Pancreatic GHRHomas in Patients with or without Multiple Endocrine Neoplasia Type 1 (MEN 1) : An Analysis of 36 Reported Cases.

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.

The lesion detection rate of Ga-68 DOTATATE PET/MR in multiple endocrine neoplasia type 1.

INTRODUCTION: The purpose of the study was to determine the usefulness of Ga-68 DOTATATE PET/MR in the identification of tumours in individuals with multiple endocrine neoplasia type 1 (MEN1). METHODS: In this retrospective investigation, five individuals who had tested positive for a hereditary MEN1 variant underwent Ga-68 DOTATATE PET/MR between May 2020 and January 2023. Several types of tumours associated with MEN1 were studied. MEN1-related tumours included pituitary, parathyroid, gastroenteropancreatic, and adrenal. The rates of lesion identification between MRI, Ga-68 DOTATATE PET, and Ga-68 DOTATATE PET/MRI were examined. The maximum and mean standard uptake values (SUVmax and SUVmean) were evaluated in carefully delineated volumes of interest (VOI) for the relevant tumours. RESULTS: Of the 24 primary lesions, 14 were identified by Ga-68 DOTATATE PET, 18 by MRI, and 20 by Ga-68 DOTATATE PET/MRI. Two pituitary tumours were detected by all three techniques. All parathyroid tumours that were not detected by Ga-68 DOTATATE PET and MRI were found by Tc-99m MIBI SPECT/CT or/and EUS. Ga-68 DOTATATE PET/MR detected more gastroenteropancreatic lesions. All adrenal tumours not identified by Ga-68 DOTATATE PET were found by MRI or CT. The median SUVmax for lesions identified on Ga-68 DOTATATE PET/MRI was 18.4 (range, 3.8-85.2), and the median SUVmean was 12.0 (range, 2.3-49.8). CONCLUSION: The combination of Ga-68 DOTATATE PET and MRI demonstrated a higher detection rate and may be more useful in the work-up of MEN1 providing a panoramic view of MEN1-related lesions. To increase the identification of MEN1-associated neuroendocrine lesions in the parathyroid gland, approaches other than Ga-68 DOTATATE PET/MRI should be used.

Genetic disorders and insulinoma/glucagonoma.

Insulinoma and glucagonoma are two rare functioning neoplasms of the neuroendocrine cells of the pancreas, respectively, characterized by an uncontrolled over-secretion of insulin or glucagon, responsible for the development of the hypoglycemic syndrome and the glucagonoma syndrome. They prevalently arise as sporadic tumors; only about 10% of cases develop in the context of rare inherited tumor syndromes, such as multiple endocrine neoplasia type 1 (MEN1), neurofibromatosis type 1 (NF1), and tuberous sclerosis complex (TSC), being the result of an autosomal-dominant germline heterozygous loss-of-function mutation in a tumor-suppressor gene. Here, we reviewed the main epidemiological and clinical aspects of insulinoma and glucagonoma in the context of genetic syndromes.

[Comparative analysis of bone complications/manifestations in sporadic and MEN1-related primary hyperparathyroidism].

BACKGROUND: Multiple endocrine neoplasia type 1 (MEN1) - is a rare syndrome with an autosomal dominant inheritance pattern caused by a mutation in the tumor suppressor gene (MEN1). Parathyroid involvement is the most common MEN1 manifestation resulting in primary hyperparathyroidism (mPHPT). Data on the prevalence and structure of bone disease in mPHPT compared to sporadic one (sPHPT) are often incomplete and contradictory. AIM: The purpose of this study was to compare the severity of bone involvement between mPHPT and sPHPT. MATERIALS AND METHODS: A single-center retrospective study was conducted among young patients in the active phase of PHPT and without prior parathyroidectomy in anamnesis. The analysis included the main parameters of calcium-phosphorus metabolism, bone remodeling markers, as well as an assessment of disease complications. Bone mineral density (BMD) was measured using dual-energy X-ray absorptiometry (DXA) at sites of lumbar spine, femur and radius. Trabecular bone score (TBS) was applied to estimate trabecular microarchitecture. All patients included in the study underwent genetic testing. RESULTS: Group 1 (mPHPT) included 26 patients, and group 2 (sSHPT) included 30 age-matched patients: the median age in group 1 was 34.5 years [25; 39], in group 2 - 30.5 years [28; 36], (p=0.439, U-test). Within group 1, the subgroup 1A (n=21) was formed with patients without other hormone-produced neuroendocrine neoplasms (NEN) in the gastrointestinal tract (GI) and the anterior pituitary gland. The duration of PHPT was comparable in both groups: mPHPT - 1 year [0; 3] versus sPHPT - 1 year [0; 1], (p=0.533, U-test). There were no differences in the main parameters of calcium-phosphorus metabolism, as well as in the prevalence of kidney complications. In the mPHPT group, bone abnormalities were observed significantly more often compared to sPHPT: 54 vs 10% (p=<0.001; F-test). Statistically significant differences were revealed both in BMD and in Z-score values of the femoral neck and total hip, which were lower in the mPHPT group. These differences remained significant when comparing subgroup 1A with sPHPT. CONCLUSION: MEN1-associated PHPT may be accompanied by a more severe decrease in BMD in the femoral neck and total hip compared to sPHPT regardless of the other hormone-producing NEN. Clarifying the role of mutation in the MEN1 gene in these processes requires further study.

Microwave ablation for recurrent primary hyperparathyroidism in four patients with multiple endocrine neoplasia type 1: a case series report.

Multiple endocrine neoplasia type 1 (MEN1), a rare tumor syndrome, is inherited in an autosomal dominant pattern, mainly manifested as primary hyperparathyroidism (PHPT). Surgery is preferred for patients with MEN1 and PHPT. Thermal ablation has been widely applied for PHPT but rarely for postoperative recurrent PHPT in MEN1 patients. Based on a series of cases, we aimed to investigate the clinical efficacy and safety of ultrasound-guided percutaneous microwave ablation in the treatment of MEN1 patients with postoperative recurrence of PHPT.

[Tumor predisposition in endocrinology - from MEN to FIPA]. / Tumorprädisposition in der Endokrinologie ­ von MEN bis FIPA.

Understanding genetic predisposition has a significant impact on the management of patients with endocrine tumours, including therapy, early detection and prevention. These tumours, which develop as part of a familial predisposition, often manifest early in life and frequently affect several endocrine organs. In the following article, both common syndromes, such as multiple endocrine neoplasia (MEN) syndromes, and rare syndromes, such as familial isolated pituitary adenoma (FIPA), are presented based on their indicator diseases.

[Plasma miRNA expression in patients with genetically confirmed multiple endocrine neoplasia type 1 syndrome and its phenocopies].

BACKGROUND: MEN-1 is a rare autosomal dominant disease caused by mutations in MEN1 gene encoding the menin protein. This syndrome is characterized by the occurrence of parathyroid tumors, gastroenteropancreatic neuroendocrine tumors, pituitary adenomas, as well as other endocrine and non-endocrine tumors. If a patient with the MEN-1 phenotype carry no mutations in the MEN1 gene, the condition considers a phenocopy of syndrome (phMEN1). The possible cause of this changes could be changes in epigenetic regulation, particularly in microRNA expression that might affect menin signaling pathways. AIM: to identify differently expressed circulating miRNAs in plasma in patients with genetically confirmed MEN-1 syndrome, its phenocopies and healthy controls. MATERIALS AND METHODS: single-center, case-control study was conducted. We assessed plasma microRNA expression in patients with genetically confirmed MEN-1 (gMEN1), phMEN1 and healthy controls. Morning plasma samples were collected from fasting patients and stored at -80°C. Total RNA isolation was performed using miRNeasy Mini Kit with QIAcube. The libraries were prepared by the QIAseq miRNA Library Kit following the manufacturer. Circulating miRNA sequencing was done on Illumina NextSeq 500 (Illumina). Subsequent data processing was performed using the DESeq2 bioinformatics algorithm. RESULTS: we enrolled 21 consecutive patients with gMEN1 and 11 patients with phMEN1, along with 12 gender matched controls. Median age of gMEN1 was 38,0 [34,0; 41,0]; in phMEN1 - 59,0 [51,0; 60,0]; control - 59,5 [51,5; 62,5]. The gMEN1 group differed in age (p<0.01) but not gender (р=0.739) or BMI (р=0.116) compared to phMEN1 and controls group, the last two groups did not differ by these parameters (p>0.05). 25 microRNA were differently expressed in groups gMEN1 and phMEN1 (21 upregulated microRNAs, 4 - downregulated). Comparison of samples from the phMEN-1 group and relatively healthy controls revealed 10 differently expressed microRNAs: 5 - upregulated; 5 - downregulated. In the gMEN-1 and control groups, 26 differently expressed microRNAs were found: 24 - upregulated; 2 - downregulated. The miRNAs most differing in expression among the groups were selected for further validation by RT-qPCR (in the groups of gMEN1 vs phMEN1 - miR-3613-5p, miR-335-5p, miR-32-5p, miR-425-3p, miR-25-5p, miR-576-5p, miR-215-5p, miR-30a-3p, miR-141-3p, miR-760, miR-501-3p; gMEN1 vs control - miR-1976, miR-144-5p miR-532-3p, miR-375; as well as in phMEN1 vs control - miR-944, miR-191-5p, miR-98-5p). CONCLUSION: In a pilot study, we detected microRNAs that may be expressed differently between patients with gMEN-1 and phMEN-1. The results need to be validated using different measurement method with larger sample size.

[Individualized approach for MEN1-associated duodenopancreatic neuroendocrine neoplasms]. / Individualisiertes Vorgehen bei MEN1-assoziierten duodenopankreatischen neuroendokrinen Neoplasien.

BACKGROUND: Multiple endocrine neoplasia type 1 (MEN1)-associated duodenopancreatic neuroendocrine neoplasms (dpNEN) represent the most frequent syndrome-associated cause of death, but the adequate treatment is sometimes considered controversial. OBJECTIVE: Presentation of possible diagnostic and therapeutic options for MEN1-associated dpNENs. MATERIAL AND METHODS: In this review article retrospective case studies, expert recommendations, national and international guidelines as well as personal experiences were analyzed and evaluated. RESULTS: Due to early detection programs and the use of the most modern imaging techniques, dpNEN are nowadays diagnosed much earlier. Nonfunctional pNENs currently represent the most frequent dpNENs with about 70%, followed by gastrinomas and insulinomas. Regardless of their functional activity, dpNENs with a size of > 2 cm are generally an indication for surgery. The choice of the optimal treatment strategy, however, in most cases remains the subject of controversial discussions, although nowadays surgery should always be performed in an organ-preserving and minimally invasive way when feasible. Recurrences or new dpNENs are expected in more than 60% of cases, necessitating a reoperation in up to 40% of these cases. Duodenopancreatic resections and reoperations can be carried out safely by experienced practitioners and with an acceptable level of risk. CONCLUSION: The planning of treatment requires careful consideration of the suitable timing, the extent of the operation, the risk of recurrence and potential morbidities. Furthermore, preserving pancreatic function and the quality of life is of utmost importance. In view of the complexity of the disease, MEN1 patients should be treated in specialized centers.

Whole-Exome Screening and Analysis of Signaling Pathways in Multiple Endocrine Neoplasia Type 1 Patients with Different Outcomes: Insights into Cellular Mechanisms and Possible Functional Implications.

Multiple endocrine neoplasia type 1 (MEN1) is a syndrome characterized by tumors in multiple organs. Although being a dominantly inherited monogenic disease, disease phenotypes are unpredictable and differ even among members of the same family. There is growing evidence for the role of modifier genes in the alteration of the course of this disease. However, genome-wide screening data are still lacking. In our study, we addressed the different outcomes of the disease, focusing on pituitary and adrenocortical tumors. By means of exome sequencing we identified the affected signaling pathways that segregated with those symptoms. Most significantly, we identified damaging alterations in numerous structural genes responsible for cell adhesion and migration. Additionally, in the case of pituitary tumors, genes related to neuronal function, survival, and morphogenesis were repeatedly identified, while in patients with adrenocortical tumors, TLR10, which is involved in the regulation of the innate immunity, was commonly modified. Our data show that using exome screening, it is possible to find signatures which correlate with the given clinical MEN1 outcomes, providing evidence that studies addressing modifier effects in MEN1 are reasonable.

[Multiple neuroendocrine tumors of the pancreas]. / Multiple neuroendokrine Tumoren des Pankreas.

Multiple neuroendocrine tumors (NET) of the pancreas often have a hereditary background. Sporadic and hereditary NET do not differ morphologically or with regard to their hormone expression. The most important clues for a hereditary background are provided by examination of the peritumoral pancreatic tissue, especially the morphology and hormone expression of the endocrine islets. Hyperplastic or dysplastic islets and microtumors with aberrant distribution of insulin and glucagon are the main features of hereditary NET. Morphological diagnosis of potentially hereditary NET has a relevant impact on the prognosis and clinical care of patients.

Impact of Early Diagnostic and Therapeutic Interventions and Clinical Course in Children and Adolescents with Multiple Endocrine Neoplasia Types 1 and 2.

PURPOSE: Multiple endocrine neoplasia types 1 (MEN1) and 2 (MEN2) are inherited endocrine tumor syndromes caused by mutations in the MEN1 or RET genes. This study aimed to investigate clinical outcomes and molecular characteristics among children with MEN. METHODS: This study included eight patients from seven unrelated families. Data on clinical course, biochemical findings, and radiologic studies were collected by retrospective chart review. All diagnoses were genetically confirmed by Sanger sequencing of MEN1 in three MEN1 patients and RET in four patients with MEN2A and one patient with MEN2B. RESULTS: Three patients with MEN1 from two families presented with hypoglycemia at a mean age of 11±2.6 years. Four patients with MEN2A were genetically diagnosed at a mean of 3.0±2.2 years of age by family screening; one of them was prenatally diagnosed by chorionic villus sampling. Three patients with MEN2A underwent prophylactic thyroidectomy from 5 to 6 years of age, whereas one patient refused surgery. The patient with MEN2B presented with a tongue neuroma and medullary thyroid carcinoma at 6 years of age. Subsequently, he underwent a subtotal colectomy because of bowel perforation and submucosal ganglioneuromatosis at 18 years of age. CONCLUSION: This study described the relatively long clinical course of pediatric MEN with a mean follow-up duration of 7.5±3.8 years. Insulinoma was the first manifestation in children with MEN1. Early diagnosis by family screening during the asymptomatic period enabled early intervention. The patient with MEN2B exhibited the most aggressive clinical course.

Recurrence After Surgery for Primary Hyperparathyroidism in 517 Patients With Multiple Endocrine Neoplasia Type 1: An Association Francophone de Chirurgie Endocrinienne and Groupe d'étude des Tumeurs Endocrines study.

OBJECTIVE: To assess recurrence according to the type of surgery for primary hyperparathyroidism (pHPT) in multiple endocrine neoplasia type 1 ( MEN1 ) patients and to identify the risk factors for recurrence after the initial surgery. BACKGROUND: In MEN1 patients, pHPT is multiglandular, and the optimal extent of initial parathyroid resection influences the risk of recurrence. METHODS: MEN1 patients who underwent initial surgery for pHPT between 1990 and 2019 were included. Persistence and recurrence rates after less than subtotal parathyroidectomy (LTSP) and subtotal parathyroidectomy (STP) were analyzed. Patients with total parathyroidectomy with reimplantation were excluded. RESULTS: Five hundred seventeen patients underwent their first surgery for pHPT: 178 had LTSP (34.4%) and 339 STP (65.6%). The recurrence rate was significantly higher after LTSP (68.5%) than STP (45%) ( P < 0.001). The median time to recurrence after pHPT surgery was significantly shorter after LTSP than after STP: 4.25 (1.2-7.1) versus 7.2 (3.9-10.1) years ( P < 0.001). A mutation in exon 10 was an independent risk factor of recurrence after STP (odds ratio = 2.19; 95% CI: 1.31; 3.69; P = 0.003). The 5 and 10-year recurrent pHPT probabilities were significantly higher in patients after LTSP with a mutation in exon 10 (37% and 79% vs 30% and 61%; P = 0.016). CONCLUSIONS: Persistence, recurrence of pHPT, and reoperation rate are significantly lower after STP than LTSP in MEN1 patients. Genotype seems to be associated with the recurrence of pHPT. A mutation in exon 10 is an independent risk factor for recurrence after STP, and LTSP may not be recommended when exon 10 is mutated.

A Japanese Family Meeting the Clinical Diagnostic Criteria for MEN1 with a MEN1 Variant of Uncertain Significance.

Multiple gastroenteric, pancreatic, and pituitary neuroendocrine neoplasms (NENs) were diagnosed in a 74-year-old man with a history of primary hyperparathyroidism (PHPT). Germline testing demonstrated a variant of MEN1 (c.1694T>A, p.L565Q), whose pathogenicity was classified as a variant of uncertain significance (VUS) according to the ACMG/AMP guidelines. The same germline variant was detected in the patient's son and daughter, who also showed PHPT or hypercalcemia and met the clinical diagnostic criteria for multiple endocrine neoplasia type 1 (MEN1). During surveillance of the son, multiple pancreatic tumors suggestive of NENs were detected. The pathogenicity of the current MEN1 variant was re-evaluated as likely pathogenic, based on additional family data.

Menin Reduces Parvalbumin Expression and is Required for the Anti-Depressant Function of Ketamine.

Dysfunction of parvalbumin (PV) neurons is closely involved in depression, however, the detailed mechanism remains unclear. Based on the previous finding that multiple endocrine neoplasia type 1 (Protein: Menin; Gene: Men1) mutation (G503D) is associated with a higher risk of depression, a Menin-G503D mouse model is generated that exhibits heritable depressive-like phenotypes and increases PV expression in brain. This study generates and screens a serial of neuronal specific Men1 deletion mice, and found that PV interneuron Men1 deletion mice (PcKO) exhibit increased cortical PV levels and depressive-like behaviors. Restoration of Menin, knockdown PV expression or inhibition of PV neuronal activity in PV neurons all can ameliorate the depressive-like behaviors of PcKO mice. This study next found that ketamine stabilizes Menin by inhibiting protein kinase A (PKA) activity, which mediates the anti-depressant function of ketamine. These results demonstrate a critical role for Menin in depression, and prove that Menin is key to the antidepressant function of ketamine.

Beyond the three P's: adrenal involvement in MEN1.

Adrenal lesions (ALs) are often detected in patients with multiple endocrine neoplasia type 1 (MEN1). However, they are not well described in MEN1, making their clinical management unclear. This study examined the prevalence and outcomes of ALs found in MEN1. We performed a retrospective chart review of patients diagnosed with MEN1 from 1990 to 2021. ALs were diagnosed using abdominal or thoracic imaging and classified as being unilateral or bilateral, having single or multiple nodules, and as having diffuse enlargement or not. Measurable nodular lesions were analyzed for their size and growth over time. Patients' clinical and radiographic characteristics were collected. We identified 382 patients with MEN1, 89 (23.3%) of whom had ALs. The mean age at detection was 47 ± 11.9 years. We documented 101 measurable nodular lesions (mean size, 17.5 mm; range, 3-123 mm). Twenty-seven nodules (26.7%) were smaller than 1 cm. Watchful waiting was indicated in 79 (78.2%) patients, of whom 28 (35.4%) had growing lesions. Functional lesions were diagnosed in 6 (15.8%) of 38 that had functional work-up (diagnoses: pheochromocytoma (n = 2), adrenocorticotropic hormone-dependent hypercortisolism (n = 2), hyperandrogenism (n = 1), hyperaldosteronism (n = 1)); surgery was indicated for 5 (83.3%; n = 12 nodules), 2 of whom had bilateral, diffuse adrenal enlargement. Two patients were diagnosed with adrenocortical carcinoma and two with neoplasms of uncertain malignant potential. Radiographic or clinical progression of ALs is uncommon. Malignancy should be suspected on the basis of a lesion's growth rate and size. A baseline hormonal work-up is recommended, and no further biochemical work-up is suggested when the initial assessment shows nonfunctioning lesions.

Primary hyperparathyroidism in patients with multiple endocrine neoplasia type 1: Impact of genotype and surgical approach on long-term postoperative outcomes.

BACKGROUND: Protein-truncating germline pathogenic variants in the N- and C-terminal exons (2, 9, and 10) of the MEN1 gene may be associated with aggressive pancreatic neuroendocrine tumors. However, the impact of these variants on parathyroid disease is poorly understood. We sought to investigate the effects of genotype and surgical approach on clinical phenotype and postoperative outcomes in patients with multiple endocrine neoplasia type 1 (MEN1)-related primary hyperparathyroidism. METHODS: We identified patients with MEN1 evaluated at our institution from 1985 to 2020 and stratified them by genotype, (truncating variants in exons 2, 9, or 10, or other variants), and index surgical approach, (less-than-subtotal parathyroidectomy [