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Adrenal (Excluding Mineralocorticoids)

ORF13-01 - Expanding the Clinical, Genetic, and Histopathological Spectrum of Primary Pigmented Nodular Adrenocortical Disease: Insights from a Brazilian Referral Cohort

Saturday, June 13, 2026
1:45 PM - 1:50 PM CT
Location: Room W183A
Disclosure(s):
Marina Buchpiguel, M.D.: No financial relationships to disclose
Berenice Bilharinho Mendonca, MD, PhD: No financial relationships to disclose
Ana Claudia Latronico, MD, PhD: No financial relationships to disclose
Madson Almeida, MD, PhD: No financial relationships to disclose

Context: Primary pigmented nodular adrenocortical disease (PPNAD) is a rare cause of ACTH-independent Cushing syndrome (CS), occurring in isolation or, more commonly, as part of Carney complex (CNC). Despite advances in understanding its molecular basis, population-level data from Latin America remain limited.

Objective: To deliver an integrated clinical, biochemical, imaging, histopathological, and genetic characterization of Brazilian patients with PPNAD, with or without CNC, evaluated at a single high-volume tertiary referral center (HCFMUSP).

Methods: We evaluated 18 index patients with PPNAD (with/without CNC) and performed cascade testing in relatives; clinical/hormonal/imaging phenotyping was integrated with histopathology and germline/somatic genetic analyses.

Results: Among 18 index cases (88% female; mean age 24.2 years), 83% presented with overt Cushing syndrome and 17% with cyclic disease. Extra-adrenal manifestations were frequent, particularly lentigines (61%) and cardiac myxomas (22%). Germline PRKAR1A pathogenic/likely pathogenic variants were found in 11/18 (61%) probands, including four previously unreported to our knowledge; PRKACA duplications in 2/18 probands. Among individuals with available tissue, somatic second-hit alterations were detected in 23%, including PRKACA duplication, PRKAR1A frameshift deletion, and 17q24.2 loss of heterozygosity. Cascade testing revealed 20 additional variant-positive relatives, eight of whom were asymptomatic carriers. No index case met criteria for mild autonomous cortisol secretion (MACS) at presentation; MACS was identified exclusively among variant-positive relatives detected through cascade genetic screening, highlighting incomplete penetrance and the value of genetic surveillance. Histopathology predominantly demonstrated classic PPNAD, nonclassical patterns were also observed, supporting a continuum of PRKAR1A-related adrenal pathology.

Conclusion: This study expands the clinical and genetic spectrum of PPNAD/CNC in Brazil, identifies novel PRKAR1A variants, and highlights wide phenotypic variability and incomplete penetrance. These findings reinforce the need for systematic genetic evaluation and lifelong, individualized surveillance in affected families.