bluuebunny/crossref_metadata_2025 huggingface dataset:
SUN-LB19 Novel Homozygous Mutation in BMP1 Causing Osteogenesis Imperfecta
Authors: Choksi Ishani , Carpenter Thomas O , Robinson Cemre
Published: May 2020

Background: Osteogenesis imperfecta (OI) is characterized by bone fragility and increased fracture susceptibility. Most mutations occur in COL1A1 and COL1A2 genes. Rarely, mutations in BMP1 have been reported in association with OI type XIII. Disease severity is generally more severe when the mutation affects both gene products encoded by BMP1 that serve as procollagenases: bone morphogenic protein 1 and mammalian tolloid (mTLD) [1].

Clinical Case: A 7-year-old Hispanic boy, with speech and gross motor delays, sustained five bilateral tibial fractures with minimal trauma since age 2.5 years. At age 6 years, he developed severe back pain after a minor fall. Diffuse spinal osteopenia and multiple vertebral compression fractures (VCF) at T9, L1, L3 were identified radiographically, with progressive vertebral height loss in the ensuing 9 months. Fatigue was reported after walking >10 min, with difficulty running and climbing stairs. There was no family history of musculoskeletal disorders.

Stature was consistently between 10-15th% for age. Subtle facial dysmorphism included micrognathia and small chin, with patchy blue-gray sclerae, and normal dentition. The lumbar spine was tender to percussion. Gait was slow and antalgic with external rotation of the right hip.

Laboratory evaluation revealed normal serum calcium, iPTH, magnesium, phosphate, 25-hydroxyvitamin D and alkaline phosphatase for age. P1NP was slightly high (193 µg/L, 30-110 µg/L) and CTX was slightly low (554 pg/mL, n: 574-1849 pg/mL), the latter being atypical for OI. Total hip BMD (adjusted for height Z-score) was normal (Z-score = 1.76) and adjusted femoral neck BMD was high (Z-score = 2.67). VCFs precluded assessment of lumbar spine BMD. Genomic analysis revealed a homozygous missense mutation in exon 4 of BMP1 resulting in an amino acid substitution (c. C505T; p.Arg169Cys) in both the bone morphogenetic protein 1 and mTLD gene products of BMP1. The mutation is predicted to be damaging to both proteins, and associated with this rare form of OI.

Conclusion: We report a novel homozygous mutation in BMP1 identified in a child with autosomal recessive OI. Unlike most forms of OI, patients with type XIII often have normal or increased BMD [1], making a correlation between BMD and fracture risk difficult. While bisphosphonates (BP) may help reduce recurrent fractures and provide symptomatic relief, the broad phenotypic spectrum and concern for further increasing BMD complicate management. A high resolution peripheral quantitative CT scan to assess bone microarchitecture and quality may aid in the decision of BP therapy. As evidence is limited on the effectiveness of BP in this rare form of OI, it is important to consider each case individually.

1.

Sangsin, A., et al., Two novel compound heterozygous BMP1 mutations in a patient with osteogenesis imperfecta: a case report. BMC Med Genet, 2017. 18(1): p. 25.
SAT-LB36 Distinct Vitamin D Receptor DNA Methylation Profiles Are Associated With the Outcome of Pediatric Patients With Adrenocortical Tumors
Authors: Bueno Ana Carolina , Stecchini Monica Freire , de Lima Neto Daniel F , Coeli-Lacchini Fernanda B , Ramalho Leandra N Z , Moreira Ayrton Custodio , Brandalise Silvia , Yunes Andres , Castro Margaret De , Vêncio Ricardo Z N , Antonini Sonir R R
Published: May 2020

Pediatric adrenocortical tumors (pACT) are rare, display complex genomic background and lack robust prognostic markers. Very recently, distinct genomic methylation profiles of pACT were associated with prognosis. The vitamin D receptor (VDR) was shown to be underexpressed in ACT, especially in carcinomas (ACC). In adult ACC, VDR inactivation by methylation was demonstrated. On the other hand, VDR activation was shown to inhibit ACC proliferation in vitro and in vivo.

Aim: To evaluate VDR DNA methylation profile and its clinical and prognostic significance in pediatric ACT.

Methods: Genomic DNA methylation from 57 pACTs [40 girls; median age: 2.1 (0.2-16.4) years] was assessed using Infininium Methylation EPIC BeadChip Array. Unsupervised hierarchical clustering analysis (Ward method, R Stats Package) was performed considering the M-values of the 49 probes targeting the whole extension of VDR gene contained in the array. Clinical, histopathological and molecular features, as well as pACT VDR mRNA levels (qPCR) and nuclear immunoreactivity (IHC) were used for association analysis.

Results: Hierarchical clustering identified three clusters of pACT. Methylated VDR-targeted probes (M-values different from 0; n=37) composed the VDR methylation profile, which differed significantly between the clusters [M-values: C1=1.77 (1.1-1.9) (low), C2=2.15 (1.7-2.7) (intermediate), and C3=2.65 (2.2-3.1) (high); p<0.0001]. The C1 cluster comprised a set of patients with favorable outcome (n=18), who were younger (p=0.035), did not present metastasis at diagnosis (IPACTR stage IV) or after surgery, nor were diagnosed with carcinomas (Wieneke criteria >=4), were not carriers of somatic Beta-catenin activating mutations, or died. Although cluster C2 patients (n=21) presented intermediary disease features, only 2 patients died and the overall outcome was positive. Instead, the C3 cluster concentrated patients (n=18) with non-localized/metastatic disease (IPACTR stages I/II vs. III/IV; p=0.004), post-surgical metastasis/recurrence (p=0.009), and patients who needed adjuvant chemotherapy (p=0.005). Moreover, C3 patients had lower overall and disease-free survival rates (log-rank: p=0.001 and p=0.014, respectively). VDR methylation was not associated with sex, clinical presentation, P53 mutations, nor with tumor VDR mRNA expression or nuclear immunoreactivity.

Conclusions: Three VDR methylation profiles were associated with distinct pACT clinical features and outcome. High VDR methylation was associated with worst outcome. Fully functioning VDR may play a beneficial role against pediatric adrenocortical tumorigenesis. This finding highlights the potential of targeting VDR as an adjuvant therapeutic target.
MON-LB041 Pheochromocytoma - Illusive Myriad of Symptoms
Authors: Gunda Mouna , Bantu Sravani , Jakka Bharath , Thudi Vaishali
Published: May 2020

Background: Pheochromocytoma is a rare neuroendocrine neoplasm arising from the adrenal medullary chromaffin cells. It contributes to 80-85% of catecholamine secreting tumors. The annual incidence of pheochromocytoma is 0.8 cases per 100,000 person-years. It can be both sporadic or familial. The classic triad of headache, palpitations and diaphoresis is seen in only 4% of cases. Rare presentations include cardiomyopathy, stroke, diabetes mellitus, ventricular arrhythmias and myocardial infarction. Our patient presented concurrently with dilated cardiomyopathy, hypertensive emergency and new-onset diabetes mellitus (DM) followed by ischemic stroke within a week. Heart failure can present as takotsubo or dilated cardiomyopathy with an incidence of 10%. The underlying pathophysiology is catecholamine mediated myocardial stunning, diffuse coronary vasospasm, microvasculature dysfunction and fibrosis. DM is seen in 23% of pheochromocytoma and is due to catecholamine-induced impaired glucose tolerance, and insulin resistance. Cerebral ischemia has an incidence of 3%, and is secondary to severe hypertension and cerebral vasospasm. Clinical Case: A 47-year-old African American woman presented with a 1-week duration of worsening dyspnea, orthopnea, dizziness, and palpitations. Past medical history includes HTN, non-ischemic cardiomyopathy on carvedilol and pravastatin. Physical exam: BP 182/119, HR 120, mild pulmonary crackles. Labs: proBNP 3533 (1-150 pg/ml), HbA1c 13.1%. Echocardiogram: moderate global hypokinesis with left ventricle ejection fraction (LVEF) of 30-35%. On imaging, CT of chest revealed an incidental finding of 4.7 cm right adrenal adenoma. MRI abdomen confirmed heterogeneously enhancing 4.3 cm right adrenal mass. Further testing showed high plasma catecholamines of 9963 (242-1125 pg/ml), 24-hour urine catecholamines of 2125 (50-100 mcg), thus confirming the diagnosis of pheochromocytoma. Further, her clinical course was complicated by left-sided weakness. MRI brain reported an acute infarct in right corona radiata. Pre-operative blockade was done with phenoxybenzamine and metoprolol. Subsequently, she underwent right adrenalectomy and tissue diagnosis confirmed pheochromocytoma. On follow up visit, her symptoms resolved. Also noted normalized catecholamine levels, HbA1c of 5.4% and LVEF of 40- 45%. Conclusion: Pheochromocytoma can rarely present with multi-organ failure. It warrants a high index of suspicion in non-ischemic cardiomyopathy. As per recent Mayo Clinic criteria, diagnosis of takotsubo cardiomyopathy mandates ruling out pheochromocytoma. As seen in our patient, it is a reversible cause of left ventricular dysfunction, focal weakness and DM. Based on our knowledge, this is the only contingently diagnosed pheochromocytoma with varied clinical presentations. It has been aptly described as “The Great Masquerader”.
SAT-LB312 Central Diabetes Insipidus as Presenting Manifestation of Suprasellar Epidermoid Cyst
Authors: Bokhari Samia Abdullah
Published: May 2020

Back Ground: Epidermoid cysts (ECs) result from the inclusion of squamous epithelial elements during neural tube closure. ECs are tumors constituting 02-1.8% of all brain tumors. ECs are typically found in cerebellopontine angle, but occasionally develop in sellar region. ECs are usually clinically silent, but may produce signs of mass effect as headaches, visual field defects. ECs presenting with Central Diabetes insipidus is reported but rare. Only two cases were reported in literature (Ref: 1).Here we report a case of sellar Epidermoid cyst presenting with Diabetes insipidus. Case Description: 49-year male presented with one-month history of polyuria, polydipsia and weight loss. The initial work up identified normal blood glucose, serum calcium and renal function. The water deprivation test confirmed the diagnosis of central Diabetes insipidus. Further pituitary hormonal assessment revealed panhypopituitarism along with diabetes insipidus. The MRI of brain showed evidence of large sellar supracellar cystic mass with a differential diagnosis of craniopharyngioma, Rathkeys cyst. Surgery performed in order to remove the tumor. The pathological report confirmed the tumor as epidermoid cyst. He did well through hospital stay. DI and along with panhypopituitarism persisted post operatively and treated with hormonal replacement. Conclusion: ECs of sellar region vary in presentation depending upon their location, and extension into surrounding areas producing mass effects. Diabetes Insipidus is a rare presentation in these rare tumors. References: 1: CW huo, C Caputo,YY Wang: Supracellar keratinous cyst: A case report and review on its radiological features and treatment: Surgical Neurology International 2018,9;15
SUN-194 Adrenal Incidentaloma to Pheochromocytoma (Variant of Unknown Significance of Von Hippel Lindau Syndrome, VHL)
Authors: Oo Yin Htwe
Published: May 2020

Introduction

The majority of adrenal masses are found incidentally during imaging for non-adrenal causes. Approximately 5% of adrenal incidentalomas have proved to be pheochromocytomas. The majority of incidentalomas are benign and non-secretory.

Case

A 73 years-old white male with pre-diabetes and morbid obesity has been followed by endocrine service for right adrenal incidentaloma overall several years. A 1.6 cm right adrenal nodule with 31 Hounsfield Unit was found incidentally in 2009 CT abdomen for abdominal pain. It was a lipid poor adenoma with >60% absolute contrast washout in 10 minutes. Biochemically it was non-secretory. The size of nodule was gradually increased over next seven years measuring at 1.9 x 1.6 cm in 2010 and 2.1 x 1.6 cm in 2012 but remained non-secretory. In 2015 CT scan, it was measured at 3.0 x 2.3 cm with absolute washout value of 45% and relative washout value of 34%. The size was overall stable again for next three years measuring at 3.2 x 2.2 cm in 2018 scan. Repeat plasma and urine metanephrine were about 2-folds higher than upper normal reference level in 2015 and 3-folds higher in 2017. Clinically he was asymptomatic except anxiety. He has normocalcemia. He underwent laproscopic right adrenectomy after alpha blockage with doxazosin. Pathology showed 4.5 cm pheochromocytoma with positive chromogranin and synaptophysin. Fulgent paraganglioma-pheochromocytoma comprehensive panel with negative for RET,NF1,FH,SDHB,SDHD,SDHC,SDHAF2,SDHA,MAX,TMEM127 and VHL but noted to have heterozygous VUS of VHL c.205>G(p.Arg69Gly). He has no significant family history or personal history to suggest VHL.

Discussion

In a patient with lipid poor adrenal incidentaloma, pheochromocytoma should be ruled out biochemically with either plasma or 24hr urine fractionated metanephrine. Both tests have similar specificity and sensitivity. Even with initial negative biochemical assessment, repeat screening should be performed annually based on clinical suspicion and radiology characteristics. Imaging can be performed annually or biannually to assess the stability of nodule. VHL is an autosomal dominant hereditary disease with del/dup mutation in the VHL gene and associated with multisystem tumor such as CNS or retinal hemagioblastomas, RCC, pheochromocytoma, pancreatic NET, endolymphatic sac tumor, epididymal and broad ligament cystadenoma and visceral cysts.

Learning points

Lipid poor adrenal incidentaloma needs interval biochemical and imaging follow up. The frequency of monitoring can be individualized based on clinical suspicion and radiology findings. Pheochromocytoma can be clinically silent especially if it is small, however, it can be lethal with late or missed diagnosis. This is the first published case report of c.205C>G VHL variant associated with pheochromocytoma.
OR28-05 Approaching Indeterminate Thyroid Nodules in the Absence of Molecular Markers. “The BETH-TR Score”
Authors: Kannan Subramanian , Khadilkar Kranti , Siddegowda Shivaprasad Kumbenahalli
Published: May 2020

Context: Given the lack of easy access to molecular markers, for indeterminate thyroid nodules (Bethesda (BETH) category III, IV), the clinician can either decide to get a second opinion from an expert high volume thyroid cytopatholgist, re-do the FNAC after a period of 3-6 months or send the patient for a diagnostic hemithyroidectomy. Reviewing the sonographic risk features is also one way of triaging these nodules. The ACR-TIRADS (TR) is an objective method of sonographic risk assessment and is superior to other forms of sonographic classification. Aim: We propose combining the scoring of TR category and BETH category (both expressed as numerical value and summated) and look at the score which could potentially guide the clinician in deciding whom to send for surgery. Settings and Design: Observational Prospective collection of consecutive patient data from Thyroid FNAC clinic. Statistical analysis used: The BETH categories were represented numerically and summated with the TR category. The categorical outcome variables of Benign and Malignant nodules and the summated score was analysed using Kruskal-Wallis test. Results: We analysed 450 FNAC data, out of which 403 were thyroid nodule aspirates. Out of these nodules, 96 of them underwent surgery and 64% of these nodules were malignant on final histopathology (Malignant=62 and Benign=34). The mean (sd) size of the benign nodules was 3.6 (2.2)cm compared to 2.8 (1.8)cm of the malignant nodules. After excluding those with BETH 1 (n=4), the mean BETH-TR score for benign nodules was 6(1.4) and malignant nodules 9.4(2.1) (p<0.0001). The BETH-TR score progressively increased from 7.3(0.92) in Follicular thyroid cancers (FTC) to 8.6(1.4) in Follicular variant Papillary thyroid cancer (FVPTC) to 10(1.3) in classic Papillary thyroid cancers (PTC). Among the indeterminate nodules (BETH III & IV; n=40), the BETH-TR score of benign nodules was 6.75(1) and malignant nodules was 7.5(0.72) (p value=0.01). A BETH-TR score >=7 gave a sensitivity of 92% specificity of 74% and correctly identified malignant nodules in 86% of cases (Likelihood ratio 3.5; ROC area: 0.8841; CI 0.79-0.94). Conclusion: A combined sono-cytological BETH-TR score is one way to triage management of indeterminate thyroid nodules. A BETH-TR score >=7 gave a sensitivity of 92% specificity of 74% and correctly identified malignant nodules in 86% of cases.
SAT-LB118 Euglycemic Diabetic Ketoacidosis in Type 2 Diabetes Mellitus
Authors: Arao Kevin A , Bhatt Harikrashna , Capistrano Christina M , Zhang Hui , Cosgrove Christopher
Published: May 2020

Introduction

Diabetic ketoacidosis (DKA) is a potentially life-threatening complication of diabetes. It is characterized by the triad of hyperglycemia (>250mg/dL), high anion gap metabolic acidosis (HAGMA), and ketonemia. Rarely, it would present with normal or mildly increased glucose levels (<200mg/dL) making it a diagnostic challenge. We present a case of euglycemic DKA in type 2 diabetes mellitus (T2DM).

Case Presentation

A 77-year-old woman living in a nursing home with a history of T2DM treated with insulin glargine, but for the past three days refused medications with decreased caloric intake. There were no new medications or ingestion of alcohol or toxic substances. She then developed worsening altered mental status hence admission to the hospital. Her vital signs were within normal limits. Physical examination revealed no abdominal tenderness. Initial laboratory studies showed glucose 83 mg/dL, bicarbonate 10 mmol/L, and anion gap 23 meq/L. Urinalysis significant with trace ketones. The following day, further work-up was done remarkable with beta-hydroxybutyrate 8.3 mmol/L, lactic acid 0.8 mmol/L, and toxicology panel negative. Arterial blood gas showed pH 7.137, pCO2 14 mmHg, and bicarbonate 4.8 mmol/L. DKA protocol was initiated and she was treated with insulin drip, bicarbonate drip, and intravenous fluid administration with D5W. After two days, DKA resolved and was subsequently transitioned to subcutaneous insulin.

Discussion

Similar to the findings of Burge et al, our case showed that decreased caloric intake predisposes patients with diabetes mellitus to euglycemic DKA during periods of insulin deficiency. A proposed mechanism for the accelerated ketosis is due to the effects of elevated levels of glucagon or catecholamines on lipolysis. Other causes of euglycemic DKA include pregnancy, heavy alcohol use, SGLT2 inhibitors, cocaine abuse, pancreatitis, sepsis, and chronic liver disease. It is also important to rule out other causes of HAGMA. In our case, although she has decreased caloric intake, starvation ketoacidosis usually leads to serum bicarbonate levels >18mmol/L. Management is similar to DKA but important difference is the dextrose administration to prevent hypoglycemia.

Conclusion

Euglycemic DKA is a medical emergency that may be overlooked as patients present without marked hyperglycemia. Physicians should have a high suspicion as this may result in delayed management and potential adverse metabolic consequences.
SUN-LB103 The Relationship Between Alcohol Consumption Patterns and Insulin Sensitivity in Obesity
Authors: Han Katrina , Reeds Dominic Nicholas , Dunn Julia Passyn
Published: May 2020

BACKGROUNDThe effects of alcohol intake on insulin sensitivity have produced conflicting results with both beneficial and adverse effects observed. This study aimed to compare the relationship between patterns of alcohol consumption and insulin sensitivity in obese Veterans. METHODSWe performed a cross-sectional study of obese (BMI 30.0-45.0 kg/m2), nondiabetic U.S. Military Veterans without active mental health diagnoses, including no report of dependent alcohol use within the last 12 months. Alcohol exposure over the previous 12 months (mos) was assessed using a study-developed questionnaire and Michigan Alcoholism Screening Test (MAST). Fasting insulin, glucose, and a 75gm OGTT were completed to determine Homeostatic Model Assessment of Insulin Resistance (HOMA-IR) and prediabetes (preDM) score of 0, 1, or 2 based on fulfilling 0, 1, or at least 2 of the ADA criteria for preDM, respectively. Linear regression was used to assess for associations between measures of insulin resistance and alcohol consumption; unstandardized β and p-value are reported for variable of interest. RESULTS104 Veterans participated (66% males; 44±8years (range: 25-60); BMI 36±4kg/m2 (range: 29-45); 53% White, 46% African American, 2% Alaskan/Native American, 1% Other). 83 participants reported any alcohol intake in the previous 12 mos and neither preDM score (p=0.57) nor HOMA-IR (p=0.14) were predicted by this question. PreDM score groups were similar in gender, BMI, and weight, but age predicted both preDM score (r2=0.09, β=0.025, p=0.006) and HOMA-IR (r2=0.05, β=-0.09, p=0.034); therefore, all regressions were adjusted for age. There was a negative association between the number of days of alcohol intake with HOMA-IR (β=-0.271, p=0.037) but no association occurred with preDM score (p=0.15). Fewer days of binge drinking was associated with higher HOMA-IR (β= -0.342, p=0.058) and preDM score (β=-0.075, p=0.05). There was no significant association between total quantity of alcohol intake and HOMA-IR (p=0.13) nor preDM score (p=0.15). There was no association between MAST score and HOMA-IR (p=0.7) or preDM score (p=0.3). CONCLUSIONIn our cohort of obese, non-alcohol dependent Veterans, the reported number of days of alcohol intake and days of binge drinking in the previous 12 mos were lower in those with markers of insulin resistance. These results suggest that drinking patterns among obese patients may have unique effects on insulin sensitivity that warrant further investigation.
SAT-511 Alpha Gal Allergy in a Hypothyroid Patient
Authors: Slayden Tanner A , Bauer Elizabeth M , Shakir Mohamed K M , Hoang Thanh Duc
Published: May 2020

Background: The IgE-mediated allergy to galactose-alpha-1,3-galactose (alpha-gal), a carbohydrate expressed on nonprimate mammalian proteins, has gained more clinical significance as it can present with serious, potentially fatal anaphylaxis or angioedema. In general, recognizing a specific allergy is the first step in prescribing avoidance; but with delayed symptoms, uncertain prevalence, and unclear diagnostic approach, alpha-gal allergies are difficult to recognize and prevent. To further complicate the clinical picture, some patients can tolerate small portions of nonprimate mammalian meat or tolerate one kind of meat over another. We hereby present a case that highlights the lack of guidance and resources currently available to treat a patient with alpha-gal allergy and hypothyroidism. Case Presentation: A 45-year-old woman with a history of an alpha-gal allergy and follicular thyroid neoplasm status post right hemithyroidectomy presented with postoperative hypothyroidism. After the surgery, she had undetectable serum thyroglobulin levels; her thyroid stimulating hormone (TSH) levels were ranging 5–6 µIU/mL (not on thyroid replacement). The goal was to prescribe thyroid replacement to initiate cancer suppressive strategy. The American Thyroid Association (ATA) recommends a TSH of 0.5-to-2 mcIU/mL in low risk patients postoperatively. The standard treatment of choice for correcting hypothyroidism is synthetic thyroxine (T4, levothyroxine). Commercially available levothyroxine, liothyronine, combo, and desiccated thyroid formulations - whether brand name, generic, tablet, soft gel capsule, or liquid - all contain meat byproducts and can be a concern for anaphylaxis or angioedema if one has an alpha gal allergy. Because of the possible reactions with all common formulations of thyroid hormone replacement in this patient, choosing a safe option was complicated and involved a multidisciplinary team, including allergy and immunology consultation. Daily parenteral synthetic thyroid hormone therapy was considered; however, it is not practical and was not feasible for the patient. She was eventually prescribed pure Levothyroxine, with a plant-based filler and vegetarian capsule. She tolerated this pure levothyroxine well without any adverse reactions, and the TSH goal was achieved. Conclusion: This case emphasizes the importance of recognizing various risk factors and common drugs associated with the alpha-gal allergy. Further research and pharmaceutical attention to this allergy is needed.
SAT-LB1 Detection of Serum Macro-Luteinizing Hormone
Authors: Ogura-Ochi Kanako , Itoshima Koichi , Kamada Yasuhiko , Otsuka Fumio
Published: May 2020

Macromolecules of prolactin (PRL) and thyrotropin (TSH), so called macro-PRL and macro-TSH, respectively, are rarely detected in the patients’ serum containing high concentrations of these hormones. The macromolecules are involved in increasing the serum concentrations due to aggregation with the autoantibodies in serum. Here we show a case having macromolecules of luteinizing hormone (LH), possibly due to the complex to immunoglobulin-G (IgG). A 35-year-old Japanese female who has complained menstrual irregularity and had a past surgical history of thyroid cancer was referred to our hospital. Laboratory examination showed an extremely high concentration of serum LH (>200 mIU/ml), while serum levels of follicle-stimulating hormone, estradiol, thyroid hormones, human chorionic gonadotropin, testosterone, and prolactin were all within the normal ranges. MRI study showed a normal pituitary shape without any tumorous lesion. Responses of gonadotropins to LH-releasing hormone (LHRH) stimulation were marginally blunted but showed an LH-dominant pattern such as polycystic ovary syndrome. We suspected the presence of macro-LH because of the divergence between the clinical features and the LH level. Of note, the recovery rate of LH levels after precipitation with polyethylene glycol (PEG) was less than 5%, and the gel-filtration analysis further demonstrated an LH peak slightly earlier fraction than IgG. One case report documented the presence of macro-LH in the serum from a young female patient complicated with autoimmune thyroiditis, suggesting the formation of macro-LH related to some latent autoimmune diseases. To assume macro-LH and to re-examine LH levels after serum precipitation by PEG or protein A/G and fractionation are important to avoid unnecessary treatment to increased LH conditions. In clinical practice, we should suspect the presence of macro-LH, if serum LH levels are unexpectedly high compared to the clinical signs.
MON-LB037 Adrenocortical Carcinoma: A Case Report
Authors: Ebadi Farha Naz , Karim Marcus , Chen Kenneth , Abraham Reshma
Published: May 2020

Introduction:

Unilateral adrenal tumors are relatively common; adrenal incidentaloma has a prevalence of 4% on CT imaging. These masses are classified by their functional and malignant potential. We present here a case of adrenocortical carcinoma (ACC), a rare and often aggressive tumor that accounts for 2% of all adrenal incidentalomas. ACC has a worldwide incidence of disease of 0.5-2 cases per million population per year. While some instances of ACC are associated with hereditary conditions, most cases are sporadic mutations.

Case:

A 44-year-old male with a past medical history of hypertension, polysubstance use, and anasarca presented with a one-year onset of abdominal swelling. This was associated with a 16 pound weight loss over the prior 4 months and bilateral lower extremity swelling for the previous 3 weeks. Of note the patient had been detained in an adult corrections institution for over 5 years. Review of systems was negative for night sweats, nausea, vomiting, headaches, confusion, or palpitations. CT of the abdomen demonstrated a large mass involving the left adrenal gland measuring 28 x 27 x 31 cm, with punctate and delayed calcifications. Also noted were numerous bilateral lung nodules, and multiple liver lesions. Bilateral lower extremity ultrasound revealed a DVT involving the left gastrocnemius vein. A heparin drip was initiated and the patient was transitioned to Xarelto. CT scan of the chest demonstrated gastroesophageal junction lymphadenopathy, right hilar lymphadenopathy, numerous lung metastases and a prominent lesion in the left lower lung. Laboratory studies included both a low and high dexamethasone suppression test demonstrating a cortisol level 24 mcg/dL, metanephrines < 0.2 nmol/L, low testosterone 2.1 ng/dL (free) and 54 ng/dL (total), and DHEA 7.1 ng/mlL. Aldosterone <4.0 ng/dL and ACTH < 5 pg/mL. Biopsy for the adrenal mas was consistent with cortical neoplasm. Surgery recommend against debulking due to wide-spread metastases. Oncology recommended chemotherapy; a regimen of mitotane, etoposide, doxorubicin, and cisplatin, with glucocorticoid replacement in 28-day cycles x 6 through venous port.

Conclusion:

Adrenocortical carcinoma is a rare, aggressive tumor that often secretes excess cortisol and/or androgens. In the case presented a large advanced stage ACC was nonfunctional. First-line therapy for ACC includes resection with debulking surgery, radiation therapy, and/or chemotherapy. 5-year survival rates range 62-82% for those with disease confined to the adrenal gland and 13% for tumors associated with distant metastases. Repeat CT scans for our patient demonstrated stable appearance after four cycles of chemotherapy, thus indicating this treatment regimen may be beneficial for such an aggressive disease.
SAT-LB98 Early Atherosclerosis in Polycystic Ovary Syndrome. a Systematic Review, Meta-Analysis and Meta-Regression
Authors: Parolin Matteo , Beghetto Marco , Fallo Francesco , Vincenzo Angelo Di , Vettor Roberto , Mioni Roberto , Aguiari Paola , Milanesi Anna , Rossato Marco , Pagano Claudio
Published: May 2020

Backgroung. Polycystic ovary syndrome (PCOS) is a common disorder affecting reproductive age women and is a cluster of endocrine and metabolic alterations ranging from impaired ovulation and androgen excess to abdominal obesity and metabolic syndrome leading to increased cardiovascular risk profile. Aim. To perform a meta-analysis on the effect of PCOS on surrogate markers of atherosclerosis, namely intima media thickness (IMT), flow-mediated dilation (FMD) and pulse wave velocity (PWV) and to run a meta-regression on the potential determinants of preclinical atherosclerosis. Methods. A search through Pubmed/Medline and ISI-web of knowledge retrieved 90 studies that were used for meta-analysis. Selected outcomes were IMT (n=6199), FMD (n=3090), and PWV (n=2477) while age, BMI, waist circumference, total testosterone, free androgen index (FAI), total-, HDL- and LDL-cholesterol, HOMA-index, systolic and diastolic blood pressure were used for meta-regression analysis. Results. Random effect meta-analysis showed that IMT was significantly increased (ES 0.47, 95% C.I. 0.64 to 0.30, p<0.0001), FMD was significantly impaired (ES -0.92, 95% C.I. -0.69 to -1.15, p<0.0001) and PWV was significantly increased (ES 0.28, 95% C.I. 0.48 to 0.08, p=0.006) in PCOS compared to controls. Meta-regression analysis showed that FMD was positively correlated with FAI (p=0.018) while negative correlations were found between Effect Size (IMT) and BMI (p=0.02), waist circumference (p=0.05) and total cholesterol (p=0.02). Conclusions. This meta-analysis shows a clear effect of PCOS on all markers of preclinical atherosclerosis (IMT, FMD and PWV). Heterogeneity of results is explained in part by the androgen status that was positively linked to impairment of FMD while increasing of anthropometric and metabolic variables (waist, BMI and total cholesterol) seem to overcome PCOS on preclinical atherosclerosis.
MON-LB85 Aberrant Glycan Expression Changes With the Phenotype of Follicular Thyroid Tumours
Authors: Lee Kai Yin , Sreenivasan Dinesh Kumar , Feng Pan , Yang Peiling , Parameswaran Rajeev
Published: May 2020

Glycosylation is the most common post-translational modification of proteins and plays an important role in cell communication, interaction and adhesion. Aberration of glycosylation is a hallmark of cancer cells and plays an important role in oncogenesis and cancer progression including metastasis1. One of the markers of aberrant glycosylation (O-linked) is the binding of the lectin Helix pomatia agglutinin (HPA), and this has been shown in a wide range of human cancers2, especially in tumours with a more aggressive phenotype. To study the alteration in cellular glycosylation, detected by lectin Helix pomatia agglutinin (HPA) binding in various phenotypes of follicular thyroid tumours, ranging from adenoma to carcinoma and metastatic follicular thyroid cancers. Lectin histochemistry was performed on archival paraffin wax-embedded specimens of 6 follicular adenomas, 10 minimally invasive follicular carcinomas, 13 widely invasive follicular cancers and 4 metastatic follicular thyroid cancers. For positive controls, sections of rat kidney were used, which shows strong and characteristic HPA labelling were included in each labelling experiment. For negative controls, the lectin was omitted and the specificity of binding was confirmed by incubating the sections with HPA in the presence of 0·1-mol/l GalNAc. Sections were scored as positive when 5% or more of the cancer cells labelled positive and scored as negative when less than 5% labelled positive for HPA binding. Assessments of HPA binding were performed by two observers who were blinded to the identity of the sample, and their results were compared. Positive labelling was seen in 20% of adenomas, 60% of minimally invasive carcinomas, 77% of widely invasive carcinomas and 100% of metastatic carcinomas (p<0.05). In the minimally invasive carcinoma group, all tumours that showed vascular invasion showed positive HPA labelling, whereas only 20% of patients with capsular invasion showed positivity. We speculate that as the phenotype of the thyroid tumours changes from benign to the malignant phenotype, the glycan expressions change. However, the underlying molecular mechanisms leading to this change needs to be further investigated.

References:1. Magalhães, A., Duarte, H.O. & Reis, C.A. 2017, “Aberrant Glycosylation in Cancer: A Novel Molecular Mechanism Controlling Metastasis”, Cancer Cell, vol. 31, no. 6, pp. 733-735.2. Parameswaran, R., Sadler, G. & Brooks, S. 2011, “Helix pomatia Agglutinin Binding Glycoproteins in Thyroid Tumors”, World Journal of Surgery, vol. 35, no. 10, pp. 2219-2227.3.

Parameswaran, R., Tan, W.B., Nga, M.E., Soon, G.S.T., Ngiam, K.Y., Brooks, S.A., Sadler, G.P. & Mihai, R. 2018, “Binding of aberrant glycoproteins recognizable by Helix pomatia agglutinin in adrenal cancers”, BJS open, vol. 2, no. 5, pp. 353-359.
SUN-LB107 Functional Characterisation of Human Heterozygous Non-Synonymous MC3R Variants
Authors: Melvin Audrey , Cowan Ceili , Lam Brian , Buller Sophie , Rainbow Kara , Yeo Giles S , O’Rahilly Stephen
Published: May 2020

Background: Melanocortin 3 receptor (MC3R) is a member of the melanocortin family of G-protein coupled receptors predominantly expressed in hypothalamic tissue. Rodent models have implicated MC3R in the pathogenesis of obesity, however in humans the relationship between obesity phenotypes and impaired MC3R function is less well established than that observed for loss of function mutations in the homologous MC4R.

Aim: Recently three heterozygous MC3R variants identified from candidate gene sequencing of an obese human cohort were reported to be pathogenic. We sought to functionally characterise the these MC3R non-synonymous variants (p.Q11X, p.I50T and p.A149V) in vitro and examine their associations to body mass index in an unselected population-based cohort.

Methodology: Functional characterisation of each variant was undertaken in HEK293 cells transiently overexpressing either wild-type MC3R or the respective MC3R mutant where cAMP-dependant luciferase activity in response to alpha-melanocyte stimulating hormone (α-MSH) was measured. Body mass index (BMI) was compared between heterozygous carriers of the MC3R variants of interest and control participants (matched for age and sex and ethnicity) identified within the UK Biobank whole exome sequencing dataset.

Results: Impairment of the canonical MC3R cAMP signalling response to α-MSH was observed for both p.Q11X and p.A149V MC3R variants when compared to wild-type MC3R receptor function in vitro. In contrast the cAMP signalling response of MC3R p.I50T to α-MSH was non-inferior to wild-type. Thirty-nine (male=18) heterozygous carriers of MC3R p.I50T were identified in the UK Biobank whole exome cohort. There was no statistical difference in median (IQR) BMI for female carriers 27.1(7.8) kg/m2 vs. matched female control participants 26.2(5.5) kg/m2 or male carriers 27.7(5.4) kg/m2 vs. matched male control participants 27.4(4.9) kg/m2. A single participant heterozygous for the MC3R p.Q11X variant (BMI= 28.3 kg/m2) and two participants heterozygous for MC3R p.A149V (BMI= 24.7 and 25.1 kg/m2 respectively) variant were identified in the UK Biobank whole exome cohort. BMI did not significantly differ from the match control population median for either of these variants.

Conclusion: In vitro assessment and phenotype correlates suggest that MC3R p.I50T is not an obesity causing mutation. Despite evidence of impaired receptor function in vitro, MC3R p.Q11X and p.A149V did not associate with obesity in this unselected population and further study are required to elucidate their pathogenicity in humans.
SAT-LB6 First Human Trial of an Oral Native Testosterone Shows Physiological Levels of Testosterone and Dht in Both Fasted and Fed State in Hypogonadal Men
Authors: Newell-Price John D C , Porter John , Quirke Jo , Daniel Eleni , Mumdzic Enis , Ross Richard John M
Published: May 2020

Introduction: The prevalence of male hypogonadism is estimated to be 6% in the USA (1). Current therapies have limited acceptability: gels can be messy and risk inadvertent dosing of others; injections are painful; and oral testosterone undecanoate (TU) delivers variable testosterone levels, requires concurrent ingestion of a fatty meal and may produce supraphysiological dihydrotestosterone (DHT) levels. We present the first human trial of an oral native testosterone preparation formulated to deliver physiological levels of testosterone irrespective of food intake. Aim: To compare the pharmacokinetics of DITEST (Diurnal Ltd Cardiff, UK) to an oil based oral TU formulation (Andriol Testocaps MSD, UK) and explore the effect of food on DITEST bioavailability. Methods: Single centre, phase 1b study of DITEST in 25 adult males with hypogonadism, one subject withdrawn after single period and only included in safety analysis (Clinicaltrials.gov: NCT02966652). Part 1 compared the pharmacokinetics of 80mg TU with 120mg DITEST after a high fat meal. Part 2 the pharmacokinetics of 200mg of DITEST administered in either fed or fasted states. Results are baseline adjusted. Results: DITEST showed a testosterone dose response between 120mg and 200mg with Cmax 550 (19.1) and 877 (30.4) ng/dl (nmol/l) and AUC0-10h 59.5 and 88.6 h*nmol/L. DITEST 200mg gave an equivalent Cmax and AUC0-10h to TU 80mg: Cmax 877 (30.4) vs 906 (31.4) ng/dl (nmol/l) and AUC0-10h 88.6 vs 102 h*nmol/L. Fed and fasted DITEST had similar pharmacokinetics: Cmax 764 (26.5) vs 877 (30.4) ng/dl (nmol/L), AUC0-10h 87.0 vs 88.6. DITEST resulted in lower levels of DHT than TU: Cmax 84 (2.9), 131 (4.5) & 194 (6.7) ng/dl (nmol/l); AUC0-10h 11.0, 16.7 & 36.3 h*nmol/L for DITEST 120mg, 200mg & 80mg TU, respectively. There was one serious adverse event (urinary retention) in the study during TU dosing. There were no emerging safety concerns, and adverse event frequency and severity was similar between the two treatments. Discussion: These results demonstrate that 200mg DITEST provides similar testosterone exposure with more physiological DHT exposure than 80mg TU given with a high fat meal. Administration of DITEST in fed and fasted states provides similar testosterone and DHT exposure. Compared to published literature on a self-emulsifying formulation of TU at 200mg, DITEST at 200mg provides a similar testosterone Cmax and no requirement for a fatty meal (2). Conclusion: DITEST is an oral native testosterone formulation with anticipated advantages over current oral therapy of dosing without food and a lower risk of supraphysiological DHT levels. References: 1. Basaria S. Male hypogonadism. Lancet 2014; 383:1250-1263. 2. Yin AY, et al., J Androl 2012; 33:190-201.
SUN-LB78 Hyperfunctioning Papillary Thyroid Carcinoma With a BRAF Mutation
Authors: Shinkai Shinsuke , Ohba Kenji , Matsushita Akio , Kuroda Go , Sakai Yuki , Nishino Nobuhiko , Kakudo Kennichi , Oki Yutaka , Sasaki Shigekazu
Published: May 2020

Background: Hyperfunctioning papillary thyroid carcinoma (PTC) is a rare tumor and accounts for less than 0.1% of all thyroid tumors. Information about its driver mutations is limited. Our literature search yielded 16 cases wherein a mutational analysis was conducted. Thyrotropin receptor (TSHR) mutations were identified in 11 of these cases. One case revealed a combination of TSHR and KRAS mutations. No mutations were identified in the other four cases. BRAFV600E is a prominent oncogene in PTC; however, hyperfunctioning PTC with this mutation has not yet been reported.

Clinical Case: In a 48-year-old man, ultrasonography (US) during an annual medical checkup revealed a nodule at the right lobe of the thyroid gland. He visited the outpatient clinic for further evaluation. Thyroid function tests indicated that he was hyperthyroid with TSH level of 0.01 mIU/L (reference range: 0.05-5.00), free thyroxine level of 1.8 ng/dL (reference range: 0.9-1.7), and free triiodothyronine level of 4.3 pg/mL (reference range: 2.3-4.0). Serum thyroglobulin was 62.1 ng/mL (reference range: <33.7) and TSHR autoantibodies (TRAb) was <0.8 IU/L (reference range: <2.0 IU/L). B-mode US revealed a hypoechoic, heterogeneous nodule with largest diameter of 25 mm, and it had a jagged border and microcalcification. Color Doppler US revealed increased intranodular vascularity. The 99mTc thyroid scintigram revealed a round, right-sided focus of tracer uptake by the nodule with suppression in the remainder of the gland. These findings were consistent with an autonomously-functioning thyroid nodule. The patient underwent total thyroidectomy because fine-needle aspiration cytology revealed a malignant cytological diagnosis. The histopathological diagnosis of the patient was PTC, tall cell variant, pT2, pEx0, pN1b, and M0. Subsequent mutational analysis of BRAF (exon 15), TSHR (exons 9 and 10), GNAS (exons 7-10), KRAS, NRAS, HRAS (codons 12, 13, and 61), and TERT promoter (C250T and C228T) only identified a heterozygous point mutation in BRAFV600E in tissue samples.

Conclusion: We report for the first time a case of hyperfunctioning papillary thyroid carcinoma with a BRAF mutation.
MON-LB57 Impact of Imputation Method and Response Cutoffs on Results From the Phase 3 OPTIMAL Study of Oral Octreotide Capsules in Adult Patients With Acromegaly
Authors: Samson Susan Leanne , Nachtigall Lisa B , Fleseriu Maria , Gordon Murray B , Jensterle Mojca , Elenkova Atanaska , Ludlam William Henry , Patou Gary , Haviv Asi , Biermasz Nienke , Trainer Peter James , Strasburger Christian Joseph , Kennedy Laurence , Melmed Shlomo
Published: May 2020

Objective: The phase 3 CHIASMA OPTIMAL study assessed efficacy and safety of oral octreotide capsules (OOC) in patients with acromegaly controlled on injectable somatostatin receptor ligands (SRLs). Sensitivity analyses were conducted for efficacy endpoints using two methods of imputation (i.e., the process of replacing clinical data with substitution values) to address missing data points due to some subjects reverting back to their prior injectable SRL treatment. Methods: Patients were ≥18 years of age and had evidence of active acromegaly with an average IGF-I ≤ 1.0 x ULN (utilizing the IDS iSYS assay calibrated to WHO recombinant reference standard 02/254). At baseline, patients were randomized to receive OOC or placebo for 36 weeks. The primary endpoint was proportion of patients maintaining biochemical response, defined as IGF-I ≤1.0 x ULN (2-value average at weeks 34 and 36) (Samson et al. ENDO 2020). Per study protocol, patient study discontinuations were considered non-responders regardless of clinical response at the time of discontinuation (non-response imputation). Additional exploratory analyses were performed utilizing the last observation carried forward (LOCF) analysis, as well as a completers analysis of response among the subgroup that completed the entire 36 weeks on study drug. The response rates reported for the primary end point are slightly adjusted for stratification differences as prespecified in the statistical analysis plan. Results: Twenty-eight patients received OOC and 12 failed to maintain biochemical response based on the primary endpoint. Seven of these 12 patients discontinued treatment early - 5 due to treatment failure and 2 due to AEs. The remaining 5 patients completed the 36-week protocol on study drug. Of these 5 patients, 4 had IGF-I values between >1.0 and ≤1.3 x ULN and 1 completed the study with an IGF-I of 1.7 x ULN with no clinical symptoms. 58.2% of patients in the OOC group met the primary endpoint of maintenance of biochemical response at the end of study using the non-response imputation. Using LOCF imputation, 64.3% (18/28) of patients met this endpoint. Of those completing the study (N=21), 76.2% maintained response. Conclusion: CHIASMA OPTIMAL primary endpoint was assessed using the non-response imputation for patients who discontinued treatment early, with a 58.2% response rate. However, when assessing the response rate based on LOCF imputation, or in study completers, similar to other phase 3 studies for acromegaly, the rate was imputed at 64.3% and 76.2%, respectively.
MON-LB5 A Longitudinal Cohort Study of Serum Decorin Levels in Normal and Preeclamptic Pregnant Women
Authors: Cano – Bermúdez Maria Alejandra , Rodríguez – Navarro Haiver Antonio , Buell – Acosta Julieth Daniela , Acosta – Álvarez Jaidy , Parra- Pineda Mario Orlando , Parada - Baños Arturo José , Caminos Jorge Eduardo , Garces Maria Fernanda
Published: May 2020

Background: Decorin (DCN) is a leucine-rich proteoglycan that regulates diverse cellular processes such as organization and stability of extracellular matrix, extracellular signaling by the maintenance of surface receptors and growth factors and enzymes activities. Additionally, DCN is an important mediator of inflammation, angiogenesis, trophoblast migration, placentation, tumor growth and autophagy. Objective: We aimed to evaluate DCN serum levels throughout gestation in a longitudinal cohort study in normal and preeclamptic pregnant women. Methods: In this nested case-control study design within a prospective cohort of 450 pregnant women, 50 healthy and 20 preeclamptic pregnant women were followed during each pregnancy trimester and three months postpartum. Likewise, healthy non-pregnant women in the follicular and luteal phase of their menstrual cycle were included (n = 20). Serum DCN concentrations were measured by ELISA. Results: In healthy non-pregnant women, DCN levels did not differ significantly between the two stages of the menstrual cycle. On the other hand, serum DCN levels decreased significantly in both healthy and preeclamptic pregnant women in each trimester of pregnancy when compared to non - pregnant women (p <0.001) and were re-established three months postpartum (p <0.001). Moreover, serum DCN levels were significantly lower in the second trimester of gestation in normal pregnant women (p <0.05). On the other hand, serum DCN was significantly higher in preeclamptic compared to healthy pregnant women in the third trimester of pregnancy (p <0.01). Conclusion: The present study found that DCN serum levels decreased significantly throughout pregnancy in healthy and preeclamptic pregnant women. Thus, low levels of DCN may play crucial physiological and pathological roles during pregnancy. DCN has been shown to inhibit different growth factors such as vascular endothelial growth factor (VEGF), transforming growth factor-beta (TGF-β) and platelet-derived growth factor (PDGF). Hence, low levels of DCN during pregnancy might play a critical role in the control of angiogenic process.