bluuebunny/crossref_metadata_2025_split huggingface dataset:
THU533 Cowden Syndrome: A Rare Disease With A Lasting Impact
Authors: Hastings Camden S , Patrick Stephanie A , James Deirdre 
Published: October 2023

Abstract
Disclosure: C.S. Hastings: None. S.A. Patrick: None. D. James: None.
Introduction: Cowden Syndrome (CS) is a genetic condition caused by an autosomal dominant mutation in the phosphatase and tensin homolog (PTEN) tumor suppressor gene. The prevalence of CS is approximately one in 200,000 and onset is typically in the second decade of life. It is characterized by multiple benign or malignant skin tumors, non-medullary thyroid cancer, breast carcinoma, endometrial carcinoma, gastrointestinal hamartomas, renal cell carcinoma, and/or developmental delay. CS is typically underdiagnosed due to the variety of phenotypic presentations. Case Description: We present a case series of Cowden Syndrome. The first patient was a 51-year-old male with follicular thyroid cancer status post radiation and thyroidectomy, multiple gastrointestinal polyps, trichilemmomas, and an extensive family history of cancer. These factors led to an increased suspicion for CS. The patient underwent genetic testing for PTEN mutations in 2022 and was heterozygous for the c.723dupT pathogenic PTEN mutation as well as p.S598L mutation. The second patient was an 18-year-old female with developmental delay, autoimmune hypothyroidism, multinodular goiter who presented with an increasing number of thyroid nodules on annual thyroid ultrasounds. Her thyroid nodule biopsy revealed follicular and papillary thyroid carcinoma requiring total thyroidectomy. Her mother had a known history of CS. Genetic testing revealed she was heterozygous for the p.S1701 pathogenic mutation in the PTEN gene. Diagnosis of CS involves a combination of family history, presence of mucocutaneous lesions, and either thyroid, breast, or endometrial carcinoma. Given the higher likelihood of cancers in these patients, routine screening for thyroid, breast, kidney, and colon cancers should begin at an earlier age. Treatment includes topical agents such as fluorouracil or excision surgery for skin lesions. Treatment of malignancy is similar to sporadic counterparts and involves systemic immunosuppressants, chemotherapy, or surgery. Conclusion: Cowden Syndrome is a rare genetic condition resulting in tumors in a variety of organ systems, placing patients at a higher risk of malignancy. A strong family history of malignancy, as well as skin, breast, GI, or thyroid findings should prompt further investigation. Collaboration between dermatology, oncology, gastroenterology, endocrinology, and neurology is essential for successful treatment. Routine screening for these patients includes thyroid studies every 3-4 months, thyroid ultrasound yearly, colonoscopy every two years, and renal CT or MRI yearly. Early diagnosis of the condition is pivotal for close cancer surveillance and management.
Presentation: Thursday, June 15, 2023
THU534 Humoral Hypercalcemia Of Malignancy As Initial Presentation Of Hepatocellular Carcinoma And Monoclonal Gammopathy Of Undetermined Significance
Authors: Jovanovic Filip , Raghavan Aravind , Sudhakar Aboorva 
Published: October 2023

Abstract
Disclosure: F. Jovanovic: None. A. Raghavan: None. A. Sudhakar: None.
Background: Humoral hypercalcemia of malignancy can be initial metabolic manifestation of different neoplasms, and it is exceedingly rare in hepatocellular carcinoma (HCC).1 In this case report, we present a patient with humoral hypercalcemia secondary to HCC and monoclonal gammopathy of undetermined significance (MGUS) in the context of nonalcoholic steatohepatitis. Case Report: A 73-year-old Caucasian male with liver cirrhosis secondary to nonalcoholic steatohepatitis presented to the emergency department with a two-week history of constipation and progressive confusion. The patient was jaundiced on exam and tender to palpation in left and right middle abdominal quadrants. Laboratory findings on admission showed serum calcium 12.7 mg/dL (7.9–10.6), albumin 2.6 g/dL (3.5–5), platelets 85x103/µL (138–338), alkaline phosphatase 349 unit/L (50–136), alanine aminotransferase 234 unit/L (15-53), aspartate aminotransferase 133 unit/L (15–37), alpha-fetoprotein 1912.7 ng/mL (0–8), parathyroid hormone &lt;3 pg/mL (14–72), and ammonia 40 mmol/L (11–32). The patient’s altered mental status improved with lactulose and rifaximin. Serum calcium levels persisted despite lactated Ringer’s solution, but improved with zoledronic acid 5 mg infusion to a nadir of 9.1 mg/dL during the hospital stay. The patient was administered repeat zoledronic acid before discharge, but was readmitted 5 days later with worsening mental status and corrected serum calcium 13.1 mg/dL. The CT abdomen and pelvis showed a mass (4.2 x 3.7 cm) in the lower right hepatic lobe. The send out labs returned with PTH-related peptide 48 pg/mL (11–20), 1,25 hydroxyvitamin D 20 pg/mL (20–45), and serum protein electrophoresis with a monoclonal M spike 1.33 g/dL in the gamma globulin region. The patient’s hypercalcemia was found to be PTH–independent and with the new hepatic mass on CT imaging, he was diagnosed with MGUS and humoral hypercalcemia secondary to HCC. The literature review shows only one case report with alcoholic cirrhosis and similar clinical presentation, which is in contrast to nonalcoholic steatohepatitis as seen in our patient.2 The patient’s family refused further treatment and opted for hospice care. Conclusion: We recommend that the patients with HCC and resistant hypercalcemia undergo diagnostic evaluation for monoclonal paraprotein as part of humoral hypercalcemia workup.
References:
(1) Luo JC, Hwang SJ, Wu JC, Li CP, Hsiao LT, Lai CR, Chiang JH, Lui WY, Chang FY, Lee SD. Paraneoplastic syndromes in patients with hepatocellular carcinoma in Taiwan. Cancer. 1999 Sep 1;86(5):799-804.
(2) Gentric A, Pennec Y, Jouquan J, et al. [Hepatoma manifesting monoclonal gammapathy and hypercalcemia]. Ann Gastroenterol Hepatol (Paris). 1984 Jul-Sep;20(4): 211-2.
Presentation: Thursday, June 15, 2023
THU546 A Lasofoxifene/Elacestrant Hybrid Antiestrogen Shows Effective Anti-tumoral Activities In Y537S ESR1 Breast Cancer Xenografts
Authors: Young Kristen S , Hancock Govinda R , Kregel Steven , Fanning Sean William 
Published: October 2023

Abstract
Disclosure: K.S. Young: None. G.R. Hancock: None. S. Kregel: None. S.W. Fanning: Advisory Board Member; Self; Olema Oncology. Grant Recipient; Self; Olema Oncology.
In the United States, breast cancer is the second leading cause of cancer related deaths among women. Over 70 percent of these breast cancer cases are classified as overexpressing Estrogen Receptor alpha (ERα), denoting that the hormone estrogen fuels the cancer growth. In ER+ breast cancer patients, a distinct tyrosine to serine missense mutation at position 537 (Y537S) leads to hormone- independent ERα activity, causing drug resistance and increased metastatic potential. By favoring the active conformation of ERα, the Y537S mutation reduces binding affinity of small molecule drugs by 5-10 fold. Additionally, this mutation adversely effects the allosteric rearrangement of the receptor that is needed to achieve therapeutic efficacy. Recently, we identified a common structural interaction that distinguishes effective versus ineffective therapeutic antagonists in Y537S breast cancer cells. Based on this relationship, we have developed a new isoquinoline- based antiestrogen (T6I-29-1A) to aid in interpretation of the relationship between ligand binding pose and antagonistic efficacy. Our data suggest that this novel pose effectively antagonizes mutant ERα in breast cancer cells by significantly blunting cell proliferation and downregulating transcriptional activity. Importantly, T6I-29-1A shows potent anti-tumoral activity in ectopic murine xenografts of Y537S ESR1 MCF7 cells, is orally available, and shows a favorable DMPK and ADME profile. Additionally, mice treated with T6I-29-1A exhibited decreased distant metastases compared to hormone-only control. Collectively, these studies point to a distinct relationship between ERα ligand binding pose and novel anti-metastatic activities in drug resistant Y537S ESR1 breast cancer cells.
Presentation: Thursday, June 15, 2023
FRI227 Functional Transformation Of An Initially Non-functional Paraganglioma In A Patient With Cyanotic Congenital Heart Disease
Authors: McConnell Megan , Kanin Maralee , Auerbach Martin S , Yu Run 
Published: October 2023

Abstract
Disclosure: M. McConnell: None. M. Kanin: None. M.S. Auerbach: None. R. Yu: None.
Background: Most pheochromocytomas and about half of paragangliomas (P-PGLs) are functional in that they produce catecholamines. Transformation of non-functional to functional P-PGLs is exceedingly rare. We present a case of such transformation in a young male with cyanotic congenital heart disease (CCHD), resulting in catecholamine-induced cardiomyopathy. Clinical Case: A 27-year-old male with CCHD presented to the hospital with tachycardia, hypertension, and hypoxia. He had a newly depressed ejection fraction of &lt;20% and was in florid heart failure. Despite intervention, he decompensated rapidly, requiring extracorporeal membrane oxygenation (ECMO). Five years prior to this presentation, he had had normal 24-hour urine fractionated metanephrines, vanillylmandelic acid (VMA), and homovanillic acid (HVA) levels; on imaging, he had been incidentally found to harbor a 3.3 x 1.6 x 2.5-cm nodule in the upper aortocaval space which could represent a paraganglioma. Subsequent imaging showed slow growth of this mass. Given this pertinent history, urine and plasma free metanephrine studies were repeated during the hospitalization while he was not on vasopressors. 24-hour urine normetanephrines were elevated at 2,644 mcg/d (81-667 mcg/d), metanephrines at 405 mcg/d (55-320 mcg/d) while plasma free metanephrines were elevated at 0.92 nmol/L (0-0.49 nmol/L) and normetanephrines at 11.85 nmol/L (0-0.89 nmol/L). DOTATATE PET/CT revealed a soft tissue mass measuring 4.3 x 3.1 x 4.9 cm with intense DOTATATE activity in the right paravertebral space between the aorta and cava. He was treated with alpha-adrenergic blockade with improvement in blood pressure. Two months later, he underwent resection of the mass with pathology confirming a 4.9 cm paraganglioma. Conclusion: It is very rare for a paraganglioma to undergo transformation from non-functional to functional status although it is reported in the literature. This scenario is supported by our patient’s normal 24-hour urine metanephrines, VMA, and HVA results on initial presentation followed by marked elevation in urine and plasma metanephrines 5 years later when he presented with heart failure. The functional transformation in this patient was accompanied by significant growth of the paraganglioma. We surmise that alterations in gene expression during tumor growth may be responsible for the functional transformation. It is crucial to reassess the functionality of a paraganglioma if the clinical condition suggests catecholamine excess.
Presentation: Friday, June 16, 2023
FRI228 Primary Adrenal T-cell Lymphoma: A Case Report
Authors: Tabassum Humera , Xu Shiming , Manavalan Anjali 
Published: October 2023

Abstract
Disclosure: H. Tabassum: None. S. Xu: None. A. Manavalan: None.
Introduction: Primary T-cell adrenal lymphoma (PAL) is exceedingly rare. Adrenal insufficiency (AI) is common in these cases. Here we describe a patient with bilateral, large, T-cell PAL with rapid progression, without adrenal insufficiency. Clinical Case: A 62-year-old male, with coronary artery disease and recent coronary intervention, hyperlipidemia and hypertension presented to the hospital with abdominal pain, fever, night sweats and weight loss for a month. Work up revealed a 5.8 cm left adrenal mass with 14% absolute washout, measuring 34 Hounsfield Units (HU) pre-contrast, 68 HU postcontrast, and 63 HU on delayed images, and a 5.2 cm right adrenal mass with 42% absolute washout, measuring 35 HU pre-contrast, 81 HU postcontrast, and 62 HU on the delayed images with no other suspicious lesions or lymphadenopathy. The patient demonstrated no clinical symptoms or signs of adrenal hormone excess or deficiency. Levels of renin, aldosterone, serum cortisol, ACTH, 24-hour urine free cortisol, serum metanephrines, and thyroid function were normal. Additional tests to rule out adrenal cortical carcinoma (ACC) revealed normal levels of androstenedione, 17-hydroxyprogesterone, dehydroepiandrosterone sulfate, and estradiol. Persistent non-significant elevation of 11-deoxycortisol was observed at 51 ng/dL and 63ng/dL (Ref &lt; 42 ng/dL). Adrenal biopsy was suggested but deferred due to the increased risk of hemorrhage given recent coronary revascularization and use of dual antiplatelet therapy. Follow up imaging in a few weeks revealed diffuse, retroperitoneal lymphadenopathy with unchanged adrenal masses. A lymph node biopsy confirmed a diagnosis of peripheral T-cell lymphoma. The left adrenal gland demonstrated an uptake SUV of 22.7 and the right, 19.17 on FDG PET. The patient was initiated on chemotherapy with etoposide, prednisone, vincristine sulfate, cyclophosphamide, and doxorubicin. Imaging three months later revealed a marked decrease in FDG activity SUV 6.98 g/mL on the left and SUV up to 3.32 g/mL on the right. Adrenal function remained intact on follow up. Conclusion: Peripheral T-cell lymphoma with adrenal involvement is an extremely rare and aggressive disease with rapid progression. Mostly seen in males over the age of 50, it may present with abdominal pain, B symptoms or both. While ACC is usually unilateral, lymphoma and metastatic disease may present bilaterally, however, other imaging features can be similar. AI is expected when 90% of the adrenal glands are destroyed by tumor infiltration, however, this does not always correlate with tumor size. In our patient, AI was not observed on presentation or follow up. As adrenal insufficiency can occur at any time in the disease course and may mimic symptoms of cancer or chemotherapy, the clinician should always be vigilant for its development in these cases.
Presentation: Friday, June 16, 2023
FRI233 Adrenal Insufficiency Due To An Unusual Culprit
Authors: Decamps Scarlett , Yeung Kay T , McCowen Karen 
Published: October 2023

Abstract
Disclosure: S. Decamps: None. K.T. Yeung: None. K. McCowen: None.
Background: Chronic exogenous use of glucocorticoids is the most common cause of reversible secondary adrenal insufficiency (AI). There is a significant risk of cortisol deficiency if the medication is abruptly discontinued. Chronic glucocorticoid therapy may cause hypothalamic-pituitary-adrenal (HPA) axis suppression, resulting in low ACTH, atrophy of the adrenal zona fasciculata and decreased cortisol production. Immunotherapy rarely causes reversible central AI, usually permanent. We present a case of an immunotherapy-receiving patient who presented with biochemical evidence of adrenal insufficiency after using an oral solution (swish and spit) of dexamethasone as prophylaxis for mucositis. Patient Summary: A 52-year-old woman with stage IIb triple negative breast cancer receiving neoadjuvant Datopotamab, Dertuxtecan and Durvalumab was evaluated for adrenal insufficiency. Prior to starting therapy, serum cortisol level measured 7.9 mcg/dL at 11 AM (normal 6.0-18.4 mcg/dL at 6-10 A.M). She had received a single dose of dexamethasone 10 mg IV with her first cycle, but not thereafter. As part of the immunotherapy protocol, serial cortisol levels were obtained, and 2 weeks after the baseline, noon serum cortisol was 1.0 ug/dL. Patient was asymptomatic. At no point were glucocorticoids replaced, but 1-week later serum cortisol level was 0.6ug/dL at 11:00 AM along with an ACTH of 5 pg/mL. Immunotherapy-induced AI was strongly suspected. Her only glucocorticoid exposure had been a dexamethasone oral mouth rinse (swish 10mL for 1 minute and spit out, four times daily). Cortisol level at 7AM a week later measured 3.5 mcg/dL with ACTH 18.7 pg/mL and a dexamethasone level 108.2 ng/dL (normal &lt; 50 ng/dL for patients not on dexamethasone). Technique of swish and spit was reviewed with the patient, and she was not ingesting the medication. An observational approach was pursued at this time given hemodynamic stability, treatment was continued and several weeks later repeat labs showed cortisol levels of 3.3 (7AM), with a dexamethasone level of 84.3 ng/dL. Her course of therapy has been completed, so she has been off the dexamethasone solution, continues to be asymptomatic and repeat labs now show a 9AM Cortisol level of 9.5 mcg/dL and, given lack of other sources, it is most likely that these low cortisol levels along with elevated dexamethasone levels are related to the use of dexamethasone swish and spit rather than immunotherapy induced permanent HPA axis suppression. Conclusion: There is no literature on dexamethasone swish and spit being absorbed systemically possibly leading to potentially reversible HPA suppression. Our case will raise awareness of help guide clinicians expand their differential when working up these patients.
Presentation: Friday, June 16, 2023
FRI243 Hypertension And Virilization In A 4 Year Old Female
Authors: Ismail Esraa , Miller Jennifer Lynne , Bernier Angelina Valladares 
Published: October 2023

Abstract
Disclosure: E. Ismail: None. J.L. Miller: None. A.V. Bernier: None.
Background: Congenital adrenal hyperplasia (CAH) is the most common cause of virilization of an XX female neonate. More than 95% of CAH cases are due to 21 hydroxylase deficiency which is detected in the newborn screen by detection of elevated 17 hydroxyprogesterone (17 OHP). 11 beta hydroxylase deficiency (11 BOHD) is the second most common cause of CAH, but considered extremely rare accounting for only 0.2-8% of cases. 11-BOHD is not part of the newborn screen, as it does not present with life-threatening salt wasting crisis. Hypertension (HTN) is observed in 2/3 of cases and is due to mineralocorticoid excess in the form of deoxycorticosterone (DOC). Therefore, 11-BOHD should be strongly considered in a virilized female with HTN and accelerated growth. Clinical case: 4-year-old female admitted for evaluation of severe persistent HTN. She had surgical repair of posterior labial fusion at 5 months of age. She was seen at 21 months of age for concerns of precocious puberty and virilization. Her work up included XX karyotype, 17 OHP and electrolytes within normal limits, however, she had an elevated DHEAS and testosterone level, with a bone age of 5 years at 21 months of age. Hypertension was recorded at the visit, but she was lost to follow up. At a primary care appointment her blood pressure was notably elevated, so she was sent to the ED. On admission, she was found to have both weight and height &gt;99% for age, hyperpigmentation of gums and scars, and virilization (clitoromegaly with tanner 3 pubic hair). She had no thelarche. Initial hormonal evaluation revealed prepubertal gonadotropins, low aldosterone and low plasma renin activity. High dose ACTH stimulation test revealed elevated 11 deoxycortisol and 11 deoxycorticosterone levels. Her peak stimulated cortisol was inadequate at 8.7 mcg/dl (normal=&gt;18 mcg/dl). Genetic testing for CAH revealed compound heterozygosity for 2 variants in the CYP11B1 gene, confirming the diagnosis of 11-BOHD. She was started on hydrocortisone replacement (12 mg/m2/day) and required spironolactone to achieve adequate blood pressure control. At the time of diagnosis, her father reported that he also had hypertension before 10 years of age, as well as early puberty, and significantly darker skin color than his family members. Conclusions: The HTN seen with 11-OHD is associated with suppressed aldosterone/renin activity and hypokalemia and is responsive to glucocorticoid therapy. However, this cause of CAH is not included in the newborn screen so can go unrecognized until features of virilization and rapid growth with bone age advancement are noted. If HTN is persistent despite glucocorticoid treatment, spironolactone is the preferred antihypertensive, as it is both a mineralocorticoid and androgen receptor antagonist. This case serves as a reminder to pay attention to BP at every clinic visit.
Presentation: Friday, June 16, 2023
FRI252 Novel Mutation Presenting With Hypoaldosteronism In X-Linked Adrenal Hypoplasia Congenita
Authors: Ismail Esraa , Jacobsen Laura 
Published: October 2023

Abstract
Disclosure: E. Ismail: None. L. Jacobsen: None.
Background: X-linked adrenal hypoplasia congenita (AHC) is a rare disorder due to a mutation in DAX-1/NR0B1, a nuclear factor that is important for the development and function of the adrenals and reproductive system. It usually presents with adrenal insufficiency in infancy and later hypogonadotropic hypogonadism. Here we describe a patient who presented with a salt wasting crisis due to hypoaldosteronism and genetic testing revealed a novel frameshift mutation in NR0B1/DAX-1 resulting in premature protein termination. Clinical Case: A 4 week old male presented with poor feeding, failure to thrive, hyponatremia, hyperkalemia, and acidosis. No hypoglycemia present. He also had an undetectable aldosterone level, high renin, normal cortisol, high ACTH, and normal 17OHP. Adrenal ultrasound (US) failed to show the right adrenal gland. With suspicion for primary hypoaldosteronism, he was started on salt supplementation and fludrocortisone with improved growth, electrolytes, and renin. His genitalia were that of a typical male infant without cutaneous hyperpigmentation. ACTH level continued to trend up despite appropriate baseline cortisol. Stimulation test with 250 mcg of Cosyntropin was done which revealed suboptimal peak cortisol of 11.5 mcg/dL (normal &gt;18 mcg/dL), so he was started on stress dose precautions of hydrocortisone without physiologic replacement. Repeat US 2 months later did not visualize his adrenals. With suspicion for AHC, genetic testing was obtained which revealed a novel frame shift variant in NR0B1 (c.1069del, p.Gln357Argfs*15, hemizygous), resulting in premature protein termination. He was then started on daily hydrocortisone replacement. As this is an X-linked mutation, genetic testing for mother and older brother is pending. To the best of our knowledge this variant has not been reported in the literature. Conclusion: DAX-1 mutations should be considered in male infants presenting with primary hypoaldosteronism. ACTH stimulation testing is necessary to assess glucocorticoid function, especially if ACTH is elevated, which can precede cortisol deficiency. There is a wide heterogeneity in the presentation of this rare disorder, so genetic diagnosis is important to guide management, later monitoring for hypogonadism and fertility, and family testing.
Presentation: Friday, June 16, 2023