Primary pigmented nodular adrenal disease (PPNAD) is a form of bilateral adrenocortical hyperplasia characterised by small to normal sized adrenal glands containing multiple small cortical pigmented nodules1. It may occur independently, but 90% of cases are a manifestation of the Carney complex. Most cases of PPNAD are diagnosed before age 30, and are the result of a germline mutation in PRKAR1A or PDE11A, leading to upregulation of cAMP signalling. It is a cause of ACTH-independent Cushings syndrome. The cause of the black/brown pigmentation in PPNAD has not been definitively established, although some authors have ascribed it to lipofuscin, a product of lysosomal breakdown.
Paraffin-embedded bilateral adrenalectomy specimens from five paediatric patients with PPNAD were subjected to a series of histological and immunohistochemical staining techniques. Haematoxylin and eosin staining revealed intracellular deposits of a brown pigment that was removed by permanganate bleaching. The pigment was negative on Ziehl-Neelsen staining, and strongly positive with the PERLS and Masson-Fontana stains. Immunohistochemistry showed strong staining within the nodules for the melanosome marker HMB-45. These findings identify the pigment as melanin. The adrenal nodules in all five cases immunostained strongly positive for the melanocortin-1 receptor (MC1R), and for 11β-hydroxylase, the final enzyme in the steroidogenic pathway leading to cortisol production.
We suggest that the autonomously activated cAMP signaling pathway associated with PPNAD leads to upregulation of the MC1R, induction of steroidogenic enzymes, and generation of melanin within melanosomes. We hypothesise that the mechanism for hyperpigmentation in Carney complex skin lesions has a similar aetiology.
Reference: 1. Horvath, A. & Stratakis, C. A. Primary pigmented nodular adrenocortical disease and Cushings syndrome. Arq Bras Endocrinol Metabol 51, 12381244 (2007).