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Problemy Endokrinologii Jan 2024MEN-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...
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.
Topics: Humans; MicroRNAs; Case-Control Studies; Epigenesis, Genetic; Multiple Endocrine Neoplasia Type 1; Pilot Projects; Gene Expression Profiling; Circulating MicroRNA; Phenotype
PubMed: 38311997
DOI: 10.14341/probl13357 -
Journal of Endocrinological... Jul 2024Multiple endocrine neoplasia type 1 (MEN1) is a hereditary endocrine syndrome caused by pathogenic variants in MEN1 tumor suppressor gene. Diagnosis is commonly based on...
PURPOSE
Multiple endocrine neoplasia type 1 (MEN1) is a hereditary endocrine syndrome caused by pathogenic variants in MEN1 tumor suppressor gene. Diagnosis is commonly based on clinical criteria and confirmed by genetic testing. The objective of the present study was to report on a MEN1 case characterized by multiple pancreatic glucagonomas, with particular concern on the possible predisposing genetic defects.
METHODS
While conducting an extensive review of the most recent scientific evidence on the unusual glucagonoma familial forms, we analyzed the MEN1 gene in a 35-year-old female with MEN1, as well as her son and daughter, using Sanger and next-generation sequencing (NGS) approaches. We additionally explored the functional and structural consequences of the identified variant using in silico analyses.
RESULTS
NGS did not show any known pathogenic variant in the tested regions. However, a new non-conservative variant in exon 4 of MEN1 gene was found in heterozygosity in the patient and in her daughter, resulting in an amino acid substitution from hydrophobic cysteine to hydrophilic arginine at c.703T > C, p.(Cys235Arg). This variant is absent from populations databases and was never reported in full papers: its characteristics, together with the high specificity of the patient's clinical phenotype, pointed toward a possible causative role.
CONCLUSION
Our findings confirm the need for careful genetic analysis of patients with MEN1 and establish a likely pathogenic role for the new p.(Cys235Arg) variant, at least in the rare subset of MEN1 associated with glucagonomas.
Topics: Humans; Multiple Endocrine Neoplasia Type 1; Female; Adult; Glucagonoma; Pancreatic Neoplasms; Proto-Oncogene Proteins; Pedigree; Male; Mutation
PubMed: 38294658
DOI: 10.1007/s40618-023-02287-x -
International Journal of Molecular... Jan 2024Multiple endocrine neoplasia type 1 (MEN1) is a syndrome characterized by tumors in multiple organs. Although being a dominantly inherited monogenic disease, disease...
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, , 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.
Topics: Humans; Multiple Endocrine Neoplasia Type 1; Exome; Cell Adhesion; Adrenal Cortex Neoplasms; Signal Transduction
PubMed: 38256138
DOI: 10.3390/ijms25021065 -
Virchows Archiv : An International... May 2024Primary hyperparathyroidism with parathyroid tumors is a typical manifestation of Multiple Endocrine Neoplasia Type 1 (MEN1) and is historically termed "primary...
Primary hyperparathyroidism with parathyroid tumors is a typical manifestation of Multiple Endocrine Neoplasia Type 1 (MEN1) and is historically termed "primary hyperplasia". Whether these tumors represent a multi-glandular clonal disease or hyperplasia has not been robustly proven so far. Loss of Menin protein expression is associated with inactivation of both alleles and a good surrogate for a MEN1 gene mutation. The cyclin-dependent kinase inhibitor 1B (CDKN1B) gene is mutated in MEN4 and encodes for protein p27 whose expression is poorly studied in the syndromic MEN1 setting.Here, we analyzed histomorphology and protein expression of Menin and p27 in parathyroid adenomas of 25 patients of two independent, well-characterized MEN1 cohorts. The pattern of loss of heterozygosity (LOH) was assessed by fluorescence in situ hybridization (FISH) in one MEN1-associated parathyroid adenoma. Further, next-generation sequencing (NGS) was performed on eleven nodules of four MEN1 patients.Morphologically, the majority of MEN1 adenomas consisted of multiple distinct nodules, in which Menin expression was mostly lost and p27 protein expression reduced. FISH analysis revealed that most nodules exhibited MEN1 loss, with or without the loss of centromere 11. NGS demonstrated both subclonal evolution and the existence of clonally unrelated tumors.Syndromic MEN1 parathyroid adenomas therefore consist of multiple clones with subclones, which supports the current concept of the novel WHO classification of parathyroid tumors (2022). p27 expression was lost in a large fraction of MEN1 parathyroids and must therefore be used with caution in suggesting MEN4.
Topics: Humans; Parathyroid Neoplasms; Multiple Endocrine Neoplasia Type 1; Male; Proto-Oncogene Proteins; Cyclin-Dependent Kinase Inhibitor p27; Middle Aged; Female; Adult; Adenoma; Aged; Loss of Heterozygosity; Hyperparathyroidism, Primary; Biomarkers, Tumor; Young Adult; High-Throughput Nucleotide Sequencing; In Situ Hybridization, Fluorescence
PubMed: 38244045
DOI: 10.1007/s00428-023-03730-3 -
The Journal of Pathology Mar 2024Gastroenteropancreatic neuroendocrine tumors (GEP-NETs) are heterogeneous malignancies that arise from complex cellular interactions within the tissue microenvironment....
Gastroenteropancreatic neuroendocrine tumors (GEP-NETs) are heterogeneous malignancies that arise from complex cellular interactions within the tissue microenvironment. Here, we sought to decipher tumor-derived signals from the surrounding microenvironment by applying digital spatial profiling (DSP) to hormone-secreting and non-functional GEP-NETs. By combining this approach with in vitro studies of human-derived organoids, we demonstrated the convergence of cell autonomous immune and pro-inflammatory proteins that suggests their role in neuroendocrine differentiation and tumorigenesis. DSP was used to evaluate the expression of 40 neural- and immune-related proteins in surgically resected duodenal and pancreatic NETs (n = 20) primarily consisting of gastrinomas (18/20). A total of 279 regions of interest were examined between tumors, adjacent normal and abnormal-appearing epithelium, and the surrounding stroma. The results were stratified by tissue type and multiple endocrine neoplasia I (MEN1) status, whereas protein expression was validated by immunohistochemistry (IHC). A tumor immune cell autonomous inflammatory signature was further evaluated by IHC and RNAscope, while functional pro-inflammatory signaling was confirmed using patient-derived duodenal organoids. Gastrin-secreting and non-functional pancreatic NETs showed a higher abundance of immune cell markers and immune infiltrate compared with duodenal gastrinomas. Compared with non-MEN1 tumors, MEN1 gastrinomas and preneoplastic lesions showed strong immune exclusion and upregulated expression of neuropathological proteins. Despite a paucity of immune cells, duodenal gastrinomas expressed the pro-inflammatory and pro-neural factor IL-17B. Treatment of human duodenal organoids with IL-17B activated NF-κB and STAT3 signaling and induced the expression of neuroendocrine markers. In conclusion, multiplexed spatial protein analysis identified tissue-specific neuro-immune signatures in GEP-NETs. Duodenal gastrinomas are characterized by an immunologically cold microenvironment that permits cellular reprogramming and neoplastic transformation of the preneoplastic epithelium. Moreover, duodenal gastrinomas cell autonomously express immune and pro-inflammatory factors, including tumor-derived IL-17B, that stimulate the neuroendocrine phenotype. © 2024 The Pathological Society of Great Britain and Ireland.
Topics: Humans; Neuroendocrine Tumors; Gastrinoma; Neuroimmunomodulation; Interleukin-17; Duodenal Neoplasms; Pancreatic Neoplasms; Tumor Microenvironment; Intestinal Neoplasms; Stomach Neoplasms
PubMed: 38229586
DOI: 10.1002/path.6241 -
Surgical Case Reports Jan 2024Multiple endocrine neoplasia type 1 (MEN1) is a hereditary tumor syndrome characterized by endocrine tumors with mainly a parathyroid, pancreatic, or anterior pituitary...
BACKGROUND
Multiple endocrine neoplasia type 1 (MEN1) is a hereditary tumor syndrome characterized by endocrine tumors with mainly a parathyroid, pancreatic, or anterior pituitary origin. Low-grade fibromyxoid sarcoma (LGFMS) is a rare low-grade soft tissue tumor. There is one known report of a patient with MEN1 complicated by LGFMS, which is very rare. Our report represents the second documented case, providing valuable insights.
CASE PRESENTATION
A 31-year-old man with the chief complaint of a cough underwent chest contrast-enhanced computed tomography, which revealed a giant hypoabsorptive tumor with a maximum diameter of 23 cm in the left thoracic cavity. The patient was diagnosed with MEN1, as he also possessed a pancreatic neuroendocrine tumor and parathyroid tumor, and because his father had been found to have MEN1. To control hypercalcemia, surgery for the parathyroid tumor was initially performed, followed by surgical resection of the giant thoracic tumor for diagnosis and treatment. Histopathological examination findings of the tumor resulted in a diagnosis of LGFMS.
CONCLUSION
We experienced a very rare MEN1 with LGFMS. Although endocrine tumors generally occur more frequently in MEN1, non-endocrine tumors such as the present case should also be noted, reinforcing the importance of systemic imaging scrutiny in addition to early diagnosis and long-term follow-up of MEN1 patients.
PubMed: 38200366
DOI: 10.1186/s40792-024-01809-w -
Asian Journal of Surgery Apr 2024
Topics: Female; Humans; Multiple Endocrine Neoplasia Type 1; Hypoglycemia; Mutation
PubMed: 38191280
DOI: 10.1016/j.asjsur.2023.12.146 -
Frontiers in Endocrinology 2023Germline succinate dehydrogenase subunit B () pathogenic variants are characteristic of familial paraganglioma (PGL) syndrome type 4. This syndrome frequently presents...
CONTEXT
Germline succinate dehydrogenase subunit B () pathogenic variants are characteristic of familial paraganglioma (PGL) syndrome type 4. This syndrome frequently presents with abdominal PGL and has high tendency for locally aggressive behavior and distant metastasis. The vast majority of pituitary adenomas (PAs) are sporadic. However, PAs can be part of a number of familial tumor syndromes such as multiple endocrine neoplasia type 1 (MEN 1) or more rarely in association with pheochromocytoma and PGL (referred to as 3P syndrome). Only a limited number of PAs in association with -related PGL has been reported and the vast majority occurred subsequently or simultaneously with pheochromocytoma/PGL (collectively abbreviated as PPGL). In this report, we describe a young patient who had a giant pituitary macroprolactinoma resistant to large doses of cabergoline (CBG) and external beam radiotherapy (XRT). The patient did not have personal history of PPGL but was found to carry a germline pathogenic variant.
CASE REPORT
A 38-year-old woman presented with headache, visual disturbances and galactorrhea and was found to have a 34-mm macroprolactinoma. She was treated with CBG 3-4 mg per week but PA continued to grow and caused significant cranial pressure symptoms. She underwent two transsphenoidal surgeries with rapid tumor recurrence after each one. She received XRT but PA continued to grow. She was finally treated with temozolomide with excellent response. Whole exome and subsequent Sanger sequencing confirmed that she has a pathogenic monoallelic mutation (NM_003000:c.C343T, p.R115*). PA tissue showed loss of heterozygosity for the same mutation and absent SDHB immunostaining confirming the pathogenic role of this mutation.
CONCLUSION
Germline mutations can rarely cause PA in the absence of PPGL. They should be considered as a possible cause of aggressiveness and resistance to dopamine agonists in similar cases.
Topics: Female; Humans; Adult; Pheochromocytoma; Cabergoline; Temozolomide; Prolactinoma; Neoplasm Recurrence, Local; Paraganglioma; Adenoma; Pituitary Neoplasms; Adrenal Gland Neoplasms; Succinate Dehydrogenase
PubMed: 38152133
DOI: 10.3389/fendo.2023.1273093 -
World Journal of Nuclear Medicine Dec 2023Multiple endocrine neoplasia, type 1 (MEN1) syndrome is an autosomal dominant disease characterized by tumors involving parathyroid, pituitary, and pancreas. The...
Multiple endocrine neoplasia, type 1 (MEN1) syndrome is an autosomal dominant disease characterized by tumors involving parathyroid, pituitary, and pancreas. The diagnosis is mostly clinical and by the presence of MEN1 gene mutation. We present a case with initial presentation of neuroendocrine tumor of pancreas whose ancillary findings on Ga-DOTATATE positron emission tomography-computed tomography helped in raising suspicion of MEN1, which was confirmed on genetic testing and family history. We emphasize the importance of using gestalt approach in such cases to avoid misdiagnosis or delay. Additionally, we describe the clinical profile of affected family members with their MEN1 gene mutation status, highlighting the gestalt approach again to uncover the unknowns.
PubMed: 38152096
DOI: 10.1055/s-0043-1768448 -
Children (Basel, Switzerland) Dec 2023Multiple endocrine neoplasia 2B (MEN2B) is a rare syndrome with prevalence estimated at approximately 0.2 per 100,000; it is caused by mutation of the RET...
Multiple endocrine neoplasia 2B (MEN2B) is a rare syndrome with prevalence estimated at approximately 0.2 per 100,000; it is caused by mutation of the RET proto-oncogene. MEN2B is characterized by early-onset medullary thyroid carcinoma (MTC), ganglioneuromatosis of the aerodigestive tract, marfanoid habitus, ophthalmologic abnormalities, and pheochromocytoma in adulthood. Mutations in the RyR1 gene manifest clinically in congenital myopathies and/or malignant hyperthermia susceptibility. We present a case of a 4-year-old boy with an accidentally detected RET and RyR1 mutations in the course of diagnostic approach of short stature and delayed motor development. Due to a poor and blurred clinical picture of MEN2B syndrome, accompanied by RyR1 mutation symptoms, the diagnostic path was extended. Our patient had no family history of MTC. In the imaging studies of the thyroid gland, no abnormalities were found, whereas the serum level of calcitonin was elevated to 34 pg/mL (N < 5.0). The patient qualified for total thyroidectomy, and the histopathological examination confirmed the diagnosis of MTC. The postoperative serum calcitonin level dropped to normal ranges. This case shows how new genetic diagnostic procedures could be crucial in accidentally diagnosing rare endocrine disease with atypical symptoms, giving an opportunity for relatively early intervention.
PubMed: 38136118
DOI: 10.3390/children10121916