PDE11A – Primary Pigmented Nodular Adrenocortical Disease

Primary pigmented nodular adrenocortical disease (PPNAD) is a rare cause of ACTH-independent Cushing syndrome characterized by adrenal micronodular hyperplasia. PDE11A encodes a dual-specificity phosphodiesterase that regulates intracellular cAMP and cGMP levels in steroidogenic tissues. In a systematic review of 210 PPNAD patients, PDE11A variants were identified in a minority (3/151) of those tested for pathogenic alleles (PMID:39006359). An independent cohort of 18 PPNAD patients detected one germline PDE11A mutation, confirming its recurrent involvement (PMID:18419788). Across case reports and series, three unrelated PPNAD probands harbored heterozygous PDE11A coding variants—including c.1921A>G (p.Lys641Glu)—in the absence of other known genetic defects (PMID:35929507; PMID:19063937). Functional assays of inactivating PDE11A variants demonstrated reduced cAMP hydrolysis and elevated cyclic nucleotide signaling in human cells (PMID:17178847), and Pde11a hypomorphic knockout mice develop adrenal subcapsular hyperplasia mimicking PPNAD (PMID:33127481). Although segregation data remain absent, the concordant genetic and experimental findings support a limited but biologically plausible role for PDE11A haploinsufficiency in PPNAD pathogenesis. Key take-home: PDE11A testing may complement PRKAR1A analysis in unexplained PPNAD cases.

References

• Frontiers in endocrinology • 2024 • The clinical characteristics and pathogenic variants of primary pigmented nodular adrenocortical disease in 210 patients: a systematic review. PMID:39006359
• Clinical endocrinology • 2008 • Detection of somatic beta-catenin mutations in primary pigmented nodular adrenocortical disease (PPNAD). PMID:18419788
• Molecular medicine reports • 2022 • Functional characteristics and research trends of PDE11A in human diseases (Review). PMID:35929507
• Molecular and cellular endocrinology • 2009 • New genes and/or molecular pathways associated with adrenal hyperplasias and related adrenocortical tumors. PMID:19063937
• Cancer research • 2006 • Adrenal hyperplasia and adenomas are associated with inhibition of phosphodiesterase 11A in carriers of PDE11A sequence variants that are frequent in the population. PMID:17178847
• Molecular and cellular endocrinology • 2021 • A phosphodiesterase 11 (Pde11a) knockout mouse expressed functional but reduced Pde11a: Phenotype and impact on adrenocortical function. PMID:33127481

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