RESUMO
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.
Assuntos
Hiperparatireoidismo Primário , Neoplasia Endócrina Múltipla Tipo 1 , Humanos , Neoplasia Endócrina Múltipla Tipo 1/complicações , Neoplasia Endócrina Múltipla Tipo 1/genética , Neoplasia Endócrina Múltipla Tipo 1/cirurgia , Hiperparatireoidismo Primário/cirurgia , Hiperparatireoidismo Primário/complicações , Recidiva Local de Neoplasia/epidemiologia , Recidiva Local de Neoplasia/etiologia , Glândulas Paratireoides , Paratireoidectomia , RecidivaRESUMO
The Multiple Endocrine Neoplasia I (MEN1) locus encodes the protein MENIN, which functions as a tumor suppressor protein in neuroendocrine tissues. Gastrinomas are neuroendocrine neoplasms that overproduce the hormone gastrin and can arise sporadically or as part of the MEN1 syndrome, in which mutations in the MEN1 gene lead to loss or inactivation of MENIN protein. Gastrin is a peptide hormone that is primarily synthesized in the gastric antrum and stimulates the secretion of histamine from enterochromaffin-like (ECL) cells and subsequently acid from parietal cells in the gastric corpus. In addition, gastrin exerts a mitogenic function primarily on ECL cells and progenitor cells in the gastric isthmus. Current studies seek to understand how MEN1 mutations generate a mutant MENIN protein that abrogates its tumor suppressor function. Mutations in the MEN1 gene are broadly distributed throughout its nine protein-coding exons, making it difficult to correlate protein structure with its function. Although disruption of the Men1 locus in mice causes functional neuroendocrine tumors in the pituitary and pancreas, gastrinomas do not develop in these transgenic animal models. Prior studies of human gastrinomas suggest that tissue-specific microenvironmental cues in the submucosal foregut may contribute to tumorigenesis by reprogramming of epithelial cells toward the neuroendocrine phenotype. Accordingly, recent studies suggest that neural crest-derived cells are also sensitive to reprogramming when MEN1 is deleted or mutated. Thus, the goal of this report is to review our current understanding of how MENIN modulates gastrin gene expression while highlighting its role in the prevention/suppression of neuroendocrine cell transformation.
Assuntos
Gastrinoma , Neoplasia Endócrina Múltipla Tipo 1 , Neoplasias Pancreáticas , Humanos , Animais , Camundongos , Gastrinoma/genética , Gastrinoma/patologia , Gastrinas/genética , Gastrinas/metabolismo , Neoplasia Endócrina Múltipla Tipo 1/genética , Neoplasia Endócrina Múltipla Tipo 1/metabolismo , Fatores de Transcrição/genética , Neoplasias Pancreáticas/patologia , Expressão Gênica , Proteínas Proto-Oncogênicas/genéticaRESUMO
OBJECTIVE: Summarize and analyze the characteristics of patients with Multiple Endocrine Neoplasia type 1 (MEN-1) who were diagnosed with malignant tumors that do not belong to MEN-1 components. METHODS: Clinical data from patients with MEN-1 who visited Peking Union Medical College Hospital between April 2012 and April 2022 were collected. We compared the clinical characteristics of patients with malignant tumors outside of their MEN-1 components to those without additional tumors. MEN-1 gene testing was performed on most of these patients using Sanger sequencing, whole-exome sequencing, or MLPA. RESULTS: A total of 221 MEN-1 patients were diagnosed, of which 23 (10.40%) were found to have malignant tumors that did not belong to MEN-1 components, including papillary thyroid carcinoma (PTC) (4.52%), breast cancer (1.81%), urologic neoplasms (1.35%), primary hepatic carcinoma (PCC) (0.09%), meningeal sarcoma (0.05%), glioblastoma (0.05%), cervical cancer (0.05%), and lung carcinoma (0.05%). MEN-1 gene mutations were identified in 11 patients, including missense mutations, frameshift mutations, and splice mutations. The prevalence of each endocrine neoplasm, particularly gastroenteropancreatic neuroendocrine tumor, was higher in MEN-1 patients with other malignant tumors compared to MEN-1 patients without malignant tumors. CONCLUSION: Our retrospective study revealed a higher incidence of non-MEN-1 component malignant tumors in MEN-1 patients, especially breast cancer, PTC, and urologic neoplasms. These patients also exhibit more severe clinical phenotypes of MEN-1.
Assuntos
Neoplasia Endócrina Múltipla Tipo 1 , Humanos , Feminino , Masculino , Neoplasia Endócrina Múltipla Tipo 1/genética , Neoplasia Endócrina Múltipla Tipo 1/epidemiologia , Neoplasia Endócrina Múltipla Tipo 1/complicações , Adulto , Pessoa de Meia-Idade , Mutação , Adulto Jovem , Idoso , Adolescente , Estudos Retrospectivos , Neoplasias da Glândula Tireoide/genética , Neoplasias da Glândula Tireoide/epidemiologia , Fatores de Risco , Proteínas Proto-OncogênicasRESUMO
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.
Assuntos
Glucagonoma , Neoplasia Endócrina Múltipla Tipo 1 , Neoplasias Pancreáticas , Proteínas Proto-Oncogênicas , Adulto , Feminino , Humanos , Glucagonoma/genética , Glucagonoma/diagnóstico , Glucagonoma/patologia , Neoplasia Endócrina Múltipla Tipo 1/genética , Mutação , Neoplasias Pancreáticas/genética , Linhagem , Proteínas Proto-Oncogênicas/genéticaRESUMO
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.
Assuntos
Neoplasias do Córtex Suprarrenal , Neoplasia Endócrina Múltipla Tipo 1 , Humanos , Neoplasia Endócrina Múltipla Tipo 1/diagnóstico , Neoplasia Endócrina Múltipla Tipo 1/genética , Exoma , Adesão Celular , Transdução de Sinais/genéticaRESUMO
We aimed to provide an in-depth analysis with respect to three turning points in pancreas involvement in primary hyperparathyroidism (PHP): hypercalcemia-induced pancreatitis (HCa-P), MEN1 (multiple endocrine neoplasia)-related neuroendocrine tumors (NETs), and insulin resistance (IR). This was a comprehensive review conducted via a PubMed search between January 2020 and January 2024. HCa-P (n = 9 studies, N = 1375) involved as a starting point parathyroid NETs (n = 7) or pancreatitis (n = 2, N = 167). Case report-focused analysis (N = 27) showed five cases of pregnancy PHP-HCa-P and three reports of parathyroid carcinoma (female/male ratio of 2/1, ages of 34 in women, men of 56). MEN1-NET studies (n = 7) included MEN1-related insulinomas (n = 2) or MEN1-associated PHP (n = 2) or analyses of genetic profile (n = 3), for a total of 877 MEN1 subjects. In MEN1 insulinomas (N = 77), the rate of associated PHP was 78%. Recurrence after parathyroidectomy (N = 585 with PHP) was higher after less-than-subtotal versus subtotal parathyroidectomy (68% versus 45%, p < 0.001); re-do surgery was 26% depending on surgery for pancreatic NETs (found in 82% of PHP patients). MEN1 pathogenic variants in exon 10 represented an independent risk factor for PHP recurrence. A single pediatric study in MEN1 (N = 80) revealed the following: a PHP rate of 80% and pancreatic NET rate of 35% and 35 underlying germline MEN1 pathogenic variants (and 3/35 of them were newly detected). The co-occurrence of genetic anomalies included the following: CDC73 gene variant, glucokinase regulatory protein gene pathogenic variant (c.151C>T, p.Arg51*), and CAH-X syndrome. IR/metabolic feature-focused analysis identified (n = 10, N = 1010) a heterogeneous spectrum: approximately one-third of adults might have had prediabetes, almost half displayed some level of IR as reflected by HOMA-IR > 2.6, and serum calcium was positively correlated with HOMA-IR. Vitamin D deficiency was associated with a higher rate of metabolic syndrome (n = 1). Normocalcemic and mildly symptomatic hyperparathyroidism (n = 6, N = 193) was associated with a higher fasting glucose and some improvement after parathyroidectomy. This multilayer pancreas/parathyroid analysis highlighted a complex panel of connections from pathogenic factors, including biochemical, molecular, genetic, and metabolic factors, to a clinical multidisciplinary panel.
Assuntos
Hipercalcemia , Hiperparatireoidismo Primário , Resistência à Insulina , Pancreatite , Humanos , Hiperparatireoidismo Primário/genética , Hiperparatireoidismo Primário/cirurgia , Hiperparatireoidismo Primário/complicações , Resistência à Insulina/genética , Hipercalcemia/genética , Hipercalcemia/etiologia , Pancreatite/genética , Pancreatite/etiologia , Feminino , Masculino , Proteínas Proto-Oncogênicas/genética , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/patologia , Neoplasias Pancreáticas/complicações , Neoplasia Endócrina Múltipla Tipo 1/genética , Neoplasia Endócrina Múltipla Tipo 1/complicações , Neoplasias das Paratireoides/genética , Neoplasias das Paratireoides/complicações , Neoplasias das Paratireoides/cirurgia , Adulto , Paratireoidectomia , Tumores Neuroendócrinos/genética , Tumores Neuroendócrinos/complicações , Tumores Neuroendócrinos/patologia , Pâncreas/patologia , Pâncreas/cirurgia , Pâncreas/metabolismoRESUMO
Neuroendocrine neoplasms (NENs) are relatively rare neoplasms with 6.4-times increasing age-adjusted annual incidence during the last four decades. NENs arise from neuroendocrine cells, which release hormones in response to neuronal stimuli and they are distributed into organs and tissues. The presentation and biological behaviour of the NENs are highly heterogeneous, depending on the organ. The increased incidence is mainly due to increased awareness and improved detection methods both in the majority of sporadic NENs (non-inherited), but also the inherited groups of neoplasms appearing in at least ten genetic syndromes. The most important one is multiple endocrine neoplasia type 1 (MEN-1), caused by mutations in the tumour suppressor gene MEN1. MEN-1 has been associated with different tumour manifestations of NENs e.g. pancreas, gastrointestinal tract, lungs, thymus and pituitary. Pancreatic NENs tend to be less aggressive when arising in the setting of MEN-1 compared to sporadic pancreatic NENs. There have been very important improvements over the past years in both genotyping, genetic counselling and family screening, introduction and validation of various relevant biomarkers, as well as newer imaging modalities. Alongside this development, both medical, surgical and radionuclide treatments have also advanced and improved morbidity, quality of life and mortality in many of these patients. Despite this progress, there is still space for improving insight into the genetic and epigenetic factors in relation to the biological mechanisms determining NENs as part of MEN-1. This review gives a comprehensive update of current evidence for co-occurrence, diagnosis and treatment of MEN-1 and neuroendocrine neoplasms and highlight the important progress now finding its way to international guidelines in order to improve the global management of these patients.
Assuntos
Neoplasia Endócrina Múltipla Tipo 1/genética , Neoplasia Endócrina Múltipla Tipo 1/terapia , Tumores Neuroendócrinos/genética , Tumores Neuroendócrinos/terapia , Proteínas Proto-Oncogênicas/genética , Biomarcadores Tumorais/genética , Técnicas de Diagnóstico por Radioisótopos , Gastrinoma/patologia , Neoplasias Gastrointestinais/patologia , Predisposição Genética para Doença/genética , Humanos , Neoplasias Pulmonares/patologia , Neoplasia Endócrina Múltipla Tipo 1/diagnóstico , Tumores Neuroendócrinos/diagnóstico , Neoplasias Pancreáticas/patologiaAssuntos
Neoplasia Endócrina Múltipla Tipo 1/diagnóstico , Adulto , Pré-Escolar , Autoavaliação Diagnóstica , Testes Genéticos , Humanos , Masculino , Anamnese , Neoplasia Endócrina Múltipla Tipo 1/complicações , Neoplasia Endócrina Múltipla Tipo 1/genética , Neoplasia Endócrina Múltipla Tipo 1/terapia , Equipe de Assistência ao PacienteRESUMO
PURPOSE: Pituitary adenomas commonly arise in patients with MEN1 syndrome, an autosomal dominant condition predisposing to neuroendocrine tumor formation, and typically diagnosed in patients with a relevant family cancer history. In these patients with existing germline loss of MEN1 on one allele, somatic loss of the second MEN1 allele leads to complete loss of the MEN1 protein, menin, and subsequent tumor formation. METHODS: Whole exome sequencing was performed on the tumor and matching blood under an institutional board approved protocol. DNA extraction and analysis was conducted according to previously described methods. RESULTS: We describe a 23 year-old patient with no significant past medical history or relevant family history who underwent surgical resection of a symptomatic and medically resistant prolactinoma. Whole exome sequencing of tumor and blood samples revealed somatic loss of MEN1 at both alleles, suggesting a double hit mechanism, with no underlying germline MEN1 mutation. CONCLUSION: To our knowledge, this is the first case of pituitary adenoma to arise from somatic loss of MEN1 and in the absence of an underlying germline MEN1 mutation.
Assuntos
Adenoma , Neoplasia Endócrina Múltipla Tipo 1 , Neoplasias Hipofisárias , Prolactinoma , Humanos , Adulto Jovem , Adulto , Neoplasias Hipofisárias/genética , Neoplasias Hipofisárias/patologia , Neoplasia Endócrina Múltipla Tipo 1/genética , Adenoma/genética , Adenoma/cirurgia , Adenoma/patologia , Mutação em Linhagem GerminativaRESUMO
INTRODUCTION: Primary hyperparathyroidism (PHPT) caused by parathyroid tumours is mostly sporadic, with a genetic cause identified in 5-10% of cases. Familial parathyroid tumours can be included in complex syndromes, such as multiple endocrine neoplasia (MEN) type 1, 2A and 4 or hyperparathyroidism-jaw tumour syndrome (HPT-JT). OBJECTIVE: Characterisation of the familial parathyroid tumours followed-up at our centre and comparison of the different clinicopathological manifestations between the syndromes. METHODS: Retrospective analysis of 48 patients with familial parathyroid tumours harbouring RET (n = 11), CDC73 (n = 20) and MEN1 (n = 17) germline mutations was performed. RESULTS: Cases of PHPT in MEN2A syndrome presented with lower serum PTH (sPTH) and serum calcium (sCa) levels at diagnosis (sPTH = 108.0 (IQR 53.3) pg/mL, sCa = 10.6 ± 1.1 mg/dL) than MEN1 (sPTH = 196.9 (IQR 210.5) pg/mL, sCa = 11.7 ± 1.2 mg/dL) (p = 0.01, p = 0.03, respectively) or HPT-JT cases (sPTH = 383.5 (IQR 775.8) pg/mL, sCa = 12.9 ± 1.8 mg/dL) (p = 0.01; p < 0.001, respectively). There was a statistical difference in sCa levels between MEN1 and HPT-JT (p = 0.02), but not between sPTH (p = 0.07). The predominant first manifestation of the syndrome in MEN1 was gastroenteropancreatic neuroendocrine tumour (GEP-NET) in 47.1% of the cases, in MEN2A was medullary thyroid cancer (90.9%) and in HPT-JT was PHPT in 85% patients. In MEN1 syndrome, the number of affected parathyroid glands was significantly higher than in MEN2A (p < 0.001) and HPT-JT (p = 0.01). CONCLUSION: The first manifestation of the syndrome in MEN1 cases was GEP-NET and not PHPT. Although presenting at similar ages, patients with MEN2A exhibit less severe biochemical and clinical PHPT at diagnosis than the other familial syndromes.
Assuntos
Neoplasia Endócrina Múltipla Tipo 1 , Neoplasia Endócrina Múltipla Tipo 2a , Neoplasias das Paratireoides , Humanos , Glândulas Paratireoides , Neoplasias das Paratireoides/diagnóstico , Neoplasias das Paratireoides/genética , Neoplasia Endócrina Múltipla Tipo 2a/genética , Síndrome , Estudos Retrospectivos , Neoplasia Endócrina Múltipla Tipo 1/complicações , Neoplasia Endócrina Múltipla Tipo 1/diagnóstico , Neoplasia Endócrina Múltipla Tipo 1/genéticaRESUMO
This review provides an overview of novel insights in the clinical management of patients with Multiple Endocrine Neoplasia Type 1, focusing on the last decade since the last update of the MEN1 guidelines. With regard to Diagnosis: Mutation-negative patients with 2/3 main manifestations have a different clinical course compared to mutation-positive patients. As for primary hyperparathyroidism: subtotal parathyroidectomy is the initial procedure of choice. Current debate centres around the timing of initial parathyroidectomy as well as the controversial topic of unilateral clearance in young patients. For duodenopancreatic neuroendocrine tumours (NETs), the main challenge is accurate and individualized risk stratification to enable personalized surveillance and treatment. Thymus NETs remain one of the most aggressive MEN1-related tumours. Lung NETs are more frequent than previously thought, generally indolent, but rare aggressive cases do occur. Pituitary adenomas are most often prolactinomas and nonfunctioning microadenomas with an excellent prognosis and good response to therapy. Breast cancer is recognized as part of the MEN1 syndrome in women and periodical screening is advised. Clinically relevant manifestations are already seen at the paediatric age and initiating screening in the second decade is advisable. MEN1 has a significant impact on quality of life and US data show a significant financial burden. In conclusion, patient outcomes have improved, but much is still to be achieved. For care tailored to the needs of the individual patient and improving outcomes on an individual basis, studies are now needed to define predictors of tumour behaviour and effects of more individualized interventions.
Assuntos
Neoplasia Endócrina Múltipla Tipo 1 , Tumores Neuroendócrinos , Neoplasias Pancreáticas , Neoplasias Hipofisárias , Criança , Feminino , Humanos , Neoplasia Endócrina Múltipla Tipo 1/genética , Neoplasia Endócrina Múltipla Tipo 1/terapia , Tumores Neuroendócrinos/diagnóstico , Tumores Neuroendócrinos/patologia , Tumores Neuroendócrinos/terapia , Neoplasias Pancreáticas/diagnóstico , Qualidade de VidaRESUMO
BACKGROUND: The overall natural history, risk of death and surgical burden of patients with multiple endocrine neoplasia type 1 (MEN1) is not well known. METHODS: Patients with MEN1 from a nationwide cohort were included. The survival of patients with MEN1 was compared with that of the general population using simulated controls. The cumulative probabilities of MEN1-specific operations and postoperative mortality were assessed, and surgical sequences were analysed using sunburst charts and Venn diagrams. RESULTS: A total of 1386 patients with MEN1 were included. Life expectancy was significantly reduced in patients with MEN1 compared with simulated controls from the general population, with a lifetime difference of 15 years. Mutations affecting the JunD interaction domain had a significant negative impact on survival. Survival for patients with MEN1 compared with the general population improved over time. The probability of experiencing at least one specific MEN1 operation was above 95 per cent after 75 years, and most patients had surgery at least twice during their lifetime. Time to a 50 per cent risk of MEN1 surgery was 30.5 years for patients born after 1960, compared with 47.9 years for those born before 1960. Sex and mutations affecting the JunD interacting domain had no impact on time to first surgery. There was considerable heterogeneity in surgical sequences, with no specific clinical pathway. CONCLUSION: Life expectancy was significantly lower among patients with MEN1 compared with the general population, and further decreased in patients with mutations affecting the JunD interacting domain. Almost all patients underwent at least one MEN1-specific operation during their lifetime, but there was no standardized sequence of surgery.
Assuntos
Neoplasia Endócrina Múltipla Tipo 1 , Neoplasias Pancreáticas , Estudos de Coortes , Humanos , Expectativa de Vida , Neoplasia Endócrina Múltipla Tipo 1/genética , Neoplasia Endócrina Múltipla Tipo 1/cirurgia , Mutação , Neoplasias Pancreáticas/cirurgia , ProbabilidadeRESUMO
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.
Assuntos
Neoplasia Endócrina Múltipla Tipo 1 , Proteínas Proto-Oncogênicas/genética , Mutação da Fase de Leitura , Humanos , Neoplasia Endócrina Múltipla Tipo 1/genética , Neoplasia Endócrina Múltipla Tipo 1/metabolismo , Neoplasia Endócrina Múltipla Tipo 1/patologia , Linhagem , FenótipoRESUMO
OBJECTIVE: Multiple endocrine neoplasia type 1 (MEN1) is a rare genetic syndrome characterized by parathyroid, anterior pituitary, and/or duodenopancreatic neuroendocrine tumors. Studies have indicated that investigating primary hyperparathyroidism (pHPT) with subsequent genetic screening may be an essential tool for the early diagnosis of MEN1 in patients with pituitary tumors (PTs). This study aimed to investigate the presence of pHPT in patients with PTs and, subsequently, to screen for genetic mutations and related tumors in patients with MEN1 syndrome. METHODS: This study included 255 patients with PTs who were assessed for the presence of MEN1 by serum calcium and parathyroid hormone measurements. Mutation screening of the MEN1, CDKN1B, and AIP genes was performed in the index cases showing the MEN1 phenotype. RESULTS: Five patients with PTs presented a clinical condition compatible with MEN1. These patients had a younger age of onset and a more severe clinical condition. Genetic analysis identified a frameshift mutation in the MEN1 gene in one of the cases with the MEN1 phenotype, but point mutations in CDKN1B and AIP were not detected in any of these patients. CONCLUSION: Our results show that periodic screening for pHPT in patients with PTs may be useful to detect MEN1 syndrome; thus, it is recommended in those patients with both findings a genetic analysis of MEN1 gene and an additional search of related tumors. By contrast, our data suggest that CDKN1B and AIP mutations do not seem to play a relevant role in the pathogenesis of MEN1.
Assuntos
Hiperparatireoidismo Primário , Neoplasia Endócrina Múltipla Tipo 1 , Neoplasias Hipofisárias , Perfil Genético , Humanos , Hiperparatireoidismo Primário/diagnóstico , Hiperparatireoidismo Primário/genética , Hiperparatireoidismo Primário/patologia , Neoplasia Endócrina Múltipla Tipo 1/complicações , Neoplasia Endócrina Múltipla Tipo 1/genética , Mutação , Neoplasias Hipofisárias/complicações , Neoplasias Hipofisárias/genéticaRESUMO
Pituitary adenoma is one of the three most common neoplasms described in multiple endocrine neoplasia type 1 (MEN1), and patients with pituitary adenoma occupies 30-50% of those with MEN1-related tumor. Mixed gangliocytoma-pituitary adenoma (MGPA) is a rare clinical entity in which gangliomatous cells are intermixed with adenomatous cells. This tumor has been estimated to account for 0.52-1.26% of all pituitary tumors. We report a rare case of MGPA in a patient with MEN1. A retrospective chart review was conducted on a patient with MEN1 diagnosed with MGPA in 2019 at a single tertiary academic medical center. A review of the literature was performed on MGPA and pituitary adenoma in MEN1. MGPA is rare, with only 174 cases previously reported in the literature and only three prior case reported in a patient with MEN1. There are multiple hypotheses regarding their pathogenesis, and it is unclear whether the MEN1 gene (menin) plays a role in the pathogenesis of MGPA. This tumor in MEN1 is a rare clinical entity of unknown etiology. Further studies are required with difficulty due to its low incidence.
Assuntos
Adenoma , Ganglioneuroma , Neoplasia Endócrina Múltipla Tipo 1 , Neoplasias Hipofisárias , Adenoma/complicações , Adenoma/diagnóstico , Ganglioneuroma/complicações , Ganglioneuroma/patologia , Humanos , Neoplasia Endócrina Múltipla Tipo 1/complicações , Neoplasia Endócrina Múltipla Tipo 1/diagnóstico , Neoplasia Endócrina Múltipla Tipo 1/genética , Neoplasias Hipofisárias/genética , Estudos RetrospectivosRESUMO
BACKGROUND: Multiple endocrine neoplasia type 1 (MEN1) is a rare autosomal dominant tumor syndrome with a high degree of heterogeneity in clinical phenotypes, generally involving the parathyroid, anterior pituitary, and enteropancreas. In recent years, several new insights into the clinical features of MEN1 have been reported in the literature. However, it is not clear whether MEN1-associated primary tumors can occur in the liver. CASE PRESENTATION: We report the case of a 52-year-old man with multiple endocrine neoplasia type 1 diagnosed by genetic sequencing. After uniportal thoracoscopic right middle lobectomy, laparoscopic radical resection of the liver tumors, and radiofrequency ablation of the parathyroid space, the parathyroid hormone level decreased from 177 pg/ml to a normal level (20 pg/ml). No local tumor recurrence was observed during a follow-up of 5 months. CONCLUSION: We report the first case of MEN1 with simultaneous liver and lung involvement in which the patient underwent radical resection of the tumors, and we propose the possibility that the liver and other nonendocrine organs may also develop diseases associated with MEN1; although, this view needs further verification. Gene detection has crucial clinical significance for guiding diagnosis and treatment.
Assuntos
Neoplasia Endócrina Múltipla Tipo 1 , Abdome , Humanos , Fígado , Pulmão , Neoplasia Endócrina Múltipla Tipo 1/complicações , Neoplasia Endócrina Múltipla Tipo 1/genética , Neoplasia Endócrina Múltipla Tipo 1/cirurgia , Recidiva Local de Neoplasia/complicaçõesRESUMO
Multiple Endocrine Neoplasia type-1 (MEN1) is an autosomal dominant disorder with a combined occurrence of tumours of parathyroid glands, pancreatic islets, and anterior pituitary. About 90% of these patients carry mutations in the MEN1 gene, though the spectrum is not well defined in India. Forty clinically suspected cases of MEN1 were enrolled prospectively over six years; 32 patients (23 index-cases and nine affected relatives) with≥2 classical endocrine tumours of MEN1 were considered definite, and eight were categorised as 'MEN1-like'. Details of their clinical presentation, treatment and mutational analysis including MEN1 gene, 3' and 5' untranslated regions (UTR) of MEN1, CDKN1B, and CaSR genes were collated. Asymptomatic first-degree relatives were also screened. Among the 32 definite MEN1 patients, all had primary hyperparathyroidism, 22 (68.7%) had gastroentero-pancreatic neuroendocrine tumours, and 21 (66%) had pituitary adenoma. Of the 23 definite index-cases, 13 (56.5%) carried mutations in the MEN1 gene. Five of nine affected first-degree relatives (55.5%), and four of 10 asymptomatic relatives (40%) also had MEN1 mutations. Seven of 10 MEN1 mutation-negative definite index-cases harboured p.V109G polymorphism in the CDKN1B gene. All eight MEN1-like cases were negative for mutations and large deletions in MEN1, mutations in 3' and 5' UTR of MEN1, CaSR and CDKN1B genes. The study has helped to clearly document the pattern of mutations among Indian MEN1 patients. However, the absence of MEN1 mutation in ~44% of cases and the presence of p.V109G polymorphism in CDKN1B gene raise the question whether such polymorphisms could independently contribute to pathogenesis.
Assuntos
Neoplasia Endócrina Múltipla Tipo 1/genética , Mutação , Proteínas Proto-Oncogênicas/genética , Adolescente , Adulto , Idoso , Inibidor de Quinase Dependente de Ciclina p27/genética , Análise Mutacional de DNA , Feminino , Humanos , Índia , Masculino , Pessoa de Meia-Idade , Neoplasia Endócrina Múltipla Tipo 1/metabolismo , Linhagem , Estudos Prospectivos , Proteínas Proto-Oncogênicas/metabolismo , Receptores de Detecção de Cálcio/genética , Regiões não Traduzidas , Adulto JovemRESUMO
BACKGROUND: Multiple endocrine neoplasia type 1 (MEN1) is a syndrome characterized by pituitary neoplasia, primary hyperparathyroidism and pancreatic endocrine tumor. Here we show a case of MEN1 with a germline frameshift mutation in its gene accompanied by a giant cervical lipoma and multiple fatty deposits in the pancreas. CASE PRESENTATION: A 28-year-old man noticed the decreased visual acuity of both eyes and visited our institution. Since he was diagnosed as visual disturbance and brain computer tomography (CT) showed a mass in the pituitary fossa, he was hospitalized in our institution. Endoscopic trans-sphenoidal hypophysectomy and total parathyroidectomy with auto-transplantation were performed, and a giant cervical lipoma was resected. Furthermore, in genetic search, we found a germline frameshift mutation in MEN1 gene leading to the appearance of a new stop codon. CONCLUSIONS: We should bear in m ind that giant skin lipoma and multiple abnormal fatty deposits in the pancreas could be complicated with MEN1.
Assuntos
Mutação da Fase de Leitura , Lipoma/patologia , Neoplasia Endócrina Múltipla Tipo 1/patologia , Pancreatopatias/patologia , Proteínas Proto-Oncogênicas/genética , Adulto , Humanos , Lipoma/complicações , Lipoma/genética , Lipoma/cirurgia , Masculino , Neoplasia Endócrina Múltipla Tipo 1/complicações , Neoplasia Endócrina Múltipla Tipo 1/genética , Neoplasia Endócrina Múltipla Tipo 1/cirurgia , Pancreatopatias/complicações , Pancreatopatias/genética , Pancreatopatias/cirurgia , Paratireoidectomia , PrognósticoRESUMO
The availability of genomic sequencing for inherited diseases provides a more complete molecular basis for how an individual's genetic landscape influences clinical outcome. We describe a family where exome sequencing of a 3-year-old boy with clinical features of Cockayne syndrome (CS) confirmed the diagnosis of CS. He also had a mutation consistent with a pre-symptomatic second disease, multiple endocrine neoplasia type 1 (MEN1), each potentially affecting multiple organ systems, in addition to a poorly defined variant in fumarate hydratase (FH). Genomic sequencing may reveal coexisting pathogenic mutations and variants which complicate clinical interpretation.
Assuntos
Síndrome de Cockayne , Neoplasia Endócrina Múltipla Tipo 1 , Pré-Escolar , Síndrome de Cockayne/diagnóstico , Síndrome de Cockayne/genética , Exoma/genética , Genômica , Humanos , Masculino , Neoplasia Endócrina Múltipla Tipo 1/genética , Mutação , Linhagem , Sequenciamento do ExomaRESUMO
Multiple endocrine neoplasia type 1 (MEN1) is a rare tumor syndrome that manifests differently among various patients. Despite the mutations in the MEN1 gene that commonly predispose tumor development, there are no obvious phenotype-genotype correlations. The existing animal and in vitro models do not allow for studies of the molecular genetics of the disease in a human-specific context. We aimed to create a new human cell-based model, which would consider the variability in genetic or environmental factors that cause the complexity of MEN1 syndrome. Here, we generated patient-specific induced pluripotent stem cell lines carrying the mutation c.1252G>T, D418Y in the MEN1 gene. To reduce the genetically determined variability of the existing cellular models, we created an isogenic cell system by modifying the target allele through CRISPR/Cas9 editing with great specificity and efficiency. The high potential of these cell lines to differentiate into the endodermal lineage in defined conditions ensures the next steps in the development of more specialized cells that are commonly affected in MEN1 patients, such as parathyroid or pancreatic islet cells. We anticipate that this isogenic system will be broadly useful to comprehensively study MEN1 gene function across different contexts, including in vitro modeling of MEN1 syndrome.