Multiple Endocrine Neoplasia Research Articles

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.

Rare Combination of Multiple Endocrine Neoplasia 1 with Medullary Thyroid Carcinoma and Clinical Value of 68Ga-DOTATATE PET/CT in Diagnosing Different Lesions and Exploring Theranostic Strategy

AbstractMultiple endocrine neoplasia type 1 (MEN1) syndrome is characterized by the presence of hyperplastic or neoplastic tumors in the parathyroid, pituitary, and gastroenteropancreatic endocrine tissues. The presence of lesions in at least two out of the three glands (pituitary, parathyroid, and pancreas) is indicative of MEN1 syndrome. Medullary thyroid carcinoma (MTC) is a type of tumor that originates from the parafollicular C cells of the thyroid gland. It is frequently found as part of MEN2 syndrome. MEN1 with MTC is a relatively uncommon occurrence. We report a rare case of MTC that later on developed parathyroid carcinoma, pituitary microadenoma, pancreatic neuroendocrine tumor (NET), and duodenal NET. The case was identified as part of MEN1 syndrome using exome sequencing and somatostatin receptor–based functional imaging 68Ga-DOTATATE positron emission tomography/computed tomography was employed for exploring theranostic strategy in the management of the patient.

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.

Pancreatic insulinomas: Our 15-year surgical experience.

Insulinomas are rare endocrine tumors of the pancreas. The majority are benign, sporadic, and solitary. Surgery is the only curative treatment. In this study, we present our experiences with the perioperative management of sporadic and benign pancreatic insulinomas. Patients who underwent surgery for pancreatic insulinoma in our clinic between 2008 and 2023 were retrospectively reviewed. Demographic data, preferred radiological methods, surgical procedures, and morbidity and mortality data were evaluated. Patients with malignant, invasive, or familial multiple endocrine neoplasia mutations were excluded from the study. Nineteen patients underwent surgery, with a median age of 49 years (range: 33-85). Symptoms related to hypoglycemia were the most commonly observed. The tumor location was identified preoperatively in 74% of cases using computed tomography. Palpation and intraoperative ultrasound identified the tumor location in 88% of patients. Enucleation (53%) were the most common surgical procedures. Pancreatic fistula occurred in three patients (17%). While serious morbidity was lower in patients who underwent enucleation, the rate of fistula formation was higher. The accurate localization of insulinomas plays a crucial role in determining the appropriate surgical procedure. With high success rates and lower morbidity, enucleation is the recommended procedure for suitable patients.

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

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

Approach to the patient with thyroid nodules: considering GLP-1 receptor agonists.

Glucagon-like peptide 1 receptor agonists (GLP1RA) have rapidly changed the landscape of diabetes and obesity treatment. Enthusiasm for their use is tempered with concerns regarding their risk for inducing C-cell tumors based on preclinical studies in rodents. A black-box warning from the United States Food and Drug Administration (USFDA) recommends against using GLP1RA in patients with a personal or family history of medullary thyroid carcinoma (MTC) or multiple endocrine neoplasia syndrome type 2A or 2B (MEN2), providing clear guidance regarding this cohort of patients. However, emerging data also suggest an increased incidence of differentiated thyroid cancer (DTC) in patients treated with these agents. Other studies, though, have not confirmed an association between GLP1RA and DTC. With conflicting results concerning thyroid cancer risk, there is no clear consensus regarding the optimal approach to screening patients prior to initiating the medications and/or evaluating for thyroid cancer during GLP1RA treatment. Within the context of patient cases, this review will summarize the existing data, describe ongoing controversies, and outline future areas for research regarding thyroid cancer risk with GLP1RA use.

The molecular genetics of adrenal cushing.

Adrenal Cushing represents 20% of cases of endogenous hypercorticism. Unilateral cortisol-producing adenoma (CPA), a benign tumor, and adrenocortical carcinoma (ACC), a malignant tumor, are more frequent than bilateral adrenal nodular diseases (primary bilateral macronodular adrenal hyperplasia (PBMAH) and primary pigmented nodular adrenal disease (PPNAD)).In cortisol-producing adrenal tumors, the signaling pathways mainly altered are the protein kinase A and Wnt/β-catenin pathways. Studying components of these pathways and exploring syndromic and familial cases of these tumors has historically enabled identification of many of the predisposing genes. More recently, pangenomic sequencing revealed alterations in sporadic tumors.In ACC, mainly due to TP53 alterations causing Li-Fraumeni syndrome, germline predisposition is frequent in children, while it is rare in adults. Pathogenic variants in the DNA mismatch repair genes MLH1, MSH2, MSH6, and PMS2, which cause Lynch syndrome or alterations of IGF2 and CDKN1C (11p15 locus) in Beckwith-Wiedemann syndrome, can also cause ACC. Rarely, ACC is described in other hereditary tumor syndromes due to germline pathogenic variants in MEN1 or APC and, in very rare cases, NF1, SDH, PRKAR1A, or BRCA2. Concerning ACC somatic alterations, TP53 and genetic or epigenetic alterations at the 11p15 locus are also frequently described, as well as CTNNB1 and ZNRF3 pathogenic variants.CPAs mainly harbor somatic pathogenic variants in PRKACA and CTNNB1 and, less frequently, PRKAR1A, PRKACB, or GNAS1 pathogenic variants. Isolated PBMAH is due to ARMC5 inactivating pathogenic variants in 20 to 25% of cases and to KDM1A pathogenic variants in food-dependent Cushing. Syndromic PBMAH may be due to germline pathogenic variants in MEN1, APC, or FH, causing type 1 multiple endocrine neoplasia, familial adenomatous polyposis, or hereditary leiomyomatosis-kidney cancer syndrome, respectively. PRKAR1A germline pathogenic variants are the main alteration causing PPNAD (isolated or part of Carney complex).

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.

8683 Composite Pheochromocytoma/Paraganglioma-Ganglioneuroma: Biochemical And Radiological Features

Abstract Disclosure: S. Agarwal: None. A.P. Dackiw: None. F. Nwariaku: None. J.E. Mosquera: None. L. Jia: None. M.G. Roden: None. O. Hamidi: Advisory Board Member; Self; Corcept Therapeutics. Introduction: Composite pheochromocytoma/paraganglioma with ganglioneuroma (PHEO-GN or PGL-GN) is a rare tumor consisting of chromaffin cells or ganglia tissue combined with a developmentally related neurogenic tumor. Composite tumors can be present in up to 10% of PHEO and are rare with just over 100 cases reported in published literature. We present a case series of patients with PHEO-GN and PGL-GN seen at our tertiary care center to examine their natural history, clinical, radiological, and biochemical characteristics. Methods: We conducted a retrospective longitudinal follow-up study of consecutive adult patients with histologically-proven PHEO-GN and PGL-GN seen between 2013 and 2023. We collected and summarized data on demographics, laboratory findings, radiological results, and clinical outcomes. Results: The cohort comprised 10 patients (60% women): 8 with PHEO-GN (1 diagnosed on autopsy), 1 with PGL-GN, and 1 with PHEO-ganglioneuroblastoma. The median age at diagnosis was 47 years (interquartile range [IQR], 35-60). Most (80%) tumors were discovered incidentally. The prevalence of a genetic syndrome was 40% and included multiple endocrine neoplasia (MEN) 2A, MEN 4, Neurofibromatosis 1, and hereditary PHEO-PGL syndrome due to succinate dehydrogenase type B gene mutation. Nine patients (90%) had biochemically functional tumors with adrenergic biochemical phenotype in 89% and noradrenergic in 11%. The tumor associated with MEN 4 also had dopamine secretion. The median elevation above the upper normal limit of plasma metanephrine was 7.4 (IQR, 1.6-12), 24-hour urine metanephrine was 7.12 (IQR, 3.7-8.8), plasma normetanephrine was 1.7 (IQR, 1.5-1.9), and 24-hour urine normetanephrine was 2.9 (IQR, 2.4-3.5). The median tumor size at the time of diagnosis was 4.2 cm (IQR, 3.3-5.2). The median pre-contrast HU on CT imaging was 37 HU (IQR, 20-40). The median time to surgical excision from the diagnosis was 2.7 months (IQR, 1.9-4.6). All patients that underwent surgery were alive without recurrence of disease at last follow-up visit with a median follow-up of 14.5 months (IQR, 0.5-18.4). Conclusions We present a series of 10 consecutive patients with composite PHEO-GN and PGL-GN. The prevalence of genetic syndrome (40%) was much higher than previously reported (up to 25% in prior reports). PHEO or PGL component of these tumors is commonly biochemically functional with metanephrine and normetanephrine elevation commonly seen. Metastatic or recurrent disease was not observed in our cohort, suggesting favorable outcomes after surgical resection. Presentation: 6/2/2024

12396 A Case Of Medullary Thyroid Carcinoma Without Germline RET Mutation

Abstract Disclosure: I. Marranzini Rodriguez: None. M. Lemelman: None. L. Canham: None. Background: Medullary thyroid cancer (MTC) is a neuroendocrine tumor that originates from the parafollicular C cells of the thyroid gland. MTC accounts for approximately 5% of thyroid cancer in children, and the majority of MTC cases are associated with the autosomal dominant tumor predisposition syndrome Multiple Endocrine Neoplasia 2 (MEN2). Sporadic MTC is uncommon in the pediatric population and associated with somatic mutations of RET or RAS (1). Existing management options for metastatic disease have demonstrated some benefit, however, with systemic side effects. Selpercatinib, a highly selective RET kinase inhibitor, is FDA approved for patients &amp;gt;= 12 years of age. Here we present a case of a 10-year-old patient with metastatic MTC with encouraging results. Clinical Case: A previously healthy 10 year 2-month-old male presented with left-sided neck swelling. Imaging showed a 9.7 cm solid mass spanning nearly the entire left neck, occluding the left internal jugular vein, extending to the upper chest, and resulting in high-grade narrowing of the trachea near the thoracic inlet; the mass involved the left thyroid gland and engulfed the left common carotid. His initial lab evaluation showed an elevated TSH of 10.10 mcU/mL (0.6-5.5 mcU/mL) and Free T4 1.22 ng/dL (0.9-1.67 ng/dL). Tumor markers revealed a calcitonin of 32,264 pg/mL (normal range &amp;lt;= 6.0 pg/mL) and carcinoembryonic antigen (CEA) of 200 ng/ml (normal range 0 – 3.4 ng/mL). He underwent biopsy of the mass which showed medullary thyroid carcinoma (MTC) and genetic evaluation of tumoral tissue showed RET c.2753T&amp;gt;C, p.M918T somatic mutation. Evaluation for pheochromocytoma and hyperparathyroidism, given association of MTC with MEN2, was negative. Genetic testing was negative for germline RET mutations. He was started on selpercatinib, 120 mg every 12 hours. Follow up imaging after 2 months of therapy demonstrated a significant decrease in tumor burden. Approximately 5 months after starting he had a decrease in CEA to 14.8 ng/mL and calcitonin to 69 pg/mL, prior to surgery. Given the risk of locoregional recurrence he underwent total thyroidectomy with lateral neck dissection. However, the tumor was noted to be adherent to the trachea, encasing the left recurrent laryngeal nerve, and left carotid artery preventing full resection. He was started on levothyroxine at 62.5 mcg daily on POD#1 and re-started on selpercatinib approximately 2 weeks post-operatively. Conclusion: We present a case of RET-positive metastatic medullary thyroid carcinoma without germline RET mutation successfully treated with selpercatinib. Long-term follow-up for sustained response and tolerability is needed. Reference: 1. Bauer, Andrew J. “Pediatric Thyroid Cancer: Genetics, Therapeutics and Outcome.” Endocrinology and metabolism clinics of North America vol. 49,4 (2020): 589-611. doi:10.1016/j.ecl.2020.08.00 Presentation: 6/2/2024

7940 Insulinoma as a Rare Manifestation of MEN4

Abstract Disclosure: H. Han: None. J. Moalem: None. A.R. Shih: None. B.J. Gigliotti: None. Background/Objective: Multiple endocrine neoplasia 4 (MEN4) is a rare syndrome that is caused by germline mutations in CKDN1B. Its phenotypic expression is similar to multiple endocrine neoplasia 1 (MEN1). Manifestations include primary hyperparathyroidism (PHPT), pituitary adenomas, and pancreatic neuroendocrine tumors (NET). Prevalence of MEN4 is less than one per million. Case Report: A 55-year-old female with history of hypercalcemia presented with symptomatic hypoglycemia. She had a fasting plasma glucose of 41mg/dL, proinsulin of 84.3 pmol/L, insulin level of 24 uIU/mL, c-peptide of 5.2 ng/mL, and beta hydroxybutyrate level of 0.34 mmol/L, consistent with endogenous hyperinsulinism. She was incidentally noted to have PHPT. CT abdomen showed a 1.5 x 1.1 x 1.0 cm pancreatic lesion consistent with an insulinoma. Pathology from subsequent Whipple surgery showed that it was a well-differentiated neuroendocrine tumor with no metastasis. She became normoglycemic after surgery. Germline testing revealed a variant of unknown significance in CDKN1B (p.R93W). Discussion: Increasing evidence suggests that MEN4 exhibits subtle differences in penetrance and natural history compared to MEN1. A recent systemic review of MEN4 cases showed that most gastrointestinal NETs in MEN4 are non-functional NETs and gastrinomas; to date, no insulinomas have been reported. PHPT in MEN4 may exhibit a lower risk of recurrence after parathyroidectomy. This case highlights the importance of germline genetic testing when a patient presents with clinical manifestations of MEN1. Conclusion: This is the first reported case of insulinoma in MEN4. Presentation: 6/3/2024

7214 A Retrospective Cohort Study on Prevalence Of Pituitary Adenomas in MEN2

Abstract Disclosure: R. Ghosh: None. N. Behiri: None. J. Glod: None. S. Gubbi: None. J. Klubo-Gwiezdzinska: None. Background: Multiple endocrine neoplasia (MEN) syndromes are autosomal dominant and present with tumors in at least two or more endocrine organs. MEN2 syndromes that are driven by germline rearranged during transfection (RET) gene pathogenic variants are divided into 2A consisting of medullary thyroid carcinoma (MTC), parathyroid adenomas and pheochromocytoma and 2B presenting with MTC, pheochromocytoma, marfanoid habitus, mucosal neuromas and gastrointestinal ganglioneuromatosis. Pituitary adenomas have been rarely described in MEN2 and hence we conducted a retrospective chart review to determine their prevalence in MEN2. Methods: Retrospective chart screening of MEN2 patients followed at a tertiary referral center between August 1999- August 2022 was done to evaluate the prevalence of pituitary adenomas using biochemical hormonal evaluation and magnetic resonance imaging (MRI) of pituitary based on screening of clinical symptoms. Results: The study consisted of 91 patients (43 MEN2A and 48 MEN2B), aged 35.3±16.9 years (MEN2A) and 18.6±6.4 years (MEN2B), 20/43 (46.5%) women in MEN2A and 24/48 (50%) women in MEN2B. These patients were followed for median duration of 6.5 years (3.3-22) in MEN2A and 8.5 years (5.4-14.6) in MEN2B. RET mutation status was unavailable for 1 MEN2A patient out of 91 patients. Among MEN2A patients, majority (53.5%) were positive for RET C634X mutation followed by RET 804, 609, 631,620 and 666 mutations in the descending order. While in MEN2B cohort all patients were positive for M918T RET mutation. A total of 4/91 (4.4%) patients were found to have pituitary adenomas (3 MEN2B and 1 MEN2A). One patient had clinically symptomatic ACTH producing microadenoma which was surgically resected, and others have asymptomatic non-functioning adenomas. The patient with Cushing’s disease underwent three transsphenoidal resections leading to complete resolution but developed panhypopituitarism. Prevalence of pituitary adenomas in our cohort was significantly higher than the general population screened based on clinical suspicion (p&amp;lt;0.001). Conclusion: Prevalence of clinically symptomatic pituitary adenomas is 1 in 1000 in the general population (1). It is rarely associated with MEN2 syndromes and only few cases are reported in the literature (2). However, screening of all patients with MEN2 for pituitary adenomas, regardless of clinical suspicion, might lead to incidental discovery of asymptomatic pituitary pathology and can provide the actual prevalence. Further studies are needed to evaluate the genetics of these pituitary adenomas in MEN2 syndromes to investigate whether RET protooncogene is indeed the dominant molecular driver of these tumors.

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

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