Various neuroendocrine tumors in a multiple endocrin neoplasia type 1 family with the same genetic background

Latent Autoimmune Diabetes in the Adult, LADA has been investigated less than “classical” type 1 and type 2 diabetes and the criteria for and the relevance of a LADA diagnosis has been challenged. Despite the absence of a genetic background that is exclusive to LADA, this form of diabetes displays phenotypic characteristics that distinguish it from other forms of diabetes. LADA is heterogeneous in terms of the impact of autoimmunity and lifestyle factors, something that poses problems as to therapy and follow-up perhaps particularly in those with marginal positivity. Yet, there appears to be clear clinical utility in classifying individuals as LADA.

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Simultaneous Glucagon and Vasoactive Intestinal Peptide Producing Pancreatic Neuroendocrine Tumors in a Patient With Multiple Endocrine Neoplasia Type 1

Pancreas ◽

10.1097/mpa.0000000000000969 ◽

2018 ◽

Vol 47 (1) ◽

pp. e1-e2

Author(s):

Grace Y. Kim ◽

Sungeun Kim ◽

Raquel Kristin S. Ong ◽

Hassan Shawa

Keyword(s):

Vasoactive Intestinal Peptide ◽

Neuroendocrine Tumors ◽

Multiple Endocrine Neoplasia ◽

Multiple Endocrine Neoplasia Type ◽

Pancreatic Neuroendocrine Tumors ◽

Endocrine Neoplasia ◽

Endocrine Neoplasia Type

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MEN4 and CDKN1B mutations: the latest of the MEN syndromes

Endocrine Related Cancer ◽

10.1530/erc-17-0243 ◽

2017 ◽

Vol 24 (10) ◽

pp. T195-T208 ◽

Cited By ~ 52

Author(s):

Rami Alrezk ◽

Fady Hannah-Shmouni ◽

Constantine A Stratakis

Keyword(s):

Tumor Suppressor ◽

Neuroendocrine Tumors ◽

Pituitary Adenomas ◽

Wide Spectrum ◽

Susceptibility Gene ◽

Germline Mutations ◽

Suppressor Gene ◽

Loss Of Function ◽

Putative Tumor Suppressor

Multiple endocrine neoplasia (MEN) refers to a group of autosomal dominant disorders with generally high penetrance that lead to the development of a wide spectrum of endocrine and non-endocrine manifestations. The most frequent among these conditions is MEN type 1 (MEN1), which is caused by germline heterozygous loss-of-function mutations in the tumor suppressor geneMEN1. MEN1 is characterized by primary hyperparathyroidism (PHPT) and functional or nonfunctional pancreatic neuroendocrine tumors and pituitary adenomas. Approximately 10% of patients with familial or sporadic MEN1-like phenotype do not haveMEN1mutations or deletions. A novel MEN syndrome was discovered, initially in rats (MENX), and later in humans (MEN4), which is caused by germline mutations in the putative tumor suppressorCDKN1B. The most common phenotype of the 19 established cases of MEN4 that have been described to date is PHPT followed by pituitary adenomas. Recently, somatic or germline mutations inCDKN1Bwere also identified in patients with sporadic PHPT, small intestinal neuroendocrine tumors, lymphoma and breast cancer, demonstrating a novel role forCDKN1Bas a tumor susceptibility gene for other neoplasms. In this review, we report on the genetic characterization and clinical features of MEN4.

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Modeling Type 1 Diabetes Using Pluripotent Stem Cell Technology

Frontiers in Endocrinology ◽

10.3389/fendo.2021.635662 ◽

2021 ◽

Vol 12 ◽

Author(s):

Kriti Joshi ◽

Fergus Cameron ◽

Swasti Tiwari ◽

Stuart I. Mannering ◽

Andrew G. Elefanty ◽

...

Keyword(s):

Type 1 Diabetes ◽

Stem Cell ◽

Genetic Variants ◽

Genetic Background ◽

Pluripotent Stem Cell ◽

Cell Types ◽

Polygenic Inheritance

Induced pluripotent stem cell (iPSC) technology is increasingly being used to create in vitro models of monogenic human disorders. This is possible because, by and large, the phenotypic consequences of such genetic variants are often confined to a specific and known cell type, and the genetic variants themselves can be clearly identified and controlled for using a standardized genetic background. In contrast, complex conditions such as autoimmune Type 1 diabetes (T1D) have a polygenic inheritance and are subject to diverse environmental influences. Moreover, the potential cell types thought to contribute to disease progression are many and varied. Furthermore, as HLA matching is critical for cell-cell interactions in disease pathogenesis, any model that seeks to test the involvement of particular cell types must take this restriction into account. As such, creation of an in vitro model of T1D will require a system that is cognizant of genetic background and enables the interaction of cells representing multiple lineages to be examined in the context of the relevant environmental disease triggers. In addition, as many of the lineages critical to the development of T1D cannot be easily generated from iPSCs, such models will likely require combinations of cell types derived from in vitro and in vivo sources. In this review we imagine what an ideal in vitro model of T1D might look like and discuss how the required elements could be feasibly assembled using existing technologies. We also examine recent advances towards this goal and discuss potential uses of this technology in contributing to our understanding of the mechanisms underlying this autoimmune condition.

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Clues For Genetic Anticipation In Multiple Endocrine Neoplasia Type 1

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/clinem/dgaa257 ◽

2020 ◽

Vol 105 (7) ◽

pp. e2491-e2500

Author(s):

Medard F M van den Broek ◽

Bernadette P M van Nesselrooij ◽

Carolina R C Pieterman ◽

Annemarie A Verrijn Stuart ◽

Annenienke C van de Ven ◽

...

Keyword(s):

Neuroendocrine Tumors ◽

Multiple Endocrine Neoplasia ◽

Molecular Mechanisms ◽

Multiple Endocrine Neoplasia Type ◽

Genetic Anticipation ◽

Screening Programs ◽

Endocrine Neoplasia ◽

Endocrine Neoplasia Type ◽

Successive Generations

Abstract Context Multiple endocrine neoplasia type 1 (MEN1) is a rare autosomal dominant hereditary disease caused by the loss of function of the MEN1 gene, a tumor-suppressor gene that encodes the protein menin. It is characterized by the occurrence of primary hyperparathyroidism (pHPT), duodenopancreatic neuroendocrine tumors (dpNET), pituitary tumors (PIT), adrenal adenomas, and bronchopulmonary (bp-NET), thymic, and gastric neuroendocrine tumors. More insight into factors influencing the age-related penetrance of MEN1 manifestations could provide clues for more personalized screening programs. Objective To investigate whether genetic anticipation plays a role in the largest known MEN1 families in the Netherlands. Methods All Dutch MEN1 families with ≥ 10 affected members in ≥ 2 successive generations were identified. Age at detection of the different MEN1-related manifestations were compared among generations using regression analyses adjusted for competing risks. To correct for the beneficial effect of being under surveillance, manifestations occurring during surveillance were also separately compared. Results A total of 152 MEN1 patients from 10 families were included. A significantly decreased age at detection of pHPT, dpNET, PIT, and bp-NET was found in successive generations (P < 0.0001). Adjusted analyses led to the same results. Conclusions These results suggest the presence of genetic anticipation. However, due to a risk of residual bias, the results must be interpreted with caution. After independent validation in other cohorts and further translational research investigating the molecular mechanisms explaining this phenomenon in MEN1, the results might add to future, more personalized, screening protocols and earlier screening for future generations of MEN1 patients.

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