Shih-Chen Tung, Daw-Yang Hwang, Joseph W. Yang, Hwee-Yeong Ng and Chien-Te Lee
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.
