bluuebunny/crossref_metadata_2025 huggingface dataset:
iPSC-Derived Human Hepatocytes as a Novel Model to Investigate Thyroid Hormone Action and Signaling
Authors: De Oliveira Lorraine Soares , Lee Nora , Kaserman Joseph , Vella Kristen R , Wilson Andrew , Hollenberg Anthony Neil
Published: May 2021

Thyroid hormone (TH) actions are essential to normal metabolism and neurologic function. Abnormal TH levels can lead to significant morbidity including metabolic abnormalities, cardiac disease, and obesity. TH action is mediated by the thyroid hormone receptor (TR) isoforms and their coregulators. In the disease models of Resistance to Thyroid Hormone (RTH) it is clear that the TR isoforms play tissue-specific roles in humans, however a platform for drug discovery to potentially treat the diseases does not exist. We hypothesize that human hepatocytes (iHeps) derived from induced pluripotent stem cells (iPSCs) will serve as an ideal model to study TH signaling and to delineate mechanisms of TH diseases in humans. To investigate the TH action in humans, we have developed a serum free human iPSC hepatic differentiation protocol that utilizes sequential exposure to growth factors to mimic actual human development. iHeps are robustly responsive to TH with over 1000 regulated genes. Importantly, they allow us to use CRISPR/Cas9 to determine molecular physiology and mechanism of disease. To demonstrate the role of TRs in TH signaling in human liver cells we have focused on TRβ1 the main TR isoform expressed in liver. we knocked out TRβ1 (THRBKO) using guide RNAs (gRNAs) we engineered to specific genomic loci to truncate the expression of this isoform at the DNA binding domain. Also, to define mechanisms of TR action in the context of RTH, we used this same approach to introduce the Δ337T mutation found in human TRβ1 that causes RTH. Both THRBKO and Δ337T lines are karyotypically normal and flow cytometry analysis in both lines demonstrated that these lines differentiated normally into hepatocytes after gene editing with CRISPR/Cas9. Once clones were identified the edited iHeps were treated with PBS (vehicle) or T3 (10nM) for 24 hours. Real-time quantitative PCR (RT qPCR) was done to assess mRNA expression of T3 target genes. RT qPCR analysis confirmed the success of TRβ1 deletion as the response to T3 was lost on both positive and negative THRB targets. In the Δ337T iHeps, the response to TH was diminshed indicating the successful generation of this line. These preliminary results confirm our ability to edit IPSCs and then to differentiate into hepatocytes, allowing us to further study the action of TH and the mutations involved in RTH.
T3 Enters Axon Terminals of Mouse Cortical Neurons, Is Retrogradely Transported to the Cell Nucleus and Activates Gene Expression
Authors: Salas-Lucia Federico , Bocco Barbara M L C , Rada Kristof , Fekete Csaba , Gereben Balazs , Bianco Antonio C
Published: May 2021

Thyroid hormone (TH) is critical for brain development and function. T3 enters neurons through membrane transporters and reaches the cell nucleus where it binds to receptors (TR) to regulate gene transcription. However, neurons also express the type 3 deiodinase (D3), which is located in the cellular and nuclear membranes and inactivates T3. Here, we investigated the fate and biological impact of T3 that enters neurons through axons. Primary cortical neurons were isolated from E16.5 embryos of the TH action indicator (THAI) mice, which were engineered with a TH-responsive transgene where three copies of a T3-responsive element drive a luciferase (Luc) reporter. Neurons were seeded on a microfluidic device consisting of two independent compartments: (i) cellular, where about 70-90,000 cell bodies were located, and (ii) axonal, where a few hundred distal axons were located. Fluidic isolation of the compartments was monitored with Alexa Fluor 594 hydrazide. In the first set of experiments (repeated 3 times), 8-10-day old cultures were incubated for 48h with medium containing 1% charcoal-stripped serum (Tx-medium). Subsequently, 10nM T3 was added to the axonal compartment, and 24h later cell bodies were harvested and Luc mRNA measured by RT-qPCR. There was a 2.4 ± 0.7-fold increase in Luc mRNA levels, but the addition of 2uM Silychristin (MCT8 inhibitor) to the axonal compartment reduced T3 induction of Luc mRNA by 32 ± 4.2%. In the second set of experiments (repeated 3 times), 4.9 ± 2.2pM 125I-T3 (final concentration) was added to the cellular or axonal compartments. Medium was sampled and 125I-T3 and its metabolites were separated/quantified via UPLC linked to a flow scintillation detector. After 72h of adding 125I-T3 to the axonal compartment, about 0.73 % 125I-T3 (0.052 ± 0.025pM) was found in the cellular compartment. In addition, 3,3’-125I-T2 and 125I (0.011 ± 0.003 and 0.052 ± 0.023pM, respectively) were also detected. When 125I-T3 was added to the cellular compartment, about 1.6% 125I-T3 (0.048 ± 0.027pM), no metabolites, was detected in the axonal compartment. Only background radioactivity was detected in the opposing compartment when 125I-T3 was added in the absence of cells. We conclude that T3 can be taken up by neuronal axons, partly via MCT8, and transported retrogradely to the cell nucleus to initiate TH signaling. D3-generated T3 metabolites exit the cell body alongside with small amounts of intact T3. This pathway could explain how D2-generated T3 in tanycytes is taken up by TRH-secreting neurons to mediate negative T3 feedback. Anterograde T3 transport was also detected, the significance of which remains unknown.
Identification of Genes and Pathways Differentially Expressed in Progestin Responsive Endometrial Cancer and Hyperplasia
Authors: Gertz Jay , Rush Craig , Vahrenkamp Jeffery , Szczotka Kathryn , Dodson Mark , Jarboe Elke , Soisson Andrew
Published: May 2021

One of the oldest and most common therapies for endometrial complex atypical hyperplasia (CAH) and low-stage, low-grade endometrioid endometrial carcinoma (EEC) is the use of progestins. Importantly, the use of progestins remains the only fertility-sparing treatment available. Despite frequent initial response to progestins, relapse rates are high (35-50%). Currently, there are no biomarkers available for predicting a woman’s likelihood of successful progestin therapy.

Primary samples (n = 63) were obtained from a total of 31 patients with either CAH or EEC who underwent progestin therapy and were acquired pre- and post-treatment with progestins. Pathological review of the FFPE samples was performed to identify regions of high hyperplastic or neoplastic content for core punches and RNA extraction. RNA-seq was then performed on the FFPE RNA using the TruSeq RNA Exome approach, a method that uses targeted capture to improve sequencing from fragmented samples. Differential expression analysis was performed using two methods: DESeq2 a parametric method and Noiseq a non-parametric method. Both methods were used to obtain an overlapping subset of genes to reduce spurious results due to samples with outlier expression.

Analysis of all samples identified 137 genes significantly associated with outcome. These 137 genes were largely increased in post-treatment samples from progestin responders and were highly enriched for progestogen and estrogen responsive genes, indicating a strong hormonal gene expression response to progestin therapy. Importantly, post-treatment samples from non-responding patients did not show this expression pattern, demonstrating that this set of genes may indicate successful hormone response in post-treatment samples. We also identified a 61 gene signature that remains high in non-responders after treatment compared to responders. Overall, we find that responders show a coordinated change in expression during progestin therapy that is missing from non-responders and this signature could be used in the early evaluation of progestin treatment success.

Focusing solely on pre-treatment samples, we identified more variable expression differences across tumors, suggesting multiple reasons for progestin success/failure. We found that the combined expression of estrogen receptor alpha and progesterone receptor was predictive of progestin therapy success. In addition, non-responding tumors had increased expression of several immune-related genes that we are currently exploring. Overall, these results show that progestin therapy response could be predicted using gene expression signatures and that multiple factors may underlie progestin success/failure.
Recurrent Cushing Syndrome Secondary to Metastatic Adrenocortical Carcinoma in a Patient With Previously Resected Adenoma
Authors: Addasi Noor , Silverman Emily Christine , Ganti Apar , Kotwal Anupam
Published: May 2021

Background: ACTH-independent causes of Cushing Syndrome (CS) have mostly benign etiologies. For the majority of these conditions, surgery is the recommended treatment and is nearly 100% curative. Current guidelines do not specify follow up imaging recommendations in patients with resected adenomas. We present a case of severe CS secondary to an adrenal adenoma that was completely resected, and presented later as a metastatic adrenocortical carcinoma (ACC). Clinical Case: A 34- year-old woman presented with worsening confusion, weight gain and new onset diabetes and hypertension. Her history was significant for a 7 cm left adrenal mass and ACTH- independent CS previously treated with left adrenalectomy 2 years prior to this presentation. She was following with an endocrinologist who weaned her hydrocortisone to 10-5 mg. She completed a successful pregnancy but had worsening depression. Her steroids were stopped on admission and evaluation showed hypokalemia [2.9 mmol/L (n 3.5-5.1)], hypercortisolemia [29.9 mcg/dL (n 6.7-22.6)], and ACTH <12 pg/mL (n<46). This was followed with 1 and 8 mg dexamethasone suppression tests that she failed with cortisol levels of 37.8 and 41.6 mcg/dL respectively, late-night salivary cortisol of 0.974 ug/dL (n <0.181), and extremely elevated 24-hr urinary cortisol of 3,700.2 ug/d (n<45). Of the steroid hormone precursors, 11 deoxycortisol was elevated at 725 ng/dL (n<32) and DHEA-S was 29mcg/dL (n 35-430). A CT scan revealed multiple liver lesions, and no residual nodularity in the left adrenalectomy bed. Liver lesions were PET-avid, and biopsy confirmed metastatic ACC. Due to the extensive hepatic involvement, she was not a candidate for local therapy. She was started on mitotane and metyrapone for CS. She was treated with doxorubicin, cisplatin and etoposide chemotherapy every 4 weeks. Due to insurance issues; metyrapone was replaced by mifepristone. Over 8 weeks, mitotane level became therapeutic at 20 mcg/mL, hepatic masses decreased in size, and she transitioned form CS to adrenal insufficiency (AI) with am cortisol of 3 mcg/dL with accompanying nausea and improved glycemic control without medication. Next generation sequencing studies of the liver biopsy specimen revealed a frameshift loss of function mutation in FH that encodes the protein fumarase (c.912_918del p.F305fs; variant allele fraction - 67.8%). Conclusion: Metastatic ACC presenting with life-threatening CS presents a diagnostic and management challenge. Combination therapy with mitotane and chemotherapy demonstrated benefit in our patient. The transition from severe CS to AI due to mitotane was challenging to monitor biochemically due to mifepristone use. Loss of function FH mutation is associated with cancer progression. Patients with resected large adrenal adenomas require close monitoring to identify malignant behavior.
A Case of Adrenocortical Carcinoma With Severe Hypertension and Hypokalemia
Authors: Yamamoto Naoki , Yamamoto Masaaki , Fukumitsu Hayato , Kanzawa Maki , Fukuoka Hidenori , Ogawa Wataru
Published: May 2021

Case: 70 years old woman was pointed out for hypertension at a medical checkup and visited a primary physician. Severe hypokalemia (2.4 mmol/L) was noted, and abdominal CT scan revealed a right 99 mm diameter adrenal tumor adjacent to a 80 mm diameter liver tumor. She was referred to our hospital for further management. Despite treatment with antihypertensive agents, including ARB, MRB, and CCB, her blood pressure remained around 170/90 mmHg. In the meantime, 120 meq of potassium chloride treatment was needed to keep her serum potassium levels around 3.5 mmol/L. Both her plasma renin activity (PRA) and plasma aldosterone concentration (PAC) were high (6.4 ng/mL/h and 376 pg/mL), indicating renin-dependent hypertension. Since CT angiography revealed the right renal artery compressed downward by the adrenal tumor, renovascular hypertension was suspected. Moreover, both early morning plasma ACTH levels and serum cortisol levels were suppressed (8.5 pmol/L and 5.3 μg/dL), despite elevated urinary free cortisol levels (350 μg/day). Urinary steroid profile analysis detected various elevated precursor steroid metabolites, including deoxycorticosterone (DOC) and corticosterone. DOC levels were 5 folds more than the upper normal limit, suggesting one of the causes of her hypertension with hypokalemia, while elevated corticosterone levels were thought to be contributed to suppressing ACTH. After the right adrenalectomy and hepatic segmentectomy, both of her hypertension and hypokalemia rapidly improved with declining PRA and PAC levels to 0.2 ng/mL/h and < 0.7 pg/mL, respectively. Urinary DOC levels also fell into the normal range. From the pathological findings, she was diagnosed with adrenocortical carcinoma (ACC) infiltrating the liver (pT4N0M0, stage IV). The immunohistochemistry analysis showed disorganized expression of steroidogenic enzymes, including CYP11B1, CYP11B2, and 3β-HSD, supporting a variety production of steroid metabolites from the ACC. Although mitotane was initiated as a adjuvant chemotherapy, multiple metastasis was found at her lung, liver, and vertebrae, 6 months after the operation. Along with that, hypertension and hypokalemia recurred gradually with both of PRA and PAC elevation. However, CT angiography detected no apparent renovascular stenosis. We performed renin immunostaining of ACC specimen revealed partially positive, demonstrating renin production from this ACC. Conclusion: Although juxtaglomerular cell tumor is the most common renin-producing tumor, some cases of renin secreting ACC have been reported as a quite rare case. In the present case, renin secretion from ACC might be contributed to severe hypertension and hypokalemia, and both renal artery stenosis and DOC secretion induced by the ACC are considered to be a major cause.
A Case Report on Parathyroid Carcinoma - an Extremely Rare Endocrine Malignancy
Authors: Mandal Shobha , Bethala Mary Grace , MolsKowalczewski Barbara
Published: May 2021

Background: Parathyroid carcinoma is an extremely rare endocrine malignancy with a prevalence of &It 1%. It is associated with hyperparathyroidism-jaw tumor syndrome (HJTS), multiple endocrine neoplasia (MEN) type 1 or 2A syndromes, secondary hyperparathyroidism, and chronic kidney disease. Incidence is equal in both men and women. Patients may present with symptoms of hypercalcemia, and should be further worked up with neck ultrasound, Tc-99m sestamibi imaging, single-photon emission computed tomography, magnetic resonance imaging, positron emission tomography combined with CT scan, and biopsy of the parathyroid mass. Parathyroid carcinoma can be treated surgically with complete resection. Patients treated with En-bloc resection with microscopically negative margins remain cancer-free for at least three years to a maximum of twenty years.

Case Report: A 50-year-old female treated with laparoscopic sleeve gastrectomy for morbid obesity, came for the follow-up visit. She denied any active complaint. Routine Lab work showed mild hypercalcemia, hypophosphatemia, elevated PTH, and alkaline phosphatase. Neck ultrasound showed a cystic lesion adjacent to the right thyroid lobe. Sestamibi (MIBI) parathyroid scintigraphy showed increased radiopharmaceutical uptake by the right superior parathyroid gland without any enlarged or suspicious lymph nodes. Dexa scan was positive for osteopenia. The patient underwent right superior parathyroidectomy along with en-bloc right thyroid lobectomy. Histological examination revealed anaplastic regions, giant cells with abundant cytoplasm, and polymorphous nuclei with a Ki-67 labeling index of 10% consistent with parathyroid carcinoma. Post-surgery imaging with ultrasound and magnetic resonance imaging of the neck computed tomography of the chest, and abdomen, whole-body MIBI scintigraphy was negative for residuals or metastatic disease. She was started on oral calcium carbonate and was monitored regularly with routine lab work. The most recent lab work was within normal limits.

Conclusion: Most of the patients with parathyroid carcinoma present in the early stage with the symptoms of hypercalcemia. Many of them do not have symptoms of mass or tumor effects. Parathyroid cancer is a rare malignancy and can be missed, therefore all patients with hypercalcemia should be further evaluated with lab work, imaging, and biopsy to rule out parathyroid carcinoma. Early diagnosis and treatment have a better outcome.
Urinary Steroid Metabolome Signature Is Associated With Pre-Frailty and Frailty Phenotype in Older Adults
Authors: Singh Sumitabh , Ebbehoj Andreas , Rivard Ann L , Thomas Melinda , Singh Ravinder J , Grebe Stefan Karl Gunther , Khosla Sundeep , LeBrasseur Nathan K , Bancos Irina
Published: May 2021

Background: Frailty is characterized by an increased vulnerability and a decline in physiological reserve. Frailty has been previously linked to cortisol concentrations and blunted diurnal cortisol secretion. Our objective was to determine the association of urine steroid metabolome and its diurnal variation with frailty and prefrailty in older adults. Methods: Cross-sectional study of community-dwelling adults ≥ 50 years. Participants with adrenal disorders, end-stage renal or liver disease, on exogenous steroids or drugs affecting steroid metabolism were excluded. All participants completed day and night separate urine collection. Frailty was assessed using a phenotype model (weight loss, exhaustion, grip strength, low physical activity, and slow walking pace). Participants were characterized as frail if they met at least three criteria, pre-frail if they fulfilled one or two criteria, and robust if no criteria were met. Urine samples were analyzed with the liquid-chromatography, high-resolution, accurate-mass mass spectrometry for 25 urine steroid metabolites. Results: Of 119 participants, 60 (50.4%) were women, without sex differences in age or education status. On frailty assessment, 5 (4.2%) participants were frail and 33 (27.7%) were prefrail, with equal sex distribution. Urine steroid metabolome analysis demonstrated 21/25 steroids were higher in men vs women. In an age adjusted model, presence of prefrailty or frailty was associated with a higher ratio of total cortisol metabolites/total androgen metabolites (TCM/TAM) in men (estimate 0.64, P-value= 0.0004), but not in women. In men, after adjusting for age, among cortisol metabolites, lower day to night ratio of 5α-Tetrahydrocortisol (estimate -0.36, P-value= 0.0419) and β-Cortol (estimate -0.35, P-value= 0.0238) were associated with frail or prefrail phenotype. After adjusting for age, higher ratio of TCM/TAM was associated lower gait speed in men (estimate -1.2, P-value= 0.046) and women (estimate -3.9, P-value= 0.012); and lower hand grip strength in men (estimate -0.04, P-value= 0.046) but not in women. Conclusion: We showed that a higher glucocorticoid to androgen ratio and a flattened circadian steroid variation were associated with presence of frail or prefrail phenotype in men. Further studies should examine the role of steroid metabolism and HPA axis impairment, and the associated sex differences, in the functional decline in aging population.
Calcitonin Changed During Pregnancy in MEN2A With MTC Patient: A Case Report
Authors: Porntharukchareon Thachanun , Chutpiboonwat Phronpan , Tangjittrong Sirinrat , Houngngam Natnicha , Snabboon Thiti
Published: May 2021

Background: The diagnosis of MTC during pregnancy was challenging. No definite calcitonin (Ct) cut-off level during pregnancy was defined. Moreover, cytology analysis accuracy in MTC was lower than other thyroid cancers. Stevenson et al. reported that the plasma Ct levels in pregnant women were much higher than normal women. The change in Ct levels during pregnancy was not well described. In this report, we present a case of a pregnant woman with recurrent MTC. The change in Ct levels during pregnancy, diagnosis methods, and proper management were presented here.

Clinical Case: A 31-year Thai woman, gravida 2, para 0 at 17 weeks of pregnancy, previously diagnosed with MTC and treated with total thyroidectomy and neck dissection seven years ago. During antenatal care at 14 weeks of pregnancy, the Ct level was 126 pg/ml (raised from 34 pg/ml seven years ago). The neck’s USG demonstrates vascularized hypoechoic lesion at the right thyroid bed with multiple nodules. The Ct wash-out test from this lesion was 200,000 pg/ml. The cytology study showed several clusters of atypical cells possessing monotonous round eccentric nuclei, and the IHC for Ct was positive. Genetic analysis revealed germline mutation in exon 10 of the RET proto-oncogene (NM_020975.4: c.1858T>G, p.C620G). Finally, MEN 2A with recurrent MTC was diagnoses during pregnancy. The other associate diseases were not found (normal urine metanephrines and plasma calcium levels). The Ct level raised highest to 324 pg/ml at 28 weeks of pregnancy and declined to 236 pg/mL a few days after delivery. Within six weeks, the Ct levels raised again (335 and 362 pg/ml at six weeks and three months after delivery).

After giving birth, she underwent neck dissection; The Ct level at one month after surgery was still elevated (85 pg/ml). The CT of the chest, abdomen, and bone scan revealed multiple LN and bone metastasis. She regularly followed up in the oncology clinic and did well until nowadays (two years after delivery). After birth, her son could not pass meconium. Causing underwent exploratory laparotomy with double end ileostomy at day nine of life. The histopathology study from serial bowel biopsy demonstrated aganglionosis of the entire colon, which compatible with Hirschsprung’s disease. Genetic study from colonic tissue and blood confirmed the diagnoses of MEN 2A like his mother. Total thyroidectomy before five years of age and investigate for other associated diseases were planned.

Conclusion: The Ct levels were elevated throughout the pregnancy. Transient declined of Ct levels during delivery and raised within six weeks suggest that pregnancy did not affect the Ct levels. In this report, we want to present the change of Ct levels during pregnancy, emphasize the diagnosis of MTC and MEN2A in pregnant women, which may change the patient’s prognosis. Not only in the patients but also in their families. Clinicians should be aware of the management of these patients.
Utility of Urinary Ratio of Cortisol to Aldosterone as Inflammatory and Metabolic Parameters
Authors: Otsuka Yuki , Nakano Yasuhiro , Tokumasu Kazuki , Honda Hiroyuki , Obika Mikako , Hasegawa Kou , Hanayama Yoshihisa , Otsuka Fumio
Published: May 2021

Corticosteroids are important bioactive substances in the body that regulate inflammation, metabolism, immunity, and circulatory dynamics. Cortisol and aldosterone are two major naturally occurring steroids, which synthesized in the adrenal fasciculata and in the adrenal glomerulosa under the regulation of adrenocorticotropin (ACTH) and renin-angiotensin system (RAS), respectively. The conventional strategy for evaluating adrenocortical function has been to measure random serum cortisol or 24-hour stored levels of urine free cortisol (UFC). UFC is a more appropriate marker to avoid the effects of diurnal fluctuation of cortisol, serum cortisol-binding proteins, and cortisol clearance in the kidney. Thus, measurement of UFC has been a reliable test for diagnosis of Cushing’s disease or adrenal insufficiency. However, since the normal range of UFC varies widely, it is often difficult to evaluate whether the UFC level is optimal or not for each patient. That is because UFC is greatly affected by the amount of fluid intake or urine volume, and an immunoassay for UFC, which is the usual method for measuring UFC, is susceptible to interference from other steroid metabolites and synthetic glucocorticoids. To explore an alternative indicator, we tried to standardize the levels of UFC by the levels of urinary aldosterone concentration (UAC) in the same urinary sample. Medical records of all 246 patients in whom daily excretions of UFC and UAC had been measured between 2015 and 2018 at our department were reviewed. 142 patients (including 93 females) were included after exclusion of 104 patients because of corticosteroid replacement therapy. UFC/UAC ratio showed significant positive and negative correlations with the levels of serum cortisol (R=0.287) and aldosterone (R=-0.762), respectively. UFC/UAC ratio increased with aging in female patients, while the ratio was not altered by the levels of BMI in either gender. Markers for metabolic and inflammatory status including hemoglobin A1c (R=0.327), albumin (R=-0.331), chorine esterase (R=-0.248), C-reactive protein (R=0.317), ferritin (R=0.473), and D-dimer (R=0.569) showed correlations to the ratio of UFC/UAC that were more significant than the correlations to the serum level of cortisol or UFC alone. Of note, the UFC/UAC ratio was shown as an indicator for risks of diabetes (AUC: 0.765), hypoalbuminemia (0.839), hyper-CRPemia (0.748), and thrombophilia (0.824), in which the cut-off levels of UFC/UAC ratios were found to be around 12. These results indicate that the UFC/UAC ratio is a suitable variable for the detection of metabolic and inflammatory complications related to adrenocortical dysfunction.
Case Report: Exceptional Association of Leydig Cell Ovarian Tumor and Primary Hyperparathyroidism in a Postmenopausal Patient
Authors: Chuki Elias , Hannoush Zeina Carolina
Published: May 2021

Background: Leydig cell tumors account for less than 0.1% of all ovarian tumors and are usually unilateral and benign. They present mostly in postmenopausal women with symptoms of hyperandrogenism. On the other hand, primary hyperparathyroidism (PHPT) is a relatively common endocrine disorder, with a prevalence of one to seven cases per 1,000 adults. It most commonly presents as an isolated, sporadic clinical entity, but in approximately 10% of the cases, it presents with a clear hereditary pattern and sometimes in association with other hormone producing tumors. Clinical Case: a 55-year-old nulliparous postmenopausal woman with history of breast cancer, Type 2 Diabetes Mellitus, hypothyroidism, hypercalcemia and hypertension who presented with progressive hirsutism and male pattern hair loss. Total testosterone levels were found to be significantly elevated in the 800s ng/dL (normal range 14–76 ng/dL). Additionally, patient was found to have mild hypercalcemia with inappropriately normal PTH and hypercalciuria, consistent with primary hyperparathyroidism (PHPT). A hypoechoic lesion in the left ovary was evident on pelvic ultrasound after 1 year of repeat imaging studies, including MRI. Bone density was within normal limits. The patient underwent bilateral Hysterosalpingo-oophorectomy and pathology report was consistent with Ovarian Leydig cell tumor. During the postoperative period, the patient reported improvement of hyperandrogenism symptoms. Discussion: We are presenting this case because of the rare association of ovarian Leydig cell tumor and PHPT in a postmenopausal female patient with virilizing symptoms. Thus, this would be the second case reported in literature by this time. This could be a rare coincidence or part of an inherited or sporadic mutation yet to be discovered. This case restates the concept that in the presence of hirsutism, rare etiologies should be sought. Virilizing tumors of the ovary should be considered despite negative initial imaging studies. PHPT should be considered in patients with asymptomatic hypercalcemia with inappropriately normal PTH and hypercalciuria. Conclusion: Careful identification and report of cases with unusual clinical presentations is essential to better understand the pathophysiology of uncommon diseases and ultimately be able to guide their management.
Description of a SDHD c.129G>A (p.W43X) Mutation With Variable Presentation in Multiple Family Members
Authors: Greenberg Samantha , Luke Buchmann , Naumer Anne , Kohlmann Wendy , Garfield Kinley , Sharma Anu
Published: May 2021

Approximately 40% of paragangliomas and pheochromocytomas are attributed to hereditary mutations. SDHD mutations account for 7% of inherited mutations (PGL1 syndrome), is maternally imprinted and has variable penetrance. SDHD pathogenic variants (PV) have been previously described extensively in Dutch pedigrees, with a varying lifetime risk for tumor development. Here we report a large family (Fig 1) displaying a SDHD c.129G>A (p.W43X) variation in 12 family members, 10 of whom had screening or tumor history available. The presentation and age of diagnosis in family members showed variable penetrance. Age at first diagnosis of a pheochromocytoma/paraganglioma ranged from 10 - 45 years. Family members displayed bilateral pheochromocytomas, bilateral carotid body tumors, and paragangliomas of the head, neck and trunk with variable recurrence rates (none to multiple). No malignant lesions were detected to date. Pheochromocytomas were norepinephrine producing. Paragangliomas ranged from non-functional to dopamine and norepinephrine producing. Compared to previous reports of other SDHD mutations, the SDHD c.129G>A (p.W43X) variation displayed an earlier age at first diagnosis with a highly variable phenotype ranging from one benign, non-secreting paraganglioma to bilateral pheochromocytomas and recurrent parganagliomas along the parasympathetic chain from head to abdomen. This report contributes to the evolving understanding of the phenotypic presentations of various genetic mutations. We propose that expert guidelines that suggest screening family members with the SDHD c.129G>A (p.W43X) variation at the age of 8 for early detection of pheochromocytomas and paragangliomas is beneficial.
Gastrointestinal Stromal Tumor Mimicking an Adrenal Incidentaloma: A Case Report
Authors: Hamidi Sarah , Mercier Frédéric , Bourdeau Isabelle , Rakel Agnes
Published: May 2021

Background: The differential diagnosis of adrenal incidentalomas is broad and includes benign or malignant primary adrenal lesions, metastases, myelolipomas, infections or hemorrhage. We present here a patient with a gastrointestinal stromal tumor (GIST) presenting as an adrenal incidentaloma. Clinical Case: A 64-year-old man was referred to Endocrinology for the work-up of a left adrenal incidentaloma discovered on an abdominal CT scan performed for left upper quadrant abdominal pain. His past medical history included well-controlled type 2 diabetes and hypertension. On subsequent imaging, the mass was described as a solid homogenous nodule with a density of 31 HU and an absolute contrast washout of 22%. Between 2017 and 2020, the mass’ size increased from 14 x 13 to 24 x 19 millimeters. Further functional imaging revealed no 131I-MIBG uptake but moderate hypermetabolism on FDG PET-CT with a SUVmax of 4.5. There was discordance regarding the mass’ localization between the various imaging modalities used preoperatively: some showed a left adrenal lesion whereas others suggested that it was adjacent to, but distinct from, the adrenal gland. Biochemical workup included normal 1-mg dexamethasone suppression test, serum potassium levels, 24-hour urine fractionated catecholamines, as well as plasma free metanephrines and normetanephrines. Chromogranin A levels were also normal. In light of these findings, laparoscopic tumor resection, with or without left adrenalectomy, was scheduled. During surgery, it was discovered that the tumor was intraperitoneal, located next to the splenic hilum and originating from the greater curvature of the stomach; a partial gastrectomy was therefore performed, without left adrenalectomy. Pathological evaluation revealed that the mass was a small spindle cell-type GIST. Genetic analysis of the tumoral DNA showed a somatic mutation in exon 11 of the KIT gene (c.1658_1669del, p.Tyr553_Gln556del). Conclusion: We report a rare case of gastric GIST initially mimicking a left adrenal incidentaloma. Localization of GISTs in the adrenal area is rare, with very few cases reported to date in the literature. Unlike other cases described previously, our patient underwent the right procedure thanks to adequate tumor localization during surgery. However, as some patients have experienced unnecessary adrenalectomy for similar clinical presentations, gastric GISTs should be kept in mind in the differential diagnosis of non-functional atypical adrenal masses, especially in the presence of suspicious PET scan imaging. References: 1. Hexi Du, Jun Zhou, Cheng Yang, Li Zhang, Chaozhao Liang: Gastrointestinal stromal tumor masquerading as an adrenal tumor: a case report with literature review. Int J Clin Exp Med 2017;10(10):14883-14887.
Life-Threatening VIPoma Crisis in an Immunocompromised Patient
Authors: Borhan Marisa Khatijah , Sieng Tan Florence Hui
Published: May 2021

Background: Vasoactive intestinal peptide-secreting tumors (VIPoma) are rare neuroendocrine tumors (NETs) that present with a triad of profuse watery diarrhea, hypokalemia, and achlorhydria. The resulting renal impairment, electrolytes and acid-base imbalances pose a high risk of morbidity and mortality. We describe a case of life-threatening VIPoma crisis in an immunocompromised patient. Clinical Case: A 64-year-old man was intubated after he was brought in unconscious with tachypnea. Upon review, he had experienced persistent watery diarrhea for the past 6 months, with a weight loss of 18 kg. He had severe hypokalemia (potassium 1.9 mmol/L, n= 3.5-5.0), metabolic acidosis (blood gases pH 6.927, bicarbonate 4.8 mmol/L, base excess -25.9 mmol/L), and acute kidney injury (urea 47.9 mmol/L, creatinine 980umol/L). He continued to have electrolyte imbalances and acidosis due to persistent diarrhea, despite hydration and dialysis support. His biohazard screening results were positive for human immunodeficiency virus (HIV), with a CD4 count of 101 cells/µl. He was given courses of antibiotics for treating pathogenic infections; however, his septic workups were negative for infection, including HIV-related opportunistic infections. Later, pancreatic CT revealed a well-defined heterogeneously enhancing pancreatic head mass, size 6.8x5.2x7.5 cm. Further laboratory investigations confirmed the diagnosis of VIPoma, with elevated VIP levels (1600 pg/ml, n < 75). Eventually, subcutaneous octreotide was started, with resolution of the diarrhea and normalization of his electrolytes and renal function. After a 6-week hospital stay, he was discharged well with monthly octreotide and initiated on antiretroviral therapy (ART). After 3 months of ART, his CD4 count improved, and he remained diarrhea-free with octreotide. He is scheduled for tumor debulking surgery.

Conclusion:This case highlights the importance of having a clinical suspicion of NETs, especially in immunocompromised patients. Further investigations and imaging studies to rule out noninfectious pathologies should be considered in patients who respond poorly to standard therapy. In VIPoma, somatostatin analog is an antisecretory treatment and it is highly effective for controlling diarrhea. High-dose octreotide up to 1500 µg/day has previously been studied for treatment of refractory diarrhoea in the setting of HIV infection² and it has been found to be helpful in reducing stool volume and frequency. Lastly, delays in the diagnosis and treatment of VIPoma in immunocompromised patients can be fatal. References1/ Hoffland J., Kaltsas G., de Herder W. Advances in the Diagnosis and Management of Well-Differentiated Neuroendocrine Neoplasms. Endocrine Reviews, Volume 41, Issue 2, April 2020, Pages 371-403.2/ Farthing MJ. Octreotide in the treatment of refractory diarrhoea and intestinal fistulae. Gut 1994;35:S5-10.
Metastatic Thyroid Cancer After Thyroidectomy in Patient With Neuroendocrinal Tumor
Authors: Khalifa Maram , Aftab Hassaan , Kantorovich Vitaly
Published: May 2021

Background: Multiple endocrine neoplasia type 2 is an autosomal dominant disorder with an estimated prevalence of 1 per 30,000 in the general population. Classical multiple endocrine neoplasia 2A is the most common variant. It is a heritable predisposition to medullary thyroid cancer, pheochromocytoma, and primary parathyroid hyperplasia. The respective frequency of these tumors in classical MEN2A is over 90 percent for MTC, approximately 10 to 50 percent for pheochromocytoma, and 10 to 20 percent for multigland parathyroid hyperplasia.

Discussion: our interesting patient is a 67-year-old patient with past medical history of prophylactic total thyroidectomy at the age of 25 years after a positive pentagastrin test (sister was diagnosed with MTC, pheochromocytoma),niece with metastatic kidney cancer.at that time, patient had benign pathology. Patient presented to the ED with a complain of shortness of breath after being referred by her PCP for evaluation of possible pneumonia. In the ED, her vitals were within normal, chest X-ray was done and didn’t show pneumonia but the patient was found to have elevated procalcitonin of 22.7 ng/mL(0.09 ng/mL) CT chest was done and showed enlarged necrotic cervical lymphadenopathy which was confirmed by obtaining CT of the neck. Patient had right cervical LN core biopsy, pathology was positive for medullary thyroid cancer with Immunohistochemical studies positive for TTF-1, chromogranin, synaptophysin and calcitonin, testing for pheochromocytoma came back within normal, CEA 70.7ng/ml (<0.25 ng/ml), calcitonin 2949 pg/ml (5 pg/mL) Chromogranin was high at 453 ng/ml (25 - 140 ng/mL) had PET CT with multiple low right cervical and supraclavicular lymph nodes with internal calcifications and abnormal FDG activity, which were suspicious for medullary thyroid cancer metastases, she eventually had radical neck dissection with pathology from inferior parathyroid gland positive for medullary thyroid cancer and 12/15 regional LN positive for malignancy, after the procedure her calcitonin dropped nicely to 194pg/ml, CEA dropped to 4.0, chromogrannin to 394, she was referred to genetic testing and tested positive for pathogenic variant within RET (c.1859G>T, p.Cys620Phe), which is known to be associated with multiple endocrine neoplasia type 2A, she is currently being evaluated for Lutathera treatment.

Conclusion: In contrast to MEN1, in which the long-term benefit of early diagnosis by genetic screening is not well established, early diagnosis by screening of “at-risk” family members in MEN2 with positive RET mutation kindreds is essential because MTC is a life-threatening disease that can be cured or prevented by early thyroidectomy. Total thyroidectomy has been recommended for patients as young as 3 years for MEN2A if they contain the genetic mutation.
Neurofibromatosis Type 1 Presenting With Adrenal Pheochromocytoma
Authors: ElEbrashy Shady Ibrahim , ElShimy Lina Adel
Published: May 2021

Background: Pheochromocytomas & Paragangliomas (PCC/PGL) are amongst the rare endocrine tumours, occurring with an incidence of 0.8 per 100,0001. Though most of them have a benign nature, they are usually hormonally active causing significant cardiovascular morbidity due to the catecholamine secretion. Approximately a third of PCC/PGL have underlying germline mutations including Neurofibromatosis type 1 (NF1). Clinical Case: A 49 year old man was reviewed for symptoms of palpitation, headache, sweating, and blurred vision. physical examination revealed signs of NF1. He had multiple neurofibromas over the skin of the back, chest and neck, café-au-lait spots on the trunk and limbs. Ophthalmology assessment revealed multiple Lisch nodules bilaterally. Urinary catecholamines were significantly elevated. His initial systolic blood pressure was 190/148 mmHg. The patient’s medical history included hypertension that used to be well-controlled with Amlodipine 10 mg and Bisoprolol 5mg. however his blood pressure was harder to control during the past year. Laboratory investigations testing included measurements of urinary fractionated metanephrines which revealed high normetanephrines with a value of 690 nmol/d (N < 240). metanephrines (485 nmol/d: N < 275) and norepinephrines (456 nmol/d: N < 440). Plasma free normetanephrines were 3.20 nmol/L (N <1.20) and free metanephrines 0.4 nmol/L (N < 0.48). CT scan of the abdomen showed a 1.3 x 2.4x 3.9 mass in the left suprarenal gland which showed showed moderate uptake on A meta-iodobenzylguanidine (MIBG) scan. And no evidence of metastases. The patient underwent laparoscopic adrenalectomy of the left suprarenal gland and histopathological examination was confirmatory of pheochromocytoma postoperatively. Conclusion:This is a case demonstrating the association between the germline mutation causing neurofibromatosis type 1 with the rare catecholamine secreting tumour (pheochromocytoma). Reference:1. Lefebvre M, Foulkes WD. Pheochromocytoma and paraganglioma syndromes: genetics and management update. Curr Oncol. 2014;21(1):e8-e17. doi: 10.3747/co.21.1579. [PMC free article] [PubMed] [CrossRef] [Google Scholar]
“Relieving the Pressure” With Unilateral Adrenalectomy in a Case of Chronic Resistant Hypertension From Primary Aldosteronism
Authors: Brooks Danielle , Fernandez-Ranvier Gustavo , Rios Carlos , Shah Nirali A
Published: May 2021

Introduction: Primary aldosteronism is an under-recognized cause of resistant hypertension that is associated with an increased risk of cardiovascular disease and mortality. While surgical intervention may not lead to complete resolution of hypertension, partial success (defined by reduction in blood pressure and/or medications) can be achieved and future cardiovascular risks can be minimized. We present a case of a patient with primary aldosteronism whose chronic resistant hypertension improved significantly after unilateral adrenalectomy. Clinical Case: A 54-year-old female with resistant hypertension for 17 years and hypokalemia was diagnosed with primary aldosteronism. The patient had uncontrolled hypertension despite atenolol 50 mg, nifedipine XL 60 mg, triamterene-hydrochlorothiazide 37.5-25 mg, lisinopril 40 mg daily.

Laboratory evaluation was significant for plasma aldosterone concentration (PAC) 26.8 ng/dL (reference: 0.0–30.0 ng/dL), plasma renin activity (PRA) 0.168 ng/mL/hr (reference: 0.167–5.380 ng/mL/hr), PAC/PRA ratio 159.5, and potassium of 3.2 mmol/L (reference: 3.5–4.5mmol/L). Other workup showed plasma normetanephrines 128 pg/mL (reference: 0–145 pg/mL), metanephrines 25 pg/mL (reference: 0–62 pg/mL), and two normal midnight salivary cortisol tests. Saline infusion testing confirmed primary aldosteronism with a non-suppressed aldosterone level of 15.6 ng/dL (normal <5 ng/dL). Abdominal imaging revealed two low-density right adrenal nodules consistent with adenomas and thickening of the left adrenal gland. The patient underwent adrenal vein sampling (AVS) with cosyntropin stimulation, which showed lateralization to the right adrenal. Despite adding clonidine 0.1 mg three times daily, hydralazine 25 mg three times daily and spironolactone 100 mg daily (which substituted triamterene-hydrochlorothiazide) after AVS, her blood pressure remained uncontrolled with blood pressure ranging from 150–180/90–110 mmHg. A laparoscopic right adrenalectomy was performed. Pathology revealed two adrenal cortical adenomas. At the one-month post-operative visit, her potassium was normal, PAC was 4.3 ng/dL, and blood pressure improved on a reduced regimen of atenolol, lisinopril, and nifedipine.

Conclusion: In patients with chronic uncontrolled hypertension due to primary aldosteronism, surgical intervention may not lead to complete resolution of hypertension but may lead to partial clinical success. Residual hypertension may be due to underlying vascular changes associated with long-term exposure to elevated aldosterone. The post-operative PAC in our case was less than 5 ng/dL suggesting biochemical cure and potentially reduced cardiovascular risk. This case emphasizes that adrenalectomy should be considered in resistant hypertension, even if complete clinical cure may not be attainable to reduce future cardiovascular events.
Non-Functioning Pheochromocytoma in a Patient With Von Hippel Lindau Syndrome (VHL): Case Report
Authors: Ricardo Gustavo Piech , Scalissi Nilza , Bueno Cristina Bellotti Formiga , Scalco Renata Da Cunha , Lima Jose Viana
Published: May 2021

Background: We report the case of a patient with VHL Syndrome with an adrenal lesion compatible with non-functioning pheochromocytoma and it’s diagnostic management. Case Report: JMN, female, 32 years old, referred for screening for VHL syndrome, after diagnosis in a sister, who has clear cell renal carcinoma (ccRCC), cerebellar hemangioblastoma and genetic analysis, by next generation sequencing (NGS), which identified the allelic variant germline pathogenic c. 256C> T in heterozygosis in exon 1 of the VHL gene. The patient is asymptomatic and her physical examination is normal. Optic fundus examination with lesion suggestive of right hemangioblastoma. Family history: mother who died at 59 with a diagnosis of ccRCC, without genetic investigation. Maternal aunt diagnosed with VHL and involvement of the cerebellum, kidney and pancreas. Two brothers with genetic and clinical diagnosis of VHL syndrome, presenting pheochromocytoma and renal carcinoma. Laboratory tests: plasma metanephrine: 0.3 nmol/L (RV <0.5nmol/L), plasma normetanephrine: 0.5 nmol/L (RV <0.9nmol/L), chromogranin A 61 ng/mL (RV <93 ng/ml). Genetic evaluation by NGS identified the pathogenic variant c. 256C> T in heterozygosity in exon 1 of the VHL gene. Topographic examinations: magnetic resonance imaging (MRI) of adrenals with nodule in the left adrenal gland, hypersignal in T2, measuring 2.9 x 2.3 cm, suggestive of pheochromocytoma and whole body scintigraphy with metaiodobenzylguanidine (MIBG) positive in the left adrenal gland. She underwent resection of the tumor in the left adrenal, without complications. Anatomopathology compatible with pheochromocytoma with immunohistochemistry for ki67 <3%. Currently, the patient is clinically stable and with periodic follow-up, as well as family members, performing screening for diseases associated with VHL. Conclusion: VHL syndrome is one of the possible causes of non-functioning pheochromocytomas and paragangliomas, and adrenal lesions with negative metanephrine levels do not exclude them; thus highlighting the importance of exams such as CT or MRI and functional topographic studies (whole body scintigraphy with MIBG and / or PETCT with Galio68DOTA) for their diagnosis.