Carney complex: an update Correa, Ricardo; Salpea, Paraskevi; Stratakis, Constantine A
European journal of endocrinology,
10/2015, Letnik:
173, Številka:
4
Journal Article
Recenzirano
Odprti dostop
Carney complex (CNC) is a rare autosomal dominant syndrome, characterized by pigmented lesions of the skin and mucosa, cardiac, cutaneous and other myxomas and multiple endocrine tumors. The disease ...is caused by inactivating mutations or large deletions of the PRKAR1A gene located at 17q22–24 coding for the regulatory subunit type I alpha of protein kinase A (PKA) gene. Most recently, components of the complex have been associated with defects of other PKA subunits, such as the catalytic subunits PRKACA (adrenal hyperplasia) and PRKACB (pigmented spots, myxomas, pituitary adenomas). In this report, we review CNC, its clinical features, diagnosis, treatment and molecular etiology, including PRKAR1A mutations and the newest on PRKACA and PRKACB defects especially as they pertain to adrenal tumors and Cushing's syndrome.
The cAMP-dependent protein kinase (PKA) system represents a primary cell-signaling pathway throughout systems and across species. PKA facilitates the actions of hormones, neurotransmitters and other ...signaling molecules that bind G-protein coupled receptors (GPCR) to modulate cAMP levels. Through its control of synaptic events, exocytosis, transcriptional regulation, and more, PKA signaling regulates cellular metabolism and emotional and stress responses making it integral in the maintenance and dysregulation of energy homeostasis. Neural PKA signaling is regulated by afferent and peripheral efferent signals that link specific neural cell populations to the regulation of metabolic processes in adipose tissue, liver, pancreas, adrenal, skeletal muscle, and gut. Mouse models have provided invaluable information on the roles for PKA subunits in brain and key metabolic organs. While limited, human studies infer differential regulation of the PKA system in obese compared to lean individuals. Variants identified in PKA subunit genes cause Cushing syndrome that is characterized by metabolic dysregulation associated with endogenous glucocorticoid excess. Under healthy physiologic conditions, the PKA system is exquisitely regulated by stimuli that activate GPCRs to alter intracellular cAMP concentrations, and by PKA cellular localization and holoenzyme stability. Adenylate cyclase activity generates cAMP while phosphodiesterase-mediated cAMP degradation to AMP decreases cAMP levels downstream of GPCRs. Chronic perturbations in PKA signaling appear to be capable of resetting PKA regulation at several levels; in addition, sex differences in PKA signaling regulation, while not well understood, impact the physiologic consequences of metabolic dysregulation and obesity. This review explores the roles for PKA signaling in the pathogenesis of metabolic diseases including obesity, type 2 diabetes mellitus and associated co-morbidities through neural-peripheral crosstalk and cAMP/PKA signaling pathway targets that hold therapeutic potential.
Both direct and indirect evidence demonstrate a central role for the cAMP-dependent protein kinase (PKA) signaling pathway in the regulation of energy balance and metabolism across multiple systems. ...However, the ubiquitous pattern of PKA expression across cell types poses a challenge in pinpointing its tissue-specific regulatory functions and further characterizing its many downstream effects in certain organs or cells. Mouse models of PKA deficiency and over-expression and studies in living cells have helped clarify PKA function in adipose tissue (AT), liver, adrenal, pancreas, and specific brain nuclei, as they pertain to energy balance and metabolic dysregulation. Limited studies in humans suggest differential regulation of PKA in AT of obese compared to lean individuals and an overall dysregulation of PKA signaling in obesity. Despite its complexity, under normal physiologic conditions, the PKA system is tightly regulated by changes in cAMP concentrations upstream via adenylate cyclase and downstream by phosphodiesterase-mediated cAMP degradation to AMP and by changes in PKA holoenzyme stability. Adjustments in the PKA system appear to be important to the development and maintenance of the obese state and its associated metabolic perturbations. In this review we discuss the important role of PKA in obesity and its involvement in resistance to obesity, through studies in humans and in mouse models, with a focus on the regulation of PKA in energy expenditure, intake behavior, and lipid and glucose metabolism.
Cushing's syndrome Lacroix, André, Prof; Feelders, Richard A, MD; Stratakis, Constantine A, MD ...
The Lancet (British edition),
08/2015, Letnik:
386, Številka:
9996
Journal Article
Recenzirano
Summary Chronic exposure to excess glucorticoids results in diverse manifestations of Cushing's syndrome, including debilitating morbidities and increased mortality. Genetic and molecular mechanisms ...responsible for excess cortisol secretion by primary adrenal lesions and adrenocorticotropic hormone (ACTH) secretion from corticotroph or ectopic tumours have been identified. New biochemical and imaging diagnostic approaches and progress in surgical and radiotherapy techniques have improved the management of patients. The therapeutic goal is to normalise tissue exposure to cortisol to reverse increased morbidity and mortality. Optimum treatment consisting of selective and complete resection of the causative tumour is necessay to allow eventual normalisation of the hypothalamic-pituitary-adrenal axis, maintenance of pituitary function, and avoidance of tumour recurrence. The development of new drugs offers clinicians several choices to treat patients with residual cortisol excess. However, for patients affected by this challenging syndrome, the long-term effects and comorbidities associated with hypercortisolism need ongoing care.
Objective:
This clinical practice guideline addresses the diagnosis and treatment of primary adrenal insufficiency.
Participants:
The Task Force included a chair, selected by The Clinical Guidelines ...Subcommittee of the Endocrine Society, eight additional clinicians experienced with the disease, a methodologist, and a medical writer. The co-sponsoring associations (European Society of Endocrinology and the American Association for Clinical Chemistry) had participating members. The Task Force received no corporate funding or remuneration in connection with this review.
Evidence:
This evidence-based guideline was developed using the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) system to determine the strength of recommendations and the quality of evidence.
Consensus Process:
The evidence used to formulate recommendations was derived from two commissioned systematic reviews as well as other published systematic reviews and studies identified by the Task Force. The guideline was reviewed and approved sequentially by the Endocrine Society's Clinical Guidelines Subcommittee and Clinical Affairs Core Committee, members responding to a web posting, and the Endocrine Society Council. At each stage, the Task Force incorporated changes in response to written comments.
Conclusions:
We recommend diagnostic tests for the exclusion of primary adrenal insufficiency in all patients with indicative clinical symptoms or signs. In particular, we suggest a low diagnostic (and therapeutic) threshold in acutely ill patients, as well as in patients with predisposing factors. This is also recommended for pregnant women with unexplained persistent nausea, fatigue, and hypotension. We recommend a short corticotropin test (250 μg) as the “gold standard” diagnostic tool to establish the diagnosis. If a short corticotropin test is not possible in the first instance, we recommend an initial screening procedure comprising the measurement of morning plasma ACTH and cortisol levels. Diagnosis of the underlying cause should include a validated assay of autoantibodies against 21-hydroxylase. In autoantibody-negative individuals, other causes should be sought. We recommend once-daily fludrocortisone (median, 0.1 mg) and hydrocortisone (15–25 mg/d) or cortisone acetate replacement (20–35 mg/d) applied in two to three daily doses in adults. In children, hydrocortisone (∼8 mg/m2/d) is recommended. Patients should be educated about stress dosing and equipped with a steroid card and glucocorticoid preparation for parenteral emergency administration. Follow-up should aim at monitoring appropriate dosing of corticosteroids and associated autoimmune diseases, particularly autoimmune thyroid disease.
What is the relationship between our genes and the environment we live in with regard to health? Like the debate about nature or nurture in the determination of our personality and behavior, the ...issue of genes and environment has been discussed intensely in the last two centuries. Is it Darwin or Lamarck who is right about the basic determinants of our health, especially as we age in a rapidly changing environment? Evolutionary biology as proposed by Darwin with natural selection at its core may not be able to explain almost instant adjustments of phenotypic traits to the pressures of the environment. Epigenesis, a concept that dates from Aristotle, provides a mechanism for the environment to affect variation in genetic traits that may become heritable. Indeed, Lamarck first described the inheritance of acquired characteristics. Thus, it appears that in contemporary genetics, both Darwin and Lamarck are right: environmental pressures may affect our genes through epigenetics, in ways that allow for inheritance of the changes, a Lamarckian concept; however, evolution through natural selection is the basis for incorporation (or rejection) of new traits and their sustained inheritance, a Darwinian concept. In this review, we present the synthesis of Darwin's and Lamarck's theories, the only way to understand how our health, and that of our progeny, responds to challenging and fast-changing environmental cues. In addition, we present other examples of environment-driven changes in disease frequency or expression.
Multiple endocrine neoplasia type 1 (MEN1) is a rare hereditary tumor syndrome inherited in an autosomal dominant manner and characterized by a predisposition to a multitude of endocrine neoplasms ...primarily of parathyroid, enteropancreatic, and anterior pituitary origin, as well as nonendocrine neoplasms. Other endocrine tumors in MEN1 include foregut carcinoid tumors, adrenocortical tumors, and rarely pheochromocytoma. Nonendocrine manifestations include meningiomas and ependymomas, lipomas, angiofibromas, collagenomas, and leiomyomas. MEN1 is caused by inactivating mutations of the tumor suppressor gene
which encodes the protein menin. This syndrome can affect all age groups, with 17% of patients developing MEN1-associated tumors before 21 years of age. Despite advances in the diagnosis and treatment of MEN1-associated tumors, patients with MEN1 continue to have decreased life expectancy primarily due to malignant neuroendocrine tumors. The most recent clinical practice guidelines for MEN1, published in 2012, highlight the need for early genetic and clinical diagnosis of MEN1 and recommend an intensive surveillance approach for both patients with this syndrome and asymptomatic carriers starting at the age of 5 years with the goal of timely detection and management of MEN1-associated neoplasms and ultimately decreased disease-specific morbidity and mortality. Unfortunately, there is no clear genotype-phenotype correlation and individual mutation-dependent surveillance is not possible currently.
Protein kinase A (PKA) or cyclic‐AMP (cAMP)‐dependent kinase was among the first serine–threonine kinases to be molecularly and functionally characterized. For years, it was investigated as the ...enzyme that mediates cAMP functions in almost all cell systems and organisms studied to date. Despite PKA's critical role in signaling and the long history of investigations of cAMP in oncogenesis (dating back to the 1970s), it was not until relatively recently that PKA defects were found to be directly involved in tumor predisposition. First, PKA's main regulatory subunit, PRKAR1A, was found to be mutated in Carney complex, a genetic syndrome that predisposes to heart tumors (cardiac myxomas) and a variety of other lesions of the endocrine system, including the adrenal cortex, and several cancers, including liver carcinoma. Then, PKA's main catalytic subunit, PRKACA, was found to be mutated in sporadic adrenal tumors and fibrolamellar liver carcinoma. Not surprisingly, therefore, a new research study published in The Journal of Pathology showed PRKACA mutations in sporadic cardiac myxomas. The real question is what other pathologies will be found to be due to PRKACA (or other PKA subunit) defects. The possibilities abound and may show the way for a totally new class of medications that target cAMP signaling to be useful in fighting the corresponding tumors. Published 2017. This article is a U.S. Government work and is in the public domain in the USA.
Abstract
Carney complex is a rare, autosomal dominant, multiple endocrine neoplasia and lentiginosis syndrome, caused in most patients by defects in the
PRKAR1A
gene, which encodes the regulatory ...subunit type 1α of protein kinase A. Inactivating defects of
PRKAR1A
lead to aberrant cyclic-AMP-protein kinase A signaling. Patients may develop multiple skin abnormalities and a variety of endocrine and non-endocrine tumors. Endocrine manifestations include primary pigmented nodular adrenocortical disease, that may cause Cushing syndrome, growth-hormone secreting pituitary adenoma or pituitary somatotropic hyperplasia which can result in acromegaly, as well as gonadal and thyroid tumors. Non-endocrine tumors associated with Carney complex include myxomas of the heart, breast, and other sites, psamommatous melanotic schwannomas, breast ductal adenomas, osteochondromyxomas, and a predisposition to a number of malignancies from adrenal to pancreatic and liver cancer.
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