Genetic variations associated with hyperplasias, adenomas of adrenal cortex

Posted on February 27, 2014 by MaryO

Beuschlein F. N Engl J Med. 2014;doi:10.1056/NEJMoa1310359.

Genetic variations of the catalytic subunit of cyclic protein kinase A, or PKA, were linked to the development of bilateral adrenal hyperplasias and unilateral cortisol-producing adrenal adenomas. These effects may activate corticotropin-independent Cushing’s syndrome, according to data published in The New England Journal of Medicine.

“The current study suggests that more than one-third of cortisol-producing adenomas associated with overt Cushing’s syndrome have unique somatic mutations in PRKACA (which encodes the main catalytic subunit of PKA), resulting in constitutive PKA activation,” Felix Beuschlein, MD, of the University of Munich, and colleagues wrote.

The researchers performed an exome sequencing of tumor-tissue specimens from 10 patients with cortisol-producing adrenal adenomas and evaluated their recurrent mutations in candidate genes in 171 additional patients with adrenocortical tumors, according to data.

Somatic mutations in PRKACA were discovered in eight of 10 adenomas. These somatic mutations also were identified in 22 of 59 unilateral adenomas (37%) from patients with overt Cushing’s syndrome; mutations were not detectable in 40 patients with subclinical hypercortisolism or in 82 patients with other adrenal tumors, according to data.

Five of the 35 patients with cortisol-producing hyperplasias appeared to be carriers of the germline duplication of the genomic region on chromosome 19 that includes PRKACA, researchers wrote.

In vitro study data indicated that PKA catalytic subunit genetic mutations impaired inhibition by the PKA regulatory subunit, and cells from patients with germline chromosomal gains appeared to increase the protein levels of the subunit.

“Because PRKACA mediates most of the effects of inactivating PRKAR1A mutations and because mutations of PRKAR1 are associated with a variety of tumors in humans and mice, we would speculate that somatic PRKACA defects might also play a role in other forms of endocrine and nonendocrine tumors,” researchers wrote.

Disclosure: Beuschlein reports financial ties with the European Community, HRA Pharma, Novartis, Viropharma, and Wilhelm-Sander Stiftung.

From http://www.healio.com/endocrinology/adrenal/news/online/%7B22954d9a-0fc9-4e80-b80a-d74bbdfea1a9%7D/genetic-variations-associated-with-hyperplasias-adenomas-of-adrenal-cortex

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Polycystic ovarian syndrome and Cushing’s syndrome: A persistent diagnostic quandary

Posted on February 10, 2014 by MaryO
European Journal of Obstetrics & Gynecology and Reproductive Biology, 02/10/2014  Clinical Article

Brzana J, et al. – This study aims to retrospectively review institutional records of female patients of reproductive age with Cushing’s disease (CD) and determine if and how many had been previously diagnosed as having solely PCOS. To determine whether clinical patterns might be useful in identifying appropriate candidates for hypercortisolism screening in women suspected of PCOS. Prolonged exposure to hypercortisolism has been linked with increased mortality and morbidity. Tests for hypercortisolism in all the PCOS cases authors report led to an appropriate CD diagnosis. Future research should focus on when and which (if not all) women with suspected PCOS should be tested for hypercortisolism.

Methods

  • The study included 50 patients with pathologically proven CD at Oregon Health & Science University, Northwest Pituitary Center between 2006 and 2011.
  • Physical, clinical, and biochemical features for hypercortisolism were compared.

Results

  • Of 50 patients with pathologically proven CD, 26 were women of reproductive age.
  • Of these, half had previously been diagnosed with and treated initially solely for PCOS.
  • Hirsutism and menstrual abnormalities were more common in the group with an initial PCOS diagnosis than in the group with an initial CD diagnosis.

From http://www.mdlinx.com/endocrinology/newsl-article.cfm/5055779/ZZ4747461521296427210947/?news_id=2364&newsdt=021014&subspec_id=1509&utm_source=Focus-On&utm_medium=newsletter&utm_content=Top-New-Article&utm_campaign=article-section

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Are you carrying adrenal Cushing’s syndrome without knowing it?

Posted on November 28, 2013 by MaryO

Genetic research that will be published tomorrow in the New England Journal of Medicine suggests to Dr. André Lacroix, professor at the University of Montreal, that clinicians’ understanding and treatment of a form of Cushing’s syndrome affecting both adrenal glands will be fundamentally changed, and that moreover, it might be appropriate to begin screening for the genetic mutations that cause this form of the disease.

“Screening family members of bilateral adrenal Cushing’s syndrome patients with  may identify affected silent carriers,” Lacroix said in an editorial in the Journal. “The development of drugs that interrupt the defective genetic chemical link that causes the syndrome could, if confirmed to be effective in people, provide individualized specific therapies for hypercortisolism, eliminate the current practice of removing both , and possibly prevent disease progression in genetically affected .”

Adrenal glands sit above the kidneys are mainly responsible for releasing cortisol, a stress hormone. Hypercortiolism means a high level of the adrenal hormone cortisol, which causes many symptoms including weight gain, , diabetes, osteoporosis, concentration deficit and increased cardiovascular deaths.

Cushing’s syndrome can be caused by corticosteroid use (such as for asthma or arthritis), a tumor on the adrenal glands, or a  that releases too much ACTH. The pituitary gland sits under the brain and releases various hormones that regulate our bodies’ mechanisms.

Jérôme Bertherat is a researcher at Cochin Hospital in Paris. In the study he published today, he showed that 55% of Cushing’s Syndrome patients with bilaterally very enlarged adrenal glands have mutations in a gene that predisposes to the development of adrenal tumours. This means that bilateral adrenal Cushing’s is much more hereditary than previously thought. The new knowledge will also enable clinicians to undertake genetic screening. Hervé Lefebvre is a researcher at the University Hospital in Rouen, France. His research shows that the adrenal glands from the same type of patients with two large adrenal glands can produce ACTH, which is normally produced by the pituitary gland. Hormone receptors are the chemical link that cause a cell to behave differently when a hormone is present. Several misplaced hormone receptors cause the ACTH to be produced in the enlarged benign adrenal tissue. Knowing this means that researchers might be able to develop drugs that interrupt the receptors for these hormones and possibly even prevent the benign tissue from developing in the first place.

 Explore further: Scientists discover a curable cause for some cases of high blood pressure

More information: André Lacroix, M.D., Heredity and Cortisol Regulation in Bilateral Macronodular Adrenal Hyperplasia, New England Journal of Medicine 369;22, November 28, 2013

Estelle Louiset, Ph.D., Céline Duparc, Ph.D., Jacques Young, M.D., Ph.D., Sylvie Renouf, Ph.D., Milène Tetsi Nomigni, M.Sc., Isabelle Boutelet, Ph.D., Rossella Libé, M.D., Zakariae Bram, M.Sc., Lionel Groussin, M.D., Ph.D., Philippe Caron, M.D., Antoine Tabarin, M.D., Ph.D., Fabienne Grunenberger, M.D., Sophie Christin-Maitre, M.D., Ph.D., Xavier Bertagna, M.D., Ph.D., Jean-Marc Kuhn, M.D., Youssef Anouar, Ph.D., Jérôme Bertherat, M.D., Ph.D., and Hervé Lefebvre, M.D., Ph.D., Intraadrenal Corticotropin in Bilateral Macronodular Adrenal Hyperplasia, New England Journal of Medicine 369;22, November 28, 2013

Guillaume Assié, M.D., Ph.D., Rossella Libé, M.D., Stéphanie Espiard, M.D., Marthe Rizk-Rabin, Ph.D., Anne Guimier, M.D., Windy Luscap, M.Sc., Olivia Barreau, M.D., Lucile Lefèvre, M.Sc., Mathilde Sibony, M.D., Laurence Guignat, M.D., Stéphanie Rodriguez, M.Sc., Karine Perlemoine, B.S., Fernande René-Corail, B.S., Franck Letourneur, Ph.D., Bilal Trabulsi, M.D., Alix Poussier, M.D., Nathalie Chabbert-Buffet, M.D., Ph.D., Françoise Borson-Chazot, M.D., Ph.D., Lionel Groussin, M.D., Ph.D., Xavier Bertagna, M.D., Constantine A. Stratakis, M.D., Ph.D., Bruno Ragazzon, Ph.D., and Jérôme Bertherat, M.D., Ph.D., ARMC5 Mutations in Macronodular Adrenal Hyperplasia with Cushing’s Syndrome, New England Journal of Medicine 369;22, November 28, 2013

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Is Diabetes in Cushing’s Syndrome a Consequence of Hypercortisolism?

Posted on November 25, 2013 by MaryO
Eur J Endocrinol. 2013 Nov 19. [Epub ahead of print]

Is Diabetes in Cushing syndrome only a consequence of hypercortisolism?

Source

C Giordano, Dipartimento di Medicina Interna e Specialistica (Di.Bi.Mi.S) Sezione di Endocrinologia e Malattie del Metabolismo, University of Palermo, Palermo, Italy.

Abstract

OBJECTIVE:

Diabetes mellitus (DM) is one of the most frequent complications of Cushing syndrome (CS). Aim of the study was to define the changes in insulin sensitivity and/or secretion in relation to glucose tolerance categories in newly diagnosed CS patients.

DESIGN:

Cross-sectional study on 140 patients with CS.

METHODS:

113 women (80 with pituitary disease and 33 with adrenal disease, aged 41.7±15.7 yr) and 27 men (19 with pituitary disease and 8 with adrenal disease, aged 38.1±20.01 yr) at diagnosis were divided according to glucose tolerance into normal glucose tolerance (CS/NGT), impaired fasting glucose and/or impaired glucose tolerance (CS/prediabetes) and diabetes (CS/DM).

RESULTS:

71 patients belonged to CS/NGT (49.3%), 26 (18.5%) to CS/prediabetes and 43 (30.8%) to CS/DM. Significant increasing trends in the prevalence of family history of diabetes (p<0.001), metabolic syndrome (p<0.001), age (p<0.001) and waist circumference (p=0.043) and decreasing trends in HOMAβ (p<0.001)and Oral Dispositional Index (DIo) (p<0.002) were observed among the groups. No significant trend in fasting insulin, AUC INS, ISI-Matsuda and VAI was detected.

CONCLUSIONS:

Impairment of glucose tolerance is characterized by the inability of β-cells to adequately compensate insulin resistance through increased insulin secretion. Age, genetic predisposition and lifestyle, in combination with duration and degree of hypercortisolism, strongly contribute to the impairment of glucose tolerance in the natural history of CS. A careful phenotypic evaluation of glucose tolerance defects in patients with CS proves useful for the identification of patients at high risk for metabolic complications.

PMID:
24255133
[PubMed – as supplied by publisher]

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Outcome of Bilateral Adrenalectomy in Cushing’s Syndrome: A Systematic Review

Posted on October 5, 2013 by MaryO
  1. Katrin Ritzel,
  2. Felix Beuschlein,
  3. Anne Mickisch,
  4. Andrea Osswald,
  5. Harald J. Schneider,
  6. Jochen Schopohl and
  7. Martin Reincke

–Author Affiliations


  1. Medizinische Klinik und Poliklinik IV, Klinikum der Universität München, D-80336 München, Germany
  1. Address all correspondence and requests for reprints to: Martin Reincke, M.D., Medizinische Klinik und Poliklinik IV, Klinikum der Universität München, Ziemssenstrasse 1, D-80336 München, Germany. E-mail:Martin.Reincke@med.uni-muenchen.de.

Abstract

Background: The outcome of bilateral adrenalectomy (BADx) in patients with Cushing’s syndrome (CS) is not well characterized.

Methods: A literature search was performed with the search terms “bilateral adrenalectomy” or “total adrenalectomy” and “Cushing’s” or “Cushing.” Immediate and long-term outcomes after BADx in CS were analyzed using descriptive statistics (median [range]).

Results: From 549 screened publications, 37 studies met inclusion criteria (1320 patients, 82% having Cushing’s disease [CD], 13% having ectopic CS, and 5% having primary adrenal hyperplasia).

Surgical morbidity and mortality of BADx (23 studies, 739 patients) were 18% (6–31) and 3% (0–15), respectively. In patients with CD, surgical mortality was below 1%. Although residual cortisol secretion due to accessory adrenal tissue or adrenal remnants was found in 3–34% (5 studies, 236 patients), less than 2% had a relapse of CS.

Symptoms of hypercortisolism (eg, hypertension, obesity, or depression) improved in the majority of the patients after BADx (7 studies, 195 patients). The number of adrenal crises per 100 patient-years was 9.3 (6 studies, 203 patients).

Nelson’s syndrome occurred in 21% (0–47) of the patients (24 studies, 768 patients). Mortality (23 studies, 690 patients) was 17% (0–88) at a follow-up of 41 months (14–294). Remarkably, 46% of the patients died in the first year after surgery. The median ages at death were 62 years (CD) and 53 years (ectopic CS).

Conclusion: BADx is relatively safe and provides adequate success. Excess mortality within the first year after surgery suggests that intensive clinical care for patients after BADx is warranted.

Footnotes

  • For editorial see page 3974

  • Abbreviations:

    BADx
    bilateral adrenalectomy
    BAH
    bilateral adrenal hypercortisolism
    CD
    Cushing’s disease
    CS
    Cushing’s syndrome
    ECS
    ectopic CS
    NS
    Nelson’s syndrome
    QOL
    quality of life
    TSS
    transsphenoidal surgery.

     

From http://jcem.endojournals.org/content/98/10/3939.abstract

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