Cushing disease in a patient with multiple endocrine neoplasia type 2B

Kasturi, Kannan; Fernandes, Lucas Borges Fleury; Quezado, Martha; Eid, Mary; Marcus, Leigh; Chittiboina, Prashant; Rappaport, Mark S.; Stratakis, Constantine A.; Widemann, Brigitte C.; Lodish, Maya

doi:10.1016/j.jecr.2017.02.001

Cited by 16 publications

(15 citation statements)

References 11 publications

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“…To date, only 2 cases of CD in patients with MEN2 syndrome have been reported: a case in an adult patient with MEN2A and one in a paediatric patient with MEN2B syndrome. In both cases, CD was caused by a microcorticotropinoma …”

Section: Introductionmentioning

confidence: 92%

Genetics of Cushing's disease

Albani

Theodoropoulou

Reincke

2017

Clinical Endocrinology

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SummaryCushing's disease (CD) is a rare disabling condition caused by Adrenocorticotropic hormone (ACTH)-secreting adenomas of the pituitary. The majority of corticotropic adenomas are monoclonal and occur sporadically. Only rarely does CD arise in the context of genetic familial syndromes. Targeted sequencing of oncogenes and tumour suppressor genes commonly mutated in other tumours did not identify recurrent mutations. In contrast, next generation sequencing allowed us recently to clarify the genetic basis of CD: we identified somatic driver mutations in the ubiquitin-specific protease 8 (USP8) gene in a significant portion of corticotropinomas. These mutations represent a novel and unique mechanism leading to ACTH excess. Inhibition of USP8 or its downstream signalling pathways could represent a new therapeutic approach for the management of CD. In this review, we will focus on this new evidence and its implication for clinical care of affected patients. K E Y W O R D SAdrenocorticotropic hormone, corticotropinoma, cortisol, Cushing's syndrome, mutation, pituitary adenoma | INTRODUCTIONCushing′s disease (CD) is a rare devastating condition leading to chronic hypercortisolism. It is caused by Adrenocorticotropic hormone (ACTH)-secreting tumours (corticotropinomas) of the pituitary gland. With an incidence of 1.2-1.7 cases per million per year, its epidemiology is consistent with a classical rare disease.1 CD is associated with increased morbidity and mortality, the latter mainly due to cardiovascular events. 2Pituitary adenomas are mainly monoclonal neoplasms.3 The genetic basis of CD was unclear until recently when recurrent activating somatic driver mutations in the ubiquitin-specific protease 8 gene (USP8)were identified in almost half of corticotropinomas. 4-8 Based on this evidence, the pathophysiology of CD has become much clearer. In addition, identification of driver mutations opens up novel diagnostic and therapeutic options for CD. Abbreviations which are used throughout the text are defined in the appendix at the end of the article. | Mechanisms of tumorigenesisCorticotropinomas are characterized by altered expression of proteins regulating cell cycle progression. Overexpression of several cyclins has been frequently documented in pituitary adenomas, with overexpression of cyclin E (CCNE1) being specific for corticotropinomas. 9In contrast, cyclin-dependent kinase inhibitors such as p16/Ink4a and p27/Kip1 are downregulated in these tumours. [10][11][12] In particular, p27/ Kip1 protein is dramatically reduced in the majority of corticotropinomas.13 None of the factors that regulate p27 translation and could explain its downregulation at protein but not transcript level, such as dyskeratosis congenita (DKC1)/Dyskerin, ribosomal protein S13 (RPS13), miR221 and miR222, are deregulated in corticotropinomas.14 A recent study using quantitative real time PCR showed decreased transcripts for cyclin D1 and CCNE1 and increased for p16/Ink4 in the 10 CD tumours compared to 11 silent corticotropinomas and 22 n...

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Section: Introductionmentioning

confidence: 92%

Genetics of Cushing's disease

Albani

Theodoropoulou

Reincke

2017

Clinical Endocrinology

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“…Three patients presented with an MEN2A-like phenotype; the fourth patient presented as MEN2B; among them, two CD cases have been associated with RET mutations. 93–96 Other patients with similar phenotypes have been described in the literature, although genetic testing was not available or was negative for RET mutations. 97 Although rarely, MEN4 patients can also develop CS due to ectopic ACTH secretion from MTC.…”

Section: Genetic Alterations In Cushing’s Diseasementioning

confidence: 83%

Genetics of Cushing’s Syndrome

Hernández-Ramírez¹,

Stratakis²

2018

Endocrinology and Metabolism Clinics of North America

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The knowledge on the molecular and genetic causes of Cushing's syndrome (CS) has greatly increased in the recent years. Somatic mutations leading to overactive 3',5'-cyclic adenosine monophosphate/protein kinase A and wingless-type MMTV integration site family/beta-catenin pathways are the main molecular mechanisms underlying adrenocortical tumorigenesis. Corticotropinomas are characterized by resistance to glucocorticoid negative feedback, impaired cell cycle control and overexpression of pathways sustaining ACTH secretion. Recognizing the genetic defects behind corticotroph and adrenocortical tumorigenesis proves crucial for tailoring the clinical management of CS patients and for designing strategies for genetic counseling and clinical screening to be applied in routine medical practice.

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“…Cushing disease has been reported in MEN4 due to a heterozygous 19-bp duplication (c.59_77dup19) in CDKN1B , leading to a truncated protein (Georgitsi et al 2007). It should be noted that corticotropinomas are also observed in MEN1 (Verges, et al 2002; Stratakis et al 2010;), and very rarely in MEN2B (Kasturi, et al 2017). Interestingly, one study found the common CDKN1B rs2066827 polymorphism to play a role in corticotropinoma susceptibility and tumorigenesis through a yet unidentified mechanism or, maybe, epigenetic factors (Sekiya, et al 2014).…”

Section: Clinical Manifestations Of Men4mentioning

confidence: 97%

MEN4 and CDKN1B mutations: the latest of the MEN syndromes

Alrezk¹,

Hannah‐Shmouni²,

Stratakis³

2017

Endocrine-Related Cancer

155

104

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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 gene MEN1. 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 have MEN1 mutations or deletions. Recently, 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 suppressor CDKN1B. The most common phenotype of the 19 cases of MEN4 that have been described to date is PHPT followed by pituitary adenomas. Recently, somatic and germline mutations in CDKN1B were also identified in patients with sporadic PHPT, lymphoma, and breast cancer, demonstrating a novel role for CDKN1B as 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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Cushing disease in a patient with multiple endocrine neoplasia type 2B

Cited by 16 publications

References 11 publications

Genetics of Cushing's disease

Genetics of Cushing's disease

Genetics of Cushing’s Syndrome

MEN4 and CDKN1B mutations: the latest of the MEN syndromes

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