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Endokrynologia Polska 2019Multiple endocrine neoplasia type 1 (MEN1) has been causing problems for clinicians since it was first described in 1954 by Wermer. Not only its rarity, but also its...
INTRODUCTION
Multiple endocrine neoplasia type 1 (MEN1) has been causing problems for clinicians since it was first described in 1954 by Wermer. Not only its rarity, but also its variable clinical manifestations and lack of genotype-phenotype correlation make it hard to establish evidence-based guidelines for the management of this syndrome. Nationwide registers and population-based research are the best means to improve knowledge about this rare disease. As yet, there is no example of such research in the Polish population of MEN1 patients.
MATERIAL AND METHODS
We performed a retrospective analysis of clinical and genetic data of patients diagnosed with MEN1 syndrome and followed-up in two polish referral centres in the years 1994-2018.
RESULTS
We analysed 79 patients, of whom the majority were women. The mean age of the patient population was 43 years, mean age at MEN1 diagnosis was 37.95 years, and mean interval from initial symptoms to MEN1 diagnosis was 6.93 years. Primary hyperparathyroidism (PHP), gastroenteropancreatic neuroendocrine tumour (GEP-NET), and pituitary adenoma (PA) developed in 90%, 52%, and 47% of patients, respectively. The dominance of insulinoma with low prevalence of gastrinoma is the most vivid difference, when compared to previously described populations. Moreover, we found 3.5-fold higher risk of developing a pituitary tumour in patients with a frameshift mutation with the STOP codon of the MEN1 gene.
CONCLUSIONS
The Polish population of patients with MEN1 is different than previously described European and Asian populations, primarily in prevalence of functional NETs. A frameshift mutation with the STOP codon of the MEN1 gene significantly increases the risk of PA. Further studies with a larger cohort of patients are needed to fully describe the Polish population and improve diagnosis and management of the syndrome.
Topics: Adult; Female; Humans; Hyperparathyroidism, Primary; Intestinal Neoplasms; Male; Middle Aged; Multiple Endocrine Neoplasia Type 1; Neuroendocrine Tumors; Pancreatic Neoplasms; Phenotype; Pituitary Neoplasms; Retrospective Studies; Risk Factors; Stomach Neoplasms
PubMed: 31274185
DOI: 10.5603/EP.a2019.0031 -
Frontiers in Endocrinology 2020Multiple endocrine neoplasia type 2 (MEN2) is a neuroendocrine cancer syndrome characterized by medullary thyroid carcinoma, in combination or not with pheochromocytoma,... (Review)
Review
Multiple endocrine neoplasia type 2 (MEN2) is a neuroendocrine cancer syndrome characterized by medullary thyroid carcinoma, in combination or not with pheochromocytoma, hyperparathyroidism, and extra-endocrine features. MEN2 syndrome includes two clinically distinct forms subtyped as MEN2A and MEN2B. Nearly all MEN2 cases are caused by germline mutations of the proto-oncogene. In this review, we propose "5P" strategies for management of MEN2: prevention, prediction, personalization, psychological support, and participation, which could effectively improve clinical outcomes of patients. Based on mutations, MEN2 could be through prenatal diagnosis or preimplantation genetic testing. Identification of pathogenic mutations in can enable early diagnosis of MEN2. Combining mutation testing with measurement of serum calcitonin, plasma or urinary metanephrine/normetanephrine, and serum parathyroid hormone levels could allow risk stratification and accurately of MEN2 progression, thus facilitating implementation of precision treatments to increase disease-free survival and overall survival. Furthermore, increased awareness of MEN2 is needed, which requires of physicians, patients, family members, and related organizations. support is also important for patients with MEN2 to promote comprehensive management of MEN2 symptoms. The "5P" strategies for management of MEN2 represent a typical clinical example of precision medicine. These strategies could effectively improve the health of MEN2 patient, and avoid adverse outcomes, including death and major morbidity, from MEN2.
Topics: Disease Management; Genetic Testing; Humans; Multiple Endocrine Neoplasia Type 2a; Precision Medicine; Proto-Oncogene Mas; Proto-Oncogene Proteins c-ret
PubMed: 33071967
DOI: 10.3389/fendo.2020.543246 -
Neuroendocrinology 2011Multiple endocrine neoplasias (MEN) are autosomal dominant disorders characterized by the occurrence of tumors in at least two endocrine glands. Two types of MEN... (Review)
Review
Multiple endocrine neoplasias (MEN) are autosomal dominant disorders characterized by the occurrence of tumors in at least two endocrine glands. Two types of MEN syndromes have long been known: MEN type 1 (MEN1) and MEN type 2 (MEN2), associated with a different spectrum of affected organs. MEN1 and MEN2 are caused by germline mutations in the MEN1 tumor suppressor gene and the RET proto-oncogene, respectively. Lately, a new type of MEN was identified (named MEN4) which is due to mutations in the CDKN1B gene, encoding for p27kip1 (p27), a cyclin-dependent kinase (Cdk) inhibitor that regulates the transition of cells from G1 to S phase. p27 is a non-canonical tumor suppressor since it is usually not somatically mutated in human cancers but it is often downregulated by post-translational mechanisms. The discovery of MEN4 has defined a new role for CDKN1B as a tumor susceptibility gene for multiple endocrine tumors. To date, six germline CDKN1B mutations have been found in patients with a MEN1-like phenotype but negative for MEN1 mutations. Due to the limited number of patients so far identified, the phenotypic features of MEN4 are not clearly defined. Here, we review the clinical and molecular characteristics of the MEN4 syndrome and summarize the main functions of p27 to better comprehend how their alteration can predispose to neuroendocrine tumors.
Topics: Animals; Cyclin-Dependent Kinase Inhibitor p27; Genetic Predisposition to Disease; Germ-Line Mutation; Humans; Models, Biological; Multiple Endocrine Neoplasia; Proto-Oncogene Mas
PubMed: 20980721
DOI: 10.1159/000320366 -
Genetics in Medicine : Official Journal... Dec 2009MEN 1 is a rare hereditary cancer syndrome which manifests a variety of endocrine and non-endocrine neoplasms and lesions. Growing knowledge of this condition in both... (Review)
Review
MEN 1 is a rare hereditary cancer syndrome which manifests a variety of endocrine and non-endocrine neoplasms and lesions. Growing knowledge of this condition in both its molecular genetic underpinnings and its clinical implications have affected the entire spectrum of the clinical management of MEN patients. The MEN1 gene is a tumor suppressor gene, and mutations in it account for the development of the MEN1 clinical syndrome through impairment of several cell functions, such as cell proliferations, cell growth control, apoptosis, DNA replication and repair, gene expression, transcriptional machinery control, and hormone secretion. Currently, DNA testing makes possible the early identification of germline mutations in asymptomatic mutation carriers. The ever increrasing combination of genetic and clinical tools will allow early detection of MEN1-associated neoplasms, potentially improving clinical outcomes and quality of life for both affected patients and their relatives.
Topics: Gastrinoma; Genotype; Humans; Insulinoma; Multiple Endocrine Neoplasia Type 1; Mutation; Parathyroid Neoplasms; Phenotype; Pituitary Neoplasms; Proto-Oncogene Proteins
PubMed: 19904212
DOI: 10.1097/GIM.0b013e3181be5c97 -
Neuroendocrinology 2021Pancreatic neuroendocrine tumors (pNETs) have a high prevalence in patients with multiple endocrine neoplasia type 1 (MEN1) and are the leading cause of death. Tumor...
Reliability and Agreement of Radiological and Pathological Tumor Size in Patients with Multiple Endocrine Neoplasia Type 1-Related Pancreatic Neuroendocrine Tumors: Results from a Population-Based Cohort.
BACKGROUND
Pancreatic neuroendocrine tumors (pNETs) have a high prevalence in patients with multiple endocrine neoplasia type 1 (MEN1) and are the leading cause of death. Tumor size is still regarded as the main prognostic factor and therefore used for surgical decision-making. We assessed reliability and agreement of radiological and pathological tumor size in a population-based cohort of patients with MEN1-related pNETs.
METHODS
Patients were selected from the Dutch MEN1 database if they had undergone a resection for a pNET between 2003 and 2018. Radiological (MRI, CT, and endoscopic ultrasonography [EUS]) and pathological tumor size were collected from patient records. Measures of agreement (Bland-Altman plots with limits of agreement [LoA] and absolute agreement) and reliability (intraclass correlation coefficients [ICC] and unweighted kappa) were calculated for continuous and categorized (< or ≥2 cm) pNET size.
RESULTS
In 73 included patients, the median radiological and pathological tumor sizes measured were 22 (3-160) and 21 (4-200) mm, respectively. Mean bias between radiological and pathological tumor size was -0.2 mm and LoA ranged from -12.9 to 12.6 mm. For the subgroups of MRI, CT, and EUS, LoA of radiological and pathological tumor size ranged from -9.6 to 10.9, -15.9 to 15.8, and -13.9 to 11.0, respectively. ICCs for the overall cohort, MRI, CT, and EUS were 0.80, 0.86, 0.75, and 0.76, respectively. Based on the 2 cm criterion, agreement was 81.5%; hence, 12 patients (18.5%) were classified differently between imaging and pathology. Absolute agreement and kappa values of MRI, CT, and EUS were 88.6, 85.7, and 75.0%, and 0.77, 0.71, and 0.50, respectively.
CONCLUSION
Within a population-based cohort, MEN1-related pNET size was not systematically over- or underestimated on preoperative imaging. Based on agreement and reliability measures, MRI is the preferred imaging modality.
Topics: Adult; Cohort Studies; Diagnostic Imaging; Endosonography; Female; Humans; Magnetic Resonance Imaging; Male; Middle Aged; Multiple Endocrine Neoplasia Type 1; Pancreatic Neoplasms; Reproducibility of Results; Tomography, X-Ray Computed
PubMed: 32721974
DOI: 10.1159/000510514 -
The American Journal of Surgical... Jul 2023A clinical diagnosis of multiple endocrine neoplasia type 1 (MEN1) syndrome is usually confirmed with genetic testing in the germline. It is expected that menin protein...
A clinical diagnosis of multiple endocrine neoplasia type 1 (MEN1) syndrome is usually confirmed with genetic testing in the germline. It is expected that menin protein expression is lost in MEN1-related tumors. Therefore, we investigated the potential of menin immunohistochemistry in parathyroid adenomas as an additional tool in the recognition and genetic diagnosis of MEN1 syndrome. Local pathology archives were searched for parathyroid tumors from patients with MEN1 syndrome and without MEN1, including sporadic, patients with multiple endocrine neoplasia type 2A and hyperparathyroidism-jaw parathyroid tumors. Menin immunohistochemistry was performed and its use to identify MEN1-related tumors was assessed. Twenty-nine parathyroid tumors from 16 patients with MEN1 and 61 patients with parathyroid tumors from 32 non-MEN1 were evaluated. Immunohistochemical nuclear menin loss in one or more tumors was found in 100% of patients with MEN1 and 9% of patients with non-MEN1. In patients with multiple tumors, menin loss in at least one tumor was seen in 100% of 8 patients with MEN1 and 21% of patients with 14 non-MEN1. Using a cutoff of at least 2 tumors showing menin loss per patient, the positive and negative predictive values for the diagnosis MEN1 were both 100%. The practical and additional value of menin immunohistochemistry in clinical genetic MEN1 diagnosis is further illustrated by menin immunohistochemistry in 2 cases with a germline variant of unknown significance in the MEN1 gene. Menin immunohistochemistry is useful in the recognition of MEN1 syndrome as well as in the clinical genetic analysis of patients with inconclusive MEN1 germline testing.
Topics: Humans; Multiple Endocrine Neoplasia Type 1; Immunohistochemistry; Parathyroid Neoplasms; Genetic Testing; Germ-Line Mutation
PubMed: 37199453
DOI: 10.1097/PAS.0000000000002050 -
Frontiers in Endocrinology 2022Multiple endocrine neoplasia type 1 (MEN1), an autosomal-dominantly inherited tumor syndrome, is classically defined by tumors arising from the "3 Ps": Parathyroids,... (Review)
Review
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. From its earliest descriptions, MEN1 has been associated with other endocrine and non-endocrine neoplastic manifestations. High quality evidence supports a direct association between pathogenic variants and neoplasms of the skin (angiofibromas and collagenomas), adipose tissue (lipomas and hibernomas), and smooth muscle (leiomyomas). Although CNS tumors, melanoma, and, most recently, breast cancer have been reported as MEN1 clinical manifestations, the published evidence to date is not yet sufficient to establish causality. Well-designed, multicenter prospective studies will help us to understand better the relationship of these tumors to MEN1, in addition to verifying the true prevalence and penetrance of the well-documented neoplastic associations. Nevertheless, patients affected by MEN1 should be aware of these non-endocrine manifestations, and providers should be encouraged always to think beyond the "3 Ps" when treating an MEN1 patient.
Topics: Humans; Multiple Endocrine Neoplasia Type 1; Prospective Studies; Angiofibroma; Islets of Langerhans; Multicenter Studies as Topic
PubMed: 36325452
DOI: 10.3389/fendo.2022.1029041 -
Frontiers in Endocrinology 2022The fourth type of multiple endocrine neoplasia (MEN) is known as a rare variant of MEN presenting a MEN1-like phenotype and originating from a germline mutation in... (Review)
Review
BACKGROUND
The fourth type of multiple endocrine neoplasia (MEN) is known as a rare variant of MEN presenting a MEN1-like phenotype and originating from a germline mutation in CDKN1B. However, due to the small number of cases documented in the literature, the peculiar clinical features of MEN4 are still largely unknown, and clear indications about the clinical management of these patients are currently lacking. In order to widen our knowledge on MEN4 and to better typify the clinical features of this syndrome, we present two more cases of subjects with MEN4, and through a review of the current literature, we provide some possible indications on these patients' management.
CASE PRESENTATION
The first report is about a man who was diagnosed with a metastatic ileal G2-NET at the age of 34. Genetic analysis revealed the mutation p.I119T (c.356T>C) of exon 1 of CDKN1B, a mutation already reported in the literature in association with early-onset pituitary adenomas. The second report is about a 76-year-old woman with a multifocal pancreatic G1-NET. Genetic analysis identified the CDKN1B mutation c.482C>G (p.S161C), described here for the first time in association with MEN4 and currently classified as a variant of uncertain significance. Both patients underwent biochemical and imaging screening for MEN1-related diseases without any pathological findings.
CONCLUSIONS
According to the cases reported in the literature, hyperparathyroidism is the most common clinical feature of MEN4, followed by pituitary adenoma and neuroendocrine tumors. However, MEN4 appears to be a variant of MEN with milder clinical features and later onset. Therefore, these patients might need a different and personalized approach in clinical management and a peculiar screening and follow-up strategy.
Topics: Adenoma; Cyclin-Dependent Kinase Inhibitor p27; Germ-Line Mutation; Humans; Multiple Endocrine Neoplasia; Mutation; Pituitary Neoplasms
PubMed: 35355569
DOI: 10.3389/fendo.2022.773143 -
Frontiers in Endocrinology 2020
Topics: Early Detection of Cancer; Genetic Predisposition to Disease; Genetic Testing; Humans; Multiple Endocrine Neoplasia Type 1; Mutation; Proto-Oncogene Proteins
PubMed: 32351454
DOI: 10.3389/fendo.2020.00218 -
Neuroendocrinology 2016Pituitary adenomas are a common feature of a subset of endocrine neoplasia syndromes, which have otherwise highly variable disease manifestations. We provide here a... (Review)
Review
Pituitary adenomas are a common feature of a subset of endocrine neoplasia syndromes, which have otherwise highly variable disease manifestations. We provide here a review of the clinical features and human molecular genetics of multiple endocrine neoplasia (MEN) type 1 and 4 (MEN1 and MEN4, respectively) and Carney complex (CNC). MEN1, MEN4, and CNC are hereditary autosomal dominant syndromes that can present with pituitary adenomas. MEN1 is caused by inactivating mutations in the MEN1 gene, whose product menin is involved in multiple intracellular pathways contributing to transcriptional control and cell proliferation. MEN1 clinical features include primary hyperparathyroidism, pancreatic neuroendocrine tumours and prolactinomas as well as other pituitary adenomas. A subset of patients with pituitary adenomas and other MEN1 features have mutations in the CDKN1B gene; their disease has been called MEN4. Inactivating mutations in the type 1α regulatory subunit of protein kinase A (PKA; the PRKAR1A gene), that lead to dysregulation and activation of the PKA pathway, are the main genetic cause of CNC, which is clinically characterised by primary pigmented nodular adrenocortical disease, spotty skin pigmentation (lentigines), cardiac and other myxomas and acromegaly due to somatotropinomas or somatotrope hyperplasia.
Topics: Acromegaly; Animals; Carney Complex; Endocrine Gland Neoplasms; Humans; Multiple Endocrine Neoplasia; Pituitary Neoplasms; Prolactinoma
PubMed: 25592387
DOI: 10.1159/000371819