Integrated clinical–genetic–pathological analysis expands the phenotypic and molecular spectrum of primary pigmented nodular adrenocortical disease (PPNAD) across carney complex and isolated forms
Authors' conclusion
In this referral cohort, PPNAD/CNC displays marked phenotypic variability, incomplete penetrance with subclinical cortisol excess, and diverse molecular mechanisms, including novel germline variants and somatic second hits. Some cases lacked identifiable drivers, suggesting additional uncharacterized mechanisms.
Study context
- Population
- Index patients with primary pigmented nodular adrenocortical disease (PPNAD), a rare cause of ACTH-independent Cushing syndrome (CS), and their relatives
- Participants
- 18 index patients
- Exposure
- Carney complex (CNC) vs Isolated
- CNCn = 15
- Isolatedn = 3
- Outcome
- Clinical, genetic and pathological findings in index patients
Methodological detailsreferral cohort, cascade genetic screening, Germline and somatic analyses by targeted next-generation sequencing and copy-number assessment
- Referral cohort
- Cascade genetic screening
- Germline and somatic analyses by targeted next-generation sequencing and copy-number assessment
Main finding
As reported in the abstract
- Overt CS
- 83%
- Cyclic hypercortisolism
- 17%
- Pathogenic or likely-pathogenic germline PRKAR1A variants in probands, including four novel variants
- 70.6%
- Germline PRKACA duplications
- 2 cases
- Lentigines
- 61%
- Cardiac myxomas
- 22%
Observational data: associations, not effects.
Further findings
Cascade genetic screening in relatives
- Variant-positive relatives
- 20
- Asymptomatic variant-positive relatives, in whom mild autonomous cortisol secretion (MACS) was observed
- 8
Original publication
Integrated clinical–genetic–pathological analysis expands the phenotypic and molecular spectrum of PPNAD across carney complex and isolated forms. Eur J Endocrinol. Published 3 August 2026. doi:10.
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