A case of autonomous cortisol secretion in a patient with subclinical Cushing's syndrome, GNAS mutation, and paradoxical cortisol response to dexamethasone

Abstract

Background: Increased urinary free cortisol in response to the oral administration of dexamethasone is a paradoxical reaction mainly reported in patients with primary pigmented nodular adrenocortical disease. Here, we describe the first case of subclinical Cushing's syndrome represented by autonomous cortisol secretion and paradoxical response to oral dexamethasone administration, harboring an activating mutation in the α subunit of the stimulatory G protein (GNAS).

Case presentation: A 65-year-old woman was diagnosed with subclinical Cushing's syndrome during an evaluation for bilateral adrenal masses. Tumors of unknown origin were found in the heart, brain, thyroid gland, colon, pancreas, and both adrenal glands. Adenocarcinoma of the sigmoid colon and systemic brown-patchy skin pigmentation were also present. Her urinary cortisol levels increased in response to oral dexamethasone, while serum dehydroepiandrosterone-sulfate was not suppressed. After right adrenalectomy, genetic analysis of the resected tumor revealed the somatic GNAS activating mutation, p.R201H. Paradoxical urinary cortisol response persisted even after unilateral adrenal resection, although serum and urinary cortisol levels were attenuated.

Conclusions: This patient harbored a GNAS activating mutation, and presented with a mild cortisol- and androgen-producing adrenal adenoma. Administration of oral dexamethasone paradoxically increased cortisol levels, possibly via the stimulation of the cyclic adenosine monophosphate-dependent protein kinase A signaling pathway, which is seen in patients with pigmented nodular adrenocortical disease or Carney complex. GNAS mutations may provide clues to the mechanisms of hyper-function and tumorigenesis in the adrenal cortex, especially in bilateral adrenal masses accompanied by multiple systemic tumors. Examining GNAS mutations could help physicians detect extra-adrenal malignancies, which may contribute to an improved prognosis for patients with this type of Cushing's syndrome.

Keywords: Adrenal tumor; Cortisol; Cushing’s syndrome; Cyclic-AMP; GNAS; Protein kinase A.

Fig. 1

Imaging study of bilateral adrenal masses. Computed tomography scan shows bilateral adrenal tumors. (a) right side, 25 × 13 mm and (b) left side, 18 × 15 mm. Magnetic resonance imaging showed low intensity loci in adrenal tumors in “out phase” compared with “in phase” of chemical shift imaging on T1-weighted image. (c) right, in-phase; (d) right, out-phase; (e) left, in-phase; (f) left, out-phase. (g) ¹³¹I-adosterol scintigraphy shows bilateral adrenal accumulation. Arrows in each image designate the adrenal tumors or more accurately where the adosterol is accumulating in the adrenal tumors

Fig. 2

Imaging studies of extra-adrenal tumors in this patient. a A convexity meningioma 21 × 13 × 18 mm in size on enhanced T1WI MRI of the Head (arrow). The pituitary tumor is not marked. b A hyperechoic lesion about 14 mm in size in the interventricular septum on echocardiography (arrow). c Cervical ultra-sonography revealed four tumors in both thyroid lobes (arrow). d Colonoscopy shows tubular adenocarcinoma in the colon. This tumor was later resected, but the status of GNAS mutation was not assessed. e Enhanced abdominal computed tomography showed cystic lesions compatible with intraductal papillary mucinous neoplasm in the pancreatic body (arrow). f Brown patchy pigmentations were observed systemically. Skin appearance with patchy pigmentations of bilateral lower limbs is shown. g X-ray imaging and bone scintigraphy with ^99mTc-scintigraphy did not indicate fibrous dysplasia

Fig. 3

Histopathological examination of adrenal adenoma. a Macro-image of the resected adrenal adenoma. b Micro-image with low magnitude using hematoxylin-eosin staining. The adrenal adenoma composed of compact cells and clear cells. c-h Immunohistochemical staining was performed using anti-human antibodies as follows: c CYP17A1, d HSD3B type-1, e HSD3B type-2, f Dehydroepiandrosterone sulfotransferase, g CYP11B1, and h CYP11B2. The adrenal adenoma showed positive signal for cortisol producing enzymes and DHEA-sulfotransferase, which might be responsible for the high-normal serum level of DHEA-sulfate. CYP11B2 was absent in the adrenal tumors, but was positive in the extra-tumor area as aldosterone-producing cell cluster (arrows). Scale bars represent (a) 10 mm, (b) 300 μm, (c)-(e) 6 mm, (f) 7 mm, and (g) 6 mm. CYP, cytochrome P450; HSD, hydroxysteroid dehydrogenase; CYP, cytochrome P450; HSD3B, 3β-hydroxy-Δ5-steroid dehydrogenase.