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Appendiceal cancer (AC) is a rare malignancy, occurring in 1 to 2 individuals per million annually in the US. It is often diagnosed incidentally during appendectomies or imaging for unrelated conditions. This article explores the risk factors, clinical presentation, diagnostic methods, pathology, staging, and treatment options for AC, highlighting disparities in access to care across different demographics. This article also emphasizes the importance of early detection and tailored management strategies to enhance nurses' understanding and improve outcomes for patients with this uncommon but significant disease. This article explores the risk factors, clinical presentation, diagnostic methods, pathology, staging, and treatment options for appendiceal cancer, highlighting disparities in access to care across different demographics. [ABSTRACT FROM AUTHOR]

Multiple endocrine neoplasia syndromes are a rare but potentially fatal pathology due to the lack of early diagnosis. We have performed a narrative review of the medical literature, summarizing the main clinical concepts useful in current clinical practice, showing the importance of screening and early diagnosis during childhood. [ABSTRACT FROM AUTHOR]

Simple Summary: Pancreatic neuroendocrine tumors (PanNETs) and lung NETs (LNETs) have garnered increased attention in recent years due to their diverse clinical manifestations and challenging management. Although the vast majority of both PanNETs and LNETs are sporadic, they can also occur in the context of inherited syndromes that necessitate a high index of suspicion as the course of the disease is different and there are additional clinical implications for other family members. Our systematic review encompasses studies conducted over the past decade, focusing on the incidence, diagnosis, and treatment of PanNETs and/or LNETs encountered in hereditary syndromes such as Multiple Endocrine Neoplasia type 1 (MEN1), MEN4, von Hippel–Lindau (VHL), Tuberous Sclerosis Complex (TSC), and Neurofibromatosis type 1 (NF1). We discuss the importance of early detection and tailored management strategies, emphasizing the need for multidisciplinary collaboration among relevant healthcare professionals to optimize patients' outcomes. Moreover, we highlight the importance of active surveillance strategies for early tumor detection in high-risk individuals and the evolving landscape of personalized medicine for targeted intervention. Pancreatic neuroendocrine tumors (PanNETs) and lung NETs (LNETs) represent a rare but clinically significant subgroup of neoplasms. While the majority is sporadic, approximately 17% of PanNETs and a subset of LNETs develop in the context of monogenic familial tumor syndromes, especially multiple endocrine neoplasia type 1 (MEN1) syndrome. Other inherited syndromes associated with PanNETs include MEN4, von Hippel–Lindau (VHL) syndrome, neurofibromatosis type 1 (NF1), and tuberous sclerosis complex (TSC). These syndromes are highly penetrant and their clinical manifestations may vary even among members of the same family. They are attributed to genetic mutations involving key molecular pathways regulating cell growth, differentiation, and angiogenesis. Pancreatic NETs in hereditary syndromes are often multiple, develop at a younger age compared to sporadic tumors, and are associated with endocrine and nonendocrine tumors derived from multiple organs. Lung NETs are not as common as PanNETs and are mostly encountered in MEN1 syndrome and include typical and atypical lung carcinoids. Early detection of PanNETs and LNETs related to inherited syndromes is crucial, and specific follow-up protocols need to be employed to optimize diagnosis and management. Genetic screening is recommended in childhood, and diagnostic screening starts often in adolescence, even in asymptomatic mutation carriers. Optimal management and therapeutic decisions should be made in the context of a multidisciplinary team in specialized centers, whereas specific biomarkers aiming to identify patients denoted to follow a more aggressive course need to be developed. [ABSTRACT FROM AUTHOR]

Context The skeletal involvement of multiple endocrine neoplasia type 1-related primary hyperparathyroidism (MHPT) is not exactly the same as that of sporadic primary hyperparathyroidism (SHPT). Trabecular bone score (TBS) as a texture parameter has been reported to reflect trabecular bone damage. Objective This study aimed to compare the clinical characteristics, especially the skeletal involvement, between patients with MHPT and SHPT. Methods The clinical characteristics were retrospectively collected in 120 patients with MHPT and compared with 360 patients with SHPT in the same period. Dual-energy X-ray absorptiometry were conducted in some patients with MHPT, in whom bone mineral density (BMD) and calculated TBS derived from lumbar spine dual-energy X-ray absorptiometry images were compared with those of patients with SHPT. Results Although the duration of disease in the MHPT group was longer, the age at hospital visit was significantly lower than that in the SHPT group (43.5 [interquartile range, 31.5-52.0] vs 52.0 [interquartile range, 40.5-61.0], P <.001). The proportion of skeletal involvement in the MHPT group was significantly lower. However, in the subgroup of MHPT cases (n = 86) with data of BMD, there was no significant difference in skeletal involvement from SHPT cases matched for gender and age. Although the BMD and TBS in the lumbar spines of patients with MHPT were lower than those of patients with SHPT (BMD: 0.91 ± 0.18 g/cm2 vs 1.01 ± 0.17 g/cm2; TBS: 1.22 ± 0.14 vs 1.29 ± 0.11, P <.001). According to TBS, among 34 patients with MHPT with normal BMD, 15 patients had bone microstructure damage. Conclusion The cancellous bone microarchitecture was more severely damaged in patients with MHPT according to TBS, which suggested that TBS could be a sensitive supplemental index in addition to BMD to identify bone-involvement risk in patients with MHPT. [ABSTRACT FROM AUTHOR]

Pancreatic GHRHomas (pGHRHomas) with acromegaly have unique conditions, harboring the existence of multiple endocrine neoplasia type 1 (MEN 1). Moreover, pituitary lesions are affected by both protracted ectopic GHRH and loss of menin function. Of significance is the clarification of clinicopathological aspects of pGHRHomas in patients with or without MEN 1. From 1977-2016, thirty-six patients with pGHRHomas were reported. Twenty-two out of 36 patients (61%) had pGHRHomas with MEN 1 and 14 patients did not. The former had a tendency of male predominance, benign tumor behavior and fewer metastasis rather than the latter. The latter is a single pGHRHoma accompanied by pituitary enlargement with somatotroph hyperplasia (hyperplasia) caused by protracted ectopic GHRH. Nine patients with MEN 1 underwent transsphenoidal surgery (TSS). The hyperplasia associated with various pituitary adenomas (PAs) including three GH-related adenomas was observed in seven subjects (32%). In these patients, the resection of their pGHRHomas was feasible. Furthermore, all patients with acromegaly due to pGHRHomas without MEN 1 had non-TSS, whereas approximately 70% of those with MEN 1 had unnecessary TSS. The association with hyperplasia and various PAs suggested that formation of the three GH-related adenomas may be induced by the foundations of MEN 1 gene mutations. J. Med. Invest. 71: 1-8, February, 2024. [ABSTRACT FROM AUTHOR]

Background: Multiple endocrine neoplasia type 1 (MEN1) is a hereditary condition manifesting as an autosomal dominant genetic pattern. This genetic anomaly is marked by the formation of tumors in diverse endocrine glands, leading to a complex array of clinical manifestations. The correlation between colorectal cancer (CRC) and MEN1 mutations remains unknown. This study aimed to report an Iranian female CRC patient with a MEN1 genetic mutation. Material and method: A 37-year-old female presented to a physician complaining of rectal lesions, tubular adenoma, and rectal adenocarcinoma, suggesting moderately differentiated colorectal adenocarcinoma symptoms. HLA typing was tested for her. Finally, whole exome sequencing (WES) was performed using the patient's DNA. Based on a standard pipeline, the variant was identified and interpreted. Results: The findings demonstrated a known heterozygous missense mutation in the exon 2 of the MEN1 gene, g.64577373T-G, c.209A>C, p.Asp70Ala in the patients which has a variant uncertain significant (VUS) pathogenicity. She also had no celiac disease (HLA-DQ2/DQ8 genotypes are negative). Conclusion: The correlation between the identified genotype and the anatomical phenotype of the patient suggested that the identified variant can lead to colorectal abnormalities in the patient, contributing to the distinctive features of MEN1 disease. Understanding the underlying genetic mechanisms is important for diagnosing and treating this condition. [ABSTRACT FROM AUTHOR]

Context: Recent studies suggest that the clinical characteristics and biological behavior of pituitary tumors (PITs) in patients with multiple endocrine neoplasia type 1 (MEN1) may not be as aggressive as previously reported. Increased imaging of the pituitary as recommended by screening guidelines identifies more tumors, potentially at an earlier stage. However, it is unknown if these tumors have different clinical characteristics in different MEN1 mutations. Objective: To assess characteristics of patients with MEN1 with and without PITs, and compare among different MEN1 mutations. Methods: Data of patients with MEN1 in a tertiary referral center from 2010 to 2023 were retrospectively analyzed. Results: Forty-two patients with MEN1 were included. Twenty-four patients had PITs, 3 of which were invasive and managed with transsphenoidal surgery. One PIT enlarged during follow-up. Patients with PITs had a higher median age at MEN1 diagnosis than those without PITs. MEN1 mutations were identified in 57.1% of patients, including 5 novel mutations. In patients with PITs, those with MEN1 mutations (mutation+/PIT+ group) had more additional MEN1-associated tumors than those without (mutation-/PIT+ group). The mutation+/PIT+ group had a higher incidence of adrenal tumors and a lower median age at initial manifestation of MEN1 than the mutation-/PIT+ group. The most common neuroendocrine neoplasm was nonfunctional in the mutation+/PIT+ group and insulin-secreting in the mutation-/PIT+ group. Conclusion: This is the first study comparing characteristics of patients with MEN1 with and without PITs harboring different mutations. Patients without MEN1 mutations tended to have less organ involvement and it might be reasonable for them to receive less intensive follow-up. [ABSTRACT FROM AUTHOR]

Simple Summary: We described post-operative complications, pancreatic sequelae, and post-surgical progression/relapse of pancreatic neuroendocrine neoplasms (PNENs) in 43 patients with multiple endocrine neoplasia type 1 (MEN1), who underwent major or minimal pancreatic surgeries. The performance of a more conservative intervention, compared to both pancreaticoduodenectomy (PD) and distal pancreatectomy (DP), was associated with the absence of post-surgical complications, but required further pancreas surgeries for tumor relapse in 40.0% of the operated cases. Our data showed that major pancreatic resections (PD and DP) were effective in both preventing tumoral progression and guaranteeing a long-term PNEN relapse-free survival time in most of N+ and/or M+ patients. Pancreatic neuroendocrine neoplasms (PNENs) affect over 80% of patients with multiple endocrine neoplasia type 1 (MEN1). Surgery is usually the therapy of choice, but the real immediate and long-term therapeutic benefit of a partial extensive pancreatic resection remains controversial. We analyzed, in 43 PNEN MEN1 patients who underwent 19 pancreaticoduodenectomies (PD), 19 distal pancreatectomies (DP), and 5 minimal pancreatectomies, the prevalence of surgery-derived early complications and post-operative pancreatic sequelae, and the PNEN relapse-free survival time after surgery, comparing major (PD+DP) and minimal pancreatic surgeries. No post-operative mortality was observed. Metastatic cancers were found in 12 cases, prevalently from duodenal gastrinoma. Long-term cure of endocrine syndromes, by the 38 major pancreatic resections, was obtained in 78.9% of gastrinomas and 92.9% of insulinomas. In only one patient, hepatic metastases, due to gastrinoma, progressed to death. Out of the 38 major surgeries, only one patient was reoperated for the growth of a new PNEN in the remnant pancreas. No functioning PNEN persistence was reported in the five minimal pancreatic surgeries, PNEN relapse occurred in 60% of patients, and 40% of cases needed further pancreatic resection for tumor recurrence. No significant difference in PNEN relapse-free survival time after surgery was found between major and minimal pancreatic surgeries. [ABSTRACT FROM AUTHOR]

Primary hyperparathyroidism is a common endocrinopathy. Multiple Endocrine Neoplasia Type 1 (MEN1) is a rare autosomal dominantly inherited endocrine tumor predisposition syndrome, with one of main manifestations being primary hyperparathyroidism. We retrospectively evaluated a set of 1011 patients who underwent surgery for primary hyperparathyroidism between the years 2018-2022, and found 78 (8 %) patients who underwent reoperations and 27 patients with MEN1 syndrome. In the group of patients with MEN1 syndrome, 7 (35 %) needed reoperations. Patients with multiple endocrine neoplasia syndrome have a higher risk of needing reoperation. Genetic testing can help identify MEN1 syndrome preoperatively and to better evaluate the approach to surgery. [ABSTRACT FROM AUTHOR]

Simple Summary: In endocrinology, endoscopic ultrasound is a useful and reliable diagnostic technique in the assessment of multiple endocrine neoplasia type 1, localizing insulinomas, and identifying aldosterone-producing adenomas. In endocrinology, endoscopic ultrasound (EUS) may be used to image the adrenals, the endocrine pancreas, and other organs where endocrine neoplasms may occur. During the recent decades, EUS has been established predominantly to assess multiple endocrine neoplasia type 1, to localize insulinomas, and to identify aldosterone-producing adenomas. EUS in endocrinology requires special skills and individual experience in order to provide reliable diagnostic information. [ABSTRACT FROM AUTHOR]

Thymic neuroendocrine tumors associated with multiple endocrine neoplasia are only defined as carcinoid and are not associated with large‐cell neuroendocrine carcinoma (LCNEC). We report the case of a multiple endocrine neoplasia type 1 patient with atypical carcinoid tumors with elevated mitotic counts (AC‐h), an intermediate condition between carcinoid and LCNEC. A 27‐year‐old man underwent surgery for an anterior mediastinal mass and was diagnosed with thymic LCNEC. Fifteen years later, a mass appeared at the same site, which was determined to be a postoperative recurrence based on the pathological results of a needle biopsy and the clinical course. The patient's disease remained stable for 10 months on anti‐programmed death‐ligand 1 antibody and platinum‐containing chemotherapy. The needle biopsy specimen was submitted for next‐generation sequencing, which revealed a MEN1 gene mutation, and after further examination, a diagnosis of multiple endocrine neoplasia type 1 was made. A re‐examination of the surgical specimen from 15 years prior showed that it corresponded to AC‐h. Although thymic AC‐h is classified as thymic LCNEC according to the current definition, our data suggests that a search for multiple endocrine neoplasia is warranted in such patients. [ABSTRACT FROM AUTHOR]

Objective: This study aims to evaluate the presence of multiple endocrine neoplasia-1 mutations in patients with primary hyperparathyroidism detected on clinical and sonographical suspicion. Methods: We scanned the medical records of 361 patients with primary hyperparathyroidism between January 2010 and December 2017. Results: Fourteen of 361 patients (i.e., 2 males and 12 females) with primary hyperparathyroidism were evaluated genetically upon clinical and sonographical suspicion. Menin gene mutations were found in 3 of 14 patients (21.4%) patients. The frequency of multiple endocrine neoplasia-1 (n = 3) was estimated to be 0.83% in all patients with primary hyperparathyroidism (n = 361). Data of 4 patients with menin mutation analyses were as follows: case 1: A 37-year-old man presented with a 14-year history of recurring nephrolithiasis. He was diagnosed with primary hyperparathyroidism. Genetic analysis was reported as multiple endocrine neoplasia-1: c.643_646delACAG (p. Thr215Serfs*13) heterozygote; case 2: A 35-year-old man with primary hyperparathyroidism and prolactinoma was diagnosed. Genetic analysis was reported as multiple endocrine neoplasia-1: c.654+1G>A heterozygote; case 3: A 26-year-old woman with hyperammonemia, partial empty sella, and hyperprolactinemia was evaluated. Genetic testing revealed heterozygote genomic changes in c984c>a in the multiple endocrine neoplasia-1 gene on the seventh exon; case 4: A 27-year-old man was diagnosed with nephrolithiasis when he was 19 years old. He had both primary hyperparathyroidism and prolactinoma. Multiple endocrine neoplasia-1 and CDKN1B genetic mutation analyses were negative. Because mutation-negative syndromes could not be ruled out, a neck exploration was performed, and a parathyroid adenoma was excised. Conclusions: Patients with primary hyperparathyroidism should be evaluated for multiple endocrine neoplasia-1 mutations upon clinical and sonographical suspicion. It should be noted that an individual with the multiple endocrine neoplasia-1 gene mutation has a 100% penetrance up to the age of 40-50 years. Additionally, 2 novel multiple endocrine neoplasia-1 mutations were identified. [ABSTRACT FROM AUTHOR]

Background: Malignant thymic carcinoids are uncommon tumours among patients with multiple endocrine neoplasia type 1 (MEN-1). Current guidelines advise performance of a preventative, routine transcervical thymectomy (TCT) during parathyroidectomy, although data on the yield is scarce. In this review, we aimed to revisit available literature to investigate and summarize the efficacy of routine TCT for the prevention of thymic carcinoid tumours among MEN-1 patients after searching four databases (PubMed, Embase, Medline, and Cochrane Library). Summary: Seven eligible studies were identified: retrospective observational studies: 3 and case reports describing one or more patients: 4. A total of 122 patients were included, 56 males (45.9%) and a pooled mean age of 40 years (±10). All underwent a routine TCT as part of parathyroidectomy; no details on the extent of TCT were available. Overall, only one (0.9%) incidental carcinoid was found. However, although all other patients underwent prophylactic TCT at the time of parathyroidectomy, an additional nine (7.4%) developed a thymic carcinoid during follow-up, after a median time of 36 months (range: 8–226). Key Messages: There is currently not enough evidence to support the efficacy of a routine TCT to prevent the development of thymic carcinoid among MEN-1 patients. As this is a rare but potentially highly aggressive tumour, attention should be shifted towards improving follow-up programs and developing specific imaging-screening protocols. This enables early detection of thymic carcinoids in a timely manner and improves outcomes, even after performance of a routine TCT. [ABSTRACT FROM AUTHOR]

BACKGROUND: The differences between sporadic and multiple endocrine neoplasia type 1 (MEN-1)–associated insulinoma are not well described. Herein, we compared demographics, neoplasm characteristics, presentation, and survival in patients with sporadic vs MEN-1 insulinomas including benign and malignant disease. STUDY DESIGN: A retrospective study identified insulinoma patients. MEN-1 was defined based on genetic testing or clinically in patients with 2 or more primary MEN-1 tumor types. RESULTS: A total of 311 patients were identified: 84% benign and 16% malignant. The incidence of malignancy was similar (18% vs 16%, MEN-1 vs sporadic, p = 0.76). Within malignant patients, the median (interquartile range) age was 33 (25,44) years in MEN-1 vs 54 (41, 70) years in sporadic insulinoma (p = 0.04). There was no difference in sex or tumor size between MEN-1 and sporadic malignant insulinoma (p > 0.05). Of the 260 patients with benign insulinoma, 7% had MEN-1 syndrome. MEN-1 patients presented with insulinoma at a younger age: median (interquartile range) age was 38 (24, 49) years vs 52 (43, 65) years (p < 0.01). Resection of benign insulinoma was performed in 78% of the MEN-1 and 94% of the sporadic group (p = 0.03). Resected benign tumors were larger in the MEN-1 group: 2.0 (1.65, 2.45) cm vs 1.5 (1.2, 2.0) cm, respectively (p = 0.03). Concurrent insulinomas were more common in MEN-1 (17% vs 2%; p < 0.01). CONCLUSIONS: MEN-1 patients present with insulinoma at younger age and have larger benign pancreatic lesions at the time of resection compared with sporadic neoplasms. Younger patients and those with multifocal pancreatic neuroendocrine tumor in the setting of endogenous hyperinsulinism should be evaluated for MEN-1. [ABSTRACT FROM AUTHOR]

Objective: Lung carcinoids represent a small portion of all lung tumors and about 1%-5% are associated with ectopic adrenocorticotropic hormone secretion, representing 1%-10% of Cushing's syndrome. They occur both sporadically and rarely in association with multiple endocrine neoplasia type 1. MEN1 variations were detected in approximately 16% of sporadic cases with seldom reports about disease prognosis. This study aimed to identify MEN1 variants in our cohort of sporadic lung carcinoids to associate with disease outcome following surgery. Methods: Pathologically confirmed 5 lung carcinoid cases were retrospectively analyzed in terms of age, gender, imaging studies, clinicopathologic features, and long-term disease outcome. Genetic analysis was performed to detect copy number variations and point mutations in MEN1. Results: Totally 1 female and 4 males with cushingoid features underwent thoracoscopic lobectomy for ectopic Cushing's syndrome. Histopathological examinations revealed 2 atypical (males) and 3 typical (1 female and 2 males) carcinoids. One underwent Wedge resection, the others underwent lobectomy; none of them had any post-operative complications. Median follow-up period was 11 years (range, 5-19); all patients were alive with no recurrence or metastases, up to date. Genetic analysis revealed a novel MEN1 variant [c.1623G>T, p.(Gln541His)] in only 1 atypical carcinoid. Despite this variant, this case did not develop other components of MEN1 syndrome during long-term follow-up. Conclusion: We detected the frequency of MEN1 variation as 20%. Further studies are required to clarify the role of this variant. [ABSTRACT FROM AUTHOR]

Simple Summary: Approximately 30% of patients with multiple endocrine neoplasia type 1 (MEN1) develop the Zollinger–Ellison syndrome (ZES), caused by solitary or multiple duodenal gastrinomas. Its management, especially regarding indication, timing, and type of surgery, is highly controversial. Therefore, the present study evaluated the long-term outcomes of pancreaticoduodenectomy (PD) versus non-PD resections in MEN1-ZES with regard to biochemical cure and quality of life. We found in a series of 35 patients that initial PD is the superior surgical procedure for MEN1-ZES, leading to long-term cure in about 80% of patients, fewer duodenopancreatic reoperations and an acceptable quality of life. Based on the results of this study, MEN1-ZES should be considered a surgically curable disease. Aim: The aim of this research was to evaluate the long-term outcome of pancreaticoduodenectomy (PD) versus other duodenopancreatic resections (non-PD) for the surgical treatment of the Zollinger–Ellison syndrome (ZES) in patients with multiple endocrine neoplasia type 1 (MEN1). Methods: Prospectively recorded patients with biochemically confirmed MEN1-ZES who underwent duodenopancreatic surgery were retrospectively analyzed in terms of clinical characteristics, complications, cure rate, and long-term morbidity, including quality of life assessment (EORTC QLQ-C30). Results: 35 patients (16 female, 19 male) with MEN1-ZES due to duodenopancreatic gastrinomas with a median age of 42 (range 30–74) years were included. At the time of diagnosis, 28 (80%) gastrinomas were malignant, but distant metastases were only present in one (3%) patient. Eleven patients (31.4%) underwent pancreatoduodenectomy (PD) as the initial procedure, whereas 24 patients underwent non-PD resections involving duodenotomy with gastrinoma excision, enucleation of the pNEN from the head of the pancreas, and peripancreatic lymphadenectomy, either with or without distal pancreatectomy (i.e., either Thompson procedure, n = 12, or DUODX, n = 12). There was no significant difference in perioperative morbidity and mortality between the two groups (p ≥ 0.05). One (9%) patient of the PD group required reoperation for recurrent or metastatic ZES compared to eight (22.8%) patients of the non-PD resection groups. After a median follow-up time of 134 months (range 6–480) nine of 11 (82%) patients in the PD group, two of 12 (16%) patients in the Thompson procedure group, and three of 12 (25%) patients in the DUODX group had normal serum gastrin levels. In addition, the global health QoLScore was better in the PD group (76.9) compared to the Thompson procedure (57.4) and DUODX (59.5) groups. Conclusions: Initial PD seems to be the superior surgical procedure for MEN1-ZES, resulting in a long-term cure rate of about 80%, fewer duodenopancreatic reoperations, and an acceptable quality of life. [ABSTRACT FROM AUTHOR]

Background: Multiple endocrine neoplasia type 1 (MEN 1) syndrome is a rare, complex genetic disorder characterized by increased predisposition to tumorigenesis in multiple endocrine and non-endocrine tissues. Diagnosis and management of MEN 1 syndrome is challenging due to its vast heterogeneity in clinical presentation. Case presentation: A 23-year-old female, previously diagnosed with Polycystic Ovarian Syndrome (PCOS) and pituitary microprolactinoma presented with drowsiness,confusion and profuse sweating developing over a period of one day. It was preceded by fluctuating, hallucinatory behavior for two weeks duration. There was recent increase in appetite with significant weight gain. There was no fever, seizures or symptoms suggestive of meningism. Her Body mass index(BMI) was 32 kg/m2.She had signs of hyperandrogenism. Multiple cutaneous collagenomas were noted on anterior chest and abdominal wall. Her Glasgow Coma Scale was 9/15. Pupils were sluggishly reactive to light. Tendon reflexes were exaggerated with up going planter reflexes. Moderate hepatomegaly was present. Rest of the clinical examination was normal. Laboratory evaluation confirmed endogenous hyperinsulinaemic hypoglycaemia suggestive of an insulinoma. Hypercalcemia with elevated parathyroid hormone level suggested a parathyroid adenoma. Presence of insulinoma, primary hyperparathyroidism and pituitary microadenoma, in 3rd decade of life with characteristic cutaneous tumours was suggestive of a clinical diagnosis of MEN 1 syndrome. Recurrent, severe hypoglycaemia complicated with hypoglycaemic encephalopathy refractory to continuous, parenteral glucose supplementation and optimal pharmacotherapy complicated the clinical course. Insulinoma was localized with selective arterial calcium stimulation test. Distal pancreatectomy and four gland parathyroidectomy was performed leading to resolution of symptoms. Conclusions: Renal calculi or characteristic cutaneous lesions might be the only forewarning clinical manifestations of an undiagnosed MEN 1 syndrome impending a life-threatening presentation. Comprehensive management of MEN 1 syndrome requires multi-disciplinary approach with advanced imaging modalities, advanced surgical procedures and long-term follow up due to its heterogeneous presentation and the varying severity depending on the disease phenotype. [ABSTRACT FROM AUTHOR]

Background: MEN1 mutations can inactivate or disrupt menin function and are leading to multiple endocrine neoplasia type 1, a rare heritable tumor syndrome. Case presentation: We report on a MEN1 family with a novel heterozygous germline mutation, c.674delG; p.Gly225Aspfs*56 in exon 4 of the MEN1 gene. Diagnosis and clinical phenotyping of MEN1 was established by laboratory tests, ultrasound, biopsy, MRI imaging and endosonography. The clinical course of the disease was followed in the index patient and her family members for eight years. The mutation was associated with distinct clinical phenotypes in the index patient and three family members harboring p.Gly225Aspfs*56. Family members affected showed primary hyperparathyroidism but variable patterns of associated endocrine tumors, adrenal cortical adenomas, prolactinoma, multifocal pancreatic neuroendocrine tumors, insulinoma and nonsecretory neuroendocrine tumors of the pancreas. The mutation c.674delG; p.Gly225Aspfs*56 leads to a frameshift from codon 225 with early truncation of the menin protein. In silico analysis predicts loss of multiple protein-menin interactions in p.Gly225Aspfs*56, potentially rendering menin insufficient to control cell division and replication. However, no aggressive neuroendocrine tumors were observed in the follow-up of this family. Conclusions: We report a novel heterozygous MEN1 frameshift mutation, potentially causing (at least partial) inactivation of menin tumor suppression potential but lacking a genotype–phenotype correlation. Our study highlights the importance of personalized care with appropriate testing and counseling in MEN1 families. [ABSTRACT FROM AUTHOR]

Context: Nonfunctioning pancreatic neuroendocrine tumors (NF-pNETs) are highly prevalent and constitute an important cause of mortality in patients with multiple endocrine neoplasia type 1 (MEN1). Still, the optimal age to initiate screening for pNETs is under debate.Objective: The aim of this work is to assess the age of occurrence of clinically relevant NF-pNETs in young MEN1 patients.Methods: Pancreatic imaging data of MEN1 patients were retrieved from the DutchMEN Study Group database. Interval-censored survival methods were used to describe age-related penetrance, compare survival curves, and develop a parametric model for estimating the risk of having clinically relevant NF-pNET at various ages. The primary objective was to assess age at occurrence of clinically relevant NF-pNET (size ≥ 20 mm or rapid growth); secondary objectives were the age at occurrence of NF-pNET of any size and pNET-associated metastasized disease.Results: Five of 350 patients developed clinically relevant NF-pNETs before age 18 years, 2 of whom subsequently developed lymph node metastases. No differences in clinically relevant NF-pNET-free survival were found for sex, time frame, and type of MEN1 diagnosis or genotype. The estimated ages (median, 95% CI) at a 1%, 2.5%, and 5% risk of having developed a clinically relevant tumor are 9.5 (6.5-12.7), 13.5 (10.2-16.9), and 17.8 years (14.3-21.4), respectively.Conclusion: Analyses from this population-based cohort indicate that start of surveillance for NF-pNETs with pancreatic imaging at age 13 to 14 years is justified. The psychological and medical burden of screening at a young age should be considered. [ABSTRACT FROM AUTHOR]

Introduction: Multiple endocrine neoplasia type 1 (MEN1), an autosomal-dominantly inherited tumor syndrome, is classically defined by tumors arising from the "3 Ps": Parathyroids, Pituitary, and the endocrine Pancreas. The majority (>95%) of MEN1 patients will develop parathyroid tumors, 35% to 75% of patients will develop neuroendocrine tumors of the pancreas, <30% will have pituitary adenomas, and ... -- will develop other endocrine tumors such as adrenal adenomas and carcinomas. This case study seeks to emphasize the significance of accurately determining the underlying cause of basic signs such as hypoglycemia and conducting an in-depth examination of the patient to detect potential correlations between latent conditions. Case Report: This is the case of a 42-year-old female patient who presented at Akdeniz Hospital complaining of fatigue and hyperphagia. The patient's past medical history shows that she had surgical excision of an insulinoma in 2007 and had experienced weakness, fainting, and polyfagia over the previous three years. Blood testing showed low vitamin D levels, high calcium and PTH levels, and low glucose levels linked to high insulin and C-peptide levels. Computer tomography and parathyroid SPECT confirmed the results, which point to endocrine pancreas and parathyroid dysfunction. The patient was admitted for further investigations, including genetic testing for MEN1 syndrome. Discussions : Four smooth-bordered focal lesions were identified on the CT scan of the pancreatic tail section, the largest measuring 29x24 mm in size, compatible with Insulinoma. Additionally seen on the CT scan are bilateral nodular lesions on the adrenal glands, which raise the suspicion of pheochromocytoma. This led to the testing of catecholamine metabolites, which exhibited normal values for normetanephrine (37, 1 ug/24 h) and metanephrine (12, 7 ug/24 h). The Parathyroid SPECT detected lesions in the inferior commissure of both thyroid lobes, through an increased MIBI uptake in a hypo-isoechoic and heterogeneous area on the ultrasonography scan. A DEXA scan was conducted to assess bone density in the hip and lumbar spine due to the discovery of parathyroid dysfunction; both findings were conclusive for osteoporosis with a T-score of less than -2.5. Conclusions: The patient appears to have all the signs and symptoms of an uncommon case of MEN1 syndrome, which includes adrenal adenomas, pancreatic insulinoma, and parathyroid dysfunction. MEN1 is a complex disorder predisposing to more than 20 benign and malignant endocrine and nonendocrine neoplasms, still incompletely understood. [ABSTRACT FROM AUTHOR]

Introduction: Multiple endocrine neoplasia type 1 (MEN 1) is an infrequent autosomal dominant hereditary syndrome. Common manifestations are related to hypercalcemia, which is caused by primary hyperparathyroidism (PHPT). Brown tumors are infrequent as initial presentation of PHPT associated with MEN 1. It occurs in less than 2% of MEN 1 population. Results: A 36-year-old woman started the disease 25 years ago in an insidious and progressive manner. She presented a soft tumor in the left malar region that progressively increased in volume. We treated recurrent multiple brown tumors in a patient with PHPT and pituitary adenoma. Conclusion: The follow-up was demanding and multidisciplinar^. The long-term prognosis is uncertain; therefore, close monitoring of the patient should be carried out through clinical, laboratory and imaging evaluation. [ABSTRACT FROM AUTHOR]

Cancer derived from thyroid follicular epithelial cells is common; it represents the most common endocrine malignancy. The molecular features of sporadic tumors have been clarified in the past decade. However the incidence of familial disease has not been emphasized and is often overlooked in routine practice. A careful clinical documentation of family history or familial syndromes that can be associated with thyroid disease can help identify germline susceptibility-driven thyroid neoplasia. In this review, we summarize a large body of information about both syndromic and non-syndromic familial thyroid carcinomas. A significant number of patients with inherited non-medullary thyroid carcinomas manifest disease that appears to be sporadic disease even in some syndromic cases. The cytomorphology of the tumor(s), molecular immunohistochemistry, the findings in the non-tumorous thyroid parenchyma and other associated lesions may provide insight into the underlying syndromic disorder. However, the increasing evidence of familial predisposition to non-syndromic thyroid cancers is raising questions about the importance of genetics and epigenetics. What appears to be "sporadic" is becoming less often truly so and more often an opportunity to identify and understand novel genetic variants that underlie tumorigenesis. Pathologists must be aware of the unusual morphologic features that should prompt germline screening. Therefore, recognition of harbingers of specific germline susceptibility syndromes can assist in providing information to facilitate early detection to prevent aggressive disease. [ABSTRACT FROM AUTHOR]

Background: MEN1 is a complex, rare, syndrome inherited in an autosomal dominant tract and characterized by the development of multiple neuroendocrine tumors, requiring lifelong surveillance and multiple medical and surgical therapies throughout the patient's life. For all these reasons, a diagnosis of MEN1 can be a psychological shock for the patient, as well as his/her relatives, more so than the diagnosis of a single tumor. In the last two decades, clinicians have started to consider the emotional, psychological, relational, and social aspects of their patients' lives. The data collected in the present analyses highlight the unique features of MEN1 syndrome, and aim to evaluate the Quality of Life in the patients and their relatives. In this study, a comprehensive survey of various aspects of Health-Related Quality of Life was performed in a large series of Italian MEN1 patients, by administering five of the most common targeted questionnaires.Results: The results of the study showed that our patients, despite having a complex multi-tumor syndrome, were moderately optimistic (50%), and this corresponds with a normal Quality of Life. This positive response is strictly correlated with the fact that the patients are cared for at a dedicated Referral Center, receiving personalized care and constant follow-up, which gives them reassurance regarding the high quality of management of the disorder.Conclusions: The possibility of having access to a clinical Referral Center for their complex rare disease, together with the support of a dedicated patient association, has been demonstrated to be the ideal model for the management of post-diagnosis shock, and contributes to the preservation of a good Health-Related Quality of Life for MEN1 patients. [ABSTRACT FROM AUTHOR]

Context: Adrenal lesions are frequent among patients with sporadic neuroendocrine tumors (spNETs) or multiple endocrine neoplasia type 1 (MEN1). Armadillo repeat-containing 5 (ARMC5)-inactivating variants cause adrenal tumors and possibly other neoplasms.Objective: The objective of this work is to investigate a large cohort spNETs or MEN1 patients for changes in the ARMC5 gene.Patients and Methods: A total of 111 patients, 94 with spNET and 17 with MEN1, were screened for ARMC5 germline alterations. Thirty-six tumors (18 spNETs and 18 MEN1 related) were collected from 20 patients. Blood and tumor DNA samples were genotyped using Sanger sequencing and microsatellite markers for chromosomes. ARMC5 and MEN1 expression were assessed by immunohistochemistry.Results: In 76 of 111 (68.4%) patients, we identified 16 different ARMC5 germline variants, 2 predicted as damaging. There were no differences in the prevalence of ARMC5 variants depending on the presence of MEN1-related adrenal lesions. Loss of heterozygosity (LOH) at chromosome 16p and ARMC5 germline variants were present together in 23 or 34 (67.6%) tumors; in 7 of 23 (30.4%) their presence led to biallelic inactivation of the ARMC5 gene. The latter was more prevalent in MEN1-related tumors than in spNETs (88.9% vs 38.9%; P = .005). LOH at the chromosome 16p (ARMC5) and 11q (MEN1) loci coexisted in 16/18 MEN1-related tumors, which also expressed lower ARMC5 (P = .02) and MEN1 (P = .01) proteins compared to peritumorous tissues.Conclusion: Germline ARMC5 variants are common among spNET and MEN1 patients. ARMC5 haploinsufficiency or biallelic inactivation in spNETs and MEN1-related tumors suggests that ARMC5 may have a role in modifying the phenotype of patients with spNETs and/or MEN1 beyond its known role in macronodular adrenocortical hyperplasia. [ABSTRACT FROM AUTHOR]

Multiple endocrine neoplasia type 1 (MEN1) is an autosomal dominant disorder characterized by the combined occurrence of parathyroid tumors, pituitary adenomas, and pancreatic neuroendocrine neoplasms (PNENs). MEN1 is caused by germline MEN1 mutations in > 75% of patients, and the remaining 25% of patients may have mutations in unidentified genes or represent phenocopies with mutations in genes such as cell cycle division 73 (CDC73) , the calcium sensing receptor (CASR) , and cyclin-dependent kinase inhibitor 1B (CDKN1B) , which are associated with the hyperparathyroidism-jaw tumor syndrome, familial hypocalciuric hypercalcemia type 1, and MEN4, respectively. Here, we report a heterozygous c.1138C>T (p.Leu380Phe) CDC73 germline variant in a clinically diagnosed MEN1 patient, based on combined occurrence of primary hyperparathyroidism, acromegaly, and a PNEN. Characterization of the PNEN confirmed it was a neuroendocrine neoplasm as it immuno-stained positively for chromogranin and glucagon. The rare variant p.Leu380Phe occurred in a highly conserved residue, and further analysis using RNA-Scope indicated that it was associated with a significant reduction in CDC73 expression in the PNEN. Previously, CDC73 mutations have been reported to be associated with tumors of the parathyroids, kidneys, uterus, and exocrine pancreas. Thus, our report of a patient with PNEN and somatotrophinoma who had a CDC73 variant, provides further evidence that CDC73 variants may result in a MEN1 phenocopy. [ABSTRACT FROM AUTHOR]

BACKGROUND: Cholesteatoma is a cystic structure with the presence of keratin-producing squamous epithelium, which replaces the normal mucosa in the middle ear; its etiology is multifactorial, it is classified as congenital or acquired. Definitive treatment is surgical and aims to eradicate the disease. Patients with progeroid syndrome have an increased risk of presenting alterations in the middle ear such as cholesteatoma; hypohidrotic ectodermal dysplasia causes glandular disorders that increases the frequency of chronic infections at nasal and otic level. CLINICAL CASE: A 24-year-old female patient with cholesteatoma with right mastoidectomy autocavity with a history of progeroid syndrome, probable Wermer syndrome and hypohidrotic ectodermal dysplasia, managed with conservative treatment, without complications after 10 years of follow-up. CONCLUSIONS: Cholesteatoma of middle ear is an infrequent disease that, despite of its benign histology, may cause severe complications; thus, treatment is surgical, and its aim is to eradicate the disease. [ABSTRACT FROM AUTHOR]

Purpose: To compare the deoxyribonucleic acid (DNA) methylation signature of neuroendocrine tumors (NETs) by primary tumor site and inherited predisposition syndromes von Hippel-Lindau disease (VHL) and multiple endocrine neoplasia type 1 (MEN1).Methods: Genome-wide DNA methylation (835 424 CpGs) of 96 NET samples. Principal components analysis (PCA) and unsupervised hierarchical clustering analyses were used to determine DNA methylome signatures.Results: Hypomethylated CpGs were significantly more common in VHL-related versus sporadic and MEN1-related NETs (P < .001 for both comparisons). Small-intestinal NETs (SINETs) had the most differentially methylated CpGs, either hyper- or hypomethylated, followed by duodenal NETs (DNETs) and pancreatic NETs (PNETs, P < .001 for all comparisons). There was complete separation of SINETs on PCA, and 3 NETs of unknown origin clustered with the SINET samples. Sporadic, VHL-related, and MEN1-related PNETs formed distinct groups on PCA, and VHL clustered separately, showing pronounced DNA hypomethylation, while sporadic and MEN1-related NETs clustered together. MEN1-related PNETs, DNETs, and gastric NETs each had a distinct DNA methylome signature, with complete separation by PCA and unsupervised clustering. Finally, we identified 12 hypermethylated CpGs in the 1A promoter of the APC (adenomatous polyposis coli) gene, with higher methylation levels in MEN1-related NETs versus VHL-related and sporadic NETs (P < .001 for both comparisons).Conclusions: DNA CpG methylation profiles are unique in different primary NET types even when occurring in MEN1-related NETs. This tumor DNA methylome signature may be utilized for noninvasive molecular characterization of NETs, through DNA methylation profiling of biopsy samples or even circulating tumor DNA in the near future. [ABSTRACT FROM AUTHOR]

Summary: Thymic neuro endocrine tumor (tNET) are extremely rare malignancies with poor prognosis, requiring investigation of novel therapeutic approaches. 177Lu-DOTATATE is a successful systemic treatment modality in patients with metastatic gastroenteropancreatic but it role in tNET is not yet well established. Here we report a case of a 39-year-old man with refractory bone marrow infiltration of a tNET, treated by 4 cycles of peptide receptor radionuclide therapy (PRRT) with 177Lu DOTATATE. Since the first cycle, clinical symptoms were substantially decreased, without any severe subacute haematological toxicity. Three months after the end of PRRT, both 68Ga-DOTATOC and 18F-FDG PET confirmed a partial response, already suggested by 177Lu-DOTATATE treatment scan with a significant decrease of the bone marrow uptake between the first and fourth cycle. This report highlights that PRRT could be an effective therapeutic option for advanced bone metastatic disease tNET, with the significant benefit of alleviation of bone pain and radiologic response, without severe or irreversible haematotoxicity. [ABSTRACT FROM AUTHOR]

The contiguous gene deletion syndrome of congenital adrenal hyperplasia and Ehlers-Danlos syndrome, named CAH-X, is a rare entity that occurs because of a deletion of a chromosomal area containing 2 neighboring genes, TNXB and CYP21A. Here, we describe a patient from a consanguineous family in which coincidentally MEN-1 syndrome is associated with CAH-X, causing particular challenges explaining the phenotypic features of the patient. A 33-year-old man with salt-wasting congenital adrenal hyperplasia and classic-like Ehlers-Danlos syndrome presented with an adrenal crisis with a history of recurrent hypoglycemia, abdominal pain, and vomiting. He was found to have primary hyperparathyroidism, hyperprolactinemia, and pancreatic neuroendocrine tumors, as well as primary hypogonadism, large adrenal myelolipomas, and low bone mineral density. A bladder diverticulum was incidentally found. Genetic analysis revealed a heterozygous previously well-described MEN1 mutation (c.784-9G > A), a homozygous complete deletion of CYP21A2 (c.1-?_1488+? del), as well as a large deletion of the neighboring TNXB gene (c.11381-?_11524+?). The deletion includes the complete CYP21A2 gene and exons 35 through 44 of the TNXB gene. CGH array found 12% homozygosity over the whole genome. This rare case illustrates a complex clinical scenario with some initial diagnostic challenges. [ABSTRACT FROM AUTHOR]

Multiple endocrine neoplasia type 1 (MEN1) is an autosomal dominant disorder caused by mutations of the tumor suppressor gene MEN1. Most of the germline MEN1 gene mutations have been small mutations, and the whole gene deletion is rarely observed. In the present study, we revealed Alu retrotransposon-mediated de novo germline deletion of the whole MEN1 gene and somatic copy-neutral loss of heterozygosity (LOH) in a patient with MEN1. The patient is a 39-year-old woman who was referred to our department for the management of prolactinoma. She was also diagnosed with primary hyperparathyroidism and suspected of MEN1. Although nucleotide sequencing did not detect any MEN1 gene mutations, multiplex ligation-dependent probe amplification (MLPA) revealed a large germline deletion of the MEN1 gene. Subsequent quantitative polymerase chain reaction (qPCR)–based copy number mapping showed a monoallelic loss of approximately 18.5-kilobase region containing the whole MEN1 gene. Intriguingly, the 2 breakpoints were flanked by Alu repetitive elements, suggesting the contribution of Alu / Alu -mediated rearrangements (AAMR) to the whole MEN1 gene deletion. Furthermore, copy number mapping using MLPA and qPCR in combination with single nucleotide polymorphism analysis revealed copy-neutral LOH as a somatic event for parathyroid tumorigenesis. In conclusion, copy number mapping revealed a novel combination of Alu / Alu -mediated de novo germline deletion of the MEN1 gene and somatic copy-neutral LOH as a cytogenetic basis for the MEN1 pathogenesis. Moreover, subsequent in silico analysis highlighted the possible predisposition of the MEN1 gene to Alu retrotransposon-mediated genomic deletion. [ABSTRACT FROM AUTHOR]

Despite recent advances in genomics and the discovery of numerous genes involved in carcinogenesis, the mechanisms of malignant transformation of different tissues remain poorly understood in most cases. This review presents the current knowledge on the role of the MEN1 gene and its protein product menin in the development of multiple endocrine neoplasia type 1 (MEN1), or Wermer's syndrome. Here, we discuss the putative molecular and genetic mechanisms of carcinogenesis associated with the MEN1 gene mutation, as well as available and promising in vivo and in vitro models for studying the molecular basis of the disease. The lack of clear data on the role of the MEN1 gene in tumor initiation and progression in patients with MEN1 syndrome allows us to suggest two models for occurrence of malignant transformation in endocrine tissues. [ABSTRACT FROM AUTHOR]

Zollinger Ellison Syndrome (ZES) is characterized by a wide spectrum of conditions including severe gastroesophageal reflux disease, peptic ulcer disease, watery diarrhea, and weight loss. We present a case of a 60-year-old woman being evaluated for severe dyspepsia, vomiting, and chronic diarrhea, who was diagnosed to have ZES associated with a pancreatic neuroendocrine tumor, in the setting of multiple endocrine neoplasia (MEN) type 1. Although cases of ZES have been reported previously, we believe that our case is a classic presentation of ZES diagnosed on the basis of typical radiologic, endoscopic, and endosonographic features. [ABSTRACT FROM AUTHOR]

Background: Parathyroid carcinoma (PC) is a rare endocrine malignancy that can cause life‐threatening hypercalcemia. We queried whether comprehensive genomic profiling (CGP) of PC might identify genomic alterations (GAs), which would suggest benefit from rationally matched therapeutics. Methods: We performed hybrid‐capture‐based CGP to identify GAs and tumor mutational burden (TMB) in tumors from patients with this malignancy. Results: There were 85 total GAs in 16 cases (5.3 GAs per case), and the median TMB was 1.7 mutations per megabase (m/Mb), with three cases having >20 m/Mb (18.7%). The genes most frequently harboring GA were CDC73 (38%), TP53 (38%), and MEN1 (31%). All MEN1‐mutated cases also had loss of heterozygosity at that locus, but in contrast all CDC73‐mutated cases retained heterozygosity. GAs suggesting potential benefit from matched targeted therapy were identified in 11 patients (69%) and most frequently found in PTEN (25%), NF1 (12.5%), KDR (12.5%), PIK3CA (12.5%), and TSC2 (12.5%). A patient whose tumor harbored KDR T668 K and who was treated with cabozantinib experienced a > 50% drop in parathyroid hormone level and radiographic partial response of 5.4 months with duration limited by toxicity. Conclusion: CGP identified GAs in PC that suggest benefit from targeted therapy, as supported by an index case of response to a matched tyrosine kinase inhibitor. Moreover, the unexpectedly high frequency of high TMB (>20 m/Mb) suggests a subset of PC may benefit from immune checkpoint inhibitors. Implications for Practice: Parathyroid carcinoma (PC) is a rare endocrine malignancy that can cause life‐threatening hypercalcemia. However, its molecular characteristics remain unclear, with few systemic therapeutic options available for this tumor. Hybrid‐capture‐based comprehensive genomic profiling of 16 primary cancers demonstrated presence of potentially actionable genomic alterations, including PTEN, NF1, KDR, PIK3CA, and TSC2, and a subset of hypermutated cancers with more than 20 mutations per megabase, the latter of which could benefit from immune checkpoint inhibitor therapy. A case benefiting from rationally matched targeted therapy for activating KDR mutation is also presented. These findings should be further investigated for their therapeutic potential. Results from comprehensive genomic profiling in a cohort of patients with advanced parathyroid carcinoma are reported. [ABSTRACT FROM AUTHOR]

Summary: Objective: Literature concerning the impact of multiple endocrine neoplasia type 1 (MEN 1) on fertility is limited to case reports despite the early onset of endocrinopathies, such as primary hyperparathyroidism and prolactinoma, that may impact fertility. This study describes the impact of unrecognized and untreated MEN 1 on fertility and pregnancy outcomes in a multigenerational cohort of the Tasman 1 MEN 1 kindred. Methods: All MEN 1 positive (MEN 1+, n = 63) and MEN 1 negative (MEN 1−, n = 75) descendants born between 1825 and 1951 of a common founder. Review of birth, death, marriage and medical records provided data on date of birth and death, gender, MEN 1 status and the number of pregnancies and children per parent. Results: Compared to MEN 1− parents, MEN 1+ parents had more children (RR 1.30, 1.02‐1.66) and live births (RR 1.31, 1.02‐1.67) with no excess of stillbirths (RR 1.24, 0.24‐6.36). Compared to the era‐matched Tasmanian fertility rate, MEN 1+ parents had more children (4.87 ± 4.11 vs 3.40 ± 0.61, P = 0.048), whereas MEN 1− parents had similar numbers of children (3.67 ± 3.27 vs 3.36 ± 0.62, P = 0.55). MEN 1+ parents had a similar number of MEN 1+ and MEN 1− offspring (2.1 ± 1.9 vs 2.5 ± 2.3, P = 0.31). Indirectly assessed miscarriage rate was similar between MEN 1+ and MEN 1− mothers (P = 0.77). Clinically overt pituitary disease reduced MEN 1+ kindred member likelihood of parenthood (33% vs 97%). Conclusions: There was no adverse impact of MEN 1 on patient fertility overall; however, MEN 1‐related pathology may have impaired the reproductive potential of a subset of individuals with pituitary disease. [ABSTRACT FROM AUTHOR]

We report our experience about somatotrophinomas without clinical manifestation of acromegaly having radiological- and surgical-verified invasion of the cavernous sinus. We present the clinical, radiological and hormonal status of three patients affected by invasive GH-secreting pituitary adenomas without clinical signs and symptoms of acromegaly with elevation of serum IGF-1 from a series of 142 pituitary adenomas operated in our institute with the aid of intraoperative magnetic resonance imaging (MRI). Total tumor removal was possible in two of the three cases; the patients show normal hormonal status and no recurrence at long-term follow-up. In the third case, due to the different features of the tumor, complete resection was not possible and a multimodal treatment was performed that allowed regularization of the hormonal status and control of the residual tumor. GH-secreting adenomas without clinical manifestation of acromegaly are uncommon lesions. Total microsurgical excision can be curative. However, in case of partial removal, a tailored adjuvant treatment should be considered to preserve the quality of life of the patient and avoid regrowth of the lesion. In not resectable tumors, preoperative medical treatment with somatostatin analogues is always an option. [ABSTRACT FROM AUTHOR]

Background: The choice of surgical treatment for patients with Multiple Endocrine Neoplasia type 1 (MEN1)-related primary hyperparathyroidism (PHPT) remains controversial and it has not been specifically addressed in young patients. Methods: This is a retrospective case series study. The study includes the surgical data and the follow-up of 38 patients younger than 30 years of age, all diagnosed with MEN1, collected and followed-up between 1991 and 2017 at the Regional Referral Center for Inherited Endocrine Tumors of the Tuscany Region, and operated by parathyroidectomy. Genetic and/or clinical MEN1 diagnosis was made before surgery in all patients. Subtotal (9/38 patients) or total parathyroidectomy with auto-transplantation (28/38 patients) were performed in all patients but one, in whom a single mediastinal adenoma was excised from the aorto-pulmonary window. All patients but one, who was operated in 2017, had a post-operatory follow-up of at least 12 months. Results: Total parathyroidectomy (TPTX), with auto-transplantation, was the most frequently adopted operation both as primary (20/38 patients) and secondary (8/38 patients) surgery, followed by subtotal parathyroidectomy (SPTX; 9/38 patients) and limited parathyroidectomy (1/38 patient). At follow-up, lasting a mean of 11.8 ± 6.6 years (range 0–23 years), no persistent PHPT was observed. PHPT recurred in 4/28 TPTX (14%) and in 2/9 SPTX (22%). Permanent hypoparathyroidism showed no statistically significant difference between the procedures (2/9 in SPTX and 5/28 in TPTX). Conclusions: Data from this retrospective study showed the efficacy of TPTX for the treatment of MEN1-PHPT, also in adolescent and young patients, showing, in our series, no risk of PHPT permanence and a longer disease-free period and, subsequently, the possibility to postpone re-intervention with respect to both limited PTX and SPTX. The risk of permanent hypoparathyroidism in TPTX was comparable to STPX, and could be mitigated over the years. [ABSTRACT FROM AUTHOR]

Multiple Endocrine Neoplasia type 1 (MEN1) is a rare autosomal dominant inherited condition, causing significant morbidity, and a reduction of life expectancy. A timely and accurate diagnosis of MEN1 is paramount to improve disease outcomes. This enables early identification of tumor manifestations allowing timely treatment for reducing morbidity and improving survival. Current management of MEN1 poses two challenges regarding the MEN1 diagnosis: diagnostic delay and the issue of phenocopies. A delay in diagnosis can be caused by a delay in identifying the index case, and by a delay in identifying affected family members of an index case. At present, lag time between diagnosis of MEN1 in index cases and genetic testing of family members was estimated to be 3.5 years. A subsequent delay in diagnosing affected family members was demonstrated to cause potential harm. Non-index cases have been found to develop clinically relevant tumor manifestations during the lag times. Centralized care, monitoring of patients outcomes on a national level and thereby improving awareness of physicians treating MEN1 patients, will contribute to improved care. The second challenge relates to “phenocopies.” Phenocopies refers to the 5–25% of clinically diagnosed patients with MEN1in whom no mutation can be found. Up to now, the clinical diagnosis of MEN1 is defined as the simultaneous presence of at least two of the three characteristic tumors (pituitary, parathyroids, or pancreatic islets). These clinically diagnosed patients undergo intensive follow up. Recent insights, however, challenge the validity of this clinical criterion. The most common mutation-negative MEN1 phenotype is the combination of primary hyperparathyroidism and a pituitary adenoma. This phenotype might also be caused by mutations in the CDKN1B gene, causing the recently described MEN4 syndrome. Moreover, primary hyperparathyroidism and pituitary adenoma are relatively common in the general population. Limiting follow-up in patients with a sporadic co-occurrence of pHPT and PIT could reduce exposure to radiation from imaging, healthcare costs and anxiety. [ABSTRACT FROM AUTHOR]

Multiple endocrine neoplasia (MEN) type 1 syndrome is an autosomal dominant disorder caused by germline mutations in MEN1 gene, characterized by tumours in endocrine and nonendocrine organs. Giant prolactinoma is defined as tumours larger than 40mm with very high prolactin secretion. We report two unrelated Sri Lankan patients (8-year-old boy and a 20-year-old female) who presented with giant prolactinomas with mass effects of the tumours. The female patient showed complete response to medical therapy, while the boy developed recurrent resistant prolactinoma needing surgery and radiotherapy. During follow-up, both developed pancreatic neuroendocrine tumours. Genetic analysis revealed that one was heterozygous for a nonsense mutation and other for missense mutation in MEN1 gene. Screening confirmed familial MEN-1 syndrome in their families. High clinical suspicion upon unusual clinical presentation prompted genetic evaluation in these patients and detection of MEN1 gene mutation. Pituitary adenomas in children with MEN-1 syndrome are larger tumours with higher rates of treatment resistance. This report emphasizes importance of screening young patients with giant prolactinoma for MEN-1 syndrome and arranging long-term follow-up for them expecting variable treatment outcomes. Sri Lanka requires further studies to describe the genotypic-phenotypic variability of MEN-1 syndrome in this population. [ABSTRACT FROM AUTHOR]

Summary: Context: Bronchopulmonary neuroendocrine tumours (bpNETs) and thymic carcinoid (ThC) are features of multiple endocrine neoplasia type 1 (MEN 1), and surveillance guidelines recommend periodic thoracic imaging. The optimal thoracic imaging modality and screening frequency remain uncertain as does the prognosis of small lung nodules when identified. Objectives: To evaluate fluorodeoxyglucose positron emission tomography/computed tomography (18F‐FDG PET/CT) for identification and prognostic assessment of thoracic lesions in MEN 1. Design: Retrospective observational study. Setting and participants: Fifty consecutive MEN 1 patients undergoing screening with 18F‐FDG PET/CT at a tertiary referral hospital between July 2011 and December 2016. Interventions: 18F‐FDG PET/CT. Outcome measures: Pulmonary and thymic lesion prevalence, size, functional characteristics and behaviour. Results: Thirteen patients (26.0%) exhibited pulmonary nodules with multiple nodules identified in nine (18.0%). An asymptomatic 31 mm FDG‐avid ThC was identified in one patient (2%). Of the 13 patients with pulmonary nodules, four (8.0%) exhibited 13 FDG‐avid nodules (mean size 10.1 ± 9.1 mm), and nine (18.0%) demonstrated 26 FDG nonavid nodules (mean size 6.9 ± 5.8 mm). All FDG‐avid lesions increased in size vs 11 (42.3%) FDG nonavid lesions (P = .0004). For FDG‐avid and nonavid nodules, the median doubling time was 24.2 months (IQR 11.4‐40.7) and 48.6 months (IQR 37.0‐72.2), respectively. Nodule resection was undertaken in two patients, typical bronchial carcinoid diagnosed in one (FDG nonavid) and metastatic renal cell carcinoma in the second (FDG avid). Conclusion: Thoracic imaging with 18F‐FDG PET/CT effectively identifies pulmonary nodules and ThC. FDG‐avid pulmonary lesions are significantly more likely to progress than nonavid lesions. [ABSTRACT FROM AUTHOR]

Pancreatic neuroendocrine tumours (PNETs) might occur as a non-familial isolated endocrinopathy or as part of a complex hereditary syndrome, such as multiple endocrine neoplasia type 1 (MEN1). MEN1 is an autosomal dominant disorder characterized by the combined occurrence of PNETs with tumours of the parathyroids and anterior pituitary. Treatments for primary PNETs include surgery. Treatments for non-resectable PNETs and metastases include biotherapy (for example, somatostatin analogues, inhibitors of receptors and monoclonal antibodies), chemotherapy and radiological therapy. All these treatments are effective for PNETs in patients without MEN1; however, there is a scarcity of clinical trials reporting the efficacy of the same treatments of PNETs in patients with MEN1. Treatment of PNETs in patients with MEN1 is challenging owing to the concomitant development of other tumours, which might have metastasized. In recent years, preclinical studies have identified potential new therapeutic targets for treating MEN1-associated neuroendocrine tumours (including PNETs), and these include epigenetic modification, the β-catenin-wingless (WNT) pathway, Hedgehog signalling, somatostatin receptors and MEN1 gene replacement therapy. This Review discusses these advances. [ABSTRACT FROM AUTHOR]

Background: Nonfunctioning pancreatic neuroendocrine tumors (NFPanNETs) may be sporadic or inherited because of germline mutations associated with von Hippel-Lindau disease (VHL) or multiple endocrine neoplasia type 1 (MEN1). The clinical behavior of NFPanNETs is difficult to predict, even in tumors of the same stage and grade. The authors analyzed genotype-specific patterns of transcriptional messenger RNA (mRNA) levels of NFPanNETs to understand the molecular features that determine PanNET phenotype.Methods: Thirty-two samples were included for genome-wide mRNA gene expression analysis (9 VHL-associated, 10 MEN1-associated, and 9 sporadic NFPanNETs and 4 purified normal islet cell [NIC] samples). Validation of genes was performed by real-time polymerase chain reaction analysis and immunohistochemistry. Gene expression profiles were analyzed by tumor genotype, and pathway analysis was curated.Results: Consensus clustering of mRNA expression revealed separate clustering of NICs, VHL-associated NFPanNETs, and MEN1-associated NFPanNETs; whereas some sporadic tumors clustered with MEN1. Four of 5 MEN1-like sporadic PanNET subtypes had loss of heterozygosity at the MEN1 gene locus. Pathway analysis demonstrated subtype-specific pathway activation, comprising angiogenesis and immune response in VHL; neuronal development in MEN1; protein ubiquitination in the new MEN1/sporadic subtype; and cytokinesis and cilium/microtubule development in sporadic NFPanNETs. Among many genes, platelet-derived growth factor receptor β (PDGFRB), lymphoid enhancer-binding factor-1 (Lef-1), cyclin-dependent kinase 4 (CDK4), and CDK6 were upregulated in VHL or MEN1 NFPanNETs, providing potential subtype-specific treatment targets.Conclusions: Distinct mRNA expression patterns were identified in sporadic-associated, VHL-associated, and MEN1-associated NFPanNETs. The current results uncover new pathways involved in NFPanNETs that are subtype-specific and provide potential new diagnostic or therapeutic targets based on tumor subtype. Cancer 2018;124:636-47. © 2017 American Cancer Society. [ABSTRACT FROM AUTHOR]

Objective: To evaluate the natural history of MEN1-related bronchial endocrine tumors (br-NETs) and to determine their histological characteristics, survival and causes of death. Summary background data: br-NETs frequency ranges from 3 to 13% and may reach 32% depending on the number of patients evaluated and on the criteria required for diagnosis. Methods: The 1023-patient series of symptomatic MEN1 patients followed up in a median of 48.7 [35.5-59.6] years by the Groupe d'étude des Tumeurs Endocrines was analyzed using time-to-event techniques. Results: br-NETs were found in 51 patients (4.8%, [95% CI 3.6-6.2%]) and were discovered by imaging in 86% of cases (CT scan, Octreoscan, Chest X-ray, MRI). Median age at diagnosis was 45 years [28-66]. Histological examination showed 27 (53%) typical carcinoids (TC), 16 (31%) atypical carcinoids (AC), 2 (4%) large cell neuroendocrine carcinomas (LCNEC), 3(6%) small cell neuroendocrine carcinomas (SCLC), 3(6%) TC associated with AC. Overall survival was not different from the rest of the cohort (HR 0.29, [95% CI 0.02-5.14]). AC tended to have a worse prognosis than TC ( p = 0.08). Seven deaths were directly related to br-NETs (three AC, three SCLC and one LCNEC). Patients who underwent surgery survived longer ( p = 10) and were metastasis free, while 8 of 14 non-operated patients were metastatic. There were no operative deaths. Conclusions: Around 5% of MEN1 patients develop br-NETs. br-NETs do not decrease overall survival in MEN1 patients, but poorly differentiated and aggressive br-NETs can cause death. br-NETs must be screened carefully. A biopsy is essential to operate on patients in time. [ABSTRACT FROM AUTHOR]

Multiple endocrine neoplasia (MEN1) is a rare autosomal dominant disorder characterized by primary hyperparathyroidism, enteropancreatic neuroendocrine tumors, and anterior pituitary adenomas. A 16-year-old male presented to the emergency outpatient clinic with tonic convulsions. Physical examination in the postconvulsive period was unremarkable and revealed a muscular, postpubertal adolescent. Biochemical tests at admission were consistent with hyperinsulinemic hypoglycemia and remarkable for elevated levels of liver transaminases and creatine kinase. Work-up for a potential inborn error of metabolism and Doppler ultrasound for congenital portal-hepatic shunt were negative. When the patient was questioned, he reported using the anabolic steroid stanozolol to strengthen his muscles. His enzyme levels normalized after cessation of stanozolol. Hypoglycemia did not recur on diazoxide therapy. Magnetic resonance imaging showed two discrete lesions in the pancreas. Distal pancreatectomy revealed two masses 1.1 and 1.4 cm in diameter: a solid pseudopapillary tumor and an insulinoma. The patient also had asymptomatic primary hyperparathyroidism. DNA sequence analysis of the MEN1 gene in the index patient and his father and brother revealed a previously reported "pW183S" heterozygous mutation. This case further adds to the "pancreatic tumor" phenotype of MEN1 with the presence of a solid pseudopapillary tumor. This case report also confirms the need to meticulously question drug abuse in adolescents presenting to clinics with diagnostic challenges. [ABSTRACT FROM AUTHOR]

Objective Thymic neuroendocrine tumour ( TH- NET) accounts for almost 20% of multiple endocrine neoplasia type 1 ( MEN1)-associated mortality. Identifying risk factors for the development of these rare tumours and prognostic factors for clinical outcomes will be helpful in clinical practice. Design and Patients We performed a retrospective analysis of patients treated for TH- NET associated with MEN1 in a single institution and meta-analysis of literature reports. We used a fixed effect model to pool results across studies to evaluate the prevalence, clinical features and prognosis. Results TH- NET was detected in 9 (7.4%) of 121 patients with MEN1 seen in our institution, and 5 (55.6%) were women. Seven additional studies were identified through a systematic review of the literature. The pool estimate of TH- NET prevalence was 3.7% (n = 99) in MEN1 (n = 2710), sex ratio was 79:20 (male vs female), and the median age at diagnosis was 43.0 years (range, 16.0-72.0 years). Forty-three patients died with a median survival time of 8.4 years. Older age at diagnosis ( HR = 1.4, 95% CI = 1.0-1.8, P = .03), maximum tumour diameter ( HR = 1.5, 95% CI = 1.0-2.3, P = .04) and presence of metastasis ( HR = 1.6, 95% CI = 1.0-2.5, P = .04) were associated with worse outcome. A male predominance (91.9% vs 59.5%, P < .001) and history of smoking (59.0% vs 23.5%, P = .015) were more common in American/European series compared to Asian reports. Conclusion TH- NET is a rare but fatal component of MEN1. Earlier detection of TH- NET in patients with MEN1 may be recommended which should theoretically result in better outcomes. Different genetic backgrounds (race) appear to result in clinical difference. [ABSTRACT FROM AUTHOR]

Upper gastrointestinal neuroendocrine tumors (NETs) are rare tumors which are increasingly recognised by practising endoscopists. After confirmation by endoscopic biopsies of these focal lesions, many questions may arise. As NETs are less frequently encountered compared to other malignancies or gastrointestinal pathology, many endoscopists may not fully understand the natural history, diagnosis and management of these tumors. In this review, we aim to update the practising endoscopist on the key clinical features and management of patients with upper gastrointestinal NET. [ABSTRACT FROM AUTHOR]