Primary Pigmented Nodular Adrenocortical Disease (PPNAD): Disease Characteristics Research Report

Target disease: Primary Pigmented Nodular Adrenocortical Disease (PPNAD)
Category: Mendelian adrenal hyperfunction disorder causing ACTH-independent Cushing syndrome
MONDO ID / OMIM / Orphanet / MeSH / ICD-10/11: Not retrieved with the available tools in this run; requires direct lookup in OMIM/Orphanet/MONDO/MeSH/ICD resources. (sun2024theclinicalcharacteristics pages 1-2)

Executive summary (current understanding)

PPNAD is a rare, typically bilateral micronodular adrenocortical disease that produces cortisol autonomously (ACTH-independent / pituitary-independent hypercortisolism) and often presents in childhood or young adulthood. It can occur as an isolated condition or as the most common endocrine manifestation of Carney complex (CNC). The dominant mechanistic paradigm is dysregulated cAMP–PKA signaling (most often due to loss-of-function PRKAR1A), driving autonomous steroidogenesis, abnormal adrenal differentiation, increased proliferation, and resistance to apoptosis; downstream pathway involvement includes mTORC1 and Wnt signaling, with translational hypotheses for targeted therapy (e.g., mTORC1 inhibition; KIT inhibition) supported by experimental models. (sun2024theclinicalcharacteristics pages 1-2, sahutbarnola2010cushingssyndromeand pages 1-2, joussineau2014mtorpathwayis pages 1-2, almeida2012activationofcyclic pages 6-6, nadella2020ckitoncogeneexpression pages 1-3)

1. Disease information

1.1 Definition and overview

Human clinical / aggregated evidence.
PPNAD is a rare cause of endogenous Cushing syndrome (CS) due to primary adrenal, ACTH-independent cortisol excess. In a 2024 systematic review, PPNAD is described as a rare cause of endogenous CS affecting children and young adults and characterized histologically by multiple pigmented micronodules. (sun2024theclinicalcharacteristics pages 1-2)

A classic transcriptomic study defines PPNAD as: “another form of bilateral adrenocortical hyperplasia that is often associated with ACTH-independent Cushing’s syndrome and is characterized by small to normal-sized adrenal glands containing multiple small cortical pigmented nodules.” (PMID not available in tool output; J Clin Endocrinol Metab, Feb 2006; URL: https://doi.org/10.1210/jc.2005-1301) (horvath2006serialanalysisof pages 1-1)

The NIH observational protocol similarly characterizes PPNAD as a pituitary-independent primary adrenal hypercortisolism with dexamethasone resistance, loss of diurnal rhythm, and distinctive bilateral histopathology including pigmented nodules and extranodular cortical atrophy. (ClinicalTrials.gov NCT00001452; first posted 1995-12-14; URL: https://clinicaltrials.gov/study/NCT00001452) (NCT00001452 chunk 1)

1.2 Synonyms / alternative names

From the 2024 systematic review: “PPNAD … also termed i-PPNAD, familial isolated PPNAD, isolated PPNAD or micronodular adrenal disease.” (sun2024theclinicalcharacteristics pages 1-2)

1.3 Data provenance

Evidence in this report is derived from: - Aggregated disease-level sources: systematic review of 210 published cases (Sun et al., 2024). (sun2024theclinicalcharacteristics pages 1-2, sun2024theclinicalcharacteristics pages 4-5) - Individual patient reports/series: e.g., PRKACA amplification case report (2024) and a 5-patient case series (2006). (yang2024germlineprkacaamplificationassociated pages 2-4, zhu2006primarypigmentednodular pages 1-2) - Experimental models: adrenal cortex–specific Prkar1a knockout mouse, cell lines, xenografts. (sahutbarnola2010cushingssyndromeand pages 1-2, nadella2020ckitoncogeneexpression pages 1-3, joussineau2014mtorpathwayis pages 1-2)

2. Etiology

2.1 Disease causal factors

Primary cause: Mendelian or mosaic genetic dysregulation of cAMP/PKA signaling leading to autonomous cortisol production via bilateral micronodular adrenal disease (PPNAD). (chevalier2021bilateraladrenalhyperplasia pages 1-3, robinsonwhite2006prkar1amutationsandprotein pages 1-2)

Major causal/associated genes in recent aggregated evidence (2024): PRKAR1A, PDE11A, PRKACA, CTNNB1, PDE8B, ARMC5 were reported among genetically tested PPNAD cases, with PRKAR1A predominant. (sun2024theclinicalcharacteristics pages 1-2, sun2024theclinicalcharacteristics pages 4-5)

2.2 Risk factors

Genetic risk factors (causal genes / susceptibility): - PRKAR1A pathogenic variants (most common in tested PPNAD cases; see Section 4). (sun2024theclinicalcharacteristics pages 1-2, sun2024theclinicalcharacteristics pages 4-5) - PDE11A variants (often co-occurring with PRKAR1A in the 2024 review). (sun2024theclinicalcharacteristics pages 4-5) - PRKACA copy-number gain/amplification reported as a causal event in at least one pediatric case report. (yang2024germlineprkacaamplificationassociated pages 2-4)

Non-genetic risk factors: No robust environmental/lifestyle risk factors were identified in the evidence retrieved for this run; PPNAD is primarily genetic. (chevalier2021bilateraladrenalhyperplasia pages 1-3)

2.3 Protective factors

No protective genetic or environmental factors were identified in the retrieved evidence. (sun2024theclinicalcharacteristics pages 1-2)

2.4 Gene–environment interactions

Not established in the retrieved evidence; currently appears primarily genotype-driven. (sun2024theclinicalcharacteristics pages 1-2)

3. Phenotypes (clinical spectrum)

3.1 Core phenotype: ACTH-independent Cushing syndrome / hypercortisolism

Key features (HPO suggestions in parentheses): - Hypercortisolism with loss of circadian rhythm (Abnormal circulating cortisol concentration [HP:0008207]; Abnormality of circadian rhythm [HP:0001270 as proxy]; Cushing syndrome [HP:0000863]). Loss of cortisol rhythm was reported in 98.59% (70/71) of cases with data in the 2024 systematic review. (sun2024theclinicalcharacteristics pages 4-5) - Low/undetectable ACTH (Decreased circulating ACTH level [no exact HPO term; use Abnormality of pituitary hormone level HP:0000851 + ACTH annotation]) reported in 78.57% (77/98). (sun2024theclinicalcharacteristics pages 4-5) - Classical Cushingoid appearance: moon facies, buffalo hump, plethora, violaceous striae (e.g., Moon facies [HP:0000270], Dorsocervical fat pad [HP:0002775], Facial plethora [HP:0031307], Purple striae [HP:0001055]). (zhu2006primarypigmentednodular pages 1-2)

Course: PPNAD may be mild, subclinical, or cyclic in some cases (not consistently quantified in the retrieved evidence). (NCT00001452 chunk 1)

3.2 Skeletal phenotype

• Osteoporosis/osteopenia (Osteoporosis [HP:0000939], Osteopenia [HP:0012055]) in 94.29% (33/35) in the 2024 systematic review. (sun2024theclinicalcharacteristics pages 1-2, sun2024theclinicalcharacteristics pages 4-5)

3.3 Cardiometabolic phenotype

• Hypertension (Hypertension [HP:0000822]) in 67.50% (81/120). (sun2024theclinicalcharacteristics pages 4-5)
• Weight gain/obesity (Weight gain [HP:0004324], Obesity [HP:0001513]) in 59.17% (71/120). (sun2024theclinicalcharacteristics pages 4-5)
• Diabetes/impaired glucose tolerance reported in case series and case report (HPO: Diabetes mellitus [HP:0000819], Impaired glucose tolerance [HP:0001959]). (zhu2006primarypigmentednodular pages 1-2, yang2024germlineprkacaamplificationassociated pages 2-4)

3.4 Pigmentary / syndromic features (Carney complex association)

Among PPNAD patients in the 2024 review, 31.43% (66/210) had concurrent CNC; among these, 71.21% (47/66) had spotty skin pigmentation (HPO: Lentigines [HP:0001003], Hyperpigmentation [HP:0000953]). (sun2024theclinicalcharacteristics pages 4-5)

3.5 Quality-of-life impact

Direct QoL instrument data (SF-36/EQ-5D/PROMIS) were not identified in the retrieved sources. Clinically, the high frequency of osteoporosis, hypertension, and metabolic disease implies substantial morbidity in untreated hypercortisolism. (sun2024theclinicalcharacteristics pages 4-5)

4. Genetic / molecular information

4.1 Causal genes and inheritance

Inheritance: Often autosomal dominant in the context of PRKAR1A-related CNC/PPNAD (tumor-suppressor model with haploinsufficiency/second hit described in reviews). (chevalier2021bilateraladrenalhyperplasia pages 6-7, chevalier2021bilateraladrenalhyperplasia pages 1-3)

Genes implicated in the 2024 systematic review (151 tested; 132 with pathogenic variants): PRKAR1A, PDE11A, PRKACA, CTNNB1, PDE8B, ARMC5; PRKAR1A was most frequent (79.47%). (sun2024theclinicalcharacteristics pages 1-2, sun2024theclinicalcharacteristics pages 4-5)

High-yield statistic: In the 2024 review, genetic testing had 87.42% (132/151) yield for a pathogenic variant in reported cases. (sun2024theclinicalcharacteristics pages 1-2)

4.2 Pathogenic variants and functional classes

• PRKAR1A loss-of-function: Reviews describe many PRKAR1A mutations as premature stop codons leading to nonsense-mediated decay and haploinsufficiency; other mutations may generate altered proteins (some degraded; some potentially dominant-negative). (chevalier2021bilateraladrenalhyperplasia pages 6-7)
• PRKACA amplification (copy-number gain): A 2024 case report describes germline PRKACA copy-number gain on chr19p13.13p13.12 associated with pediatric-onset PPNAD and CNC features. (yang2024germlineprkacaamplificationassociated pages 1-2, yang2024germlineprkacaamplificationassociated pages 2-4)

Population allele frequency / gnomAD / ClinVar classifications: Not retrievable in this run because ClinVar/gnomAD tools were not available.

4.3 Genotype–phenotype association

Sun et al. (2024) reports a significant association between PRKAR1A pathogenic variants and spotty skin pigmentation in CNC with concurrent PPNAD. (sun2024theclinicalcharacteristics pages 1-2, sun2024theclinicalcharacteristics pages 4-5)

5. Environmental information

No specific environmental toxins, lifestyle exposures, or infectious triggers were identified in the retrieved evidence. Current literature captured here supports PPNAD as primarily a genetic disease driven by cAMP/PKA pathway dysregulation. (chevalier2021bilateraladrenalhyperplasia pages 1-3)

6. Mechanism / pathophysiology

6.1 Core pathway: cAMP–PKA dysregulation (upstream → downstream causal chain)

Upstream trigger: Germline inactivating PRKAR1A (PKA regulatory subunit RIα) or other cAMP/PKA pathway alterations. (chevalier2021bilateraladrenalhyperplasia pages 6-7, chevalier2021bilateraladrenalhyperplasia pages 1-3)

Cellular consequence: Increased PKA catalytic activity and altered signaling, leading to autonomous cortisol production and adrenal hyperplasia.

In vivo mechanistic evidence (mouse model): In adrenal cortex–specific Prkar1a knockout (AdKO) mice, PRKAR1A loss caused increased PKA activity and pituitary-independent Cushing syndrome, with autonomous steroidogenic gene expression, deregulated differentiation, increased proliferation, and resistance to apoptosis. The abstract explicitly states: “AdKO mice develop pituitary-independent Cushing's syndrome with increased PKA activity.” (PLoS Genet, Jun 2010; URL: https://doi.org/10.1371/journal.pgen.1000980) (sahutbarnola2010cushingssyndromeand pages 1-2)

Ontology suggestions: - GO Biological Process: cAMP-mediated signaling (GO:0019933), protein kinase A signaling (GO:?), steroid biosynthetic process (GO:0006694), regulation of apoptotic process (GO:0042981), cell proliferation (GO:0008283). - Cell types (CL): adrenocortical cell (use CL term for adrenal cortical cell), steroidogenic cell.

6.2 mTORC1 activation and apoptosis resistance

A mechanistic study reports that mTOR pathway is activated by PKA in adrenocortical cells and contributes to apoptosis resistance in PPNAD; BAD phosphorylation is highlighted as a downstream effector, and rapamycin (mTORC1 inhibitor) restored apoptosis sensitivity in vivo in the mouse model. (Hum Mol Genet, Oct 2014; URL: https://doi.org/10.1093/hmg/ddu265) (joussineau2014mtorpathwayis pages 1-2)

Translational implication: mTORC1 is a candidate therapeutic target for PPNAD when surgery is not optimal (hypothesis supported by mechanistic in vivo work). (joussineau2014mtorpathwayis pages 1-2)

6.3 KIT/SCF as a potential therapeutic axis

In PRKAR1A-mutant PPNAD tissue, c-KIT and SCF are upregulated in certain nodular areas; in vitro, PRKAR1A deficiency and forskolin-induced cAMP signaling increased c-KIT expression, and PRKACA knockdown reduced it. KIT inhibition with imatinib reduced growth and induced apoptosis in a PRKAR1A-deficient adrenocortical cell line and inhibited growth in xenografts. (Endocr Relat Cancer, Oct 2020; URL: https://doi.org/10.1530/erc-20-0270) (nadella2020ckitoncogeneexpression pages 1-3)

6.4 Wnt/cell-cycle programs downstream of PRKAR1A defects

Transcriptomic/pathway analyses in PRKAR1A-mutant adrenal lesions show overexpression of Wnt pathway genes (e.g., CCND1, CTNNB1, LEF1, LRP5) and cell-cycle regulators, supporting Wnt-linked proliferative programs downstream of cAMP/PKA activation in PPNAD. (J Clin Endocrinol Metab, Apr 2012; URL: https://doi.org/10.1210/jc.2011-3000) (almeida2012activationofcyclic pages 6-6)

Omics datapoint (SAGE): The 2006 SAGE study reported increased expression in PPNAD of steroidogenesis-related genes including steroidogenic acute regulator and steroidogenic enzymes CYP17A1 and CYP21A2. (URL: https://doi.org/10.1210/jc.2005-1301) (horvath2006serialanalysisof pages 1-1)

7. Anatomical structures affected

7.1 Primary organ

• Adrenal cortex (bilateral) (UBERON suggestion: adrenal gland UBERON:0002369; adrenal cortex subregion). PPNAD is characterized by multiple small pigmented nodules with extranodular cortical atrophy. (sun2024theclinicalcharacteristics pages 1-2, NCT00001452 chunk 1)

7.2 Secondary system involvement (complications of hypercortisolism)

• Skeletal system: osteoporosis/osteopenia. (sun2024theclinicalcharacteristics pages 4-5)
• Cardiovascular/metabolic systems: hypertension, diabetes/metabolic syndrome features. (sun2024theclinicalcharacteristics pages 4-5, zhu2006primarypigmentednodular pages 1-2)

7.3 Subcellular/cellular compartments

Not specifically described in retrieved evidence; however, pathway data imply cytosolic/nuclear PKA signaling and mTORC1 signaling complexes (GO Cellular Component suggestions: cytosol, nucleus, mTOR complex 1).

8. Temporal development

• Typical onset: childhood to young adulthood; in Sun et al. 2024, 71.88% were 10–30 years. (sun2024theclinicalcharacteristics pages 4-5)
• Course: can be prolonged and misdiagnosed; diagnostic difficulty emphasized in systematic review and NIH protocol. (sun2024theclinicalcharacteristics pages 1-2, NCT00001452 chunk 1)

9. Inheritance and population

9.1 Epidemiology

Precise prevalence/incidence estimates were not identified in the retrieved sources.

A 2006 clinical review/case series stated PPNAD accounts for ~0.6%–1.9% of all Cushing syndrome (statement within that article’s text; not independently validated here). (Chinese Medical Journal, May 2006; URL: https://doi.org/10.1097/00029330-200605010-00015) (zhu2006primarypigmentednodular pages 2-4)

9.2 Demographics (from 2024 systematic review)

Median age 22; female:male 2:1. (sun2024theclinicalcharacteristics pages 1-2)

10. Diagnostics

10.1 Clinical and laboratory tests

Key biochemical findings: - Elevated cortisol with loss of circadian rhythm (98.59% where reported). (sun2024theclinicalcharacteristics pages 4-5) - Low/undetectable ACTH (78.57% where reported). (sun2024theclinicalcharacteristics pages 4-5)

Paradoxical / absent dexamethasone suppression: In the 2024 systematic review, 31/31 (100%) with reported testing had no suppression or paradoxical increase on high-dose dexamethasone/Liddle-type testing. (sun2024theclinicalcharacteristics pages 4-5)

Example case report wording: “LDDST and HDDST revealed that the patient’s UFC level was not inhibited… indicating a paradoxical increase.” (Archives Endocrinol Metab, Jan 2024; URL: https://doi.org/10.20945/2359-4292-2022-0491) (yang2024germlineprkacaamplificationassociated pages 2-4)

10.2 Imaging

Imaging may be subtle; small bilateral nodules may be seen on MRI/CT in some cases (e.g., “multiple small adrenal nodules” in a CNC case report; bilateral thickening/nodular change ~10 mm in PRKACA amplification case). (yang2024germlineprkacaamplificationassociated pages 2-4)

10.3 Pathology

2024 systematic review/WHO 2022-oriented description: multiple beaded pigmented micronodules (<10 mm, often 2–5 mm), CYP11B1 positivity confirming cortisol production, and inter-nodular cortical atrophy. (sun2024theclinicalcharacteristics pages 1-2)

NIH protocol: pigmented nodular adenomas with loss of normal zonation and extranodular cortical atrophy. (NCT00001452 chunk 1)

10.4 Genetic testing strategy

Given high yield in the systematic review (87.42% of tested patients), Sun et al. recommend considering genetic testing prior to surgery due to diagnostic difficulty and syndromic implications (CNC surveillance). (sun2024theclinicalcharacteristics pages 1-2)

10.5 Differential diagnosis

Not comprehensively extracted in this run; key differentiations include other causes of ACTH-independent Cushing syndrome (e.g., cortisol-producing adenoma; PBMAH) and ACTH-dependent Cushing disease. (NCT00001452 chunk 1)

11. Outcome / prognosis

• Long-term outcome statistics (survival, mortality, QoL scores) were not identified in the retrieved evidence.
• The NIH protocol emphasizes the need to “establish prognosis for carriers/affected individuals,” highlighting that natural history is an ongoing research aim. (NCT00001452 chunk 1)

Complications expected from chronic hypercortisolism include osteoporosis, hypertension, diabetes, and thromboembolic risk in CNC due to myxomas; embolism rates are discussed in the 2024 review in the context of recurrent myxomas (not PPNAD-specific mortality). (sun2024theclinicalcharacteristics pages 11-12)

12. Treatment

12.1 Surgical (real-world implementation)

Surgery is the dominant real-world definitive therapy for cortisol excess.

In Sun et al. 2024 (patients with reported surgery data, n=122): - Bilateral adrenalectomy: 50.82% (62/122) - Unilateral adrenalectomy: 33.61% (41/122) - Two-stage bilateral adrenalectomy: 12.30% (15/122)

Unilateral adrenalectomy was discussed as an option in selected patients (including fertility considerations), but some unilateral cases required completion because hypercortisolism persisted/returned. (sun2024theclinicalcharacteristics pages 4-5, sun2024theclinicalcharacteristics pages 12-14)

MAXO suggestions: adrenalectomy (MAXO term for adrenalectomy), unilateral adrenalectomy, bilateral adrenalectomy.

12.2 Pharmacotherapy for hypercortisolism (bridging or recurrence)

Sun et al. list steroidogenesis inhibitors used in persistent/recurrent hypercortisolism: ketoconazole, metyrapone, mitotane, trilostane, and note fluconazole proposed as a safer alternative to ketoconazole in some contexts. (sun2024theclinicalcharacteristics pages 11-12)

MAXO suggestions: pharmacological inhibition of steroid biosynthesis; glucocorticoid replacement therapy (post-bilateral adrenalectomy).

12.3 Targeted/experimental therapeutics (mechanism-informed)

• mTORC1 inhibition (rapamycin): restored apoptosis sensitivity in vivo in a mouse model, supporting mTORC1 as a candidate target. (joussineau2014mtorpathwayis pages 1-2)
• KIT inhibition (imatinib): reduced growth and induced apoptosis in PRKAR1A-deficient adrenocortical cells and inhibited xenograft growth. (nadella2020ckitoncogeneexpression pages 1-3)

These are not established standard-of-care treatments for PPNAD but represent translational directions grounded in mechanistic evidence.

12.4 Clinical trials

No interventional trials specific to PPNAD were identified in the retrieved clinical trial set; however, an NIH cohort study focused on PPNAD/CNC genetics and natural history enrolled 1,387 participants (NCT00001452; initiated 1995-12-14). (NCT00001452 chunk 1)

13. Prevention

Primary prevention is not currently established because PPNAD is primarily genetic.

Secondary prevention / early detection: Genetic counseling and cascade testing in families with PRKAR1A-related disease and surveillance for CNC manifestations are supported conceptually; the NIH protocol notes that “there are no standardized screening tests” for family members at present (historical context, 1995 protocol). (NCT00001452 chunk 1)

14. Other species / natural disease

No naturally occurring veterinary/other-species PPNAD analogs were identified in the retrieved evidence.

15. Model organisms

Adrenal cortex–specific Prkar1a knockout mouse (AdKO): recapitulates key human features (ACTH-independent Cushing syndrome, bilateral adrenal hyperplasia) and provides in vivo evidence that PRKAR1A loss is sufficient for PPNAD-like disease. (PLoS Genet, Jun 2010; https://doi.org/10.1371/journal.pgen.1000980) (sahutbarnola2010cushingssyndromeand pages 1-2)

Mechanism-focused mouse work: AdKO model used to show PKA→mTORC1 activation contributing to apoptosis resistance; rapamycin reversed apoptosis resistance in vivo. (joussineau2014mtorpathwayis pages 1-2)

Cellular/xenograft systems: PRKAR1A-deficient adrenocortical cell lines (e.g., CAR47) and H295 xenografts used to test KIT inhibition (imatinib). (nadella2020ckitoncogeneexpression pages 1-3)

Recent developments (prioritizing 2023–2024)

1) Largest recent synthesis of clinical/genetic data: Systematic review of 210 PPNAD patients (Jun 2024) quantifying phenotype frequencies, gene frequencies, and surgical patterns; highlights diagnostic yield of genetic testing and pregnancy/fertility considerations for unilateral adrenalectomy. (https://doi.org/10.3389/fendo.2024.1356870; Jun 2024) (sun2024theclinicalcharacteristics pages 1-2, sun2024theclinicalcharacteristics pages 4-5)

2) PRKACA copy-number gain as a causal mechanism: 2024 case report describing germline PRKACA amplification-associated PPNAD with paradoxical dexamethasone response and micronodular pathology; reinforces expansion of genetic causes beyond PRKAR1A. (https://doi.org/10.20945/2359-4292-2022-0491; Jan 2024) (yang2024germlineprkacaamplificationassociated pages 2-4)

Key quantitative evidence table (Sun et al., 2024)

Table: This table compiles the main quantitative findings from Sun et al. 2024’s systematic review of 210 PPNAD patients, including demographics, phenotype frequencies, diagnostic findings, genetic results, and surgery patterns. It is useful as a concise evidence summary for knowledge-base curation and clinical overview.

References

1. (sun2024theclinicalcharacteristics pages 1-2): Julian Sun, Lin Ding, Liping He, Hang Fu, Rui Li, Jing Feng, Jianjun Dong, and Lin Liao. The clinical characteristics and pathogenic variants of primary pigmented nodular adrenocortical disease in 210 patients: a systematic review. Frontiers in Endocrinology, Jun 2024. URL: https://doi.org/10.3389/fendo.2024.1356870, doi:10.3389/fendo.2024.1356870. This article has 12 citations.

2. (sahutbarnola2010cushingssyndromeand pages 1-2): Isabelle Sahut-Barnola, Cyrille de Joussineau, Pierre Val, Sarah Lambert-Langlais, Christelle Damon, Anne-Marie Lefrançois-Martinez, Jean-Christophe Pointud, Geoffroy Marceau, Vincent Sapin, Frédérique Tissier, Bruno Ragazzon, Jérôme Bertherat, Lawrence S. Kirschner, Constantine A. Stratakis, and Antoine Martinez. Cushing's syndrome and fetal features resurgence in adrenal cortex–specific prkar1a knockout mice. PLoS Genetics, 6:e1000980, Jun 2010. URL: https://doi.org/10.1371/journal.pgen.1000980, doi:10.1371/journal.pgen.1000980. This article has 128 citations and is from a domain leading peer-reviewed journal.

3. (joussineau2014mtorpathwayis pages 1-2): Cyrille de Joussineau, Isabelle Sahut-Barnola, Frédérique Tissier, Typhanie Dumontet, Coralie Drelon, Marie Batisse-Lignier, Igor Tauveron, Jean-Christophe Pointud, Anne-Marie Lefrançois-Martinez, Constantine A. Stratakis, Jérôme Bertherat, Pierre Val, and Antoine Martinez. Mtor pathway is activated by pka in adrenocortical cells and participates in vivo to apoptosis resistance in primary pigmented nodular adrenocortical disease (ppnad). Human molecular genetics, 23 20:5418-28, Oct 2014. URL: https://doi.org/10.1093/hmg/ddu265, doi:10.1093/hmg/ddu265. This article has 48 citations and is from a domain leading peer-reviewed journal.

4. (almeida2012activationofcyclic pages 6-6): Madson Q. Almeida, Monalisa F. Azevedo, Paraskevi Xekouki, Eirini I. Bimpaki, Anelia Horvath, Michael T. Collins, Lefkothea P. Karaviti, George S. Jeha, Nisan Bhattacharyya, Chris Cheadle, Tonya Watkins, Isabelle Bourdeau, Maria Nesterova, and Constantine A. Stratakis. Activation of cyclic amp signaling leads to different pathway alterations in lesions of the adrenal cortex caused by germline prkar1a defects versus those due to somatic gnas mutations. The Journal of Clinical Endocrinology & Metabolism, 97:E687-E693, Apr 2012. URL: https://doi.org/10.1210/jc.2011-3000, doi:10.1210/jc.2011-3000. This article has 71 citations.

5. (nadella2020ckitoncogeneexpression pages 1-3): Kiran Nadella, Fabio R Faucz, and Constantine A Stratakis. C-kit oncogene expression in prkar1a-mutant adrenal cortex. Oct 2020. URL: https://doi.org/10.1530/erc-20-0270, doi:10.1530/erc-20-0270. This article has 1 citations and is from a domain leading peer-reviewed journal.

6. (horvath2006serialanalysisof pages 1-1): Anelia Horvath, Ludmila Mathyakina, Queenie Vong, Vanessa Baxendale, Alan L. Y. Pang, Wai-Yee Chan, and Constantine A. Stratakis. Serial analysis of gene expression in adrenocortical hyperplasia caused by a germline prkar1a mutation. The Journal of clinical endocrinology and metabolism, 91 2:584-96, Feb 2006. URL: https://doi.org/10.1210/jc.2005-1301, doi:10.1210/jc.2005-1301. This article has 71 citations.

7. (NCT00001452 chunk 1): Defining the Genetic Basis for the Development of Primary Pigmented Nodular Adrenocortical Disease (PPNAD) and the Carney Complex. Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD). 1995. ClinicalTrials.gov Identifier: NCT00001452

8. (sun2024theclinicalcharacteristics pages 4-5): Julian Sun, Lin Ding, Liping He, Hang Fu, Rui Li, Jing Feng, Jianjun Dong, and Lin Liao. The clinical characteristics and pathogenic variants of primary pigmented nodular adrenocortical disease in 210 patients: a systematic review. Frontiers in Endocrinology, Jun 2024. URL: https://doi.org/10.3389/fendo.2024.1356870, doi:10.3389/fendo.2024.1356870. This article has 12 citations.

9. (yang2024germlineprkacaamplificationassociated pages 2-4): Wang-Rong Yang, Xing-Huan Liang, Ying-Fen Qin, Hai-Yan Yang, Shu-Zhan He, Zhen-Xing Huang, Yu-Ping Liu, and Zuo-Jie Luo. Germline prkaca amplification-associated primary pigmented nodular adrenocortical disease: a case report and literature review. Archives of Endocrinology and Metabolism, Jan 2024. URL: https://doi.org/10.20945/2359-4292-2022-0491, doi:10.20945/2359-4292-2022-0491. This article has 8 citations.

10. (zhu2006primarypigmentednodular pages 1-2): Yu ZHU, Yu-xuan WU, Wen-bin RUI, Ding-yi LIU, Wen-long ZHOU, Rong-ming ZHANG, Fu-kang SUN, Chong-yu ZHANG, and Zhou-jun SHEN. Primary pigmented nodular adrenocortical disease. Chinese Medical Journal, 119(9):782-785, May 2006. URL: https://doi.org/10.1097/00029330-200605010-00015, doi:10.1097/00029330-200605010-00015. This article has 2 citations and is from a peer-reviewed journal.

11. (chevalier2021bilateraladrenalhyperplasia pages 1-3): Benjamin Chevalier, Marie-Christine Vantyghem, and Stéphanie Espiard. Bilateral adrenal hyperplasia: pathogenesis and treatment. Biomedicines, 9:1397, Oct 2021. URL: https://doi.org/10.3390/biomedicines9101397, doi:10.3390/biomedicines9101397. This article has 35 citations.

12. (robinsonwhite2006prkar1amutationsandprotein pages 1-2): Audrey Robinson-White, Elise Meoli, Sotirios Stergiopoulos, Anelia Horvath, Sosipatros Boikos, Ioannis Bossis, and Constantine A. Stratakis. prkar1amutations and protein kinase a interactions with other signaling pathways in the adrenal cortex. The Journal of Clinical Endocrinology & Metabolism, 91:2380-2388, Jun 2006. URL: https://doi.org/10.1210/jc.2006-0188, doi:10.1210/jc.2006-0188. This article has 83 citations.

13. (chevalier2021bilateraladrenalhyperplasia pages 6-7): Benjamin Chevalier, Marie-Christine Vantyghem, and Stéphanie Espiard. Bilateral adrenal hyperplasia: pathogenesis and treatment. Biomedicines, 9:1397, Oct 2021. URL: https://doi.org/10.3390/biomedicines9101397, doi:10.3390/biomedicines9101397. This article has 35 citations.

14. (yang2024germlineprkacaamplificationassociated pages 1-2): Wang-Rong Yang, Xing-Huan Liang, Ying-Fen Qin, Hai-Yan Yang, Shu-Zhan He, Zhen-Xing Huang, Yu-Ping Liu, and Zuo-Jie Luo. Germline prkaca amplification-associated primary pigmented nodular adrenocortical disease: a case report and literature review. Archives of Endocrinology and Metabolism, Jan 2024. URL: https://doi.org/10.20945/2359-4292-2022-0491, doi:10.20945/2359-4292-2022-0491. This article has 8 citations.

15. (zhu2006primarypigmentednodular pages 2-4): Yu ZHU, Yu-xuan WU, Wen-bin RUI, Ding-yi LIU, Wen-long ZHOU, Rong-ming ZHANG, Fu-kang SUN, Chong-yu ZHANG, and Zhou-jun SHEN. Primary pigmented nodular adrenocortical disease. Chinese Medical Journal, 119(9):782-785, May 2006. URL: https://doi.org/10.1097/00029330-200605010-00015, doi:10.1097/00029330-200605010-00015. This article has 2 citations and is from a peer-reviewed journal.

16. (sun2024theclinicalcharacteristics pages 11-12): Julian Sun, Lin Ding, Liping He, Hang Fu, Rui Li, Jing Feng, Jianjun Dong, and Lin Liao. The clinical characteristics and pathogenic variants of primary pigmented nodular adrenocortical disease in 210 patients: a systematic review. Frontiers in Endocrinology, Jun 2024. URL: https://doi.org/10.3389/fendo.2024.1356870, doi:10.3389/fendo.2024.1356870. This article has 12 citations.

17. (sun2024theclinicalcharacteristics pages 12-14): Julian Sun, Lin Ding, Liping He, Hang Fu, Rui Li, Jing Feng, Jianjun Dong, and Lin Liao. The clinical characteristics and pathogenic variants of primary pigmented nodular adrenocortical disease in 210 patients: a systematic review. Frontiers in Endocrinology, Jun 2024. URL: https://doi.org/10.3389/fendo.2024.1356870, doi:10.3389/fendo.2024.1356870. This article has 12 citations.

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