Exophthalmos: A Forgotten Clinical Sign of Cushing’s Syndrome

Case Reports in Endocrinology
Volume 2013 (2013), Article ID 205208, 3 pages
Case Report

Exophthalmos: A Forgotten Clinical Sign of Cushing’s Syndrome

1Department of Internal Medicine, Cleveland Clinic Foundation, 9500 Euclid Avenue Desk NA10, Cleveland, OH 44195, USA
2Department of Endocrinology, Diabetes and Metabolism, Cleveland Clinic Foundation, 9500 Euclid Avenue Desk F20, Cleveland, OH 44195, USA

Received 3 February 2013; Accepted 22 February 2013

Academic Editors: C. Capella, T. Cheetham, M. Demura, and K. Iida

Copyright © 2013 Aldo Schenone Giugni et al. This is an open access article distributed under theCreative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.


Exophthalmos is typically associated with Graves’ ophthalmopathy. Although originally described by Harvey Cushing, exophthalmos is an underappreciated sign of Cushing’s syndrome. We present a case of a 38-year-old female who presented with severe bilateral proptosis and was subsequently diagnosed with Cushings disease. We discuss the possible mechanisms causing exophthalmos in patients with either endogenous or exogenous hypercortisolemia.

1. Case Presentation

A 38-year-old female noticed progressively worsening bilateral proptosis for a period of two years, to the point causing episodes of ocular dislocation from her sockets. She also noted irregular menstrual cycles during this time and was amenorrheic for 6 months prior to referral. She underwent extensive workup by her primary care physician including thyroid tests which were normal. She then underwent orbital decompression surgery in June 2011 with transient improvement of symptoms. However in the next 12 months she gained 60 lbs and developed proximal muscle weakness, purplish abdominal striae, facial hirsutism, and easy bruisability. She was also diagnosed with new onset diabetes and hypertension during this time and was treated with Metformin and Lisinopril, respectively. Physical examination revealed an obese female with a BMI of 43 and BP . She had frank stigmata of Cushings syndrome (CS). She had bilateral proptosis with Hertel’s exophthalmometry readings of 26 mm (right) and 27 mm (left) (Figure 1). Visual acuity was  bilaterally. There was no corneal/conjunctival congestion or lid retraction/lag. Fundus exam was normal. Extraocular movements were intact and visual fields were normal on confrontation. Tonometry was not performed. Labs done prior to referral indicated midnight salivary cortisol of 654 ng/dL (normal 112 ng/dL) and post 1 mg dexamethasone cortisol of 16.9 mcg/dL. Random ACTH level was 50 (8–42 pg/mL). MRI of pituitary gland revealed 1.6 cm macroadenoma with deviation of the stalk to the right (Figure 2). MRI also indicated bilateral exophthalmos with increased retrorbital fat (Figure 2). Prolactin was 40 (2–17.4 ng/mL) consistent with stalk effect, gonadotropins were low, and IGF-1, free T4 were normal. Patient underwent trans-sphenoidal removal of the tumor which stained diffusely with ACTH (Figure 3). Patient is being treated with hydrocortisone and followed closely by her ophthalmologist. Although the exophthalmos persisted after the pituitary surgery, episodes of ocular dislocation had not occurred at 3 months followup.

Figure 1: Bilateral exophthalmos as seen on MRI.
Figure 2: MRI of pituitary (coronal view) (arrows showing the macroadenoma and stalk deviation).
Figure 3: Histology: (a) H&E stain showing basophilic cells at magnification 200. (b) Positive ACTH staining.

2. Discussion

Exophthalmos or proptosis refers to forward displacement of the eyeball. It has to be differentiated from retraction of the eyelids, which can cause an illusion of exophthalmos. Conventionally, exophthalmos refers to ocular proptosis secondary to endocrinopathies. Graves’ disease is the most common endocrine cause of exophthalmos. Although described in 1932 by Harvey Cushing in 4 of his 12 patients with Cushings disease, this is an often forgotten clinical sign [1] in patients with CS. We have presented a case highlighting the importance of exophthalmos and its association with hypercortisolemia.

Exophthalmos is seen in about 30–45% of patients with Cushings syndrome (CS) [13]. Kelly reported that exophthalmos (exceeding 16 mm) occurred in 45% of active CS, 21% of iatrogenic CS, and 20% of treated CS in comparison to 2% in controls [3]. Cases of severe exophthalmos preceding the evolution of CS have been reported in the literature [45].

The cause of exophthalmos in CS is still unknown. Multiple theories have been proposed including fat redistribution and increased retro-orbital fat, associated thyroid disease, and an exophthalmos causative factor. It has been proposed that retro-orbital fat deposition is also part of the fat re-distribution seen in CS, resulting in increase in volume of the retro-orbital tissues and a consequent rise in intra-orbital pressure [36]. Orbital fat volume was increased in patients with CS and orbital muscles are relatively spared [78]. In contrast to patients with Graves’ disease the retrorbital fat in CS is devoid of inflammatory cell infiltration. Whether differential fat deposition in the orbits is due to increased glucocorticoid receptor density, defective lipolysis or increased lipoprotein lipase activity is not known.

Conflict of Interests

The authors report no conflict of interests.


  1. H. Cushing, “The basophil adenomas of the pituitary body and their clinical manifestation,”Bulletin Johns Hopkins Hospital, vol. 50, pp. 173–195, 1932.
  2. T. A. Howlett, L. H. Rees, and G. M. Besser, “Cushing’s syndrome,” Clinics in Endocrinology and Metabolism, vol. 14, no. 4, pp. 911–945, 1985. View at Scopus
  3. W. Kelly, “Exophthalmos in cushing’s syndrome,” Clinical Endocrinology, vol. 45, no. 2, pp. 167–170, 1996.
  4. M. Nezu, I. Miwa, K. Minai, and T. Kagami, “A case of Cushing’s syndrome associated with severe exophthalmos,” Nihon Naika Gakkai, vol. 76, no. 8, pp. 1290–1293, 1987. View at Scopus
  5. A. Boschi, M. Detry, T. Duprez et al., “Malignant bilateral exophthalmos and secondary glaucoma in iatrogenic Cushing’s syndrome,” Ophthalmic Surgery and Lasers, vol. 28, no. 4, pp. 318–320, 1997. View at Scopus
  6. S. W. Panzer, J. R. Patrinely, and H. K. Wilson, “Exophthalmos and iatrogenic Cushing’s syndrome,” Ophthalmic Plastic and Reconstructive Surgery, vol. 10, no. 4, pp. 278–282, 1994.View at Scopus
  7. R. G. Peyster, F. Ginsberg, J. H. Silber, and L. P. Adler, “Exophthalmos caused by excessive fat: CT volumetric analysis and differential diagnosis,” American Journal of Roentgenology, vol. 146, no. 3, pp. 459–464, 1986. View at Scopus
  8. G. Forbes, D. G. Gehring, C. A. Gorman, M. D. Brennan, and I. T. Jackson, “Volume measurements of normal orbital structures by computed tomographic analysis,” American Journal of Roentgenology, vol. 145, no. 1, pp. 149–154, 1985. View at Scopus

From http://www.hindawi.com/crim/endocrinology/2013/205208/

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.

Cushing's Awareness Challenge 2013


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 & 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…?

Signifor® (Pasireotide) is now Commercially Available

November 7, 2012 The US Food and Drug Administration’s (FDA) Endocrinologic and Metabolic Drugs Advisory Committee (EMDAC) voted unanimously in support of the use of Signifor® (pasireotide) for the treatment of patients with Cushing’s disease who require medical therapeutic intervention. The recommendation was based on data from clinical trials of pasireotide, including PASPORT-CUSHINGS (PASireotide clinical trial PORTfolio – CUSHING’S disease), the largest randomized Phase III study to evaluate a medical therapy in patients with Cushing’s disease.

Patient Assistance for SIGNIFOR support for patients includes:
– Therapy-specific support programs for out-of-pocket costs
– Alternative assistance searches and referrals to Federal and State assistance programs
– Referrals to Independent Charitable Foundations for assistance with co-pay costs
– Patient assistance for low-income and uninsured patients

For more information, or to speak to a Patient Assistance NOW Endocrinology representative, please call 1-877-503-3377 (select option #3 for SIGNIFOR) Monday to Friday 8 am – 8 pm ET.

Cushing’s Syndrome, Prostate Cancer and Adrenocortical Carcinoma

Orphagen has identified and characterized small molecule antagonists to steroidogenic factor-1 (SF-1). SF-1 binds to and regulates DNA promoter elements in the major transporters and enzymes required for adrenal steroid synthesis. It is also required for development of the adrenal gland. SF-1 antagonists inhibit cortisol secretion in adrenal cells and have potential application in two orphan indications, Cushing’s syndrome and adrenocortical carcinoma. In addition, SF-1 appears to have an important role in the progression of advanced prostate cancer.




Cushing’s syndrome:
An estimated 20,000 people in the US have Cushing’s, with more than 3,000 new cases diagnosed each year. The incidence is similar in Europe. Cushing’s syndrome disproportionately affects females, who make up about 75% of the diagnosed cases. Symptoms of Cushing’s syndrome can include obesity, diabetes, psychiatric disorders, osteoporosis and immune suppression. Cushing’s syndrome is caused by elevated secretion of cortisol from the adrenal gland, in association with pituitary, adrenal or other cancers.

Orphagen has identified small molecule antagonists to SF-1 that have the potential to suppress cortisol levels in all Cushing’s patients without serious side effects.

Adrenocortical carcinoma (ACC):
ACC is a rare malignancy with an extremely poor prognosis (5-year overall survival: 37-47%). Complete surgical resection offers hope for long-term survival but surgery is not an option in up to two-thirds of patients because metastasis has usually occurred by the time of diagnosis.

SF-1 is recognized as a potential mechanism-based therapeutic target for control of ACC and an SF-1 antagonist could be used in the treatment of ACC.

Pediatric ACC:
Pediatric ACC is a very rare but aggressive cancer with a long-term survival rate of about 50%. Approximately 60% of children with adrenocortical tumors are diagnosed before the age of four. The SF-1 gene is amplified and SF-1 protein is overexpressed in the vast majority of childhood adrenocortical tumors strongly implicating SF-1 in pediatric adrenocortical tumorigenesis.

Castration resistant prostate cancer (CRPC):
CRPC is the most common cancer in males. Surgery is not an option if the cancer has spread beyond the prostate gland, at which point patients typically receive hormonal therapy, essentially chemical castration. This course of therapy usually fails within two years, resulting in castration resistant prostate cancer (CRPC). Most patients eventually succumb to CRPC, which is the second leading cause of cancer deaths in men.
SF-1 antagonists may: (1) block the adrenal androgens that circumvent chemical castration, and are a primary cause of CRPC; and (2) inhibit synthesis of androgens within the prostate tumor itself, where SF-1 may control induction of enzymes for de novo androgen synthesis in treatment-resistant cancers.

From http://www.orphagen.com/research_cushings.html

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