Heterogeneous Clinical Manifestations of Cushing's Syndrome in a Family with Primary Pigmented Nodular Adrenocortical Disease

Purpose: To evaluate the clinical manifestations of Cushing’s Syndrome (CS) and associated genetic mutation in patients with Primary Pigmented Nodular Adrenocortical Disease (PPNAD). Methods: Seven family members were screened for mutations of the PRKAR1A gene. Gene mutation screening used genomic DNA (from peripheral blood leukocytes and, in some cases, adrenal gland tissue) and subsequent DNA sequencing. The five patients showing genetic mutation were assessed clinically for baseline cortisol and adrenocorticotropic hormone and adrenal imaging studies (abdominal computed tomography and adrenal scintigraphy). Low-dose and high-low dexamethasone suppression tests were performed in these five patients. Results: PRKAR1A gene mutation was detected in five of the seven family members. Four of the five gene mutation-positive patients presented with overt CS due to pathology-proven PPNAD. After unilateral adrenalectomy in these four patients, overt CS persisted for two patients and CS symptoms abated for the other two. The remission period of CS was >11 years in one instance (case III-2) and continues for >12 years in the other (case II-4), with no observable disease of the contralateral non-resected adrenal gland. For each of the two remission patients, one adrenal gland had been larger (by abdominal computed tomography) and had had stronger function (by 131I-6β- iodomethyl-19-norcholesterol scintigraphy) than the other. In one (case III-2) of the two remission patients, one adrenal displayed focal PPNAD while the other displayed diffuse PPNAD. The clinical manifestations of CS did not resolve after unilateral adrenalectomy in case II-2 and III-7. The fifth gene mutation-positive patient (case III-4) is still in the latent stage of CS. Conclusions: The clinical manifestations of CS and adrenal image features in patients with PPNAD are heterogeneous. Detailed adrenal imaging of these patients is necessary to assist with the decision to perform unilateral adrenalectomy.