Cushing Syndrome Due to Primary Pigmented Nodular Adrenal Disease in Three Related Adolescent Girls With Carney Complex

Abstract

Primary pigmented nodular adrenal disease (PNNAD) is a rare cause of Cushing syndrome particularly during childhood and adolescence. Females are preferentially affected. The present work is aimed at assessing if there is a relationship between puberty and the development of Cushing syndrome due to PPNAD. We have followed an extended family with Carney complex (CNC) due to a dominantly inherited mutation of the gene encoding the regulatory subunit 1alpha (R1A) of the protein kinase A (PRKAR1A). The large majority of family members presenting with Cushing syndrome due to PPNAD were women (six out of seven). One of them died of an adrenocortical carcinoma at age 27 years. Genetic screening of entire family allowed follow-up of those family members harboring the mutation but without clinical manifestations of hypercortisolism. During the last 2 years, three related adolescent girls developed subclinical hypercortisolism starting shortly after menarche. None of their male relatives carrying the same mutation showed abnormal adrenal function. The first abnormality noticed in the patients was loss of the normal circadian variation of cortisol production. A low dose dexamethasone test (Liddles test) elicited a paradoxical increase in urinary excretion of free cortisol greater than 50% of basal values. Several months later, they complained of insidious manifestations of hypercortisolism including weight gain, hypertension and oligomenorrhea. They underwent laparoscopic bilateral adrenalectomy. Pathologically, the excised glands showed PPNAD. We conclude that female gender is a predisposing factor for expressing PPNAD. A paradoxical rise of urinary free cortisol (UFC) in response to dexamethasone is an early and specific laboratory marker of the disorder, allowing timely bilateral adrenalectomy which may not only prevent severe complications of hypercortisolism, but may also preclude the development of adrenocortical carcinoma.




J Endocrinol Metab. 2015;5(4):261-266
doi: http://dx.doi.org/10.14740/jem299w