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

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

Medullary Thyroid Carcinoma in Children.

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.

Multiple endocrine neoplasia: an update.

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.

Medullary Thyroid Carcinoma: Prognostic Variables And Tumour Markers Affecting Survival.

BACKGROUND: Medullary thyroid carcinoma (MTC) is a relatively rare thyroid malignancy and its clinical course varies among patients due to its familial association. A number of prognostic factors have been studied, but the significance of these factors remains controversial. We evaluated the progression free survival (PFS) and overall survival (OS) of MTC and its association with tumour marker rising velocity and serum calcitonin (Ct) doubling time (DT). METHODS: Analysis of 83 (8.7%) consecutive MTC patients registered at a single centre between 1995 and 2015. The impact of tumour respectability, TNM stage, multiple endocrine neoplasia (MEN) syndrome, local recurrence, Ct DT and Ct rising velocity on PFS and OS was analysed. Median follow-up was 4.3 years (range: 1-18 years). RESULTS: Eighty-three (8.7%) of all thyroid cancers registered at our centre were MTC. Fifty-five males, 28 females. Mean age 39 years [range: 17-72 years]. Twenty-two were unresectable and 61 resectable. Five-year and 10-year OS was 84% and 77% respectively. Of 68 with follow up greater than a year; 20 (29.4%) were cured, 15 (22.1%) had biochemical evidence of disease, three (4.4%) had stable macroscopic disease and 30 (44.1%) had recurrent/progressive disease. Sixteen (23.5%) died. On multivariate analysis, T4 tumour, male gender, nodal and distant metastases, tumour resectibility, Ct DT less than two years and tumour marker rising velocity of greater than 0.05pg/ml/month were poor prognostic factors (pvalue <0.05). Age and association with MEN syndrome had no statistically significant survival impact. Radiotherapy reduced local relapse in patients with nodal disease. Total thyroidectomy with nodal clearance lessened relapses. CONCLUSION: Clinical stage and pathological aspects are predictors of disease progression. Persistent biochemical evidence of MTC does not affect OS, however, Ct DT < 2 years and rapid rate of tumour marker rise predict disease progression.

Management of familial hyperparathyroidism syndromes: MEN1, MEN2, MEN4, HPT-Jaw tumour, Familial isolated hyperparathyroidism, FHH, and neonatal severe hyperparathyroidism.

While primary hyperparathyroidism (PHPT) generally represents a common endocrine disorder, being the more frequent cause of hypercalcemia in outpatients, familial forms of PHPT (FPHPT) account for no more than 2-5% of the overall PHPT. In the last decades, many technical progresses in both molecular and biochemical-radiological evaluation have been made, and substantial advancements in understanding these disorders have been reached. Differences both in the pathogenesis and clinical presentation exist among the various hyperparathyroid syndromic forms, and, since FPHPT is frequently associated to other endocrine, proliferative and/or functional disorders, as also non-endocrine tumours, with varying clinical spectrum of occurrence in each syndrome, its early clinically detection for appropriately preventing complications (i.e. kidney and bone disorders) is strictly advised. In this review, the clinical-biochemical features and diagnostic procedures of each FPHPT form will be summarized and a general overview on surgical and pharmacological approaches to FPHPT has been also considered.

[Multiple endocrine neoplasia]. / Multiple endokrine Neoplasie.

Multiple endocrine neoplasia type 1 and 2 are hereditary cancer syndromes. They are characterized by the occurrence of many benign and malignant tumor types, in MEN1 parathyroid tumors, pituitary tumors, and pancreas tumors, in MEN2 medullary thyroid carcinoma, pheochromocytoma, and parathyroid tumors. The autosomal dominant inherited tumor syndromes are caused by mutations in the MEN1 gene, a tumor suppressor gene, and mutations in the RET gene, an activated oncogene, in MEN2. The clinical expression of the different tumors can vary within and between families, with a good genotype-phenotype correlation in MEN2. Early diagnosis and therapy is possible by using biochemical and imaging screening in the families. Early thyroidectomy in young patients with MEN2 results in a high cure rate of MTC.

Oral mucosal stigmata in hereditary-cancer syndromes: From germline mutations to distinctive clinical phenotypes and tailored therapies.

Numerous familial tumor syndromes are associated with distinctive oral mucosal findings, which may make possible an early diagnosis as an efficacious marker for the risk of developing visceral malignancies. In detail, Familial Adenomatous Polyposis (FAP), Gardner syndrome, Peutz-Jeghers syndrome, Cowden Syndrome, Gorlin Syndrome, Lynch/Muir-Torre Syndrome and Multiple Endocrine Neoplasia show specific lesions of the oral mucosa and other distinct clinical and molecular features. The common genetic background of the above mentioned syndromes involve germline mutations in tumor suppressor genes, such as APC, PTEN, PTCH1, STK11, RET, clearly implied in both ectodermal and mesodermal differentiation, being the oral mucosal and dental stigmata frequently associated in the specific clinical phenotypes. The oral and maxillofacial manifestations of these syndromes may become visible several years before the intestinal lesions, constituting a clinical marker that is predictive for the development of intestinal polyps and/or other visceral malignancies. A multidisciplinary approach is therefore necessary for both clinical diagnosis and management of the gene-carriers probands and their family members who have to be referred for genetic testing or have to be investigated for the presence of visceral cancers.

Multiple Endocrine Neoplasia Syndromes.

Multiple endocrine neoplasia (MEN) is a term used to describe a group of hereditary carcinoma syndromes. Patients carrying a characteristic autosomal dominant gene aberration exhibit various endocrine carcinomas, as well as other anatomical abnormalities. Unfortunately, familial endocrine carcinoma patients are too often unrecognized by primary care providers, resulting in delayed diagnosis and treatment, with profound consequences related to morbidity and mortality. This article will introduce the various MEN syndromes and the infusion nurse's role in the care of these individuals and their families.

Multiple endocrine neoplasia syndromes 1 and 2: manifestations and management in childhood and adolescence.

The identification of the genetic causes of the multiple endocrine neoplasia (MEN) syndromes 1 and 2, and associated genotype-phenotype relationships, has revolutionised the clinical care of affected patients. A genetic diagnosis can be made during infancy and careful clinical surveillance, coupled with early intervention, has the potential to improve both morbidity and mortality. These developments have seen the management of patients with MEN move into the arena of paediatric medicine. In this review article, we consider the genetic causes of MEN together with the clinical manifestations and management of these syndromes.

PTCH 1 staining of pancreatic neuroendocrine tumor (PNET) samples from patients with and without multiple endocrine neoplasia (MEN-1) syndrome reveals a potential therapeutic target.

Pancreatic neuroendocrine tumors (PNETs) are rare, indolent tumors that may occur sporadically or develop in association with well-recognized hereditary syndromes, particularly multiple endocrine neoplasia type 1 (MEN-1). We previously demonstrated that the hedgehog (HH) signaling pathway was aberrantly up-regulated in a mouse model that phenocopies the human MEN-1 syndrome, Men1l/l;RipCre, and that inhibition of this pathway suppresses MEN-1 tumor cell proliferation. We hypothesized that the HH signaling pathway is similarly upregulated in human PNETs. We performed immunohistochemical (IHC) staining for PTCH1 in human fresh and archival PNET specimens to examine whether human sporadic and MEN-1-associated PNETs revealed similar abnormalities as in our mouse model and correlated the results with clinical and demographic factors of the study cohort. PTCH1 staining was positive in 12 of 22 PNET patients (55%). Four of 5 MEN-1 patients stained for PTCH1 (p = 0.32 as compared with sporadic disease patients). Nine of 16 patients with metastatic disease stained for PTCH1 as compared with zero of 3 with localized disease only (p = 0.21). No demographic or clinical features appeared to be predictive of PTCH 1 positivity and PTCH 1 positivity per se was not predictive of clinical outcome. PTCH1, a marker of HH pathway up regulation, is detectable in both primary and metastatic tumors in more than 50% of PNET patients. Although no clinical or demographic factors predict PTCH1 positivity and PTCH1 positivity does not predict clinical outcome, the frequency of expression alone indicates that perturbation of this pathway with agents such as Vismodegib, an inhibitor of Smoothened (SMO), should be examined in future clinical trials.

Endocrine cancer syndromes: an update.

Endocrine neoplasms comprise a variety of benign and malign tumors that arise from the endocrine glands or neuroendocrine tissues. Although most endocrine neoplasms are sporadic, others are secondary to mutations of many known tumor-predisposing genes. Endocrine cancer syndromes, including Multiple Endocrine Neoplasia type 1 (MEN1), Multiple Endocrine Neoplasia type 2 (MEN2A and MEN2B), Multiple Endocrine Neoplasia type 4 (MEN4) syndromes, and inherited syndromes with different endocrine neoplasms (von Hippel-Lindau disease, Carney complex, Neurofibromatosis type 1, others) are heterogeneous group of cancer susceptibility syndromes that affect one or more of the endocrine glands or neuroendocrine tissues. Genetic studies and researches as well as technological possibilities allowed for detection of new endocrine cancer syndromes and genes leading to tumor susceptibility. In addition, early detection of children at risk for endocrine cancer syndromes using molecular analysis methods provided opportunity to regular monitoring of potential malignancies and timely intervention for these cases (e.g. early prophylactic thyroidectomy in MEN2). This review will describe the clinical, genetic, diagnostic and therapeutic options for endocrine cancer syndromes based on the current literature data.

[Multiple endocrine neoplasia (MEN)]. / Multiple endokrine Neoplasie (MEN).

CLINICAL ISSUE: Multiple endocrine neoplasia (MEN) types 1 and 2 are hereditary cancer syndromes. They are characterized by the occurrence of many benign and malignant tumor types. STANDARD TREATMENT: Carriers of a MEN1 or RET gene mutation can be identified before manifestation of the disease. Family screening allows the early diagnosis and therapy of gene carriers. TREATMENT INNOVATIONS: Early thyroidectomy in young patients with MEN2 results in a high cure rate of medullary thyroid carcinoma (MTC). Treatment with tyrosine kinase inhibitors (TKI), such as vadetanib and cabozantinib, represents an important new therapeutic option for patients with progressive metastatic MTC. Neuroendocrine tumors (MEN1) are treated surgically and progressive disease is treated with somatostatin or everolimus. DIAGNOSTICS: The most important imaging methods for monitoring of MTC are sonography of the neck and upper abdomen and computed tomography (CT) of the lungs. In cases of MEN1 metastases can be localized by DOTATOC positron emission tomography CT (PET/CT). PERFORMANCE: Using these methods up to 70 % of tumors and metastases can be detected, depending on the localization, size and endocrine activity. Follow-up investigations with CT is an important tool for monitoring changes in tumor mass which are important criteria for decisions concerning TKI therapy. ACHIEVEMENTS: Together with the doubling time of tumor markers, tumor progression monitored by imaging methods or response evaluation criteria In solid tumors (RECIST) are prognostic factors and provide indications for initiating systemic therapy (e.g. TKI) PRACTICAL RECOMMENDATIONS: Patients with MEN syndromes should be treated in specialized centers because of the complexity and rarity.

Multiple endocrine neoplasia (MEN) syndromes.

Multiple endocrine neoplasia (MEN) syndromes are characterised by the combined occurrence of two or more endocrine tumours in a patient. These autosomal dominant conditions occur in four types: MEN1 due to inactivating MEN1 mutations; MEN2A and MEN2B (MEN3) due to activating mutations of RET and MEN4 due to inactivating cyclin-dependent kinase inhibitor 1B (CDKN1B) mutations. Each MEN syndrome exhibits different combinations of pancreatic islet, anterior pituitary, parathyroid, medullary thyroid and adrenal tumours. This article provides an overview of the clinical features, treatments and molecular genetics of each endocrine tumour syndrome.

Inherited cancer syndromes and the thyroid: an update.

PURPOSE OF REVIEW: Knowledge related to hereditary thyroid cancer syndromes has expanded enormously. This review identifies contributions that have changed approaches to diagnosis and broadened treatment options for patients with hereditary medullary and nonmedullary thyroid cancers related to multiple endocrine neoplasia type 2 (MEN2), Cowden syndrome, and familial adenomatous polyposis (FAP). RECENT FINDINGS: A new risk-stratification scheme based on type of RET gene mutation informs the age at which prophylactic thyroidectomy and diagnostic screening for MEN-associated endocrine diseases should occur. Two new US Food and Drug Administration-approved targeted medical therapies are now available for medullary thyroid cancer. There is better understanding of more aggressive clinical features and increased lifetime cancer risks for patients with well differentiated thyroid cancers as part of families with and without Cowden syndrome or FAP. This has led to a clearer appreciation for the role and timing of thyroid ultrasound screening in these populations. It has also informed the appropriate extent of thyroid surgery and the circumstances in which prophylactic thyroidectomy is reasonable to consider as part of hereditary syndromes other than MEN2. SUMMARY: Recognition and early diagnosis of these syndromes allows for comprehensive medical care and may improve thyroid cancer-related outcomes. Ultrasound-based screening programs to detect thyroid disease are advised for patients and family members with hereditary cancer syndromes.

A differential diagnosis of inherited endocrine tumors and their tumor counterparts.

Inherited endocrine tumors have been increasingly recognized in clinical practice, although some difficulties still exist in differentiating these conditions from their sporadic endocrine tumor counterparts. Here, we list the 12 main topics that could add helpful information and clues for performing an early differential diagnosis to distinguish between these conditions. The early diagnosis of patients with inherited endocrine tumors may be performed either clinically or by mutation analysis in at-risk individuals. Early detection usually has a large impact in tumor management, allowing preventive clinical or surgical therapy in most cases. Advice for the clinical and surgical management of inherited endocrine tumors is also discussed. In addition, recent clinical and genetic advances for 17 different forms of inherited endocrine tumors are briefly reviewed.

Multiple endocrine neoplasia: the enigma of MEN.

Multiple endocrine neoplasia (MEN) is an array of tumors found in various endocrine glands throughout the human body. A wide spectrum of clinical manifestations accompanies this syndrome. The complexities of the glandular function and subtle development of symptoms can cause the diagnosis to be missed, and individuals with MEN can be an enigma to the care team. Appropriate differential diagnosis and assessment are critical for these individuals to receive optimal care. An interprofessional team of health care providers, including an endocrinologist and an advanced practice endocrine nurse, must work in concert to orchestrate a plan of care across the continuum. Those specialized nurses who encounter individuals with MEN in a critical care setting are positioned to support the patient, the family, and the care team through this maze of multiple endocrinopathies and tumors.

A differential diagnosis of inherited endocrine tumors and their tumor counterparts

Inherited endocrine tumors have been increasingly recognized in clinical practice, although some difficulties still exist in differentiating these conditions from their sporadic endocrine tumor counterparts. Here, we list the 12 main topics that could add helpful information and clues for performing an early differential diagnosis to distinguish between these conditions. The early diagnosis of patients with inherited endocrine tumors may be performed either clinically or by mutation analysis in at-risk individuals. Early detection usually has a large impact in tumor management, allowing preventive clinical or surgical therapy in most cases. Advice for the clinical and surgical management of inherited endocrine tumors is also discussed. In addition, recent clinical and genetic advances for 17 different forms of inherited endocrine tumors are briefly reviewed.