RESUMO
Multiple endocrine neoplasia (MEN) syndromes are rare autosomal dominant diseases that are associated with a mixture of both endocrine and non-endocrine tumors. Traditionally, there are 2 types of MEN that have unique clinical associations: MEN 1 (parathyroid hyperplasia, pancreatic neuroendocrine tumors, and pituitary tumors) and MEN 2 (medullary thyroid carcinoma and pheochromocytoma), which is further classified into MEN 2A (adds parathyroid adenomas) and 2B (adds ganglioneuromas and marfanoid habitus). Many of the endocrine tumors are resected surgically, and the pre, intra, and postoperative management strategies used must take into account the high recurrence rates asscioated with MEN tumors.
Assuntos
Neoplasia Endócrina Múltipla , Humanos , Neoplasia Endócrina Múltipla/cirurgia , Neoplasia Endócrina Múltipla/diagnóstico , Neoplasia Endócrina Múltipla/genéticaRESUMO
Multiple endocrine neoplasia (MEN) is a group of syndromes with a genetic predisposition to the appearance of endocrine tumors, and shows autosomal dominant transmission. The advent of molecular genetics has led to improvements in the management of MEN in terms of diagnosis, prognosis and therapy. The genetics of MEN is the subject of regular updates, which will be presented throughout this paper. MEN1, the first to be described, is associated with the MEN1 gene. MEN1 is well known in terms of the observed phenotype, with genetic analysis being conclusive in 90% of patients with a typical phenotype, but is negative in around 10% of families with MEN1. Improvement in analysis techniques and the identification of other genes responsable for phenocopies allows the resolution of some, but not all, cases, notably non-familial forms suspected to be fortuitous assocations with tumors. MEN4 is a rare phenocopy of MEN1 linked to constitutional mutations in the CDKN1B gene. Though it closely resembles the phenotype of MEN1, published data suggests the appearance of tumors is later and less frequent in MEN4. MEN2, which results from mutations in the RET oncogene, shows a strong genotype-phenotype correlation. This correlation is particularly evident in the major manifestation of MEN2, medullary thyroid carcinoma (MTC), in which disease aggressiveness is dependent on the pathogenic variant of RET. However, recent studies cast doubt on this correlation between MTC and pathogenic variant. Lastly, the recent description of families carrying a mutation in MAX, which is known to predispose to the development of pheochromocytoma and paraganglioma, and presents a phenotypic spectrum that evokes MEN, suggests the existence of another syndrome, MEN5.
Assuntos
Neoplasias das Glândulas Suprarrenais , Carcinoma Neuroendócrino , Neoplasia Endócrina Múltipla , Feocromocitoma , Neoplasias da Glândula Tireoide , Humanos , Neoplasia Endócrina Múltipla/diagnóstico , Feocromocitoma/genética , Neoplasias da Glândula Tireoide/genética , Neoplasias das Glândulas Suprarrenais/genéticaRESUMO
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.
Assuntos
Adenoma , Adenoma Hipofisário Secretor de Hormônio do Crescimento , Neoplasia Endócrina Múltipla Tipo 1 , Neoplasia Endócrina Múltipla , Neoplasias Hipofisárias , Humanos , Neoplasias Hipofisárias/diagnóstico , Neoplasias Hipofisárias/genética , Neoplasias Hipofisárias/terapia , Adenoma/terapia , Neoplasia Endócrina Múltipla Tipo 1/genética , Neoplasia Endócrina Múltipla Tipo 1/terapia , Neoplasia Endócrina Múltipla Tipo 1/diagnóstico , Neoplasia Endócrina Múltipla/diagnóstico , Neoplasia Endócrina Múltipla/genética , Neoplasia Endócrina Múltipla/terapia , Predisposição Genética para Doença/genéticaRESUMO
PURPOSE: Multiple endocrine neoplasia type 4 (MEN4) is a rare multiglandular endocrine neoplasia syndrome, associated with a wide tumor spectrum but hallmarked by primary hyperparathyroidism, which represents the most common clinical feature, followed by pituitary (functional and non-functional) adenomas, and neuroendocrine tumors. MEN4 clinically overlaps MEN type 1 (MEN1) but differs from it for milder clinical features and an older patient's age at onset. The underlying mutated gene, CDKN1B, encodes the cell cycle regulator p27, implicated in cellular proliferation, motility and apoptosis. Given the paucity of MEN4 cases described in the literature, possible genotype-phenotype correlations have not been thoroughly assessed, and specific clinical recommendations are lacking. The present review provides an extensive overview of molecular genetics and clinical features of MEN4, with the aim of contributing to delineate peculiar strategies for clinical management, screening and follow-up of the last and least known MEN syndrome. METHODS: A literature search was performed through online databases like MEDLINE and Scopus. CONCLUSIONS: MEN4 is much less common that MEN1, tend to present later in life with a more indolent course, although involving the same primary organs as MEN1. As a consequence, MEN4 patients might need specific diagnostic and therapeutic approaches and a different strategy for screening and follow-up. Further studies are needed to assess the real oncological risk of MEN4 carriers, and to establish a standardized screening protocol. Furthermore, a deeper understanding of molecular genetics of MEN4 is needed in order to explore p27 as a novel therapeutic target.
Assuntos
Adenoma , Neoplasia Endócrina Múltipla Tipo 1 , Neoplasia Endócrina Múltipla , Tumores Neuroendócrinos , Humanos , Neoplasia Endócrina Múltipla/diagnóstico , Neoplasia Endócrina Múltipla/genética , Neoplasia Endócrina Múltipla/patologia , Neoplasia Endócrina Múltipla Tipo 1/genética , Neoplasia Endócrina Múltipla Tipo 1/diagnóstico , Tumores Neuroendócrinos/genética , Adenoma/genética , SíndromeRESUMO
RATIONALE: Hyperparathyroidism is caused by parathyroid tumors combined with gastroenteropancreatic tumors and pituitary tumors, which is common in patients with multiple endocrine neoplasia 1 syndrome (MEN-1). As its main pathogenic factor involves genetic mutations, it can cause a variety of different clinical symptoms. However, cases with negative genetic testing results and multiple nonfunctional malignant neuroendocrine tumors (NETs) with metastasis are relatively rare. PATIENT CONCERNS: A 33-year-old man was admitted to the hospital for hyperparathyroidism. Imaging examination revealed multiple nodules in the parathyroid gland, pancreas, thymus, and adrenal gland, and multiple metastases to the lung, liver, thoracolumbar, as well as mediastinal lymph nodes. DIAGNOSES: After multidisciplinary consultation, this patient was diagnosed with MEN-1 syndrome with various original tumors and multiple systemic metastases. INTERVENTIONS: The patient underwent parathyroid tumor resection and metastasis biopsy. OUTCOMES: The patient received denosumab and sorafenib treatment. LESSONS: As an autosomal dominant hereditary disease, MEN-1 patients present with parathyroid hyperplasia, pancreatic and intestinal tumors, pituitary tumors, and so on, which are caused by genetic mutations. These patients would have hyperparathyroidism, hypoglycemia, gastric ulcer, and gastrointestinal diseases. However, some patients with MEN-1 syndrome cannot be diagnosed by genetic testing and simultaneously present with multiple nonfunctional NETs with systemic metastasis. This increases the difficulty of diagnosis and the subsequent treatment.
Assuntos
Hiperparatireoidismo , Neoplasia Endócrina Múltipla Tipo 1 , Neoplasia Endócrina Múltipla , Tumores Neuroendócrinos , Neoplasias Pancreáticas , Neoplasias das Paratireoides , Neoplasias Hipofisárias , Masculino , Humanos , Adulto , Neoplasia Endócrina Múltipla Tipo 1/diagnóstico , Tumores Neuroendócrinos/complicações , Tumores Neuroendócrinos/diagnóstico , Neoplasias Hipofisárias/diagnóstico , Neoplasia Endócrina Múltipla/diagnóstico , Hiperparatireoidismo/diagnóstico , Neoplasias das Paratireoides/complicações , Neoplasias das Paratireoides/diagnóstico , Neoplasias das Paratireoides/genética , Neoplasias Pancreáticas/complicações , Neoplasias Pancreáticas/diagnóstico , Neoplasias Pancreáticas/cirurgiaRESUMO
Multiple endocrine neoplasia (MEN) are genetic predisposition syndromes to endocrine tumors including MEN1, MEN2 and exceptionally MEN4. MEN are transmitted in an autosomal dominant fashion with a high penetrance. Classically, there is no genotype/phenotype correlation for NEM1 whereas this is the case for NEM2. Patients with NEM1, linked to an inactivating mutation of the menin gene, may present with: primary hyperparathyroidism, pituitary adenoma, duodeno-pancreatic neuroendocrine tumors (NETs), bronchial tumors with an increased risk of thymoma, adrenal cortical tumors, an increased risk of breast cancer and characteristic skin involvement such as collagenomas, lentiginomas and an increased risk of skin cancer. These patients require at least annual follow-up. Screening of children is proposed from the age of 5 years. Patients with NEM2, linked to an activating mutation of the RET proto-oncogene, all present with medullary thyroid carcinoma (MTC) at a variable age depending on the genotype. Some patients present a pheochromocytoma (50 %) and hyperparathyroidism (20 %). Pediatric forms with aggressive CMT, ganglioneuromatosis and marfanoid syndrome exist (rare NEM2B). Some mutations are associated with a risk of aggressive CMT, justifying prophylactic thyroidectomy before 6 months of age. The age of genetic testing depends on the mutation subtype in the NEM2 parent. NEM4, related to a mutation in the CDKN1B gene, are rare, with a less well-known pathogenesis and their follow-up is not well codified.
Assuntos
Neoplasias das Glândulas Suprarrenais , Neoplasia Endócrina Múltipla , Feocromocitoma , Neoplasias da Glândula Tireoide , Humanos , Neoplasia Endócrina Múltipla/diagnóstico , Neoplasia Endócrina Múltipla/genética , Feocromocitoma/diagnóstico , Neoplasias das Glândulas Suprarrenais/diagnóstico , Testes Genéticos , Mutação , SíndromeRESUMO
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.
Assuntos
Adenoma , Neoplasia Endócrina Múltipla , Neoplasias Hipofisárias , Adenoma/genética , Inibidor de Quinase Dependente de Ciclina p27/genética , Mutação em Linhagem Germinativa , Humanos , Neoplasia Endócrina Múltipla/diagnóstico , Neoplasia Endócrina Múltipla/genética , Neoplasia Endócrina Múltipla/patologia , Mutação , Neoplasias Hipofisárias/patologiaRESUMO
CONTEXT: Pathogenic germline MAX variants are associated with pheochromocytoma and paraganglioma (PPGL), pituitary neuroendocrine tumors and, possibly, other endocrine and nonendocrine tumors. OBJECTIVE: To report 2 families with germline MAX variants, pheochromocytomas (PCs) and multiple other tumors. METHODS: Clinical, genetic, immunohistochemical, and functional studies at University hospitals in Australia on 2 families with germline MAX variants undergoing usual clinical care. The main outcome measures were phenotyping; germline and tumor sequencing; immunohistochemistry of PC and other tumors; functional studies of MAX variants. RESULTS: Family A has multiple individuals with PC (including bilateral and metastatic disease) and 2 children (to date, without PC) with neuroendocrine tumors (paravertebral ganglioneuroma and abdominal neuroblastoma, respectively). One individual has acromegaly; immunohistochemistry of PC tissue showed positive growth hormone-releasing hormone staining. Another individual with previously resected PCs has pituitary enlargement and elevated insulin-like growth factor (IGF-1). A germline MAX variant (c.200C>A, p.Ala67Asp) was identified in all individuals with PC and both children, with loss of heterozygosity in PC tissue. Immunohistochemistry showed loss of MAX staining in PCs and other neural crest tumors. In vitro studies confirmed the variant as loss of function. In Family B, the proband has bilateral and metastatic PC, prolactin-producing pituitary tumor, multigland parathyroid adenomas, chondrosarcoma, and multifocal pulmonary adenocarcinomas. A truncating germline MAX variant (c.22G>T, p.Glu8*) was identified. CONCLUSION: Germline MAX mutations are associated with PCs, ganglioneuromas, neuroblastomas, pituitary neuroendocrine tumors, and, possibly, parathyroid adenomas, as well as nonendocrine tumors of chondrosarcoma and lung adenocarcinoma, suggesting MAX is a novel multiple endocrine neoplasia gene.
Assuntos
Fatores de Transcrição de Zíper de Leucina e Hélice-Alça-Hélix Básicos/genética , Mutação em Linhagem Germinativa , Neoplasia Endócrina Múltipla/genética , Adolescente , Neoplasias das Glândulas Suprarrenais/diagnóstico , Neoplasias das Glândulas Suprarrenais/genética , Adulto , Idoso , Austrália , Pré-Escolar , Família , Feminino , Humanos , Lactente , Masculino , Pessoa de Meia-Idade , Neoplasia Endócrina Múltipla/classificação , Neoplasia Endócrina Múltipla/diagnóstico , Neoplasias Primárias Múltiplas/diagnóstico , Neoplasias Primárias Múltiplas/genética , Tumores Neuroendócrinos/diagnóstico , Tumores Neuroendócrinos/genética , Linhagem , Feocromocitoma/diagnóstico , Feocromocitoma/genética , Adulto JovemRESUMO
The present study reported a rare case with thymic carcinoid as the first manifestation of multiple endocrine neoplasia type 1 (MEN1) syndrome, which presented with gene mutations of the MEN1 and glucokinase regulatory protein (GCKR). In this report, a 40-year-old male was diagnosed as MEN1 syndrome with thymic carcinoid, pancreatic cancer, hyperparathyroidism, and insulinoma with intrahepatic metastasis. Genetic testing showed the mutations of the MEN1 (c.378 G>A, p. Trp126*) in the patient, his children and two sisters, and GCKR (c.151C>T, p. Arg51*) gene in the patient and his children. The pathological examination showed that neuroendocrine tumor (NET) of the pancreas was characterized as 6 mitoses per 10 high-power fields (HPF), infiltration of adipose tissue, no intravascular tumor thrombus and nerve infiltration. In addition, NET of the liver was characterized as 4 mitoses per 10 HPF, no intravascular tumor thrombus and nerve infiltration. Immunohistochemical staining showed Ckpan (+), Syn (+), CgA (+), CD 56 (+), PGP 9.5 (+), and Ki67-positive cells (8-10%) in NET. Therefore, we suggested that genetic testing in family members of MEN1 patient, which may be helpful for early diagnosis.
Assuntos
Tumor Carcinoide/patologia , Neoplasia Endócrina Múltipla Tipo 1/diagnóstico , Neoplasia Endócrina Múltipla Tipo 1/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/genética , Adulto , Tumor Carcinoide/genética , Humanos , Masculino , Neoplasia Endócrina Múltipla/diagnóstico , Neoplasia Endócrina Múltipla/genética , Neoplasia Endócrina Múltipla/metabolismo , Neoplasia Endócrina Múltipla Tipo 1/genética , Tumores Neuroendócrinos , Neoplasias Pancreáticas , Proteínas Proto-Oncogênicas/genética , Timoma/diagnóstico , Timoma/metabolismo , Timoma/patologia , Neoplasias PancreáticasRESUMO
The vast majority of medullary thyroid carcinomas (MTC) in children are inherited as part of the multiple endocrine neoplasia (MEN) syndromes MEN2A and MEN2B, and the related variant, familial MTC. Prophylactic surgery in infants and children identified through genetic screening leads to the highest survival in these patients. This article summarizes the current recommendations for screening, treatment, and surveillance of children with MTC to provide a concise clinically relevant review for pediatric practitioners.
Assuntos
Carcinoma Neuroendócrino , Testes Genéticos , Neoplasia Endócrina Múltipla , Neoplasias da Glândula Tireoide , Tireoidectomia , Antineoplásicos/uso terapêutico , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Carcinoma Neuroendócrino/diagnóstico , Carcinoma Neuroendócrino/genética , Carcinoma Neuroendócrino/terapia , Quimioterapia Adjuvante , Criança , Detecção Precoce de Câncer , Humanos , Neoplasia Endócrina Múltipla/diagnóstico , Neoplasia Endócrina Múltipla/genética , Neoplasia Endócrina Múltipla/terapia , Esvaziamento Cervical , Metástase Neoplásica , Cuidados Pós-Operatórios/métodos , Procedimentos Cirúrgicos Profiláticos , Neoplasias da Glândula Tireoide/diagnóstico , Neoplasias da Glândula Tireoide/genética , Neoplasias da Glândula Tireoide/terapia , Resultado do TratamentoAssuntos
Inibidor de Quinase Dependente de Ciclina p27/genética , Doenças do Sistema Imunitário/genética , Neoplasia Endócrina Múltipla/complicações , Neoplasia Endócrina Múltipla/genética , Adenoma/complicações , Adenoma/genética , Adenoma/patologia , Idoso , Feminino , Humanos , Hiperprolactinemia/complicações , Hiperprolactinemia/genética , Hiperprolactinemia/patologia , Doenças do Sistema Imunitário/etiologia , Neoplasia Endócrina Múltipla/diagnóstico , Neoplasia Endócrina Múltipla/patologia , Neoplasias das Paratireoides/complicações , Neoplasias das Paratireoides/genética , Neoplasias das Paratireoides/patologia , Fenótipo , Neoplasias Hipofisárias/complicações , Neoplasias Hipofisárias/genética , Neoplasias Hipofisárias/patologiaRESUMO
INTRODUCTION: Single parathyroid adenomas are the most common cause of primary hyperparathyroidism (PHP) in our population. Parathyroidectomy is still the only potentially curative treatment and requires preoperative localization imaging studies to perform selective surgery. In patients with negative results on conventional tests, PET/CT has demonstrated higher sensitivity rates. METHODS: A prospective cohort study was designed, including 34 patients diagnosed with PHP between 2017 and 2019, candidates for surgery with negative preoperative localization tests with scintigraphy and MIBI SPECT/CT. All patients underwent PET/CT with 18F-Fluorocholine. The clinical, biochemical and postoperative outcome results were compared with a control group of 30 patients with positive standard tests. RESULTS: Hyperfunctional parathyroid tissue was detected in 85% of the patients that had undergone choline PET/CT. The selective resection of the adenoma identified in these patients achieved curative criteria in 87% of the cases without undergoing bilateral cervical surgical exploration. The preoperative levels of PTH, calcemia and gland weight were significantly lower in this group compared to the control group. No differences were identified in cure criteria or approach between the 2groups. CONCLUSION: In our study, choline PET/CT showed higher detection rates compared to the gold standard. The increase provides the opportunity to perform unilateral selected adenoma resection, especially in patients with smaller adenomas associated with lower calcemia and PTH levels and patients with previous cervical surgery.
Assuntos
Colina/análogos & derivados , Hiperparatireoidismo Primário/patologia , Neoplasias das Paratireoides/diagnóstico por imagem , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada/métodos , Idoso , Cálcio/sangue , Estudos de Casos e Controles , Colina/administração & dosagem , Colina/química , Feminino , Humanos , Hiperparatireoidismo Primário/diagnóstico , Masculino , Pessoa de Meia-Idade , Neoplasia Endócrina Múltipla/diagnóstico , Neoplasia Endócrina Múltipla/patologia , Neoplasias das Paratireoides/cirurgia , Paratireoidectomia/métodos , Fosfatos/sangue , Período Pós-Operatório , Período Pré-Operatório , Estudos Prospectivos , Cintilografia/normas , Sensibilidade e EspecificidadeRESUMO
About 5% of gastroenteropancreatic and thoracic neuroendocrine neoplasms (NENs) arise in the context of an inherited tumour syndrome. The two most frequent syndromes are: multiple endocrine neoplasia type 1 (MEN1), associated with a large spectrum of endocrine and non endocrine tumours, including duodenopancreatic, thymic and bronchial NENs, and the von Hippel-Lindau syndrome VHL, associated with pancreatic NENs. Two inherited syndromes have a low incidence of NENs: neurofibromatosis type 1 (NF1), associated with duodenal somatostatinomas, and tuberous sclerosis (TSC), associated with pancreatic NENs. Two rare syndromes have a high incidence of NENs: multiple endocrine neoplasia type 4 (MEN4), with a tumour spectrum similar to that of MEN1, and glucagon cell hyperplasia neoplasia (GCHN), involving only the pancreas. It is likely that other syndromes remain to be characterized, especially in familial small-intestinal NENs. The diagnosis is usually raised because of the suggestive clinical setting: young age at diagnosis, multiple tumours in multiple organs, familial history. Except in VHL and NF1, tumours themselves do not show specific pathological features; they usually are well differentiated and of low histological grade; their prognosis is good, except for MEN1-associated thymic NENs. The most suggestive pathological feature is their combination with various endocrine and/or non endocrine lesions in the adjacent tissue. Pathological examination is important, for a correct diagnosis and for an accurate management of the patients and their families, who must be referred to expert centers.
Assuntos
Síndromes Neoplásicas Hereditárias , Tumores Neuroendócrinos/patologia , Neoplasias Duodenais/diagnóstico , Predisposição Genética para Doença , Humanos , Neoplasias Intestinais/complicações , Neoplasias Intestinais/diagnóstico , Neoplasias Intestinais/genética , Neoplasias Intestinais/patologia , Intestinos/patologia , Neoplasia Endócrina Múltipla/complicações , Neoplasia Endócrina Múltipla/diagnóstico , Neoplasia Endócrina Múltipla/genética , Neoplasia Endócrina Múltipla/patologia , Neoplasia Endócrina Múltipla Tipo 1/complicações , Neoplasia Endócrina Múltipla Tipo 1/diagnóstico , Neoplasia Endócrina Múltipla Tipo 1/genética , Neoplasia Endócrina Múltipla Tipo 1/patologia , Síndromes Neoplásicas Hereditárias/complicações , Síndromes Neoplásicas Hereditárias/diagnóstico , Síndromes Neoplásicas Hereditárias/patologia , Tumores Neuroendócrinos/complicações , Tumores Neuroendócrinos/diagnóstico , Tumores Neuroendócrinos/genética , Pâncreas/patologia , Neoplasias Pancreáticas/complicações , Neoplasias Pancreáticas/diagnóstico , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/patologia , Neoplasias Gástricas/complicações , Neoplasias Gástricas/diagnóstico , Neoplasias Gástricas/genética , Neoplasias Gástricas/patologia , Neoplasias Torácicas/diagnóstico , Tórax/patologia , Esclerose Tuberosa/etiologia , Esclerose Tuberosa/patologia , Doença de von Hippel-Lindau/complicações , Doença de von Hippel-Lindau/diagnóstico , Doença de von Hippel-Lindau/genética , Doença de von Hippel-Lindau/patologiaRESUMO
Screening guidelines in patients with inherited endocrine syndromes and others at high risk for developing endocrine cancers have significant implications as early tumor detection is associated with improved outcomes. Given the unique challenges in diagnosis and treatment, patients at high risk for developing endocrine cancers require multidisciplinary care. The complexity of decision making and rarity of these syndromes support referral to high-volume centers with the experience and knowledge to treat these at-risk patients.
Assuntos
Neoplasias das Glândulas Endócrinas/diagnóstico , Neoplasia Endócrina Múltipla/diagnóstico , Carcinoma Ductal Pancreático/diagnóstico , Detecção Precoce de Câncer/métodos , Humanos , Neoplasias Pancreáticas/diagnóstico , Guias de Prática Clínica como Assunto , Neoplasias da Glândula Tireoide/diagnósticoRESUMO
BACKGROUND: Multiple endocrine neoplasia type 1 (MEN1) is a rare autosomal dominant inherited condition affecting multiple endocrine organs, resulting in significant morbidity and decreased life expectancy. Early tumor identification allows for timely patient management, reduces morbidity, and improves disease outcomes. Patients with MEN1 typically present with primary hyperparathyroidism caused by multiple parathyroid tumors, however, thymic and bronchial carcinoid tumors are also less common manifestations. MEN1-related neuroendocrine tumors often show hematogenous metastasis, with the liver being the most common metastatic site. Skeletal metastases from neuroendocrine tumors are extremely rare. As few as 50 case reports were identified in a recently published literature review on skeletal metastases from carcinoid tumors. To our knowledge, studies related to MEN1 have not been previously conducted. CASE PRESENTATION: We present a case of MEN1-related atypical ovarian carcinoid presenting as the first disease manifestation in a 30-year old woman. After two years, another atypical carcinoid was incidentally diagnosed in the contralateral ovary during a caesarean section. Syndromic MEN1 was not diagnosed clinically despite her young age and bilateral involvement. The patient remained disease-free for two years without further adjuvant treatment prior to clinic presentation with complaints of chest discomfort and body pain. Radiologic and pathologic investigations identified multifocal simultaneous neuroendocrine tumors involving the parathyroid, thymus, pancreas, and adrenal glands, in addition to multiple other metastatic sites. The findings ultimately resulted in the patient being diagnosed with MEN1. CONCLUSIONS: This extremely rare case emphasizes that ovarian carcinoids, especially when bilateral, could be the initial manifestation of MEN1. The significance of this differential diagnosis was highlighted by the subsequent detection of widespread skeletal metastasis resulting from the carcinoid tumors. A low threshold of suspicion, systemic diagnostic work-up, and regular follow-up are of utmost importance to timely diagnosis of MEN1.
Assuntos
Tumor Carcinoide/diagnóstico , Diagnóstico Diferencial , Neoplasia Endócrina Múltipla/diagnóstico , Neoplasias Ovarianas/diagnóstico , Adulto , Tumor Carcinoide/diagnóstico por imagem , Tumor Carcinoide/patologia , Feminino , Humanos , Neoplasia Endócrina Múltipla/diagnóstico por imagem , Neoplasia Endócrina Múltipla/patologia , Neoplasias Ovarianas/diagnóstico por imagem , Neoplasias Ovarianas/patologia , Ovário/diagnóstico por imagem , Ovário/patologiaRESUMO
The multiple endocrine neoplasia (MEN) syndromes include MEN1, MEN2 (formerly MEN2A), MEN3 (formerly MEN2B) and the recently identified MEN4. Clinical presentations are varied and often relate to the overproduction of specific hormones. Understanding the genetics of each syndrome assists in determining screening timelines. Treatments for each manifestation are dependent on location, risk of recurrence or malignancy, hormone excess and surgical morbidity. Multidisciplinary management should include geneticists, genetic counsellors, endocrinologists and endocrine surgeons.
Assuntos
Neoplasia Endócrina Múltipla/diagnóstico , Neoplasia Endócrina Múltipla/genética , Neoplasia Endócrina Múltipla/terapia , Terapia Combinada , Procedimentos Cirúrgicos Endócrinos , Marcadores Genéticos , Testes Genéticos , Humanos , Neoplasia Endócrina Múltipla/classificação , RecidivaRESUMO
Individuals with a familial predisposition to the development of parathyroid tumors constitute a small minority of all patients with primary hyperparathyroidism (PHPT). These familial syndromes exhibit Mendelian inheritance patterns and the main causative genes in most families have been identified. They include multiple endocrine neoplasia (MEN; types 1, 2A, and 4), hyperparathyroidism-jaw tumor (HPT-JT) syndrome, familial isolated hyperparathyroidism, familial hypocalciuric hypercalcemia (FHH), and neonatal severe PHPT. Each MEN type is associated with the various combinations of specific tumors. MEN1 is characterized by the occurrence of parathyroid, enteropancreatic, and pituitary tumors; MEN2A is characterized by medullary thyroid carcinoma and pheochromocytoma, and MEN4 is characterized by a pathological spectrum similar to that of MEN1 in association with tumors of the adrenal, kidney, and reproductive organs. HPT-JT is characterized by PHPT, ossifying fibromas of maxillary bones, kidney disease, and uterine neoplasias. The prompt diagnosis of these diseases is of great importance for planning appropriate surveillance of the mutant carriers and correct surgical management. The search for mutation is also useful for the identification of the family members who do not carry the mutation and can avoid unnecessary biochemical and instrumental evaluations. Surgery remains the treatment of choice in all familial forms except FHH.
Assuntos
Hiperparatireoidismo Primário/diagnóstico , Hiperparatireoidismo Primário/genética , Neoplasia Endócrina Múltipla/diagnóstico , Neoplasia Endócrina Múltipla/genética , HumanosRESUMO
BACKGROUND: Ganglioneuromas (GNs) are composed of mature ganglion cells and Schwann cells with a fibrous stroma; GNs are most often observed in children and young adults. The majority of non-cranial GNs are located in the retroperitoneum and posterior mediastinum. Other reported rare sites include the adrenal gland, small intestine, colon and urinary bladder. However, para-testicular GNs are even more rare. CASE PRESENTATION: Herein, we report the case of a patient with concurrent adrenal GN and thyroid papillary carcinoma who developed paratesticular GN eighteen years later. CONCLUSIONS: We conclude that there is an association among papillary thyroid carcinoma, GN and MEN2 syndromes. This case report may provide important information for the proposed association. However, further studies are required.
Assuntos
Neoplasias das Glândulas Suprarrenais/diagnóstico , Glândulas Suprarrenais/patologia , Ganglioneuroma/diagnóstico , Neoplasia Endócrina Múltipla/diagnóstico , Segunda Neoplasia Primária/diagnóstico , Células de Schwann/patologia , Neoplasias Testiculares/diagnóstico , Câncer Papilífero da Tireoide/diagnóstico , Neoplasias da Glândula Tireoide/diagnóstico , Glândulas Suprarrenais/diagnóstico por imagem , Adrenalectomia , Humanos , Imageamento por Ressonância Magnética , Masculino , Anamnese , Pessoa de Meia-IdadeRESUMO
Background Loss-of-function germline MEN1 gene mutations account for 75-95% of patients with multiple endocrine neoplasia type 1 (MEN1). It has been postulated that mutations in non-coding regions of MEN1 might occur in some of the remaining patients; however, this hypothesis has not yet been fully investigated. Objective To sequence for the entire MEN1 including promoter, exons and introns in a large MEN1 cohort and determine the mutation profile. Methods and patients A target next-generation sequencing (tNGS) assay comprising 7.2 kb of the full MEN1 was developed to investigate germline mutations in 76 unrelated MEN1 probands (49 familial, 27 sporadic). tNGS results were validated by Sanger sequencing (SS), and multiplex ligation-dependent probe amplification (MLPA) assay was applied when no mutations were identifiable by both tNGS and SS. Results Germline MEN1 variants were verified in coding region and splicing sites of 57/76 patients (74%) by both tNGS and SS (100% reproducibility). Thirty-eight different pathogenic or likely pathogenic variants were identified, including 13 new and six recurrent variants. Three large deletions were detected by MLPA only. No mutation was detected in 16 patients. In untranslated, regulatory or in deep intronic MEN1 regions of the 76 MEN1 cases, no point or short indel pathogenic variants were found in untranslated, although 33 benign/likely benign and three new VUS variants were detected. Conclusions Our study documents that point or short indel mutations in non-coding regions of MEN1 are very rare events. Also, tNGS proved to be a highly effective technology for routine genetic MEN1 testing.