Cushing syndrome: uncovering Carney complex due to novel PRKAR1A mutation

Abstract

Carney complex (CNC) is a rare multiple neoplasia syndrome characterized by spotty pigmentation of the skin and mucosa in association with various non-endocrine and endocrine tumors, including primary pigmented nodular adrenocortical disease (PPNAD). A 20-year-old woman was referred for suspected Cushing syndrome. She had signs of cortisol excess as well as skin lentigines on physical examination. Biochemical investigation was suggestive of corticotropin (ACTH)-independent Cushing syndrome. Unenhanced computed tomography scan of the abdomen did not reveal an obvious adrenal mass. She subsequently underwent bilateral laparoscopic adrenalectomy, and histopathology was consistent with PPNAD. Genetic testing revealed a novel frameshift pathogenic variant c.488delC/p.Thr163MetfsX2 (ClinVar Variation ID: 424516) in the PRKAR1A gene, consistent with clinical suspicion for CNC. Evaluation for other clinical features of the complex was unrevealing. We present a case of PPNAD-associated Cushing syndrome leading to the diagnosis of CNC due to a novel PRKAR1A pathogenic variant. Learning points: PPNAD should be considered in the differential for ACTH-independent Cushing syndrome, especially when adrenal imaging appears normal. The diagnosis of PPNAD should prompt screening for CNC. CNC is a rare multiple neoplasia syndrome caused by inactivating pathogenic variants in the PRKAR1A gene. Timely diagnosis of CNC and careful surveillance can help prevent potentially fatal complications of the disease.

Keywords: 2019; ACTH; Adolescent/young adult; Adrenal; Adrenalectomy; Anxiety; Buffalo hump; CT scan; Carney complex; Cortisol; Cortisol (serum); Cushing's syndrome; DNA sequencing; Dehydroepiandrostenedione; Dexamethasone suppression (high dose); Dexamethasone suppression (low dose); Error in diagnosis/pitfalls and caveats; Facial plethora; Facies - moon; Female; Fludrocortisone; Genetics; Glucocorticoids; Haematoxylin and eosin staining; Hirsutism; Histopathology; Hydrocortisone; Laparoscopic adrenalectomy; March; Mineralocorticoids; Molecular genetic analysis; Necrosis; Obesity; Skin pigmentation - spotty; Striae; United States; Weight gain; White.

Figure 1

Skin examination was notable for lentigines on the lips (A) and a café-au-lait spot on the neck (B).

Figure 2

Bilateral adrenal glands (arrows) appeared normal on computed tomography without significant hyperplasia or obvious adrenal nodules.

Figure 3

Gross examination showed left (A) – 5.1 g, 4.7 × 3.2 × 1.2 cm – and right (B) – 5.0 g, 4.5 × 3.0 × 1.5 cm – adrenal glands within normal weight and size. Multiple tan-brown nodules were seen on the capsule and within the cortex on cross-sectioning (C and D).

Figure 4

Adrenal histology with hematoxylin and eosin stain: objective magnification ×4 (A) and ×10 (B). Well-circumcised nodules are seen containing brown pigment and cells with round-to-oval nuclei and eosinophilic cytoplasm.

Figure 5

Gene sequencing revealed a novel pathogenic variation in the PRKAR1A gene. Deletion of the cytosine base (c.488delC) changes codon Threonine 163 to a Methionine residue and creates a premature Stop codon at position 2 of the new reading frame (p.THr163MetfsX2).