Exophthalmos and Cushing’s Syndrome

Posted on February 4, 2015 by MaryO

A woman experienced red, irritated and bulging eyes. She saw an ophthalmologist who strongly suspected Graves’ ophthalmopathy. However, the patient did not have and never had hyperthyroidism.

Indeed, she had primary hypothyroidism optimally treated with levothyroxine. Her thyroid stimulating hormone level was 1.197 uIU/mL.

An MRI of the orbits showed normal extraocular muscles without thickening, but there was mild proptosis and somewhat increased intraorbital fat content. Both thyroid-stimulating immunoglobulins as well as thyrotropin receptor antibodies were negative.

The patient presented to her primary care physician a few months later. She had experienced a 40-lb weight gain over only a few months and also had difficult-to-control blood pressure.

After failing to respond to several antihypertensive medications, her primary care physician astutely decided to evaluate for secondary causes of hypertension. A renal ultrasound was ordered to evaluate for renal artery stenosis, and the imaging identified an incidental right-sided adrenal mass. A CT confirmed a 3.4-cm right-sided adrenal mass. Her morning cortisol was slightly high at 24.7 ug/dL (4.3 – 22.4) and her adrenocorticotropic hormone was slightly low at 5 pg/mL (10-60).

At this point I saw the patient in consultation. She definitely had many of the expected clinical exam findings of Cushing’s syndrome, including increased fat deposition to her abdomen, neck, and supraclavicular areas, as well as striae. Her 24-hour urine cortisol was markedly elevated at 358 mcg/24hrs (< 45) confirming our suspicions.

She asked me, “Do you think that my eye problem could be related to this?”

“I’ve not heard of it before,” I replied, “but that doesn’t mean there can’t be a connection. Wouldn’t it be wonderful if your eyes got better after surgery?”

The patient underwent surgery to remove what fortunately turned out to be a benign adrenal adenoma.

When we saw her in follow-up 2 weeks later, her blood pressures were normal off medication and her eye symptoms had improved. I had a medical student rotating with me, so I suggested that we do a PubMed literature search.

The first article to come up was a case report titled “Exophthalmos: A Forgotten Clinical Sign of Cushing’s Syndrome.” Indeed, not only did Harvey Cushing describe this clinical finding in his original case series in 1932, but others have reported that up to 45% of patients with active Cushing’s syndrome have exophthalmos.

The cause is uncertain but is theorized to be due to increased intraorbital fat deposition. Unlike exophthalmos due to thyroid disease, the orbital muscles are relatively normal — just as they were with our patient.

Some of you may have seen exophthalmos in your Cushing’s patients; however, this was the first time I had seen it. Just because one has not heard of something, does not mean it could never happen; no one knows everything. “When in doubt, look it up” is a good habit for both attending physicians and their students.

For more information:

Giugni AS, et al. Case Rep Endocrinol. 2013; 2013: 205208.

From http://www.healio.com/endocrinology/adrenal/news/blogs/%7B779bf3e5-e1da-459e-af27-955c9b4274a5%7D/thomas-b-repas-do-facp-face-cde/exophthalmos-and-cushings-syndrome

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Cushing’s Syndrome – Epidemiology Forecast to 2023

Posted on November 3, 2014 by MaryO

It’s NOT as rare as they thought…

Epidemiologists forecast an increase in the diagnosed prevalent cases of CS in the 6MM, from 32,634 diagnosed prevalent cases in 2013 to 34,573 diagnosed prevalent cases in 2023, with an annual growth rate of 0.59% in the forecast period. In 2023, the US will have the highest number of diagnosed prevalent cases of CS, with 17,162 diagnosed prevalent cases.

For this analysis, The publisher epidemiologists used data available from Orphanet to construct the 10-year epidemiological forecast for the diagnosed prevalent cases of CS, Cushing’s disease, ectopic ACTH CS, adrenal adenoma CS, and adrenal carcinoma CS in the 6MM. The forecast provides the age- and sex-specific diagnosed prevalent cases of CS subtypes in the six markets, providing a comprehensive view of CS. In addition, this analysis provided detailed, clinically relevant segmentations for Cushing’s disease in order to improve the management of the disease.

Scope

  • The Cushing’s syndrome (CS) EpiCast Report provides an overview of the risk factors, comorbidities, and the global and historical epidemiological trends for CS in the six major markets (6MM) (US, France, Germany, Italy, Spain, and UK). The report also includes a 10-year epidemiological forecast for the diagnosed prevalent cases of CS, Cushing’s disease, ectopic- adrenocorticotropic hormone (ACTH) CS, adrenal adenoma CS, and adrenal carcinoma CS segmented by age (18 to =85 years) and sex in these markets.
  • The CS epidemiology report is written and developed by Masters- and PhD-level epidemiologists.
  • The EpiCast Report is in-depth, high-quality, transparent and market-driven, providing expert analysis of disease trends in the 6MM.

Read the article here: http://www.businesswire.com/news/home/20141103006612/en/Research-Markets-EpiCast-Report-Cushings-Syndrome–#.VFgvl5PF9HA

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Mutations in PKA catalytic subunit associated with Cushing’s syndrome

Posted on March 18, 2014 by MaryO

1. Somatic mutations resulting in constitutive activation of PRKACA, which encodes the catalytic subunit of protein kinase A, were found in 37% of patients with Cushing’s syndrome due to an adrenal adenoma. 

2. Germline duplications of PRKACA were detected in patients with bilateral adrenal hyperplasia and overt Cushing’s syndrome. 

Study Rundown: This study found that 37% of patients with overt Cushing’s syndrome due to an adrenal adenoma have a somatic mutation in PRKACA, which encodes the catalytic subunit of cyclic AMP-dependent protein kinase A (PKA), present in their tumor cells. The most commonly identified variant, Leu206Arg, results in impaired interaction between the catalytic and regulatory subunits of PKA, thereby causing constitutive activation of PKA. Additionally, a subset of patients with cortisol-producing bilateral adrenal hyperplasia harbored germline duplications of PRKACA.

This is the first study to identify an association between genetic alterations of the catalytic subunit of PKA and Cushing’s syndrome. It is significant that 37% of patients with overt Cushing’s syndrome were found to have tumors with PRKACA mutations; previous research had revealed only very rare mutations. Of note, this study did not find PRKACA mutations in any patients with subclinical Cushing’s syndrome or inactive adenomas. This suggests that Cushing’s syndrome and subclinical Cushing’s are distinct entities. Patients involved in this study were recruited from only three centers; the frequency of PRKACA mutations in Cushing’s syndrome may be different in other study populations. Further research will be needed to identify biochemical causes of overt Cushing’s syndrome in patients without PRKACA mutations.

Relevant Reading: Abnormalities of cAMP signaling are present in adrenocortical lesions associated with ACTH-independent Cushing’s syndrome despite the absence of mutations in known genes

In-Depth: In this study, exome sequencing of tumor specimens from 10 patients with unilateral cortisol-producing adenomas and overt Cushing’s syndrome was performed. Eight of 10 adenomas had somatic mutations in PRKACA; 7 of these patients had the same mutation (p.Leu206Arg). Subsequently, PRKACA was sequenced in 129 additional patients with adrenal adenomas. Patients were classified as having overt Cushing’s syndrome (at least three abnormal biochemical tests or catabolic features plus two abnormal tests), subclinical Cushing’s (at least one abnormal biochemical test without catabolic signs) or as having an inactive adenoma. The Leu206Arg variant was identified in tumor tissue of 14/129 patients and all 14 had overt Cushing’s syndrome. Overall, 37% (22/59) of patients with overt Cushing’s syndrome due to an adenoma had a PRKACA mutation; in contrast, PRKACA mutations were not found in any patients with subclinical Cushing’s or an inactive adenoma. Of 35 patients with overt Cushing’s syndrome due to cortisol-secreting bilateral adrenal hyperplasia, 5 patients had copy-number gains of a region on chromosome 19p that contains PRKACA.

Analysis of holoenzyme structure revealed that the Leu206Arg mutation is located in the active-site cleft of the catalytic subunit of PKA. To evaluate the functional consequences of this mutation, cells were transfected with either nonmutant or variant C-alpha, which encodes the catalytic subunit of PKA. Investigators determined that the mutation causes constitutive activation of the catalytic subunit by impairing interaction with the regulatory subunit of PKA.

From http://www.2minutemedicine.com/mutations-in-pka-catalytic-subunit-associated-with-cushings-syndrome/

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