Multiple Endocrine Neoplasia Type Research Articles

Improving early diagnosis of multiple endocrine neoplasia type 1 by assessing the gastrointestinal symptoms, hypercalcemia, and elevated serum gastrin

Despite advancements in the field, early diagnosis of multiple endocrine neoplasia type 1 (MEN1) remains unachievable. This letter to the editor highlighted the importance of carefully assessing gastrointestinal symptoms, hypercalcemia, and elevated serum gastrin levels, as suggested by Yuan et al in their paper. They focused on a patient with recurrent abdominal pain and diarrhea whose diagnostic path led to establishing a MEN1 diagnosis within a year. This emphasized the need for clinicians to consider MEN1 in patients with similar presentations, particularly when gastrointestinal symptoms persist or recur after discontinuation of proton pump inhibitors, especially knowing that early recognition and intervention are crucial for improving patient outcomes.

Primary hyperparathyroidism in multiple endocrine neoplasia type 1 (MEN1): Northern Ireland's (N.I) experience

Primary hyperparathyroidism in multiple endocrine neoplasia type 1 (MEN1): Northern Ireland's (N.I) experience

Targeting Menin in Acute Myeloid Leukemia: Therapeutic Advances and Future Directions

Germline mutations in the MEN1 gene encoding menin protein cause multiple endocrine neoplasia type 1 (MEN1) syndrome. Recent evidence suggests that inhibiting the interaction of menin with its crucial oncogenic protein partners represents a promising therapeutic strategy to AML. Menin plays a critical role in lysine methyltransferase 2A (KMT2A)-gene-rearranged and NPM1-m acute leukemias, both associated with adverse outcomes with current standard therapies, especially in the relapsed/refractory setting. Disrupting the menin–KMT2A interaction affects the proleukemogenic HOX/MEIS transcription program. This disruption leads to the differentiation of KMT2Ar and NPM1-m AML cells. Small molecular inhibitors of the menin–KMT2A interaction target the central cavity of MEN1 to inhibit the MEN1-KMT2A interaction and could target a similar transcriptional dependency in other leukemia subsets, broadening their therapeutic potential. These agents, both as monotherapies and in combination with synergistic drugs, are undergoing preclinical and clinical evaluation with promising early results. With the growing literature around menin inhibitors in AML, we discussed the biology of menin, its mechanism of action, its interacting partners in leukemia, possible inhibitors, their implications, synergistic drugs, and future therapeutic strategies in this review.

Endocrine Perspective of Cutaneous Lichen Amyloidosis: RET-C634 Pathogenic Variant in Multiple Endocrine Neoplasia Type 2

Background: Medullary thyroid carcinoma (MTC), the third most frequent histological type of thyroid malignancy, may be found isolated or as part of multiple endocrine neoplasia type 2 (MEN2). One particular subtype of this autosomal dominant-transmitted syndrome includes an association with cutaneous lichen amyloidosis, although, generally, a tide genotype–phenotype correlation is described in patients who carry RET proto-oncogene pathogenic variants. Methods: Our objective was to provide an endocrine perspective of a case series diagnosed with RET-positive familial MTC associated with cutaneous primary lichen amyloidosis amid the confirmation of MEN2. Six members of the same family had cutaneous lesion with different features (from hyperpigmented, velvety to red/pink appearance) and four of them harbored a RET pathogenic variant at 634 codon (exon 11): c.1900T>G, p.634G (TGC634CGC). Results: All six patients were females with the lesion at the interscapular region. Except for two women, four of these subjects were investigated and had MTC (three of them with postoperatory confirmation). The youngest affected individual was 6 years old. The three adult females were confirmed with RET pathogenic variant during their 30s, while the girl underwent the familial screening as a newborn. None of them had primary hyperparathyroidism until the present time, except for one subject, and two out of the three adults also had bilateral pheochromocytoma. Notably, all patients were rather asymptomatic from the endocrine perspective at the moment when endocrine tumor/cancer was confirmed, and the skin was progressively affected a few years before the actual MEN2 confirmation. Conclusions: This case series highlights the following key message: awareness of the dermatologic findings in MTC/MEN2 patients is essential since lesions such as cutaneous lichen amyloidosis might represent the skin signature of the endocrine condition even before the actual endocrine manifestations. These data add to the limited published reports with respect to this particular presentation, noting the fact that RET-C634 is the most frequent pathogenic variant in MEN2-associated lichen amyloidosis; females are more often affected; the interscapular region is the preferred site; the age of diagnosis might be within the third decade of life, while we reported one of the youngest patients with the lesion. The same RET pathogenic variant is not associated with the same dermatologic features as shown in the vignette. The same RET mutation does not mean that all family members will present the same skin anomaly.

Molecular Pathophysiology of Parathyroid Tumorigenesis-The Lesson from a Rare Disease: The "MEN1 Model".

Primary hyperparathyroidism represents the third most prevalent endocrine disease in the general population, consisting of an excessive secretion of parathyroid hormone from one or, more frequently, more of the parathyroid glands, leading to a dysregulation of calcium homeostasis. Schematically, its development occurs primarily by pathophysiological events with genetic mutation, at the germline and/or somatic level, that favor the neoplastic transformation of parathyroid cells and promote their aberrant proliferation, and mutations determining the shift in the PTH "set-point", thus interfering with the normal pathways of PTH secretion and leading to a "resetting" of Ca2+-dependent PTH secretion or to a secretion of PTH insensitive to changes in extracellular Ca2+ levels. Familial syndromic and non-syndromic forms of primary hyperparathyroidism are responsible for approximately 2-5% of primary hyperparathyroidism cases and most of them are inherited forms. The history of the genetic/molecular studies of parathyroid tumorigenesis associated with multiple endocrine neoplasia type 1 syndrome (MEN1) represents an interesting model to understand genetic-epigenetic-molecular aspects underlying the pathophysiology of primary hyperparathyroidism, both in relation to syndromic and non-syndromic forms. This minireview aims to take a quick and simplified look at the MEN1-associated parathyroid tumorigenesis, focusing on the molecular underlying mechanisms. Clinical, epidemiological, and observational studies, as well as specific guidelines, molecular genetics studies, and reviews, have been considered. Only studies submitted to PubMed in the English language were included, without time constraints.

Bone mineral density over ten years after primary parathyroidectomy in multiple endocrine neoplasia type 1

Abstract Primary hyperparathyroidism (PHPT) associated with multiple endocrine neoplasia type 1 (MEN1) impairs bone mineral density and causes osteoporosis already in young patients. We aimed to investigate BMD in a contemporary cohort of patients with MEN1-related PHPT after long term follow-up and compare these results to that of healthy controls. Thirty-five patients with genetically confirmed MEN1 were diagnosed with MEN1 at mean age 28.7 ± 13.6 yrs. Thirty-two (91.4%) underwent primary parathyroidectomy at mean age 33.3 ± 13.7 yrs, twelve had undergone at least two surgeries with on average 7.3 ± 5.9 yrs between the operations. BMD was assessed by DXA at the end of mean follow-up, 13.2 yrs after the primary parathyroidectomy and compared to that of 35 age- and gender-matched controls. More than 10 yrs after the first parathyroidectomy, mean BMD in patients with MEN1 is in the normal range. However, it is still significantly lower compared to healthy controls.

Pheochromocytoma-Paraganglioma Syndrome: A Multiform Disease with Different Genotype and Phenotype Features.

Pheochromocytoma and paraganglioma (PPGL) are rare tumors derived from the adrenal medulla and extra-adrenal chromaffin cells. Diagnosis is often challenging due to the great variability in clinical presentation; the complexity of management due to the dangerous effects of catecholamine excess and the potentially malignant behavior require in-depth knowledge of the pathology and multidisciplinary management. Nowadays, diagnostic ability has certainly improved and guidelines and consensus documents for treatment and follow-up are available. A major impulse to the development of this knowledge has come from the new findings on the genetic and molecular characteristics of PPGLs. Germline mutation in susceptibility genes is detected in 40% of subjects, with a mutation frequency of 10-12% also in patients with sporadic presentation and genetic testing should be incorporated within clinical care. PPGL susceptibility genes include "old genes" associated with Neurofibromatosis type 1 (NF1 gene), Von Hippel Lindau syndrome (VHL gene) and Multiple Endocrine Neoplasia type 2 syndrome (RET gene), the family of SDHx genes (SDHA, SDHB, SDHC, SDHD, SDHAF2), and genes less frequently involved such as TMEM, MAX, and FH. Each gene has a different risk of relapse, malignancy, and other organ involvement; for mutation carriers, affected or asymptomatic, it is possible to define a tailored long-life surveillance program according to the gene involved. In addition, molecular characterization of the tumor has allowed the identification of somatic mutations in other driver genes, bringing to 70% the PPGLs for which we know the mechanisms of tumorigenesis. This has expanded the catalog of tumor driver genes, which are identifiable in up to 70% of patients Integrated genomic and transcriptomic data over the last 10 years have revealed three distinct major molecular signatures, triggered by pathogenic variants in susceptibility genes and characterized by the activation of a specific oncogenic signaling: the pseudo hypoxic, the kinase, and the Wnt signaling pathways. These molecular clusters show a different biochemical phenotype and clinical behavior; they may also represent the prerequisite for implementing customized therapy and follow-up.

Multiple Endocrine Neoplasia Type 2B: Early Diagnosis by Multiple Mucosal Neuroma

Multiple Endocrine Neoplasia Type 2B: Early Diagnosis by Multiple Mucosal Neuroma

Long term outcomes of pituitary adenomas in Multiple Endocrine Neoplasia type 1: a nationwide study.

Historically, Multiple Endocrine Neoplasia type 1 (MEN1)-related pituitary adenomas (PAs) were considered more aggressive and treatment-resistant than sporadic PAs. However, recent studies suggest similarities in their behavior. This study aimed to evaluate the long-term outcomes of MEN1 PAs and identify predictive factors. Nationwide multicenter retrospective cohort study of MEN1-related PAs with a minimum 1-year follow-up, collecting patient demographics, germline MEN1 pathogenic variants (PV), PA size, secretory profile, radiological characteristics, treatments, and outcomes. We analyzed 84 PAs, 69%in females and 31% in males (P<0.001), diagnosed at a mean age of 35.2±14.9 years, mostly through screening (60.7%). Median follow-up was 9 years (IQR:4-16). Prolactin-secreting PAs (PRLomas) (53.5%) and microadenomas (65.5%) were most common. Dopamine agonist treatment was first line for 16 macroPRLomas and 25 microPRLomas, 60.9% of them achieved PRL normalization. There was no significant association observed with tumor size, sex, treatment duration or MEN1 PV. The risk of progression from micro-PA to invasive macro-PA was 7.2% (4/55), after 8 years (IQR:4-13), all of them were microPRLomas. Kaplan-Meier estimation curve showed significantly higher progression probability in microPRLomas than in other microadenomas subtypes (P=0.017) or microNFPAs (P=0.032). No differences were found between sex, age, or germline MEN1 PV. MEN1-related micro-PAs have a low risk of progressing to invasive macro-PAs, regardless of sex, age at diagnosis, or MEN1 germline PV. The risk is higher for microPRLomas over the long term. Therefore, long-term surveillance with reduced frequency, rather than intensive short-term monitoring, may be appropriate for patients with MEN1-related PAs.

Challenges in Managing Insulinomas and Hyperparathyroidism in MEN1: A Clinical Case Study

Pancreatic insulinoma is an uncommon neuroendocrine tumor with an incidence of approximately 1 per million people annually. While the majority of insulinomas are sporadic, a minority are associated with Multiple Endocrine Neoplasia type 1 (MEN1), a rare genetic disorder transmitted in an autosomal dominant pattern. MEN1 is characterized by the presence of hyperplastic or adenomatous parathyroid glands, pancreatic islet cell tumors, and pituitary tumors. The disorder can also involve lesions in the duodenum, adrenal glands, thymus, and bronchi. We report a case of MEN1 presenting with multiple insulinomas in a 37-year-old male, who exhibited symptoms of intermittent hypoglycemia over a decade. Diagnostic workup included biochemical assays , and imaging studies that revealed elevated insulin and C-peptide levels and hypervascular pancreatic lesions, , and pathological findings consistent with MEN1. Surgical intervention involved the enucleation of insulinomas and distal pancreatectomy, followed by removal of parathyroid adenomas. The postoperative evolution was marked by the resolution of hypoglycemic episodes and the persistence of primary hyperparathyroidism. This case underscores the complexity of diagnosing and managing insulinomas within the context of MEN1. It highlights the importance of a multidisciplinary approach to treatment and the need for ongoing surveillance to address both endocrine manifestations and psychological impacts. The findings advocate for comprehensive management strategies and support systems to improve patient outcomes and quality of life.

12406 Epidemiology Of Multiple Endocrine Neoplasia Type 1 In South Korea: A Nationwide Cohort Study

Abstract Disclosure: K. Kim: None. Y. Hwang: None. M. Yu: None. S. Moon: None. N. Hong: None. Y. Rhee: None. Multiple Endocrine Neoplasia Type 1 (MEN1) is one of the rarest endocrine disorders, with a scarcity of comprehensive epidemiological data globally. This deficiency in data is even more pronounced in Asian populations, where MEN1 remains an under-researched area. Therefore, our aim is to identity the prevalence, demographic characteristics, and patterns of comorbidities associated with MEN1.This nationwide cohort study assessed likely MEN1 cases from the Korean National Health Insurance Service database (2003-2020), selected via two operational definitions: one requiring an ICD-10 code for MEN1 (D44.8) and the other mandating at least two related procedures for MEN1-associated conditions (Primary Hyperparathyroidism, Pituitary Adenomas, and Duodenopancreatic Neuroendocrine Tumors). Cases were 1:10 matched by age, sex, and index year with controls who did not have any MEN-1 associated tumors. Our study evaluated 412 patients with likely MEN1 (mean age 43.6 ± 15.8 years; 35.4% male) against an age-sex matched control group of 4,120. Baseline characteristics showed a higher prevalence of comorbidities in MEN1 patients, including diabetes mellitus (22.6% vs 4.8%), hypertension (38.1% vs 16.4%), and dyslipidemia (20.6% vs 11.2%), all with p&amp;lt;0.001. Cancer prevalence was markedly elevated in MEN1 patients across most types, compared to controls. Adrenal involvements were observed in 34.7% of MEN1 patients, with adrenal adenoma being the most common (31.6%). Parathyroid, pituitary, and duodenopancreatic involvements were identified in 58.6%, 22.3%, and 19.9% of MEN1 patients, respectively. Mortality analysis revealed MEN1 patients had a higher mortality rate (16.0 per 1000 person-years) and a younger mean age at death (60.1 years) compared to controls (68.0 years), with an adjusted mortality hazard ratio of 3.1. Additionally, mortality risk varied with organ involvement; parathyroid involvement showed an adjusted HR of 2.7, pituitary involvement 4.7, and duodenopancreas involvement 4.0. The risk increased significantly with multi-organ involvement, where patients affected in more than two organs had HRs from 2.8 to 7.3. Our findings indicate that MEN1 significantly impacts patient morbidity and mortality, necessitating improved surveillance and tailored management to enhance early detection and optimize care for this vulnerable patient group. These insights underscore the pressing need for further research into MEN1 and other rare diseases to advance patient care and outcomes. Presentation: 6/2/2024

8184 A Case With Primary Hyperparathyroidism Caries A New Variant Of Uncertain Significance (VUS) Of The Multiple Endocrine Neoplasia Type 1 (MEN1) Gene

Abstract Disclosure: E. Caliskan Guzelce: None. E. Fieg: None. C. Pallias: None. Background: Multiple endocrine neoplasia type 1 (MEN1) is a rare, autosomal dominant disorder caused by mutations in the MEN1 tumor suppressor gene. MEN1 syndrome is classically characterized by a predisposition to tumors of the parathyroid glands, anterior pituitary, and pancreatic islet cells. However, the clinical spectrum of this disorder has been expanded: carcinoid tumors,adrenal adenomas and lipomas are more common than in the general population.We report a case whose personal and family history is highly suggestive of and consistent with a monogenic disorder such as MEN1, also found to be a carrier of a new variant of uncertain significance (VUS) of the MEN1 gene. A study performed with the French Universal Mutation Database (UMD) for the MEN1 gene showed that one-third of the missense MEN1 variants were VUSs, mainly due to the lack of clinical and segregation data. Therefore, it is very important to identify and report the subjects with VUS of the MEN1 gene. Case report: 68-year-old female with a past medical history significant for hypertension, type 2 diabetes mellitus, hyperlipidemia, CKD stage 4, and nephrolithiasis, GERD who presented with chief complaints of nausea and upper abdominal/epigastric pain and dark stools and found to have moderate hypercalcemia c/w primary hyperparathyroidism, several pancreatic cystic lesions most likely branch duct intraductal papillary mucinous neoplasms, and multinodular goiter and adrenal adenoma. Family history significant for recurrent hyperparathyroidism and nephrolithiasis; her daughter and brother had nephrolithiasis; her daughter has undergone parathyroidectomy twice. The patient's mother died at a young age because of gastric ulcer-related complications. Hyperparathyroidism-related genes were analyzed; AP2S1, CASR, CDC73, CDKN1B, GNA11, RET, MEN1, and only a Variant of Uncertain Significance, c.247_249dup (p.Leu83dup), was identified in MEN1 gene. The patient’s daughter and granddaughter are found to have the same mutation. Conclusion: This variant, c.247_249dup, results in the insertion of 1 amino acid(s) of the MEN1 protein (p. Leu83dup), but otherwise preserves the integrity of the reading frame. This variant is not present in population databases (gnomAD no frequency). The literature has not reported this variant in individuals affected with MEN1-related conditions. Presentation: 6/3/2024

8207 Insights From a Case of Insulinoma and Possible Genetic Variants in a Young Woman With Recurrent Hypoglycemia

Abstract Disclosure: M.A. Brandao: None. A. Bharara: None. V.I. Moncada Castro: None. T.C. Tsai: None. Y. Wu: None. S. Marquez Flores: None. K. Divari: None. Introduction: Insulinomas are neuroendocrine neoplasms causing hyperinsulinemic hypoglycemia. They are rare, with a prevalence of 1-4 people per million of the general population. Key features are symptoms of hypoglycemia, low plasma glucose, and symptom relief by correcting hypoglycemia. Here, we report a patient with recurrent hypoglycemia who was found to have insulinoma. Several variants of uncertain significance (VUS) were detected in this patient. This gives us some insights into a broader perspective. Clinical case: A 28-year-old healthy female was found unresponsive by her partner. Blood glucose (BG) was 40 mg/dL when paramedics arrived. She received dextrose and rapidly recovered. She was briefly hospitalized and received glucose infusion with improvement. Subsequently, the patient developed episodes of blurry vision and weakness. She had been eating more frequently to prevent symptoms. Her weight was stable at 65.77 kg. She had not been on any medications. She continued to experience hypoglycemic episodes with BG dropping to 30 mg/dL, so she sought evaluation from an endocrinologist. Laboratory work-up showed Proinsulin of 530.6 pmol/L, C-peptide 5 ng/ml, TSH 1.01 mciu/ml, Beta-hydroxybutyrate (BHOB) 0.7 mg/dL, hemoglobin A1c 4.7%, calcium 8.9 mg/dL, albumin 4.1. Abdominal computed tomography (CT) scan showed an 11 mm nodule anterior to the pancreatic tail. No discrete calcification was noted. Magnetic resonance imaging (MRI) of the abdomen redemonstrated the 10 x 6mm, slightly exophytic lesion in the pancreatic tail. Therefore, she underwent laparoscopic enucleation with pathology showing a 1.7cm well-differentiated grade 2 neuroendocrine tumor, with positive margins. Given its indolent nature, further surgical resection was not recommended. Germline testing showed several VUS: the AXIN2 gene (c.1822C&amp;gt;G), GPC3 gene (c.565G&amp;gt;T), NF2 gene (c.296A&amp;gt;G), RECQL4 gene (c.2791C&amp;gt;G). However, no pathogenic variants were identified. Surveillance MRI of the abdomen six months after the surgery has shown no evidence of recurrent disease. The patient has remained euglycemic and symptoms have not recurred. Conclusion: Insulinomas are typically sporadic but may occur due to an activating T372R mutation in the Yin Yang. It may also occur in the setting of multiple endocrine neoplasia type 1 (MEN-1) syndrome caused by MEN1 gene mutations. Although no pathogenic variant mutations associated with insulinoma were found, several VUS that have not yet been described as related to insulinoma were detected in this patient. Routine genetic testing in newly diagnosed patients is not always recommended. Therefore, further efforts are required to understand genetic mutations and epigenetic modifiers associated with insulinoma. Validation of identified VUS and additional genetic testing in young patients with insulinoma are crucial. Presentation: 6/2/2024

6454 Identifying Gaps in Obtaining Germline RET Testing for Patients with Medullary Thyroid Cancer

Abstract Disclosure: A.N. Lim: None. J. Comeaux: None. C. Ricker: None. K.S. Wei: None. T.E. Angell: None. Background: Medullary thyroid carcinoma (MTC) occurs sporadically or from germline pathogenic variants of the RET proto-oncogene in multiple endocrine neoplasia type 2 (MEN2). Current ATA guidelines recommend germline RET testing in all patients with C-cell hyperplasia or MTC. Because disparities may exist in the implementation of this recommendation, we analyzed records of patients with MTC to identify variables associated with germline RET testing. Methods: Patients with MTC were identified from a cohort study of all adult patients undergoing thyroid surgery from 2015-2022 at two affiliated academic centers: a private hospital or a safety-net hospital. Patients were categorized as RET-tested or not RET-tested. Data collection included: patient age, gender, ethnicity, nodule and lymph nodule findings on ultrasound (US), calcitonin and CEA levels, and surgical pathology results. Medical reports were reviewed for reasons that RET testing was or was not obtained. Results: Of 24 MTC patients, 50% were female, mean age ± SD was 50.8 ± 12.3, and 15 (62.5%) had Hispanic ethnicity. RET testing was performed in 14 (58.3%) patients and 3 (21.4%) had a pathogenic variant. RET-tested patients had a median nodule size of 3.45 cm (IQR 2.40-4.53) vs. 2.40 cm (IQR 0.98-3.25) in not-RET tested patients (p&amp;lt;0.05). There were no significant differences between groups in age, gender, ethnicity, preoperative US findings, preoperative calcitonin or CEA levels, or histopathologic status. RET testing was performed in 11/14 (78.6%) patients at the private hospital vs. only 5/10 (50.0%) patients at the safety-net hospital (p=0.20). Considering this, we further investigated the use of RET testing in the initial management of MTC patients. RET testing was performed or planned during initial management in 13/14 (92.9%) patients at the private hospital vs. only 5/10 (50%) patients at the safety-net hospital (p=0.05). At the private hospital, RET testing was requested for apparent sporadic disease (n=11), family history of MTC (n=1), and coexistent pheochromocytoma (n=1). At the safety-net hospital, RET testing was requested for apparent sporadic disease (n=4) and family history of MTC (n=1), but reportedly was not pursued in 5 patients because MTC appeared to be sporadic. Discussion: In this cohort of patients with MTC, larger nodule size was significantly associated with the rate of germline RET testing. Larger MTC tumor size alone may have prompted greater attention to germline testing, but also may have been associated with other findings, which could be further assessed with a larger sample size by multivariable analysis. The disparity in RET testing as part of initial management at the safety-net hospital may be multifactorial, but future analyses should explore provider decision-making, as well as facility and patient variables. Presentation: 6/1/2024

12572 Incidental Adrenal Enlargement On Ct Scan In South Brooklyn Health, How Often Is It Functional?

Abstract Disclosure: R. Ruggiero: None. N. Simon: None. Background: Incidental findings of adrenal hyperplasia are increased due to the widespread rise in cross sectional imaging, as well as improvement of imaging modalities. There is a lack of literature reporting on the prevalence of incidental adrenal hyperplasia. One study reported a prevalence of 11.3%. Adrenocortical hyperplasia can result from endocrine disorders such as ACTH dependent and independent Cushing syndrome, primary aldosteronism, Multiple Endocrine Neoplasia type 1, and congenital adrenal hyperplasia. Other reported causes are radiographic adrenal enlargement of unknown cause and without clinical or biochemical manifestations, inflammation, neoplasms, and depression. Most cases are a radiographic finding with no clinical significance. One study reported that 69.23% of cases were nonfunctional. There are currently no guidelines in place for biochemical evaluation of incidental adrenocortical hyperplasia. Patients are typically referred to endocrinology services. Objective: The purposes of this study was to: 1. Evaluate the number of patients referred to endocrinology clinic for incidental abnormal adrenal imaging. 2. Examine the percentage of abnormal adrenal imaging findings on CT scan, in particular adrenal hyperplasia, that are hormonally active. Methods: This was a retrospective study of patients who were referred to endocrinology clinic or electronic endocrine consult for incidental abnormal adrenal imaging, excluding those with clear diagnosis of masses, nodules, adenomas, or cysts. Data collected included demographics, type of study imaging and radiologist reader, hormonal studies, comorbid conditions such as diabetes mellitus, hypertension, obesity, osteoporosis, as well as visit type to endocrinology service (e-consult vs in person). Results: The total number of consults referred to endocrinology during this period was 138. Due to repeat referral or having an adrenal pathology other than hyperplasia, 83 patients were excluded from analysis. There were 55 patients with isolated adrenal hyperplasia, 86% of whom were Caucasian, 11% Hispanic, and 78% of patients were female. Median age 63 years old. Hypertension was noted in 69% of patients, 36% had diabetes mellitus or dysglycemia, 36% were obese, and 1.8% had osteoporosis. Imaging reading was performed by 3 radiologists, 75% of cases reported by one reader. Only 5% of referrals were answered as an e-consult. About 27% of patients did not show up to establish care. Hormonal workup was completed by 60% of the patients, with 16 % having abnormal findings. One patient required confirmatory workup. No patients required treatment. Conclusion: Adrenal Hyperplasia is often an incidental radiologic finding, that can be reader dependent. Most cases are nonfunctioning without abnormal findings on hormonal workup. E-Consultation can be an efficient tool to help PCP and reduce endocrine clinic visits. Presentation: 6/1/2024

12556 Medullary Thyroid Cancer With Persistent Elevation Of Carcinoembryonic Antigen: Case Report

Abstract Disclosure: M.S. Campana: None. Introduction: Medullary thyroid Cancer (MTC) is a rare neuroendocrine tumor that originates from thyroid parafollicular C-cells and represents 5 % of all thyroid cancers. MTC can be sporadic (75%) or hereditary (25%) associated with multiple endocrine neoplasia type 2 syndrome (MEN2). Serum calcitonin (Ctn) and carcinoembryonic antigen (CEA) are its tumor markers. We report a case of persistently elevated CEA levels despite an undetectable Ctn in a patient with MTC after initial thyroid lobectomy. Description of the case: A 42-year-old woman self-identified a neck lump after intentional weight loss. A neck US showed a right lobe thyroid nodule which resulted as suspicious for malignancy (Bethesda V) with subsequent right lobectomy. Pathology reported a 2.6 cm unexpected MTC with negative surgical margins, extrathyroidal extension, angioinvasion, and lymphatic invasion. No cervical lymph nodes (LNs) were removed. Immunohistochemistry was positive for CEA, chromogranin A, synaptophysin, and Ctn. T2 Nx. One month after lobectomy, the Ctn was 10.5 (0-3.0 pg/mL) and CEA 205.2 (0-3.0 ng/mL Non-smoker; 0-5.0 ng/mL smoker). The patient was then referred to our clinic for further management. Laboratories showed normal serum calcium, PTH, and fractionated plasma metanephrine/normetanephrine. A 2-month post-operative Ctn was undetectable, but CEA was elevated at 24.5. Subsequently, we broaden imaging studies to include neck US, CT neck /chest with contrast, and MRI abdomen pelvis with contrast. The only remarkable finding was a 6.7 cm pelvic mass with normal Ca-125. Genetic testing was negative for germline RET, ruling out MEN2. Patient underwent completion left lobectomy with prophylactic bilateral central neck dissection. Pathology showed benign thyroid parenchyma with multinodular hyperplasia and 0/12 LNs. Because of concerning pelvic mass, the patient was referred to OB/GYN. She underwent a laparoscopic bilateral salpingo-oophorectomy. Pathology showed a follicular ovarian cyst, negative for malignancy. A year post-completion total thyroidectomy Ctn remains undetectable, and a CEA is normal at 1.3. Discussion: Because Ctn was already undetectable 1 month after lobectomy with persistent elevated CEA a complete total thyroidectomy with prophylactic bilateral central neck dissection was indicated to achieve operative cure. Ctn is specific to MTC but variable. CEA is more reproducible with less variability; however, it is not specific to MTC and can also be elevated in smokers, benign breast and genitourinary disease, emphysema, cirrhosis, and cancer of colon, rectum, liver, genitourinary, and lung. If residual disease is present, Ctn tends to be proportionally more elevated than CEA. When the opposite occurs, poorly differentiated MTC with possibility of distant metastases vs. a second primary malignancy vs. a distant benign neoplasm known to elevate CEA need to be ruled out. Presentation: 6/2/2024

8769 A Case of Metastatic and Catecholamine Producing Bilateral Pheochromocytoma in a Patient with RET Gene Mutation

Abstract Disclosure: R.A. Mayers: None. A. Szafran-Swietlik: None. RET mutation, observed in multiple endocrine neoplasia type 2 syndromes, is implicated in the development of pheochromocytomas of the kinase signaling cluster. Such tumors have lower metastatic risk and adrenergic production compared to the ones from the other clusters. We present a case of a metastatic, bilateral, small and biochemically active pheochromocytoma .This is the case of a 27-year-old man diagnosed with MEN 2A. He underwent total thyroidectomy due to medullary thyroid carcinoma at 2 years old. He was deemed cured and started on levothyroxine replacement. Since then, his plasma metanephrines by liquid chromatography-mass spectrometry and urine metanephrines done in a yearly basis as screening, were always within range of normality. Over the years, he developed substance abuse disorder with use of Kratom and methamphetamines and was admitted in a rehabilitation center multiple times in the last three years. During this time, the patient was reported to be slightly tachycardiac which was initially attributed to the use of substances. On the last year, an echocardiogram done as evaluation of his tachycardia showed an ejection fraction of 35%. Later, his annual metanephrine levels were markedly elevated (free metanephrine: 137 pg/mL and free normetanephrine : 157 pg/mL, normal ranges reported as less than 57 pg/mL and less than 148 pg/mL respectively). Abdominal tomography showed a right adrenal nodule of 1.2 cm and a left adrenal nodule of 1.6 cm, both with more than 10 Hounsfield Units. A Metaiodobenzylguanidine scan revealed a left adrenal nodule of 1.8 cm with diffuse radiotracer uptake, a right adrenal nodule of 1.2 cm with radiotracer activity and 3 subtle areas of focally increased radiotracer activity in the liver, two in left hepatic lobe and other in posterior right upper lobe. He underwent bilateral adrenalectomy with cortical sparring. Pathology results evidenced a left adrenal with a unifocal mass of 1.8 cm and a right adrenal with a mass of 1.2 cm , both without lymphovascular, capsular, local invasion or necrosis, a mitotic rate of 1-2 without atypical mitosis, not encapsulated with clean margins and positive for synaptophysin , chromogranin and S100 stains. An additional mass of 0.7 cm on the right adrenal gland was described with similar characteristics to the described before except for the involvement of the surgical margins. Currently on the literature there are different opinions regarding screening approach for pheochromocytomas in the presence of RET mutations. There are not strong recommendations regarding the use of imaging as a screening tool in this group of patients. It is important to consider that there are cases, as the one described in this report, that might present metastatic disease even with the presence of small pheochromocytomas that belong to the cluster of kinase signaling. Presentation: 6/3/2024

9220 Machine Learning Methods In Differential Diagnosis Of Genetically Confirmed Multiple Endocrine Neoplasia Type 1 And Its Phenocopies

Abstract Disclosure: D. Trukhina: None. K. Voronov: None. E. Mamedova: None. A. Solodovnikov: None. Z. Belaya: None. Background. MEN-1 is a rare autosomal dominant disorder caused by mutations in the MEN1 gene encoding the menin protein (gMEN1). This syndrome is characterised by the occurrence of parathyroid tumours, gastroenteropancreatic neuroendocrine tumours, pituitary adenomas, and other endocrine and non-endocrine neoplasms. If a patient with the MEN-1 phenotype does not have any mutation in the MEN1 gene, the condition is considered a phenocopy of the syndrome (phMEN1). The goal of this study was to develop a machine learning algorithm to estimate the probability of gMEN-1 vs phMEN-1 based on easily available clinical features at first line differential diagnostics. Materials and methods. A single-center, one-stage, cohort, retrospective study was carried out. Patients were randomly stratified into 2 cohorts: training (80%) and test (20%). Eight machine learning algorithms were used to develop predictive models: Logistic Regression, k-nearest neighbors (kNN), Naive Bayes, binary decision tree (CART), C5.0 decision tree algorithms, Bagged CART, Random Forest, Gradient Boosting (Stochastic Gradient Boosting, GBM). Results. The study included 95 patients with genetically confirmed gMEN-1 syndrome and 60 patients with its phenocopies. As a result of preliminary data processing and selection for the most informative features, the final variables for the classification and prediction of gMEN-1 syndrome were identified: the number of affected parathyroid glands, age at diagnostics, pancreatic tumour existence, heredity, type of pituitary adenoma secretion, and gender. The kNN algorithm demonstrated the best diagnostic performance in a training sample (ROC-AUC - 0.96, sensitivity - 84%, specificity - 100%), which was confirmed in a test sample (ROC-AUC - 1.0; sensitivity - 94.4%, specificity - 100%) to determine genetically confirmed MEN-1 syndrome. Conclusion. The k-nearest neighbours (kNN) algorithm may be used as a first-line differential diagnostics method to select patients to be refered for genetic testing for gMEN-1. Presentation: 6/1/2024

7159 Brown Tumor As Primary Presentation Of Parathyroid Carcinoma In A Young Female

Abstract Disclosure: S.G. Zachariah: None. R. Anand: None. B.Y. Wong: None. H.J. Lee: None. Title Brown Tumor as Primary Presentation of Parathyroid Carcinoma in a Young Female Introduction/Background: Parathyroid carcinoma (PC) is a rare cause of hyperparathyroidism (HPT) accounting for less than 1% of primary HPT cases. The mean age of PC presentation is 62 years. Long-standing HPT can lead to the formation of osteitis fibrosis cystica (brown tumors). In today’s world of advanced screening, they are an increasingly rare presentation of HPT. We present a case of PC presenting as multiple brown tumors in a young woman. Case: A previously healthy 32-year-old woman presented to the emergency department with right shoulder pain after a mechanical fall. MRI revealed multiple osseous lesions of the proximal humerus, glenoid, and scapula, concerning for possible metastatic malignancy. Notable labs: calcium 13.6 mg/dL [8.5 - 10.5 mg/dL], phosphorus 1.7 mg/dL [2.5 - 4.5 mg/dL], alkaline phosphatase 2,369 U/L [&amp;lt; 130 U/L], 25-OH vitamin D 0.8 ng/mL [30 - 60 ng/mL], and parathyroid hormone greater than 2,500 pg/mL [20-80 pg/mL]. Albumin and renal function were normal. CT chest/abdomen/pelvis showed lytic lesions of the left 7th rib, anterior superior iliac spine (with nondisplaced fracture), pelvis, and sacrum. Subsequent pelvic biopsy showed fragmented bony trabeculae with osteoblastic rimming and rare osteoclasts, fragments of fibrous tissue with few plasma cells and hemosiderin laden macrophages, possibly consistent with brown tumor. On parathyroid ultrasound, a 2.2 cm cystic mass was seen along the left common carotid artery. CT neck confirmed the location and also reported C7-T1 spinal lesions. Calcium levels stabilized with IV fluids and 90 mg IV pamidronate. She underwent a left parathyroidectomy and left hemithyroidectomy with central neck dissection. Pathology was consistent with a low-grade parathyroid carcinoma, with a foci of angioinvasion and capsular invasion without lymph node metastases. The Ki-67 index was less than 1%. Post-operatively, the patient was started on calcium and calcitriol supplementation and did not experience hungry bone syndrome. On further discussion, the patient noted that she had a jaw tumor that was previously biopsied and found to be benign. The patient has since been referred for genetic testing. Conclusion/Clinical Lessons: Both PC and its initial presentation with brown tumors are uncommon. Even more rare is the presentation of both in a young, otherwise healthy female. In this context, it is also important to note that brown tumors can mimic osseous metastases and appropriate biochemical, imaging, and histopathological evaluation is needed. The diagnosis of PC under 40 years of age is uncommon and genetic testing is indicated. Syndromes including multiple endocrine neoplasia type 1, familial isolated hyperparathyroidism, and hyperparathyroidism-jaw tumor syndrome are potential causes of inherited PC. Presentation: 6/3/2024

7085 Myoclonus Seizure with Pseudo-Adrenal Insufficiency as the Clinical Manifestations Leading to the Diagnosed Multi-focal Insulinomas that Mimic Multiple Endocrine Neoplasia Type 1 Syndrome

Abstract Disclosure: P. Kiatpanabhikul: None. Background: Insulinoma is a rare disease that presents with varying symptoms and can be sporadic or associated with hereditary syndromes (1). These rare points of views of insulinoma-patient on clinical manifestations, hormonal responses and surgical pathology result for final diagnosis and management. Clinical Case: A 59-year-old woman presented with myoclonic seizure of right arm with consciousness duration 5-10 minutes every midday twice a week for 6 months and generalized convulsion for 20 minutes ago. She had a low FPG level (59 mg/dL; n 70-100) and was admitted to doing 72-hour fasting test that revealed hypoglycemia at 12-hour of fasting with a nadir glucose level of 55 mg/dL, insulin 3.7 uIU/mL (cutoff &amp;gt; 5), C-peptide 0.4 ng/mL (cutoff &amp;gt; 0.6), cortisol 6.22 mcg/dL (n 5-25) and normal morning ACTH level (29.8 pg/mL; n 10-65). These were appropriated response of endogenous insulinemia with inappropriate response of serum cortisol level in hypoglycemic feature. MRI pituitary gland was considered to evaluate secondary hypocortisolism which showed a small less enhancing lesion left anterior lobe 0.3x0.45-cm without any pituitary hormonal abnormalities that were considered non-functioning pituitary microadenoma which could not explain inappropriate response of cortisol level to hypoglycemic period in this patient. Five months later, she presented at the emergency room with myoclonic seizure on her extremities, blurred consciousness and slurred speech after having lunch for 1-2 hour and revealed CPG 30 mg%, severe hypoglycemia (26 mg/dL), hypocortisolism (4.49 mcg/dL), with endogenous hyperinsulinemia (insulin 55.2 uIU/mL, C-peptide 2.5 ng/mL). 250-mcg ACTH stimulation test was done and showed normal response of her HPA-axis function (serum cortisol level at 0, 30, 60 min was 9.12, 17.87, 18.61 mcg/dL). CT pancreatic protocol showed several arterial enhancing nodules scattering at pancreatic tails isoattenuation to pancreatic parenchyma on portovenous phase up to 1.7*1.6 cm. She was operated on to distal pancreatectomy with intraoperative insulin/glucose ratio monitoring. Surgical pathology confirmed 4-well-differentiated pancreatic neuroendocrine tumors with insulin-producing, sizes 0.5-1.7 cm in diameter. Her final diagnosis was multi-focal insulinomas with non-functioning pituitary microadenoma that mimic MEN-1 syndrome without secondary adrenal insufficiency. She underwent successful surgical resection with complete resolution of symptoms during 4 years of followed-up with no recurrence and no having any hypercalcemia and hyperprolactinemia. Conclusion: Multi-focal insulinomas can be presented as sporadic, more severe hypoglycemia and endogenous hyperinsulinemia during period after meal with myoclonic seizure and pseudo-adrenal insufficiency in older-aged, non-diabetes person without recurrence after treatment for 4-year of followed-up. Presentation: 6/2/2024