Myth: “Men1 and Men2 are the only genetic causes of Cushing’s”

Posted on December 19, 2014 by MaryO

Myth: “Men1 and Men2 are the only genetic causes of Cushing’s”

myth-busted

FACT: This is a Myth. More current research has explored multiple etiologies of Cushing’s. It was once thought that heredity had no influence on the development of Cushing’s Syndrome/Disease and our knowledge was once limited in this sense. Researchers have done more work in terms of exploring genetic factors in the onset of this disease. *~Robin Ess (Cushing’s educator and advocate)

The following causes for Cushing’s have all been explored:

1. Men 1

2. Men2

3. FIPA

4. CAH/BAH

5. PRKAR1A(protein kinase,cAMP-dependent, regulatory, type I, ? gene)

http://www.medscape.org/viewarticle/564106_2

6.(PDE11A)

http://www.medscape.org/viewarticle/564106_4

http://www.medscape.org/viewarticle/564106_6

7.PRKACA

http://www.nature.com/nrendo/journal/v10/n8/pdf/nrendo.2014.89.pdf?WT.ec_id=NRENDO-201408

http://www.ncbi.nlm.nih.gov/pubmed/24700472

http://www.nature.com/ng/journal/v46/n6/full/ng.2956.html

https://www.genomeweb.com/sequencing/exome-sequencing-study-narrows-new-cushings-syndrome-gene-culprit

8.ARMC5

http://www.sciencedaily.com/releases/2014/10/141013090455.htm

http://www.nejm.org/doi/full/10.1056/NEJMoa1304603

Filed under: adrenal, Cushing's, Myths and Facts, pituitary, Rare Diseases | Tagged: , , , , , | Leave a comment »

Genetics of adrenal diseases in 2014: Genetics improves understanding of adrenocortical tumours

Posted on December 17, 2014 by MaryO

2014 has seen advances in our understanding of benign and malignant tumours of the adrenal cortex, particularly in Cushing syndrome. Modern genetics has generated a flurry of data. The challenge is to give sense to them; however, the difficulties of collecting the clinical data must not be underestimated.

Download this information at http://www.nature.com/nrendo/journal/vaop/ncurrent/full/nrendo.2014.215.html

  • References
  1. Beuschlein, F. et al. Constitutive activation of PKA catalytic subunit in adrenal Cushing’s syndrome. N. Engl. J. Med. 370, 1019–1028 (2014).
  2. Goh, G. et al. Recurrent activating mutation in PRKACA in cortisol-producing adrenal tumors. Nat. Genet. 46, 613–617 (2014).
  3. Sato, Y. et al. Recurrent somatic mutations underlie corticotropin-independent Cushing’s syndrome. Science 344, 917–920 (2014).
  4. Cao, Y. et al. Activating hotspot L205R mutation in PRKACA and adrenal Cushing’s syndrome. Science 344, 913–917 (2014).
  5. Assié, G. et al. ARMC5 mutations in macronodular adrenal hyperplasia with Cushing’s syndrome. N. Engl. J. Med. 369, 2105–2114 (2013).
  6. Assié, G. et al. Integrated genomic characterization of adrenocortical carcinoma. Nat. Genet. 46, 607–612 (2014).
  7. Beuschlein, F. et al. Somatic mutations in ATP1A1 and ATP2B3 lead to aldosterone-producing adenomas and secondary hypertension. Nat. Genet. 45, 440–444 (2013).
  8. Scholl, U. I. et al. Somatic and germline CACNA1D calcium channel mutations in aldosterone-producing adenomas and primary aldosteronism. Nat. Genet. 45,1050–1054 (2013).
  9. Azizan, E. A. et al. Somatic mutations in ATP1A1 and CACNA1D underlie a common subtype of adrenal hypertension. Nat. Genet. 45, 1055–1060 (2013).
  10. Fernandes-Rosa, F. L. et al. Genetic spectrum and clinical correlates of somatic mutations in aldosterone-producing adenoma. Hypertension 64, 354–361 (2014).

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Myth: After a “cure” for Cushing’s, everyone heals and goes back to normal.

Posted on December 13, 2014 by MaryO

Myth: After a “cure” for Cushing’s, everyone heals and goes back to normal. All Cushing’s patients can easily heal with no repercussions after Cushing’s. After pituitary surgery or a Bilateral Adrenalectomy (BLA), life is great and being “cured” means having a “normal” life! After all, surgery is a “cure” and about 6 weeks later, you are back to normal. “Say, you had surgery XYZ long ago! Shouldn’t you be better by now?!!!!”

Fact: I can not even tell you how many people asked me “aren’t you better yet?!” after both of my surgeries! There are too many to count! There is a misperception that surgery means a cure and therefore, healing should happen magically and quickly. No! No! No! This is far from the truth.

The sad reality is that even some medical doctors buy into this myth and expect quick healing in their patients. However, they are not living in their patients bodies nor have they obviously read the extensive research on this. Research has shown that the healing process after surgery is a long and extensive one. One endocrinologist, expert from Northwestern, even referred to the first year after pituitary surgery for patients as “the year from hell”! He literally quoted that on a slide presentation.

It takes at least one year after pituitary surgery, for instance, to even manage hormones effectively. Surgery is invasive and hard. However, the hardest part comes AFTER surgery. This is when the body is compensating for all of the years of hormonal dysregulation and the patient is trying to get his/her levels back to normal.

There is a higher rate of recurrence of Cushing’s then we once thought. This means that after a patient has achieved remission from this illness, it is likely to come back. In these cases, a patient faces other treatments that may include radiation, the same type of surgery, or an alternative surgery.

For many pituitary patients who experience multiple recurrences, the last resort is to attack the source by removing both adrenal glands. This procedure is known as a Bilateral Adrenalectomy or BLA. In these cases, it is said that the patient “trades one disease for another”, now becoming adrenally insufficient and having Addison’s Disease. Both Pituitary and Adrenal patients are faced with a lifetime of either Secondary or Primary Adrenal Insufficiency.

Adrenal Insufficiency is also life threatening and adrenal crises can potentially lead to death. Additionally, research says that BLA patients take, on average, 3-5 years for their bodies to readjust and get anywhere near “normal”. Most patients will tell you that they never feel “normal” again!

Think of these facts the next time you feel tempted to ask your friend, family, or loved one, “why is it taking so long to get better after surgery?”. Remember that in addition to the aforementioned points; problems from Cushing’s can linger for years after surgery! One Cushing’s patient stated, “I’m 5 years post-op and I STILL have problems!” This mirrors the sentiments of many of us in the Cushing’s community. Please be conscious of this when supporting your loved one after treatment.

You can find more information in the following links:

http://onlinelibrary.wiley.com/doi/10.1111/j.1365-2265.2011.04124.x/abstract;jsessionid=CC58CF32990A60593028F4173902EC47.f03t03?deniedAccessCustomisedMessage&userIsAuthenticated=false

http://press.endocrine.org/doi/abs/10.1210/jc.2013-1470

http://press.endocrine.org/doi/abs/10.1210/jc.2012-2893

This is another article that validates the aforementioned fact about the “cure myth”: http://home.comcast.net/~staticnrg/Cushing’s/resmini%20Cushing’s%20article-2.pdf

Filed under: adrenal, adrenal crisis, Cushing's, Myths and Facts, pituitary | Tagged: , , , , , , , , , , | Leave a comment »

Mutations Drive Unrestrained Secretion

Posted on December 11, 2014 by MaryO
The USP8 mutations identified in adenomas of the pituitary gland lead to overproduction of ACTH. Panel A: ACTH-producing cells in a normal gland. The other panels show cells non-mutant (B) or mutant (C) for USP8. Credit: S. Sbiera, Universität Würzburg

The USP8 mutations identified in adenomas of the pituitary gland lead to overproduction of ACTH. Panel A: ACTH-producing cells in a normal gland. The other panels show cells non-mutant (B) or mutant (C) for USP8. Credit: S. Sbiera, Universität Würzburg

Benign tumors in the pituitary gland lead to uncontrolled secretion of the stress hormone cortisol by the cells of the adrenal cortex. An international research effort has now characterized a new mechanism that triggers the syndrome.

Many individuals who suffer from Cushing syndrome are easy to recognize: They tend to be overweight particularly around the waist, and have round faces and bull necks. In addition to these obvious features, most of them have high blood pressure, develop muscle weakness, become diabetic and are extremely susceptible to infection. Cushing syndrome can often be treated effectively by surgical intervention, but patients succumb to infections or cardiovascular disease if the condition is left untreated.

In their efforts to understand how benign tumors in the pituitary provoke the development of Cushing’s disease, researchers based in Munich, Würzburg and Tokyo led by Professor Martin Reincke (Director of LMU’s Medical Clinic IV at Munich University Medical Center) have now pinpointed a novel molecular mechanism responsible for the condition. The results of the study have just appeared in Nature Genetics.

The perils of incessant secretion

All of the symptoms that typify Cushing syndrome are attributable to the unregulated secretion of the hormone cortisol – generally referred to as cortisone. Cortisol is normally released into the bloodstream only in stress situations, and helps the organism to cope with the challenge. However, when secreted in an uncontrolled fashion, the result is physiological havoc. Cortisol is synthesized in, and secreted by specialized cells in the adrenal cortex in response to the binding of a different hormone, the adrenocorticotropic hormone (ACTH). ACTH in turn is produced in the pituitary gland. Excessive cell proliferation in the pituitary can result in the formation of benign tumors (adenomas), which may lead to overproduction of ACTH and a corresponding increase in the level of circulating cortisol. However, the connecting links between the two processes are incompletely understood.

“We have now shown that tumor cells in more than one-third of patients with Cushing’s disease carry a mutation in one specific gene, which codes for an enzyme called ubiquitin-specific protease 8,” says Martin Fassnacht (Würzburg University Hospital), one of the authors of the publication. The mutation was discovered in the course of a detailed genetic characterization of benign tumors of the pituitary gland that overproduced ACTH.

Protease defect sets off a chain reaction

Ubiquitin-specific protease 8 (USP8) is one of a family of enzymes which play a key role in the destruction of proteins that are required only transiently by cells. One such protein is the receptor for epidermal growth factor (EGF), which is degraded and disposed of only when the USP8 gene is inactive, and no USP8 protein is present. The collaboration found that the effect of the mutations identified in pituitary tumor tissues is to keep the USP8 permanently active. As a consequence, the EGF receptor escapes demolition, and is instead recycled to its site of action on the cell membrane. The upshot of this is a life-threatening chain reaction, in which unrestrained synthesis of ACTH leads to uninhibited secretion of cortisol. “The identification of mutations in USP8 is a significant finding, because it opens up entirely new diagnostic and therapeutic approaches to the management of Cushing’s disease,” Martin Reincke adds.

Long-term focus on Cushing’s disease

Indeed, this is not the first time that the collaboration between the teams in Munich and Würzburg has shed light on the pathogenesis of Cushing’s disease. The two groups have previously identified mutations in a gene that is expressed in the adrenal cortex as a frequent cause of the pathological secretion of cortisol in a different patient population. The results of that study appeared in February 2014 in the “New England Journal of Medicine“. And only last week, a paper providing a detailed characterization of the molecular effects of the latter set of mutations was published in “Nature Communications“.

Explore further: Cushing’s syndrome: A genetic basis for cortisol excess

More information: “Mutations in the deubiquitinase gene USP8 cause Cushing’s disease.” Nature Genetics (2014) DOI: 10.1038/ng.3166

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Myth: “All types of Cushing’s are the same”

Posted on December 11, 2014 by MaryO

Myth: “All types of Cushing’s are the same”

myth-busted

Fact: In the words of our dear friend and advocate, Robin Ess, “There are many genetic varieties with quite a few discovered in the past couple of years. Plus, there are several types such as adrenal, ectopic, and pituitary. And so on”….Amazingly, some doctors do not realize that there are different varieties of Cushing’s and that the symptoms can come from a different source.

For instance, a doctor might rule out a pituitary tumor and completely dismiss the patient, even with biochemical evidence of Cushing’s. That doctor, instead of dismissing the patient, should thoroughly look for other potential sources, such as an adrenal tumor, or yet another source. Did you know that tumors on one’s lungs can even cause Cushing’s? Most people don’t know that.

For more information about the different types of Cushing’s, please read: http://www.mayoclinic.org/diseases-conditions/cushing-syndrome/basics/causes/con-20032115

Another great article regarding ectopic Cushing’s can be found here: http://www.nejm.org/doi/full/10.1056/NEJM199809243391304#.VH-80v5f2s8.facebook

MaryONote: Folks might be interested in listening to this podcast episode with Jayne, a Cushing’s patient who had pituitary surgeries and a bilateral adrenalectomy before finding the true source of her ectopic Cushing’s – lung tumors.

http://www.blogtalkradio.com/cushingshelp/2008/01/31/tentative-date-an-interview-with-jayne-cyclical-cushings-patient

Filed under: adrenal, Cushing's, Myths and Facts, pituitary, podcast, Rare Diseases | Tagged: , , , , , , , , , , , , | Leave a comment »

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