ARMC5 Mutations in Macronodular Adrenal Hyperplasia with Cushing's Syndrome

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.

N Engl J Med 2013; 369:2105-2114 November 28, 2013 DOI: 10.1056/NEJMoa1304603

BACKGROUND

Corticotropin-independent macronodular adrenal hyperplasia may be an incidental finding or it may be identified during evaluation for Cushing’s syndrome. Reports of familial cases and the involvement of both adrenal glands suggest a genetic origin of this condition.

METHODS

We genotyped blood and tumor DNA obtained from 33 patients with corticotropin-independent macronodular adrenal hyperplasia (12 men and 21 women who were 30 to 73 years of age), using single-nucleotide polymorphism arrays, microsatellite markers, and whole-genome and Sanger sequencing. The effects of armadillo repeat containing 5 (ARMC5) inactivation and overexpression were tested in cell-culture models.

RESULTS

The most frequent somatic chromosome alteration was loss of heterozygosity at 16p (in 8 of 33 patients for whom data were available [24%]). The most frequent mutation identified by means of whole-genome sequencing was in ARMC5, located at 16p11.2. ARMC5 mutations were detected in tumors obtained from 18 of 33 patients (55%). In all cases, both alleles of ARMC5 carried mutations: one germline and the other somatic. In 4 patients with a germline ARMC5 mutation, different nodules from the affected adrenals harbored different secondary ARMC5 alterations. Transcriptome-based classification of corticotropin-independent macronodular adrenal hyperplasia indicated that ARMC5 mutations influenced gene expression, since all cases with mutations clustered together. ARMC5 inactivation decreased steroidogenesis in vitro, and its overexpression altered cell survival.

CONCLUSIONS

Some cases of corticotropin-independent macronodular adrenal hyperplasia appear to be genetic, most often with inactivating mutations of ARMC5, a putative tumor-suppressor gene. Genetic testing for this condition, which often has a long and insidious prediagnostic course, might result in earlier identification and better management. (Funded by Agence Nationale de la Recherche and others.)

Supported in part by grants from Agence Nationale de la Recherche (ANR-10-Blan-1136), Corticomedullosurrénale Tumeur Endocrine Network (Programme Hospitalier de Recherche Clinique grant AOM95201), Assistance Publique–Hôpitaux de Paris (Clinical Research Center Grant Genhyper P061006), Institut National du Cancer (Recherche Translationelle 2009-RT-02), the Seventh Framework Program of the European Commission (F2-2010-259735), INSERM (Contrat d’Interface, to Dr. Assié), the Conny-Maeva Charitable Foundation, and the intramural program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development.

Disclosure forms provided by the authors are available with the full text of this article at NEJM.org.

Drs. Assié, Libé, Espiard, Rizk-Rabin, Ragazzon, and Bertherat contributed equally to this article.

We thank Drs. J. Chelly and M. Delpech of the cell bank of Cochin Hospital and Dr. B. Terris of the tumor bank of Cochin Hospital for their help in sample collection; Dr. E. Clauser of the oncogenetic unit of Cochin Hospital for help in microsatellite analysis; Drs. J. Guibourdenche and E. Clauser of the hormone biology unit of Cochin Hospital for cortisol assays; Drs. F. Tissier and Pierre Colin for pathological analysis; Anne Audebourg for technical assistance; J. Metral and A. de Reynies of the Cartes d’Identité des Tumeurs program of Ligue Nationale contre le Cancer for help in genomics studies and fruitful discussions; Dr. P. Nietschke of the bioinformatics platforms of Paris Descartes University for helpful discussions; all the members of the Genomics and Signaling of Endocrine Tumors team and of the genomic platform of Cochin Institute for their help in these studies; and the patients and their families, as well as the physicians and staff involved in patient care, for their active participation.

SOURCE INFORMATION

From INSERM Unité 1016, Centre National de la Recherche Scientifique Unité Mixte de Recherche 8104, Institut Cochin (G.A., R.L., S.E., M.R.-R., A.G., W.L., O.B., L.L., S.R., K.P., F.R.-C., F.L., L. Groussin, X.B., B.R., J.B.), Faculté de Médecine Paris Descartes, Université Paris Descartes, Sorbonne Paris Cité (G.A., S.E., A.G., O.B., L.L., M.S., K.P., F.R.-C., L. Groussin, X.B., J.B.), Department of Endocrinology, Referral Center for Rare Adrenal Diseases (G.A., R.L., O.B., L. Guignat, L. Groussin, X.B., J.B.), and Department of Pathology (M.S.), Assistance Publique–Hôpitaux de Paris, Hôpital Cochin, and Unit of Endocrinology, Department of Obstetrics and Gynecology, Hôpital Tenon (N.C.-B.) — all in Paris; Unit of Endocrinology, Centre Hospitalier du Centre Bretagne, Site de Kério, Noyal-Pontivy (B.T.), Unit of Endocrinology, Hôtel Dieu du Creusot, Le Creusot (A.P.), and Department of Endocrinology Lyon-Est, Groupement Hospitalier Est, Bron (F.B.-C.) — all in France; and the Section on Endocrinology and Genetics, Program on Developmental Endocrinology and Genetics and the Pediatric Endocrinology Inter-Institute Training Program, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD (C.A.S.).

Address reprint requests to Dr. Bertherat at Service des Maladies Endocriniennes et Métaboliques, Centre de Référence des Maladies Rares de la Surrénale, Hôpital Cochin, 27 rue du Faubourg St. Jacques, 75014 Paris, France, or at jerome.bertherat@cch.aphp.fr.

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Related articles

• Are you carrying adrenal Cushing’s syndrome without knowing it?(cushieblog.com)
• ARMC5 mutation identified in patients with macronodular adrenal hyperplasia(2minutemedicine.com)

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Perspectives on the management of adrenal insufficiency

Grossman A, Johannsson G, Quinkler M, Zelissen P.

Source

Oxford Centre for Diabetes, Endocrinology and Metabolism, Churchill Hospital, University of Oxford, Headington, Oxford OX3 7EJ, UK.

Abstract

BACKGROUND:

Conventional glucocorticoid (GC) replacement for patients with adrenal insufficiency (AI) is inadequate. Patients with AI continue to have increased mortality and morbidity and compromised quality of life despite treatment and monitoring.

OBJECTIVES:

i) To review current management of AI and the unmet medical need based on literature and treatment experience and ii) to offer practical advice for managing AI in specific clinical situations.

METHODS:

The review considers the most urgent questions endocrinologists face in managing AI and presents generalised patient cases with suggested strategies for treatment.

RESULTS:

Optimisation and individualisation of GC replacement remain a challenge because available therapies do not mimic physiological cortisol patterns. While increased mortality and morbidity appear related to inadequate GC replacement, there are no objective measures to guide dose selection and optimisation. Physicians must rely on experience to recognise the clinical signs, which are not unique to AI, of inadequate treatment. The increased demand for corticosteroids during periods of stress can result in a life-threatening adrenal crisis (AC) in a patient with AI. Education is paramount for patients and their caregivers to anticipate, recognise and provide proper early treatment to prevent or reduce the occurrence of ACs.

CONCLUSIONS:

This review highlights and offers suggestions to address the challenges endocrinologists encounter in treating patients with AI. New preparations are being developed to better mimic normal physiological cortisol levels with convenient, once-daily dosing which may improve treatment outcomes.

PMID:

 

24031090

 

[PubMed - in process] 

PMCID:

 

PMC3805018

 [Available on 2013/12/1]

From http://www.mdlinx.com/endocrinology/newsl-article.cfm/4829245/ZZ4747461521296427210947/?news_id=2364&newsdt=110713&subspec_id=1509&utm_source=Focus-On&utm_medium=newsletter&utm_content=Top-New-Article&utm_campaign=article-section

Video: What if

From Adrenal Insufficiency United

A video about Adrenal Insufficiency and the need for emergency protocols.

An injection which costs about $10 could save a life.

Please help us make sure it's available to all who need it.

http://youtu.be/yKPnNNM_dIw

FDA Puts Strict Limits on Oral Ketoconazole Use

By John Gever, Deputy Managing Editor, MedPage Today

SILVER SPRING, Md. -- Oral ketoconazole (Nizoral) should never be used as first-line therapy for any type of fungal infection because of the risk of liver toxicity and interactions with other drugs, the FDA said Friday.

The agency ordered a series of label changes and a new medication guide for patients that emphasize the risks, which also include adrenal insufficiency. It noted that the restrictions apply only to the oral formulation, not topical versions.

Late Thursday, the chief advisory body for the FDA's European counterpart went further. The EU's Committee on Medicinal Products for Human Use (CHMP) recommended that member nations pull oral ketoconazole from their markets entirely.

Both the FDA and the CHMP cited studies indicating high risks of severe, acute liver injury in patients taking the drug. Studies using the FDA's adverse event reporting system and a similar database in the U.K. indicated that liver toxicity was more common with oral ketoconazole than with other anti-fungals in the azole class.

The FDA also said that oral ketoconazole "is one of the most potent inhibitors" of the CYP3A4 enzyme. This effect can lead to sometimes life-threatening interactions with other drugs metabolized by CYP3A4, and also to adrenal insufficiency, since the enzyme also catalyzes release of adrenal steroid hormones.

"This accounts for clinically important endocrinologic abnormalities observed in some patients (particularly when the drug is administered at high dosages), including gynecomastia in men and menstrual irregularities in women," the FDA said.

The only indication for oral ketoconazole still supported by the FDA is for use in life-threatening mycoses in patients who cannot tolerate other anti-fungal medications or when such medications are unavailable.

In such instances, the FDA said, physicians should assess liver function before starting the drug. It is contraindicated in patients with pre-existing liver disease, and patients should be instructed not to drink alcohol or use other potentially hepatotoxic drugs.

Adrenal function should also be monitored in patients using the drug.

The CHMP also indicated the topical formulations of ketoconazole should stay on the market, but it found no basis for keeping the oral form available for any purpose.

"Taking into account the increased rate of liver injury and the availability of alternative anti-fungal treatments, the CHMP concluded that the benefits did not outweigh the risks," the panel indicated in a statement.

It recommended that physicians stop prescribing oral ketoconazole and that they should review alternatives in patients currently receiving the drug. The committee also said that patients now taking oral ketoconazole "make a non-urgent appointment" with their physicians to discuss their treatment.

From MedPage Today

Laparoscopic Bilateral Transperitoneal Adrenalectomy For Cushing Syndrome

Surgical Laparoscopy, Endoscopy & Percutaneous Techniques, 07/16/2013  Clinical Article

Aggarwal S et al. –

Laparoscopic adrenalectomy is well established for treatment of adrenal lesions. However, bilateral adrenalectomy for Cushing syndrome is a challenging and time–consuming operation.

The authors report their experience of laparoscopic bilateral adrenalectomy for this disease in 19 patients. Laparoscopic bilateral adrenalectomy for Cushing syndrome is feasible and safe. It confers all the advantages of minimally invasive approach such as less postoperative pain, shorter hospitalization, lesser wound complications, and faster recovery.

The advantages of the laparoscopic approach have led to an earlier referral for bilateral adrenalectomy by endocrinologist in patients with failed pituitary surgery.

This article is available on PubMed

Cushing’s Syndrome is Hazardous to Your Health

People with Cushing’s syndrome, even when treated, have higher morbidity and mortality rates that comparable controls. That is the conclusion of a new study published in the June issue of the Journal of Clinical Endocrinology Metabolism. The study by Olaf Dekkers et al, examined data records from the Danish National Registry of Patients and the Danish Civil Registration System of 343 patients with benign Cushing’s syndrome of adrenal or pituitary origin (i.e., Cushing’s disease) and a matched population comparison cohort (n=34,300).  Due to the lengthy delay of many patients being diagnosed with Cushing’s syndrome, morbidity was investigated in the 3 years before diagnosis while  morbidity and mortality were assessed during complete follow-up after diagnosis and treatment.

The study found that mortality was twice as high in Cushing’s syndrome patients (HR 2.3, 95% CI 1.8-2.9) compared with controls over a mean follow-up period of 12.1 years. Furthermore, patients with Cushing’s syndrome were at increased risk for:

• venous thromboembolism (HR 2.6, 95% CI 1.5-4.7)
• myocardial infarction (HR 3.7, 95% CI 2.4-5.5)
• stroke (HR 2.0, 95% CI 1.3-3.2)
• peptic ulcers (HR 2.0, 95% CI 1.1-3.6)
• fractures (HR 1.4, 95% CI 1.0-1.9)
• infections (HR 4.9, 95% CI 3.7-6.4).

The study also found that this increased multimorbidity risk was present before diagnosis indicating that it was due to cortisol overproduction rather than treatment.

Many of the Cushing’s syndrome patients underwent surgery to remove the benign tumor. For this group, the investigators performed a sensitivity analysis of the  long-term mortality and cardiovascular risk in this  subgroup (n=186)  considered to be cured after operation (adrenal surgery and patients with pituitary surgery in combination with a diagnosis of hypopituitarism in the first 6 months after operation).  The risk estimates for mortality (HR 2.31, 95% CI 1.62-3.28), venous thromboembolism (HR 2.03, 95% CI 0.75-5.48), stroke (HR 1.91, 95% CI 0.90-4.05), and acute myocardial infarction (HR 4.38, 95% CI 2.31-8.28) were also increased in this subgroup one year after the operation.

The standard treatment for endogenous Cushing’s syndrome is surgery. This past year, Signifor (pasireotide) was approved for treatment of adults patients with Cushing’s disease for whom pituitary surgery is not an option or has not been curative.  Cushing’s disease, which accounts for the majority of Cushing’s syndrome patients, is defined as the presence of an ACTH producing tumor on the pituitary grand. In the study by Dekker’s et al, the percentage of patients with Cushing’s disease is not known. We look forward to reexamination of this dataset in a few years following the introduction of more treatment options for Cushing’s disease as well as an analysis that explores the differences in mortality/morbidity rates in the different subsets of patients that make of Cushing’s syndrome (Cushing’s disease, ectopic Cushing’s syndrome, Exogenous Cyshing’s syndrome).

References

Dekkers OM, Horvath-Pujo, Jorgensen JOL, et al, Multisystem morbidity and mortality in Cushing’s syndrome: a cohort study. J Clin Endocrinol Metab 2013 98(6): 2277–2284. doi: 10.1210/jc.2012-3582

- See more at: http://www.raredr.com/medicine/articles/cushing%E2%80%99s-syndrome-hazardous-your-health-0

An Adrenal Crisis Survey

This Survey is to gather information for the Adrenal Insufficiency Awareness Organization's grant project to create educational materials for ER personnel. 

The survey is for those of you who have been to the ER during an impending or full blown Adrenal Crisis. (you may fill it out for a child or yourself) 

Your help is appreciated! 

At the end of the survey you will have the chance to enter for a chance to win an Adrenal Insufficiency Awareness Pin.

https://www.surveymonkey.com/s/ERcare

Adrenal Glands

Anatomy of the adrenal glands:

Adrenal glands, which are also called suprarenal glands, are small, triangular glands located on top of both kidneys. An adrenal gland is made of two parts: the outer region is called the adrenal cortex and the inner region is called the adrenal medulla.

Function of the adrenal glands:

The adrenal glands work interactively with the hypothalamus and pituitary gland in the following process:

• the hypothalamus produces corticotropin-releasing hormones, which stimulate the pituitary gland.
• the pituitary gland, in turn, produces corticotropin hormones, which stimulate the adrenal glands to produce corticosteroid hormones.

Both parts of the adrenal glands -- the adrenal cortex and the adrenal medulla -- perform very separate functions.

What is the adrenal cortex?

The adrenal cortex, the outer portion of the adrenal gland, secretes hormones that have an effect on the body's metabolism, on chemicals in the blood, and on certain body characteristics. The adrenal cortex secretes corticosteroids and other hormones directly into the bloodstream. The hormones produced by the adrenal cortex include:

• corticosteroid hormones
  • hydrocortisone hormone - this hormone, also known as cortisol, controls the body's use of fats, proteins, and carbohydrates.
  • corticosterone - this hormone, together with hydrocortisone hormones, suppresses inflammatory reactions in the body and also affects the immune system.
• aldosterone hormone - this hormone inhibits the level of sodium excreted into the urine, maintaining blood volume and blood pressure.
• androgenic steroids (androgen hormones) - these hormones have minimal effect on the development of male characteristics.

What is the adrenal medulla?

The adrenal medulla, the inner part of the adrenal gland, is not essential to life, but helps a person in coping with physical and emotional stress. The adrenal medulla secretes the following hormones:

• epinephrine (also called adrenaline) - this hormone increases the heart rate and force of heart contractions, facilitates blood flow to the muscles and brain, causes relaxation of smooth muscles, helps with conversion of glycogen to glucose in the liver, and other activities.
• norepinephrine (also called noradrenaline) - this hormone has little effect on smooth muscle, metabolic processes, and cardiac output, but has strong vasoconstrictive effects, thus increasing blood pressure.

From: University of Maryland Center for Diabetes and Endocrinology

Ask your Member of Congress to join the Rare Disease Congressional Caucus

Help us strengthen the rare disease community's voice on Capitol Hill!  Please take 3 minutes to ask your Member of Congress to join the Rare Disease Caucus at http://bit.ly/RareAlert.

It's easy - the Action Center has a draft letter that will automatically be sent to your Member of Congress - just put in your name and address & click send.  We also encourage you to personalize the letter to share information about your specific disease.  If your Congress Member is already on the Caucus, the letter will automatically populate as a thank you letter instead - these are just as important to send!

It can take up to 10 letters from constituents for a Member to respond so please share this Action Alert with your friends, family & colleagues.  Join our Facebook event & invite your friends:   http://on.fb.me/17Mlpjg 

The Rare Disease Congressional Caucus will help bring public and Congressional awareness to the unique needs of the rare disease community – patients, physicians, scientists, and industry, and create opportunities to address roadblocks in access to and development of crucial treatments.  The Caucus will give a permanent voice to the rare disease community on Capitol Hill.  Working together, we can find solutions that turn hope into treatments.

Multisystem Morbidity and Mortality in Cushings Syndrome: a Cohort Study

Journal of Clinical Endocrinology and Metabolism, 03/28/2013  Clinical Article

Dekkers O.M. et al.– To examine the risks for mortality, cardiovascular disease, fractures, peptic ulcers, and infections in CS patients before and after treatment.Cushing’s syndrome (CS) is associated with hypercoagulability, insulin resistance, hypertension, bone loss, and immunosuppression. To date, no adequately large cohort study has been performed to assess the multisystem effects of CS. It was concluded that despite the apparently benign character of the disease, CS is associated with clearly increased mortality and multisystem morbidity, even before diagnosis and treatment.

Methods

• The study used Cox–regression, and computed hazard ratios (HR) with 95% confidence intervals (95% CI).
• Morbidity was investigated in the three years before diagnosis; morbidity and mortality was assessed during complete follow–up after diagnosis and treatment.

Results

• 343 CS patients and 34,300 controls were included. Mortality was twice as high in CS patients (HR 2.3, 95%CI 1.8–2.9) compared with controls.
• Patients with CS were at increased risk for venous thromboembolism (HR 2.6, 95%CI 1.5–4.7), myocardial infarction (HR 3.7, 95%CI 2.4–5.5), stroke (HR 2.0, 95%CI 1.3–3.2), peptic ulcers (HR 2.0, 95%CI 1.1–3.6), fractures (HR 1.4, 95%CI 1.0–1.9), and infections (HR 4.9, 95%CI 3.7–6.4).
• This increased multi–morbidity risk was present before diagnosis. Mortality and risk of myocardial infarction remained elevated during long–term follow–up.
• Mortality and risks for AMI, VTE, stroke and infections were similarly increased in adrenal and pituitary CS.

From MDLinx

For Cushing's Awareness Challenge Bloggers

Cushie bloggers - who would like to share your post on April 8 (Cushing's Awareness Day) with our friends at Adrenal Insufficiency United, on their blog?

Also, they are interested in sharing others of our posts from April.  Please let me know if I have your permission to share your blog post(s) with them.  I won't without your permission.

Thanks!

Cushing's Awareness Blogging Challenge 2013

Do you blog? Want to get started?

Since April 8 is Cushing's Awareness Day, several people got their heads together to create the Second Annual Cushing's Awareness Blogging Challenge.

All you have to do is blog about something Cushing's related for the 30 days of April.

Robin designed this year's version of our "official logo" to put on your blogs.

 

 If your blog wants you to upload an image from your desktop, right-click on the image above and choose "save-as". Remember where you saved it to! 

 To link to the image with the yellow border, use this URL: http://www.cushings-help.com/images/challenge-2013b.jpg 

 To link to the image without a border, use this URL: http://www.cushings-help.com/images/challenge-2013nb.jpg 

 In all cases, the URL for the site is http://www.cushings-help.com 

Please let me know the URL to your blog in the comments area of this post or and I will list it on CushieBloggers ( http://cushie-blogger.blogspot.com/ ) 

The more people who participate, the more the word will get out about Cushing's. 

  Suggested topics - or add your own!

In what ways have Cushing's made you a better person?
What have you learned about the medical community since you have become sick?
If you had one chance to speak to an endocrinologist association meeting, what would you tell them about Cushing's patients?
What would you tell the friends and family of another Cushing's patient in order to garner more emotional support for your friend?
Challenges with Cushing's? How have you overcome challenges? Stuff like that.
I have Cushing's Disease....(personal synopsis)
How I found out I have Cushing's
What is Cushing's Disease/Syndrome? (Personal variation, i.e. adrenal or pituitary or ectopic, etc.)
My challenges with Cushing's
Overcoming challenges with Cushing's (could include any challenges)
If I could speak to an endocrinologist organization, I would tell them...
. What would I tell others trying to be diagnosed? What would I tell families of those who are sick with Cushing's?
Treatments I've gone through to try to be cured/treatments I may have to go through to be cured.
What will happen if I'm not cured?
I write about my health because...
10 Things I Couldn’t Live Without.
My Dream Day.
What I learned the hard way
Miracle Cure. (Write a news-style article on a miracle cure. What’s the cure? How do you get the cure? Be sure to include a disclaimer)
Health Madlib Poem. Go to http://languageisavirus.com/cgi-bin/madlibs.pl and fill in the parts of speech and the site will generate a poem for you.
The Things We Forget. Visit http://thingsweforget.blogspot.com/ and make your own version of a short memo reminder. Where would you post it?
Give yourself, your condition, or your health focus a mascot. Is it a real person? Fictional? Mythical being? Describe them. Bonus points if you provide a visual!
5 Challenges and 5 Small Victories.
The First Time I...
Make a word cloud or tree with a list of words that come to mind when you think about your blog, health, or interests. Use a thesaurus to make it branch more.
How much money have you spent on Cushing's, or, How did Cushing's impact your life financially?
Why do you think Cushing's may not be as rare as doctors believe?
What is your theory about what causes Cushing's?
How has Cushing's altered the trajectory of your life? What would you have done? Who would you have been?
What three things has Cushing's stolen from you? What do you miss the most? What can you do in your Cushing's life to still achieve any of those goals? What new goals did Cushing's bring to you?
How do you cope?
What do you do to improve your quality of life as you fight Cushing's?
Your thoughts...?