradually increased, leading to the administration of radioactive iodine for the treatment of her Graves' disease. Discussion: This case underscores the complexities in treating a patient with Graves' disease highlighting the unpredictable and severe side effects of antithyroid drugs like agranulocytosis and ANCA vasculitis. We report the first documented case of sequential thionamide-induced complications: agranulocytosis with methimazole, followed by ANCA vasculitis with propylthiouracil. Although both can arise from immune responses to these medications, they are distinct in their pathophysiology and are not associated with one another. The unpredictable nature of these side effects complicates prevention. Educating patients to promptly report any unusual symptoms and immediate medical intervention with drug discontinuation are key to managing these adverse reactions effectively.
Presentation: 6/1/2024
8588 Cribriform Thyroid Cancer with Novel STK11 and KEAP1 Mutations
Authors: Ruiz Dannel Diaz , Chemitiganti Ramachandra Rahul V , Suravajjala Devi , Eranki Madhuri , Case James 
Published: October 2024

Abstract
Disclosure: D. Diaz Ruiz: None. R.V. Chemitiganti: None. D. Suravajjala: None. J. Case: None.
Mrs. CS is a 69-year-old female with a medical history of Hashimoto thyroiditis evaluated for incidentally detected thyroid nodules. She was euthyroid and was found to have multiple nodules on thyroid sonography - Two TI-RADS 5 (TR5) nodules in the right mid pole(3cm) and inferior pole(1.8cm) and a third TR2 nodule in the in the inferior pole (&lt;1 cm). She declined a biopsy and was lost to follow-up during the Covid pandemic. She returned for new pressure symptoms in the neck and now had a large palpable right thyroid mass. A repeat sonogram now showed a TR5 thyroid nodule (4.4 cm) of the right lower pole. The other two TR5 nodules were unchanged. Thyroid FNA biopsy indicated - malignant, poorly differentiated carcinoma of thyroid origin (Bethesda stage VI). The cytology and cell block preparations were cellular and showed sheets of epithelial cells with crowded round to ovoid nuclei. The nuclei showed rare intranuclear inclusions. Immunohistochemical stains were positive for both TTF-1 and PAX-8. BRAF p.V600E c.1799T&gt;A were negative. RET/PTC1, RET/PTC3 were not detected. She underwent an uneventful total thyroidectomy; the surgical pathology report revealed a Cribriform Thyroid Cancer (CTC) with vascular invasion. Post Thyroidectomy I-131 whole body scan was positive for only focal uptake on the right thyroid bed extending into the right lower neck. Bone scan, Head and chest CT were negative for metastases. Cancer genome sequencing studies identified Serine/threonine kinase 11 (STK11) and Kelch-like ECH-associated protein 1 (KEAP1) mutations. Adenomatous polyposis coli (APC) and beta-catenin (CTNNB1) mutations were absent. Cribriform Thyroid Cancer is proposed as a distinct form of thyroid carcinoma unrelated to other neoplasms of thyroid follicular cells. It is an extremely uncommon malignancy that usually affects younger women (18-59 yrs; mean age 33). They were initially described as cribriform variant of papillary thyroid cancer associated with familial adenomatous polyposis (FAP) syndrome. Sporadic forms are known to occur due to somatic alterations in the Wnt/beta-catenin pathway. Germline or somatic mutations of Adenomatous polyposis coli (APC) gene and somatic mutations of the beta-catenin (CTNNB1) gene are usually present in CTC. Inherited mutations in the STK11 gene are associated with Peutz-Jeghers syndrome and an increased risk of developing other cancers. While KEAP1 somatic mutations disproportionately occur in non-small-cell lung, liver, endometrial, bladder and squamous cell cancers. Human germline mutations in KEAP1 are rare. One report in a five-generation multinodular goiter family identified the first KEAP1 mutation, none are yet to be reported in a sporadic form of CTC. This case showcases and adds to our knowledge of unique mutations associated with sporadic form of CTC.
Presentation: 6/3/2024
9176 Deep Learning Analysis with Gray Scale and Doppler Ultrasonography Images to Differentiate Graves’ Disease
Authors: Baek H S , Lim D 
Published: October 2024

Abstract
Disclosure: H. Baek: None. D. Lim: None.
Abstract Context: Thyrotoxicosis requires accurate and expeditious differentiation between Graves’ disease (GD) and thyroiditis to ensure effective treatment decisions. Objective: This study aimed to develop a machine learning algorithm using ultrasonography and Doppler images to differentiate thyrotoxicosis subtypes, with a focus on GD. Methods: This study included patients who initially presented with thyrotoxicosis and underwent thyroid ultrasonography at a single tertiary hospital. A total of 7,719 ultrasonography images from 351 patients with GD and 2,980 images from 136 patients with thyroiditis were used. Data augmentation techniques were applied to enhance the algorithm’s performance. Two deep learning models, Xception and EfficientNetB0_2, were employed. Performance metrics such as accuracy, sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and F1 score were calculated for both models. Image pre-processing, neural network model generation, and neural network training results verification were performed using DEEP:PHI® platform. Results: The Xception model achieved 84.94% accuracy, 89.26% sensitivity, 73.17% specificity, 90.06% PPV, 71.43% NPV, and an F1 score of 89.66 for the diagnosis of GD. The EfficientNetB0_2 model exhibited 85.31% accuracy, 90.28% sensitivity, 71.78% specificity, 89.71% PPV, 73.05% NPV, and an F1 score of 89.99. Conclusion: Machine learning models based on ultrasound and Doppler images showed promising results with high accuracy and sensitivity in differentiating GD from thyroiditis.
Presentation: 6/1/2024
8465 Diagnostic Conundrum: The Mystery of Metastatic Papillary Thyroid Cancer with Persistently Elusive Thyroglobulin
Authors: Vemparala Pranathi , Bollineni Mohini Vijayalakshmi 
Published: October 2024

Abstract
Disclosure: P. Vemparala: None. M. Bollineni: None.
Introduction- Among endocrine malignancies, differentiated thyroid cancers account for the majority with most of them boasting a favorable prognosis. Thyroglobulin, a pivotal biochemical marker, aids in detecting recurrence or persistent disease when combined with neck ultrasound, I-131 scintigraphy, and FDG PET scans. Anti-thyroglobulin antibodies, found in a quarter of cases, can falsely lower serum thyroglobulin levels in immunometric assays. Our intriguing case features a patient with metastatic papillary thyroid cancer, yet thyroglobulin levels persistently eluded detection. CASE PRESENTATION- A 33-year-old female presented initially to an outside facility with neck swelling, leading to a diagnosis of a 4 x 3 cm papillary thyroid cancer (PTC) in the right lobe and a 0.5 x 0.5 cm focus of PTC in the left lobe, accompanied by capsular extension, malignant cells in the left lobe margin, and lymphovascular invasion. After total thyroidectomy and lymph node exploration, radioactive iodine scan detected disease in right-sided lymph nodes, treated subsequently with radioactive iodine ablation. Two years later, she presented to our clinic with neck swelling, voice changes, and fatigue. Thyroglobulin level was measured which returned at &lt;0.1 ng/ml, however thyroglobulin antibodies were elevated at 292 IU/ml, albeit decreased from a value of 431.5 IU/ml at initial diagnosis. Elevated thyroglobulin antibodies complicated interpretation, prompting liquid chromatography-mass spectrometry (LC-MS) for accurate measurement of thyroglobulin, which returned at &lt;0.5 ng/ml. Ultrasound indicated metastatic disease in right cervical lymph nodes, confirmed by fine needle aspiration. In-office ultrasound-guided FNA of additional nodes validated metastasis. Modified radical neck dissection revealed metastatic PTC in 7 out of 34 lymph nodes. Surprisingly, thyroglobulin levels remained &lt;0.5 ng/ml, pre- and post-operatively. Referred for radioactive iodine ablation, her complex journey underscored the challenges in monitoring thyroid cancer recurrence or persistent disease with thyroglobulin levels even by methods such as mass spectrometry. Conclusion- Key learnings from this case highlight the importance of cognizance in utilizing thyroglobulin levels to guide adjuvant therapy decisions and for postoperative monitoring in high risk patients, as low levels do not rule out recurrence or persistence. Anti-thyroglobulin antibodies pose challenges, necessitating techniques like LC-MS. Finally, recognizing “nonsecretor” thyroid cancers, an aggressive subgroup with poorer prognosis, is vital as they often present with low or undetectable thyroglobulin levels.
Presentation: 6/2/2024