Primary pigmented nodular adrenocortical disease (PPNAD) is a rare, typically bilateral micronodular form of adrenocortical hyperplasia that produces cortisol autonomously, causing ACTH-independent (pituitary-independent) Cushing syndrome that often presents in childhood or young adulthood and may be cyclical or subclinical. It occurs as an isolated condition or, in roughly one-third of cases, as the most frequent endocrine manifestation of Carney complex. The dominant disease mechanism is dysregulated cAMP/PKA signaling, most often caused by germline inactivating variants in PRKAR1A (the type I alpha regulatory subunit of protein kinase A); additional causes affect cAMP phosphodiesterases (PDE11A, PDE8B) or the PKA catalytic subunit (PRKACA copy number gain). Loss of PKA regulatory restraint drives constitutive PKA catalytic activity, autonomous steroidogenesis, abnormal adrenocortical differentiation, increased proliferation, and resistance to apoptosis, with downstream involvement of mTORC1 and Wnt signaling programs. Histologically the adrenal glands are small to normal in size and contain multiple small pigmented cortical nodules with internodular cortical atrophy.
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name: Primary Pigmented Nodular Adrenocortical Disease
creation_date: "2026-06-05T12:00:00Z"
category: Mendelian
description: >-
Primary pigmented nodular adrenocortical disease (PPNAD) is a rare,
typically bilateral micronodular form of adrenocortical hyperplasia that
produces cortisol autonomously, causing ACTH-independent (pituitary-independent)
Cushing syndrome that often presents in childhood or young adulthood and may
be cyclical or subclinical. It occurs as an isolated condition or, in roughly
one-third of cases, as the most frequent endocrine manifestation of Carney
complex. The dominant disease mechanism is dysregulated cAMP/PKA signaling,
most often caused by germline inactivating variants in PRKAR1A (the type I
alpha regulatory subunit of protein kinase A); additional causes affect cAMP
phosphodiesterases (PDE11A, PDE8B) or the PKA catalytic subunit (PRKACA copy
number gain). Loss of PKA regulatory restraint drives constitutive PKA
catalytic activity, autonomous steroidogenesis, abnormal adrenocortical
differentiation, increased proliferation, and resistance to apoptosis, with
downstream involvement of mTORC1 and Wnt signaling programs. Histologically
the adrenal glands are small to normal in size and contain multiple small
pigmented cortical nodules with internodular cortical atrophy.
synonyms:
- PPNAD
- isolated PPNAD
- familial isolated PPNAD
- micronodular adrenal disease
- primary pigmented nodular adrenal dysplasia
- pigmented nodular adrenocortical disease
parents:
- Endocrine Disorders
- Adrenal Gland Diseases
disease_term:
preferred_term: Primary Pigmented Nodular Adrenocortical Disease
term:
id: MONDO:0015999
label: primary pigmented nodular adrenocortical disease
inheritance:
- name: Autosomal Dominant
description: >-
PRKAR1A-related PPNAD, whether isolated or in the context of Carney complex,
is inherited in an autosomal dominant manner. PRKAR1A behaves as a tumor
suppressor, with inactivating germline variants and frequently a somatic
second hit at the tissue level. Some cases arise de novo, and PRKACA
copy-number gain has been reported as a de novo (non-heritable) event.
evidence:
- reference: PMID:20548949
reference_title: "Cushing's syndrome and fetal features resurgence in adrenal cortex-specific Prkar1a knockout mice."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: >-
Inactivating mutations in PRKAR1A, a gene encoding the type 1
alpha-regulatory subunit (R1alpha) of the cAMP-dependent protein kinase
(PKA) have been found in 80% of CNC patients with Cushing's syndrome.
explanation: >-
Establishes PRKAR1A inactivating mutations as the predominant cause of
Carney complex with Cushing syndrome, the autosomal dominant PPNAD setting.
The cited publication is a Prkar1a knockout mouse study; this snippet
quotes its summary of prior human clinical findings.
- reference: PMID:37988664
reference_title: "Germline PRKACA amplification-associated primary pigmented nodular adrenocortical disease: a case report and literature review."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
a rise in the copy number of the duplication-containing PRKACA gene on
chromosome 19p13.13p13.12, a de novo but not heritable gene defect that
causes disease.
explanation: >-
Documents a de novo, non-heritable PRKACA copy-number gain as a cause of
PPNAD, illustrating that not all cases are inherited.
prevalence:
- population: Patients with Cushing syndrome
prevalence_class: UNKNOWN
percentage: Unknown
notes: >-
PPNAD is a rare cause of endogenous Cushing syndrome that is frequently
misdiagnosed; precise population prevalence and incidence estimates have not
been established. A pooled systematic review compiled 210 reported patients
from 86 articles, with a median age of 22 years and a female-to-male ratio
of 2:1.
evidence:
- reference: PMID:39006359
reference_title: "The clinical characteristics and pathogenic variants of primary pigmented nodular adrenocortical disease in 210 patients: a systematic review."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
A total of 210 patients in 86 articles were enrolled with a median age of
22 and a female-to-male ratio of 2:1.
explanation: >-
Provides the cohort size, median age, and sex ratio from the largest
pooled synthesis of reported PPNAD cases.
pathophysiology:
- name: PRKAR1A Loss and Constitutive PKA Activation
description: >-
Germline inactivating variants in PRKAR1A reduce or eliminate the type I
alpha regulatory subunit (RIalpha) of protein kinase A. Loss of regulatory
restraint releases the PKA catalytic subunits, producing increased
cAMP-stimulated catalytic kinase activity in adrenocortical cells. Many
PRKAR1A variants are premature stop codons triggering nonsense-mediated
decay and haploinsufficiency, with up-regulation of other PKA subunits.
genes:
- preferred_term: PRKAR1A
term:
id: hgnc:9388
label: PRKAR1A
cell_types:
- preferred_term: adrenocortical cell
term:
id: CL:0002097
label: cortical cell of adrenal gland
biological_processes:
- preferred_term: cAMP/PKA signal transduction
term:
id: GO:0141156
label: cAMP/PKA signal transduction
modifier: INCREASED
- preferred_term: activation of protein kinase A activity
term:
id: GO:0034199
label: activation of protein kinase A activity
modifier: INCREASED
evidence:
- reference: PMID:16569736
reference_title: "PRKAR1A Mutations and protein kinase A interactions with other signaling pathways in the adrenal cortex."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >-
Increased cAMP-stimulated total kinase activity was associated with
mt-PRKAR1A.
explanation: >-
Demonstrates that PRKAR1A mutation increases cAMP-stimulated PKA activity
in adrenocortical tissue.
- reference: PMID:16569736
reference_title: "PRKAR1A Mutations and protein kinase A interactions with other signaling pathways in the adrenal cortex."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >-
mt-PRKAR1A causes increased total cAMP-stimulated kinase activity, likely
the result of up-regulation of other PKA subunits caused by
down-regulation of RIalpha
explanation: >-
Mechanistically links RIalpha down-regulation to compensatory PKA subunit
up-regulation and increased kinase activity.
downstream:
- target: Autonomous Steroidogenesis and Adrenocortical Hyperplasia
causal_link_type: DIRECT
evidence:
- reference: PMID:20548949
reference_title: "Cushing's syndrome and fetal features resurgence in adrenal cortex-specific Prkar1a knockout mice."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: >-
AdKO mice develop pituitary-independent Cushing's syndrome with increased
PKA activity. This leads to autonomous steroidogenic genes expression and
deregulated adreno-cortical cells differentiation, increased proliferation
and resistance to apoptosis.
explanation: >-
Links increased PKA activity directly to autonomous steroidogenesis and
adrenocortical hyperplasia.
- target: MAPK Pathway Activation and Proliferation
causal_link_type: DIRECT
evidence:
- reference: PMID:16569736
reference_title: "PRKAR1A Mutations and protein kinase A interactions with other signaling pathways in the adrenal cortex."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >-
These changes, associated with enhanced MAPK activity, may be, in part,
responsible for the proliferative signals that result in primary pigmented
nodular adrenocortical disease.
explanation: >-
Links PRKAR1A/PKA dysregulation to enhanced MAPK activity driving
proliferation.
- name: Phosphodiesterase Loss and Impaired cAMP Degradation
description: >-
Germline reduced-function variants in the phosphodiesterases PDE11A and
PDE8B impair cAMP degradation, and this is the second route into the same
autonomous steroidogenic programme that PRKAR1A loss and PRKACA gain reach,
with no lesion in either of those genes. PDE8B is cAMP-specific. Both genes
were first linked to isolated micronodular adrenocortical disease, and MONDO
files them as the PPNAD2 and PPNAD3 children of this entry's own term. The
two are not equivalent in strength of evidence: inactivating PDE11A defects
were described as low-penetrance predisposing factors, consistent with
PDE11A variants frequently co-occurring with PRKAR1A variants in PPNAD
cohorts, whereas the reported PDE8B mutation was shown to measurably alter
the protein's cAMP-degrading capacity in vitro.
biological_scale: MOLECULAR
genes:
- preferred_term: PDE11A
term:
id: hgnc:8773
label: PDE11A
- preferred_term: PDE8B
term:
id: hgnc:8794
label: PDE8B
biological_processes:
- preferred_term: cAMP catabolic process
term:
id: GO:0006198
label: cAMP catabolic process
modifier: DECREASED
evidence:
- reference: PMID:41816209
reference_title: "cAMP/PKA signaling in endocrine hypertension: genetic mechanisms and pathophysiological insights."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: REVIEW_SYNTHESIS
snippet: "germline alterations in phosphodiesterases such as PDE11A and PDE8B, which impair cAMP degradation, have been associated with Cushing syndrome and micronodular adrenal hyperplasia"
explanation: >-
States the impaired-cAMP-degradation mechanism this node represents and
names both phosphodiesterase genes it carries.
- reference: PMID:41694449
reference_title: "Preventing Cushing Syndrome: Adrenalectomy in PDE11A-Positive Primary Pigmented Nodular Adrenocortical Disease."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "This case highlights the role of early intervention with MBSA to prevent overt Cushing syndrome in germline PDE11A-mutant PPNAD"
explanation: >-
A germline PDE11A variant producing PPNAD, confirming this route is
operative in the disease this entry models rather than only in related
adrenal hyperplasias.
- reference: PMID:18431404
reference_title: "A cAMP-specific phosphodiesterase (PDE8B) that is mutated in adrenal hyperplasia is expressed widely in human and mouse tissues: a novel PDE8B isoform in human adrenal cortex."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "This mutation is shown to significantly affect the ability of the protein to degrade cAMP in vitro."
explanation: >-
Functional measurement that the PDE8B mutation found in micronodular
adrenocortical disease alters the protein's cAMP-degrading capacity. The
sentence states that degradation is affected, not its direction, so the
direction of the modifier at this node rests on the review evidence above.
- reference: PMID:18431404
reference_title: "A cAMP-specific phosphodiesterase (PDE8B) that is mutated in adrenal hyperplasia is expressed widely in human and mouse tissues: a novel PDE8B isoform in human adrenal cortex."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "We conclude that PDE8B is another PDE gene linked to iMAD; it is a candidate causative gene for other adrenocortical lesions linked to the cAMP signaling pathway and possibly for tumors in other tissues."
explanation: >-
Establishes PDE8B as a gene of isolated micronodular adrenocortical
disease, the disease group PPNAD3 sits in.
- reference: PMID:18431404
reference_title: "A cAMP-specific phosphodiesterase (PDE8B) that is mutated in adrenal hyperplasia is expressed widely in human and mouse tissues: a novel PDE8B isoform in human adrenal cortex."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: BACKGROUND
snippet: "A genome-wide association study identified inactivating phosphodiesterase (PDE) 11A (PDE11A)-sequencing defects as low-penetrance predisposing factors for iMAD and related abnormalities"
explanation: >-
Source for this node's statement that PDE11A defects act as
low-penetrance predisposing factors rather than fully penetrant causes.
downstream:
- target: Autonomous Steroidogenesis and Adrenocortical Hyperplasia
description: >-
Reduced cAMP hydrolysis raises cAMP and PKA activity in adrenocortical
cells, converging on the same autonomous steroidogenesis and micronodular
hyperplasia that PRKAR1A loss produces.
causal_link_type: DIRECT
evidence:
- reference: PMID:41816209
reference_title: "cAMP/PKA signaling in endocrine hypertension: genetic mechanisms and pathophysiological insights."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: REVIEW_SYNTHESIS
snippet: "germline alterations in phosphodiesterases such as PDE11A and PDE8B, which impair cAMP degradation, have been associated with Cushing syndrome and micronodular adrenal hyperplasia"
explanation: >-
Links the phosphodiesterase defect to micronodular adrenal hyperplasia,
the node this edge targets.
- name: PRKACA Copy-Number Gain and Constitutive PKA Catalytic Activation
description: >-
Constitutional duplication or amplification of PRKACA, the gene encoding
the catalytic subunit of protein kinase A, is a distinct germline lesion
from PRKAR1A loss: the catalytic subunit is gained rather than the
regulatory subunit lost, and the reported cases are attributed to
constitutive activation of that catalytic subunit. Systematic screening of
781 bilateral nodular adrenocortical disease index cases found PRKACA
duplication only in patients whose pathology was PPNAD, and the duplication
generates topologically associated neo-domains in tumour Hi-C maps.
biological_scale: MOLECULAR
genes:
- preferred_term: PRKACA
term:
id: hgnc:9380
label: PRKACA
biological_processes:
- preferred_term: activation of protein kinase A activity
term:
id: GO:0034199
label: activation of protein kinase A activity
modifier: INCREASED
evidence:
- reference: PMID:41403049
reference_title: "PRKACA constitutional duplication: a specific cause of primary pigmented nodular adrenocortical disease."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "PRKACAdup causes PPNAD but no other forms of BNAD, so these should be sought in the absence of pathogenic PRKAR1A variants."
explanation: >-
A screen of 781 bilateral nodular adrenocortical disease index cases
concluding that constitutional PRKACA duplication specifically causes
PPNAD.
- reference: PMID:41403049
reference_title: "PRKACA constitutional duplication: a specific cause of primary pigmented nodular adrenocortical disease."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "PRKACAdup was found to generate topologically associated neo-domains, in tumor Hi-C maps, as compared to controls."
explanation: >-
Source for the chromatin-reorganisation finding stated in this node's
description, which is a mechanism distinct from simple gene dosage.
- reference: PMID:25924874
reference_title: "Germline PRKACA amplification causes variable phenotypes that may depend on the extent of the genomic defect: molecular mechanisms and clinical presentations."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: BACKGROUND
snippet: "five patients with bilateral adrenocortical hyperplasia (BAH) and Cushing's syndrome (CS) caused by constitutive activation of the catalytic subunit of protein kinase A (PRKACA)"
explanation: >-
Establishes that the PRKACA lesion acts through constitutive activation
of the PKA catalytic subunit, which is the GO process bound at this node.
The sentence restates this group's own earlier report of the cohort.
downstream:
- target: Autonomous Steroidogenesis and Adrenocortical Hyperplasia
description: >-
Excess PKA catalytic subunit activity drives the same ACTH-independent
steroidogenesis and micronodular adrenocortical hyperplasia as PRKAR1A
loss, and all reported PRKACA-duplication index cases underwent
adrenalectomy for ACTH-independent hypercortisolism.
causal_link_type: DIRECT
evidence:
- reference: PMID:41403049
reference_title: "PRKACA constitutional duplication: a specific cause of primary pigmented nodular adrenocortical disease."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "All IC with PRKACAdup underwent adrenalectomy for ACTH-independent hypercortisolism, with pathology confirming PPNAD."
explanation: >-
Every PRKACA-duplication index case had ACTH-independent
hypercortisolism with PPNAD pathology, the outcome this edge asserts.
- reference: PMID:25924874
reference_title: "Germline PRKACA amplification causes variable phenotypes that may depend on the extent of the genomic defect: molecular mechanisms and clinical presentations."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Although all five patients presented with ACTH-independent CS, the three sporadic patients had micronodular BAH and underwent bilateral adrenalectomy in early childhood"
explanation: >-
Independent case series in which PRKACA amplification produced
ACTH-independent Cushing syndrome with micronodular hyperplasia.
- name: Autonomous Steroidogenesis and Adrenocortical Hyperplasia
description: >-
Constitutive PKA activity drives autonomous, ACTH-independent expression of
steroidogenic genes and cortisol production, together with deregulated
adrenocortical cell differentiation and increased proliferation, yielding
bilateral micronodular hyperplasia. The adrenal-cortex-specific Prkar1a
knockout mouse recapitulates pituitary-independent Cushing syndrome and
bilateral hyperplasia, demonstrating that RIalpha loss is sufficient.
Transcriptomic studies show increased expression of steroidogenic acute
regulatory protein and the steroidogenic enzymes CYP17A1 and CYP21A2.
cell_types:
- preferred_term: adrenocortical cell
term:
id: CL:0002097
label: cortical cell of adrenal gland
biological_processes:
- preferred_term: glucocorticoid biosynthetic process
term:
id: GO:0006704
label: glucocorticoid biosynthetic process
modifier: INCREASED
- preferred_term: cell population proliferation
term:
id: GO:0008283
label: cell population proliferation
modifier: INCREASED
evidence:
- reference: PMID:20548949
reference_title: "Cushing's syndrome and fetal features resurgence in adrenal cortex-specific Prkar1a knockout mice."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: >-
AdKO mice develop pituitary-independent Cushing's syndrome with increased
PKA activity. This leads to autonomous steroidogenic genes expression and
deregulated adreno-cortical cells differentiation, increased proliferation
and resistance to apoptosis.
explanation: >-
In vivo evidence that PKA activation produces autonomous steroidogenesis,
deregulated differentiation, proliferation, and apoptosis resistance.
- reference: PMID:20548949
reference_title: "Cushing's syndrome and fetal features resurgence in adrenal cortex-specific Prkar1a knockout mice."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: >-
loss of R1alpha is sufficient to induce autonomous adrenal hyper-activity
and bilateral hyperplasia, both observed in human PPNAD.
explanation: >-
Establishes that RIalpha loss is sufficient to cause the autonomous
hyperactivity and bilateral hyperplasia of human PPNAD.
- reference: PMID:16278264
reference_title: "Serial analysis of gene expression in adrenocortical hyperplasia caused by a germline PRKAR1A mutation."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Examples of well-characterized genes expressed at significantly higher
levels in PPNAD included steroidogenic acute regulator, chromogranin A,
and those coding for the steroidogenic enzymes P450 cytochromes CYP17A1
and CYP21A2.
explanation: >-
Transcriptomic profiling confirms up-regulation of steroidogenic
machinery in PPNAD adrenal tissue.
downstream:
- target: ACTH-independent Cushing syndrome
description: >-
Cortisol production that no longer depends on pituitary ACTH is the
clinical syndrome the autonomous adrenocortical nodules produce.
causal_link_type: DIRECT
evidence:
- reference: PMID:41403049
reference_title: "PRKACA constitutional duplication: a specific cause of primary pigmented nodular adrenocortical disease."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "All IC with PRKACAdup underwent adrenalectomy for ACTH-independent hypercortisolism, with pathology confirming PPNAD."
explanation: >-
Directly pairs PPNAD adrenal pathology with ACTH-independent
hypercortisolism in every index case of one genetic form.
- reference: PMID:20548949
reference_title: "Cushing's syndrome and fetal features resurgence in adrenal cortex-specific Prkar1a knockout mice."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: >-
loss of R1alpha is sufficient to induce autonomous adrenal hyper-activity
and bilateral hyperplasia, both observed in human PPNAD.
explanation: >-
In vivo demonstration that the adrenal lesion is sufficient for
autonomous, pituitary-independent adrenal hyperactivity.
- target: Increased circulating cortisol
description: >-
Autonomous expression of the steroidogenic machinery in the nodular
cortex raises circulating cortisol independently of ACTH drive.
causal_link_type: DIRECT
evidence:
- reference: PMID:16278264
reference_title: "Serial analysis of gene expression in adrenocortical hyperplasia caused by a germline PRKAR1A mutation."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Examples of well-characterized genes expressed at significantly higher
levels in PPNAD included steroidogenic acute regulator, chromogranin A,
and those coding for the steroidogenic enzymes P450 cytochromes CYP17A1
and CYP21A2.
explanation: >-
Up-regulation of the steroidogenic enzymes in PPNAD tissue is the
biosynthetic basis of the raised circulating cortisol.
- target: Pigmented micronodular adrenocortical disease
description: >-
Deregulated differentiation and proliferation of adrenocortical cells
produce the small pigmented micronodules that define the histopathology.
causal_link_type: DIRECT
evidence:
- reference: PMID:41694449
reference_title: "Preventing Cushing Syndrome: Adrenalectomy in PDE11A-Positive Primary Pigmented Nodular Adrenocortical Disease."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "initial unilateral total right mini back scope adrenalectomy (MBSA) was performed, revealing characteristic pigmented nodules (2-5 mm) on histopathology"
explanation: >-
Reports the characteristic pigmented micronodules on resected adrenal
histopathology in a genetically confirmed PPNAD patient.
- reference: PMID:25924874
reference_title: "Germline PRKACA amplification causes variable phenotypes that may depend on the extent of the genomic defect: molecular mechanisms and clinical presentations."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Although all five patients presented with ACTH-independent CS, the three sporadic patients had micronodular BAH and underwent bilateral adrenalectomy in early childhood"
explanation: >-
Micronodular bilateral adrenocortical hyperplasia as the pathology in
an independent genetic series.
- target: Decreased circulating ACTH
description: >-
Cortisol produced autonomously by the adrenal nodules is accompanied by
suppressed rather than raised corticotropin, which is the biochemical
pattern reported in genetically confirmed PPNAD.
causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
evidence:
- reference: PMID:41694449
reference_title: "Preventing Cushing Syndrome: Adrenalectomy in PDE11A-Positive Primary Pigmented Nodular Adrenocortical Disease."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "suppressed adrenocorticotropin, mild late night salivary cortisol elevation, and normal urinary free cortisol, indicating mild adrenal hypercortisolism"
explanation: >-
Suppressed ACTH measured alongside autonomous adrenal hypercortisolism
in a genetically confirmed PPNAD patient.
- target: mTORC1 Activation and Apoptosis Resistance
causal_link_type: DIRECT
evidence:
- reference: PMID:24865460
reference_title: "mTOR pathway is activated by PKA in adrenocortical cells and participates in vivo to apoptosis resistance in primary pigmented nodular adrenocortical disease (PPNAD)."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: >-
mTOR pathway is activated by PKA in adrenocortical cells and participates
in vivo to apoptosis resistance in primary pigmented nodular
adrenocortical disease (PPNAD)
explanation: >-
Links PKA-driven steroidogenic adrenocortical cells to mTOR activation
and apoptosis resistance.
- name: mTORC1 Activation and Apoptosis Resistance
description: >-
PKA activates the mTOR pathway in adrenocortical cells, and this contributes
in vivo to resistance to apoptosis in PPNAD, allowing accumulation of
autonomously functioning nodular cells. Pharmacologic mTORC1 inhibition with
rapamycin restored apoptosis sensitivity in the Prkar1a knockout mouse
model, nominating mTORC1 as a candidate therapeutic target.
cell_types:
- preferred_term: adrenocortical cell
term:
id: CL:0002097
label: cortical cell of adrenal gland
biological_processes:
- preferred_term: TOR signaling
term:
id: GO:0031929
label: TOR signaling
modifier: INCREASED
- preferred_term: negative regulation of apoptotic process
term:
id: GO:0043066
label: negative regulation of apoptotic process
modifier: INCREASED
evidence:
- reference: PMID:24865460
reference_title: "mTOR pathway is activated by PKA in adrenocortical cells and participates in vivo to apoptosis resistance in primary pigmented nodular adrenocortical disease (PPNAD)."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: >-
mTOR pathway is activated by PKA in adrenocortical cells and participates
in vivo to apoptosis resistance in primary pigmented nodular
adrenocortical disease (PPNAD)
explanation: >-
Directly establishes the PKA to mTOR to apoptosis-resistance axis in PPNAD.
- name: MAPK Pathway Activation and Proliferation
description: >-
PRKAR1A-mutant adrenocortical tissue shows enhanced MAPK signaling, with
increased phosphorylated ERK1/2, B-raf, phospho-MEK1/2, and phospho-c-Myc.
These changes are proposed to provide proliferative signals contributing to
nodule formation. Comparative whole-genome expression profiling further
shows overexpression of Wnt pathway genes (CCND1, CTNNB1, LEF1, LRP5, WISP1,
WNT3) in PRKAR1A-mutant lesions, linking cAMP/PKA activation to Wnt-driven
proliferative programs.
cell_types:
- preferred_term: adrenocortical cell
term:
id: CL:0002097
label: cortical cell of adrenal gland
biological_processes:
- preferred_term: MAPK cascade
term:
id: GO:0000165
label: MAPK cascade
modifier: INCREASED
- preferred_term: Wnt signaling pathway
term:
id: GO:0016055
label: Wnt signaling pathway
modifier: INCREASED
evidence:
- reference: PMID:16569736
reference_title: "PRKAR1A Mutations and protein kinase A interactions with other signaling pathways in the adrenal cortex."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >-
These changes, associated with enhanced MAPK activity, may be, in part,
responsible for the proliferative signals that result in primary pigmented
nodular adrenocortical disease.
explanation: >-
Links enhanced MAPK activity downstream of PRKAR1A mutation to the
proliferation underlying PPNAD.
- reference: PMID:22259056
reference_title: "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."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Genes related to the Wnt signaling pathway (CCND1, CTNNB1, LEF1, LRP5,
WISP1, and WNT3) were overexpressed in PRKAR1A-mutant lesions.
explanation: >-
Demonstrates Wnt pathway gene overexpression specifically in
PRKAR1A-mutant PPNAD lesions.
- name: c-KIT/SCF Oncogenic Axis
description: >-
In PRKAR1A-mutant adrenal cortex, the c-KIT proto-oncogene and its ligand
stem cell factor (SCF) become expressed within nodular areas, an expression
dependent on PRKAR1A status and PKA activity. KIT inhibition with imatinib
reduced viability, caused growth arrest, and induced apoptosis in
PRKAR1A-deficient adrenocortical cells and inhibited tumor growth in
xenografts, suggesting c-KIT inhibition as a potential alternative therapy.
cell_types:
- preferred_term: adrenocortical cell
term:
id: CL:0002097
label: cortical cell of adrenal gland
evidence:
- reference: PMID:32738126
reference_title: "c-KIT oncogene expression in PRKAR1A-mutant adrenal cortex."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >-
c-KIT is expressed in PPNAD, an expression that appears to be dependent on
PRKAR1A and/or PKA activity.
explanation: >-
Establishes PRKAR1A/PKA-dependent c-KIT expression in PPNAD.
- reference: PMID:32738126
reference_title: "c-KIT oncogene expression in PRKAR1A-mutant adrenal cortex."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >-
Treatment of the CAR47 cells with IM resulted in reduced cell viability,
growth arrest, and apoptosis.
explanation: >-
Shows that KIT inhibition with imatinib reduces growth and induces
apoptosis in PRKAR1A-deficient cells.
has_subtypes:
- name: PPNAD1
display_name: "PPNAD1 (PRKAR1A)"
subtype_term:
preferred_term: pigmented nodular adrenocortical disease, primary, 1
term:
id: MONDO:0012509
label: pigmented nodular adrenocortical disease, primary, 1
description: >-
PPNAD caused by inactivating variants in PRKAR1A, the most common cause and
the gene associated with Carney complex type 1. PRKAR1A was the most frequent
pathogenic variant in tested PPNAD patients, and PRKAR1A variants correlate
with spotty skin pigmentation in Carney-complex-associated PPNAD.
genes:
- preferred_term: PRKAR1A
term:
id: hgnc:9388
label: PRKAR1A
inheritance:
- name: Autosomal Dominant
inheritance_term:
preferred_term: Autosomal dominant inheritance
term:
id: HP:0000006
label: Autosomal dominant inheritance
evidence:
- reference: PMID:39006359
reference_title: "The clinical characteristics and pathogenic variants of primary pigmented nodular adrenocortical disease in 210 patients: a systematic review."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
The most common mutation was PKAR1A, accounting for 79.47% (120/151).
explanation: >-
Establishes PRKAR1A as the most common pathogenic gene among tested PPNAD
patients.
- reference: PMID:20301463
reference_title: "Carney Complex."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: REVIEW_SYNTHESIS
snippet: "The molecular diagnosis can be established in a proband with suggestive findings and a heterozygous germline pathogenic variant in PRKAR1A identified by molecular genetic testing."
explanation: >-
The GeneReviews Carney complex chapter defines the molecular diagnosis by
a heterozygous germline PRKAR1A variant, which is the lesion this row is
keyed on.
- reference: PMID:20301463
reference_title: "Carney Complex."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: REVIEW_SYNTHESIS
snippet: "CNC is inherited in an autosomal dominant manner. Approximately 70% of individuals diagnosed with CNC have an affected parent; approximately 30% have a de novo pathogenic variant."
explanation: >-
Source for the autosomal dominant inheritance recorded on this row, with
the proportion arising de novo.
- name: PPNAD2
display_name: "PPNAD2 (PDE11A)"
subtype_term:
preferred_term: pigmented nodular adrenocortical disease, primary, 2
term:
id: MONDO:0012505
label: pigmented nodular adrenocortical disease, primary, 2
description: >-
PPNAD associated with variants in PDE11A, a dual cAMP/cGMP phosphodiesterase.
Reduced phosphodiesterase activity decreases cAMP degradation, increasing
cAMP/PKA signaling. PDE11A variants frequently co-occurred with PRKAR1A in
the pooled cohort.
genes:
- preferred_term: PDE11A
term:
id: hgnc:8773
label: PDE11A
inheritance:
- name: Autosomal Dominant
inheritance_term:
preferred_term: Autosomal dominant inheritance
term:
id: HP:0000006
label: Autosomal dominant inheritance
evidence:
- reference: PMID:41694449
reference_title: "Preventing Cushing Syndrome: Adrenalectomy in PDE11A-Positive Primary Pigmented Nodular Adrenocortical Disease."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Family history included inherited primary pigmented nodular adrenocortical disease (PPNAD) due to a PDE11A pathogenic variant"
explanation: >-
A three-generation family in which PPNAD segregated with a germline
PDE11A variant, which is the dominant transmission this row records.
- reference: PMID:39006359
reference_title: "The clinical characteristics and pathogenic variants of primary pigmented nodular adrenocortical disease in 210 patients: a systematic review."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Six gene mutations (PRKAR1A, PDE11A, PRKACA, CTNNB1, PDE8B, and ARMC5)
were detected in the patients.
explanation: >-
Lists PDE11A among the genes detected in PPNAD patients.
- name: PPNAD3
display_name: "PPNAD3 (PDE8B)"
subtype_term:
preferred_term: pigmented nodular adrenocortical disease, primary, 3
term:
id: MONDO:0013616
label: pigmented nodular adrenocortical disease, primary, 3
description: >-
PPNAD associated with variants in PDE8B, a high-affinity cAMP-specific
phosphodiesterase. As with PDE11A, reduced cAMP degradation enhances
cAMP/PKA signaling in adrenocortical cells.
genes:
- preferred_term: PDE8B
term:
id: hgnc:8794
label: PDE8B
review_notes: >-
No inheritance pattern is recorded on this row. The PDE8B gene-disease
relationship rests on one index patient with isolated micronodular
adrenocortical disease plus a functional assay on that variant, and on
PDE8B appearing among the genes detected in the pooled 210-patient PPNAD
review; neither reports segregation in a family. Three PubMed searches
were run for one: `PDE8B[Title] AND (adrenal OR adrenocortical)` returns
five records, `PDE8B[Title/Abstract] AND (pigmented nodular OR
micronodular)` returns eighteen, and `PDE8B AND pedigree AND adrenal`
returns two. The only pedigree study among them, PMID:25146409, sequenced
PDE8B along with PRKAR1A, PDE11A and CTNNB1 in a PPNAD kindred and found
the causative variant in PRKAR1A, not PDE8B. The mode of inheritance is
therefore left absent rather than carried over from the dominant pattern
of the other three subtypes.
evidence:
- reference: PMID:39006359
reference_title: "The clinical characteristics and pathogenic variants of primary pigmented nodular adrenocortical disease in 210 patients: a systematic review."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Six gene mutations (PRKAR1A, PDE11A, PRKACA, CTNNB1, PDE8B, and ARMC5)
were detected in the patients.
explanation: >-
Lists PDE8B among the genes detected in PPNAD patients.
- reference: PMID:18431404
reference_title: "A cAMP-specific phosphodiesterase (PDE8B) that is mutated in adrenal hyperplasia is expressed widely in human and mouse tissues: a novel PDE8B isoform in human adrenal cortex."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "We conclude that PDE8B is another PDE gene linked to iMAD; it is a candidate causative gene for other adrenocortical lesions linked to the cAMP signaling pathway and possibly for tumors in other tissues."
explanation: >-
The report that first linked PDE8B to isolated micronodular
adrenocortical disease, the group MONDO numbers as PPNAD3.
- name: PPNAD4
display_name: "PPNAD4 (PRKACA)"
subtype_term:
preferred_term: pigmented nodular adrenocortical disease, primary, 4
term:
id: MONDO:0014359
label: pigmented nodular adrenocortical disease, primary, 4
description: >-
PPNAD associated with copy-number gain (amplification) of PRKACA, the PKA
catalytic subunit alpha. Increased PRKACA dosage directly increases PKA
catalytic activity. A germline PRKACA copy-number gain on chromosome
19p13.13p13.12 was reported as a de novo cause of pediatric PPNAD.
genes:
- preferred_term: PRKACA
term:
id: hgnc:9380
label: PRKACA
inheritance:
- name: Autosomal Dominant
inheritance_term:
preferred_term: Autosomal dominant inheritance
term:
id: HP:0000006
label: Autosomal dominant inheritance
evidence:
- reference: PMID:41403049
reference_title: "PRKACA constitutional duplication: a specific cause of primary pigmented nodular adrenocortical disease."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "PRKACAdup causes PPNAD but no other forms of BNAD, so these should be sought in the absence of pathogenic PRKAR1A variants."
explanation: >-
Systematic screening of 781 bilateral nodular adrenocortical disease
index cases found constitutional PRKACA duplication only in PPNAD.
- reference: PMID:25924874
reference_title: "Germline PRKACA amplification causes variable phenotypes that may depend on the extent of the genomic defect: molecular mechanisms and clinical presentations."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Constitutional chromosomal PRKACA gene amplification is a recently identified genetic defect associated with CS, a trait that may be inherited in an autosomal dominant manner or occur de novo."
explanation: >-
Source for the autosomal dominant inheritance recorded here and for the
de novo cases this row also covers.
- reference: PMID:37988664
reference_title: "Germline PRKACA amplification-associated primary pigmented nodular adrenocortical disease: a case report and literature review."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
a case of a female Chinese patient with PPNAD caused by the germline
PRKACA gene copy number gain of chromosome 19.
explanation: >-
Documents PRKACA copy-number gain as a cause of PPNAD.
genetic:
- name: PRKAR1A
gene_term:
preferred_term: PRKAR1A
term:
id: hgnc:9388
label: PRKAR1A
association: Germline Inactivating Variants
relationship_type: CAUSATIVE
subtype: PPNAD1
variant_origin: GERMLINE
inheritance:
- name: Autosomal Dominant
notes: >-
PRKAR1A encodes the type I alpha regulatory subunit of protein kinase A and
is the most common cause of PPNAD; it is also the Carney complex type 1 gene.
Many variants are premature stop codons leading to nonsense-mediated decay
and haploinsufficiency, with a tumor-suppressor mechanism at the tissue level.
evidence:
- reference: PMID:39006359
reference_title: "The clinical characteristics and pathogenic variants of primary pigmented nodular adrenocortical disease in 210 patients: a systematic review."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
The most common mutation was PKAR1A, accounting for 79.47% (120/151).
explanation: >-
Confirms PRKAR1A as the most frequently identified gene in tested PPNAD
patients.
- name: PDE11A
gene_term:
preferred_term: PDE11A
term:
id: hgnc:8773
label: PDE11A
association: Reduced-Function Variants
relationship_type: CAUSATIVE
subtype: PPNAD2
variant_origin: GERMLINE
notes: >-
PDE11A is a dual cAMP/cGMP phosphodiesterase; reduced-function variants
diminish cAMP degradation and enhance cAMP/PKA signaling. PDE11A variants
were detected in PPNAD patients, often co-occurring with PRKAR1A. Graded
CAUSATIVE because MONDO's PPNAD2 class is defined by PDE11A as the cause
and a truncating PDE11A variant has been reported segregating with PPNAD in
a family whose mother required bilateral adrenalectomy for severe Cushing
syndrome. Penetrance is nonetheless variable: inactivating PDE11A defects
were originally described as low-penetrance predisposing factors for
micronodular adrenocortical disease, and the index patient carrying that
segregating variant had only mild adrenal hypercortisolism with ostensibly
normal adrenal imaging.
evidence:
- reference: PMID:39006359
reference_title: "The clinical characteristics and pathogenic variants of primary pigmented nodular adrenocortical disease in 210 patients: a systematic review."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Six gene mutations (PRKAR1A, PDE11A, PRKACA, CTNNB1, PDE8B, and ARMC5)
were detected in the patients.
explanation: >-
Lists PDE11A among the pathogenic genes detected in PPNAD patients.
- name: PDE8B
gene_term:
preferred_term: PDE8B
term:
id: hgnc:8794
label: PDE8B
association: Reduced-Function Variants
relationship_type: CAUSATIVE
subtype: PPNAD3
variant_origin: GERMLINE
notes: >-
PDE8B is a high-affinity cAMP-specific phosphodiesterase; reduced-function
variants decrease cAMP degradation and increase cAMP/PKA signaling in
adrenocortical cells.
evidence:
- reference: PMID:39006359
reference_title: "The clinical characteristics and pathogenic variants of primary pigmented nodular adrenocortical disease in 210 patients: a systematic review."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Six gene mutations (PRKAR1A, PDE11A, PRKACA, CTNNB1, PDE8B, and ARMC5)
were detected in the patients.
explanation: >-
Lists PDE8B among the pathogenic genes detected in PPNAD patients.
- name: PRKACA
gene_term:
preferred_term: PRKACA
term:
id: hgnc:9380
label: PRKACA
association: Copy-Number Gain
relationship_type: CAUSATIVE
subtype: PPNAD4
variant_origin: GERMLINE
notes: >-
PRKACA encodes the PKA catalytic subunit alpha. Germline copy-number gain
(amplification) increases PKA catalytic activity and has been reported as a
de novo cause of pediatric PPNAD.
evidence:
- reference: PMID:37988664
reference_title: "Germline PRKACA amplification-associated primary pigmented nodular adrenocortical disease: a case report and literature review."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
a rise in the copy number of the duplication-containing PRKACA gene on
chromosome 19p13.13p13.12, a de novo but not heritable gene defect that
causes disease.
explanation: >-
Documents germline PRKACA copy-number gain as a de novo cause of PPNAD.
phenotypes:
- name: ACTH-independent Cushing syndrome
category: Laboratory
description: >-
PPNAD produces ACTH-independent (pituitary-independent) hypercortisolism,
the defining biochemical and clinical feature, often with a paradoxical or
absent response to dexamethasone suppression.
phenotype_term:
preferred_term: Primary hypercortisolism
term:
id: HP:0001579
label: Primary hypercortisolism
evidence:
- reference: PMID:20548949
reference_title: "Cushing's syndrome and fetal features resurgence in adrenal cortex-specific Prkar1a knockout mice."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: >-
primary pigmented nodular adrenocortical disease (PPNAD), a bilateral
adrenocortical hyperplasia causing pituitary-independent Cushing's
syndrome.
explanation: >-
Defines PPNAD as causing pituitary-independent (ACTH-independent) Cushing
syndrome.
- name: Increased circulating cortisol
category: Laboratory
description: >-
Elevated cortisol with loss of normal circadian rhythm is a hallmark
biochemical finding, reported in nearly all cases with available data.
phenotype_term:
preferred_term: Increased circulating cortisol level
term:
id: HP:0003118
label: Increased circulating cortisol level
evidence:
- reference: PMID:37988664
reference_title: "Germline PRKACA amplification-associated primary pigmented nodular adrenocortical disease: a case report and literature review."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
the patient had diabetes, mild hypertension, low bone mass, a low ACTH
level, and hypercortisolemia
explanation: >-
Case report documents hypercortisolemia in PPNAD.
- name: Decreased circulating ACTH
category: Laboratory
description: >-
Low or undetectable ACTH reflects the ACTH-independent, autonomous adrenal
source of cortisol and was reported in the majority of cases with data.
phenotype_term:
preferred_term: Decreased circulating ACTH concentration
term:
id: HP:0002920
label: Decreased circulating ACTH concentration
evidence:
- reference: PMID:37988664
reference_title: "Germline PRKACA amplification-associated primary pigmented nodular adrenocortical disease: a case report and literature review."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
the patient had diabetes, mild hypertension, low bone mass, a low ACTH
level, and hypercortisolemia
explanation: >-
Case report documents a low ACTH level consistent with ACTH-independent
disease.
- name: Pigmented micronodular adrenocortical disease
category: Histopathology
description: >-
The adrenal glands are small to normal in size and contain multiple small
pigmented cortical nodules with internodular cortical atrophy, the defining
pathological feature of PPNAD.
phenotype_term:
preferred_term: Pigmented micronodular adrenocortical disease
term:
id: HP:0001580
label: Pigmented micronodular adrenocortical disease
evidence:
- reference: PMID:34680514
reference_title: "Bilateral Adrenal Hyperplasia: Pathogenesis and Treatment."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Micronodular adrenal hyperplasia, including the primary pigmented
micronodular adrenal dysplasia (PPNAD) and the isolated micronodular
adrenal hyperplasia (iMAD), can be distinguished from the primary
bilateral macronodular adrenal hyperplasia (PBMAH) according to the size
of the nodules.
explanation: >-
Describes PPNAD as a micronodular form of bilateral adrenal hyperplasia,
defined by its small (micronodular) cortical nodules in contrast to
macronodular hyperplasia.
- reference: PMID:16278264
reference_title: "Serial analysis of gene expression in adrenocortical hyperplasia caused by a germline PRKAR1A mutation."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
primary pigmented nodular adrenocortical disease (PPNAD) tissue from two
adolescent female patients
explanation: >-
Confirms PPNAD adrenal pathology in patient tissue studied.
- name: Osteoporosis/Osteopenia
category: Physical
description: >-
Reduced bone mineral density (osteoporosis or osteopenia) is among the most
frequent complications, reported in 94.29% of cases in the pooled review,
reflecting the catabolic effect of chronic hypercortisolism on bone.
phenotype_term:
preferred_term: Osteopenia
term:
id: HP:0000938
label: Osteopenia
frequency: VERY_FREQUENT
evidence:
- reference: PMID:39006359
reference_title: "The clinical characteristics and pathogenic variants of primary pigmented nodular adrenocortical disease in 210 patients: a systematic review."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
94.29% were combined with osteoporosis/osteopenia.
explanation: >-
Establishes osteoporosis/osteopenia as a very frequent feature of PPNAD,
present in 94.29% of the pooled cohort, supporting the VERY_FREQUENT
(80-99%) frequency band.
- name: Hypertension
category: Physical
description: >-
Hypertension is a common cardiometabolic complication of chronic cortisol
excess in PPNAD.
phenotype_term:
preferred_term: Hypertension
term:
id: HP:0000822
label: Hypertension
evidence:
- reference: PMID:37988664
reference_title: "Germline PRKACA amplification-associated primary pigmented nodular adrenocortical disease: a case report and literature review."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
the patient had diabetes, mild hypertension, low bone mass, a low ACTH
level, and hypercortisolemia
explanation: >-
Case report documents hypertension in a PPNAD patient.
- name: Weight gain
category: Physical
description: >-
Weight gain and central obesity are typical manifestations of
hypercortisolism in PPNAD.
phenotype_term:
preferred_term: Increased body weight
term:
id: HP:0004324
label: Increased body weight
evidence:
- reference: PMID:37988664
reference_title: "Germline PRKACA amplification-associated primary pigmented nodular adrenocortical disease: a case report and literature review."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
The patient initially presented with kidney stones, short stature, and
obesity.
explanation: >-
Case report documents obesity at presentation in a PPNAD patient.
- name: Diabetes mellitus
category: Laboratory
description: >-
Glucose intolerance and diabetes mellitus occur as metabolic complications
of cortisol excess.
phenotype_term:
preferred_term: Diabetes mellitus
term:
id: HP:0000819
label: Diabetes mellitus
evidence:
- reference: PMID:37988664
reference_title: "Germline PRKACA amplification-associated primary pigmented nodular adrenocortical disease: a case report and literature review."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
it was discovered that the patient had diabetes, mild hypertension, low
bone mass, a low ACTH level, and hypercortisolemia
explanation: >-
Case report documents diabetes in a PPNAD patient.
- name: Short stature
category: Physical
description: >-
In pediatric PPNAD, chronic hypercortisolism impairs linear growth, causing
slow growth and short stature.
phenotype_term:
preferred_term: Short stature
term:
id: HP:0004322
label: Short stature
evidence:
- reference: PMID:37988664
reference_title: "Germline PRKACA amplification-associated primary pigmented nodular adrenocortical disease: a case report and literature review."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Pediatric patients with PPNAD typically have unusual skin lesions and slow
growth with unknown causes.
explanation: >-
Documents slow growth/short stature as typical in pediatric PPNAD.
- name: Spotty skin pigmentation (Carney complex)
category: Physical
description: >-
In Carney-complex-associated PPNAD, spotty skin pigmentation (lentigines) is
a frequent associated feature and correlates with PRKAR1A variants.
phenotype_term:
preferred_term: Multiple lentigines
term:
id: HP:0001003
label: Multiple lentigines
evidence:
- reference: PMID:39006359
reference_title: "The clinical characteristics and pathogenic variants of primary pigmented nodular adrenocortical disease in 210 patients: a systematic review."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
There was a significant correlation between PRKAR1A pathogenic variant and
spotty skin pigmentation in CNC concurrent with PPNAD (p < 0.05).
explanation: >-
Documents spotty skin pigmentation as a Carney-complex feature correlated
with PRKAR1A variants in PPNAD.
treatments:
- name: Bilateral Adrenalectomy
description: >-
Bilateral adrenalectomy has historically been the definitive treatment for
hypercortisolism in PPNAD, achieving cure of cortisol excess but requiring
lifelong glucocorticoid and mineralocorticoid replacement. More recent
practice increasingly favors unilateral or subtotal resection to avoid
permanent adrenal insufficiency.
treatment_term:
preferred_term: adrenalectomy
term:
id: NCIT:C15177
label: Adrenalectomy
evidence:
- reference: PMID:34680514
reference_title: "Bilateral Adrenal Hyperplasia: Pathogenesis and Treatment."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
the treatment of bilateral adrenal hyperplasia will be discussed, focusing
on current data on unilateral adrenalectomy.
explanation: >-
Review of treatment for bilateral adrenal hyperplasia including PPNAD;
surgical resection is the mainstay, with current data increasingly
favoring unilateral over bilateral adrenalectomy. This snippet supports
adrenalectomy as the treatment modality but not bilateral resection as the
preferred contemporary approach.
- name: Unilateral Adrenalectomy
description: >-
Unilateral adrenalectomy may be considered in selected patients, including
women with fertility needs, although some cases require completion
adrenalectomy if hypercortisolism persists or recurs.
treatment_term:
preferred_term: adrenalectomy
term:
id: NCIT:C15177
label: Adrenalectomy
evidence:
- reference: PMID:39006359
reference_title: "The clinical characteristics and pathogenic variants of primary pigmented nodular adrenocortical disease in 210 patients: a systematic review."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Unilateral adrenal resection may be considered as an option for women with
fertility needs.
explanation: >-
Supports unilateral adrenalectomy as an option for fertility preservation.
- name: Steroidogenesis Inhibitor Pharmacotherapy
description: >-
Steroidogenesis inhibitors such as ketoconazole, metyrapone, and mitotane
are used to control hypercortisolism as a bridge to surgery or in persistent
or recurrent disease.
therapeutic_modality: SMALL_MOLECULE
treatment_term:
preferred_term: Pharmacotherapy
term:
id: NCIT:C15986
label: Pharmacotherapy
therapeutic_agent:
- preferred_term: ketoconazole
term:
id: CHEBI:47519
label: ketoconazole
- preferred_term: metyrapone
term:
id: CHEBI:44241
label: metyrapone
- preferred_term: mitotane
term:
id: CHEBI:6954
label: Mitotane
evidence:
- reference: PMID:34680514
reference_title: "Bilateral Adrenal Hyperplasia: Pathogenesis and Treatment."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
the treatment of bilateral adrenal hyperplasia will be discussed, focusing
on current data on unilateral adrenalectomy.
explanation: >-
This review covers the treatment of bilateral adrenal hyperplasia including
PPNAD. The cited snippet establishes that the review addresses PPNAD
treatment but focuses on adrenalectomy rather than pharmacotherapy;
steroidogenesis inhibitors are standard pharmacologic options for
hypercortisolism but are not specifically named in this snippet, so the
support is indirect.
- name: Genetic Counseling
description: >-
Genetic counseling and cascade testing are recommended for families with
PRKAR1A-related disease, together with surveillance for Carney complex
manifestations such as cardiac myxoma.
treatment_term:
preferred_term: Genetic Counseling
term:
id: NCIT:C15240
label: Genetic Counseling
evidence:
- reference: PMID:39006359
reference_title: "The clinical characteristics and pathogenic variants of primary pigmented nodular adrenocortical disease in 210 patients: a systematic review."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Patients with PPNAD with spotty skin pigmentation should consider the
PRKAR1A pathogenic variant and pay attention to CNC.
explanation: >-
Supports genetic evaluation and Carney complex surveillance in PPNAD with
spotty skin pigmentation.
- name: Experimental mTORC1 Inhibition
description: >-
mTORC1 inhibition with rapamycin restored apoptosis sensitivity in the
Prkar1a knockout mouse model, nominating mTORC1 as a candidate therapeutic
target; this is an experimental, mechanism-informed direction rather than
standard care.
therapeutic_modality: SMALL_MOLECULE
treatment_term:
preferred_term: Pharmacotherapy
term:
id: NCIT:C15986
label: Pharmacotherapy
therapeutic_agent:
- preferred_term: sirolimus
term:
id: CHEBI:9168
label: sirolimus
evidence:
- reference: PMID:24865460
reference_title: "mTOR pathway is activated by PKA in adrenocortical cells and participates in vivo to apoptosis resistance in primary pigmented nodular adrenocortical disease (PPNAD)."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: >-
mTOR pathway is activated by PKA in adrenocortical cells and participates
in vivo to apoptosis resistance in primary pigmented nodular
adrenocortical disease (PPNAD)
explanation: >-
Provides the in vivo rationale for mTORC1 inhibition as an experimental
therapy in PPNAD.
- name: Experimental KIT Inhibition
description: >-
KIT inhibition with imatinib reduced viability and induced apoptosis in
PRKAR1A-deficient adrenocortical cells and inhibited xenograft growth,
suggesting c-KIT inhibitors as a possible alternative therapy when other
treatments are not optimal; this remains experimental.
therapeutic_modality: SMALL_MOLECULE
treatment_term:
preferred_term: Pharmacotherapy
term:
id: NCIT:C15986
label: Pharmacotherapy
therapeutic_agent:
- preferred_term: imatinib
term:
id: CHEBI:45783
label: imatinib
evidence:
- reference: PMID:32738126
reference_title: "c-KIT oncogene expression in PRKAR1A-mutant adrenal cortex."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >-
c-KIT inhibition decreased growth, suggesting that c-KIT inhibitors may be
a reasonable alternative therapy to be tested in PPNAD, when other
treatments are not optimal.
explanation: >-
Provides the experimental rationale for KIT inhibition as an alternative
therapy in PPNAD.
clinical_trials:
- name: NCT00001452
status: RECRUITING
description: >-
NIH observational study defining the genotype and clinical phenotype of
PPNAD, Carney complex, and related conditions, including genetic basis,
molecular tumor changes, carrier identification, and prognosis.
evidence:
- reference: clinicaltrials:NCT00001452
reference_title: "Definition of the Genotype and Clinical Phenotype of Primary Pigmented Nodular Adrenocortical Disease (PPNAD), Carney Complex, Peutz-Jeghers Syndrome and Related Conditions"
supports: SUPPORT
snippet: >-
Primary pigmented nodular adrenocortical disease (PPNAD) is a
pituitary-independent, primary adrenal form of hypercortisolism
explanation: >-
The trial summary characterizes PPNAD as pituitary-independent primary
adrenal hypercortisolism, the disease under study.
classifications:
harrisons_chapter:
- classification_value: ENDOCRINOLOGY_METABOLISM
datasets: []
references:
- reference: PMID:20301463
title: "Carney Complex."
tags:
- GeneReviews
Deep research results are used as seeds for research; they do not undergo the same validation as the main records and may contain errors. How we use deep research.
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)
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)
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)
From the 2024 systematic review: “PPNAD … also termed i-PPNAD, familial isolated PPNAD, isolated PPNAD or micronodular adrenal disease.” (sun2024theclinicalcharacteristics pages 1-2)
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)
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)
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)
No protective genetic or environmental factors were identified in the retrieved evidence. (sun2024theclinicalcharacteristics pages 1-2)
Not established in the retrieved evidence; currently appears primarily genotype-driven. (sun2024theclinicalcharacteristics pages 1-2)
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)
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)
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)
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)
Population allele frequency / gnomAD / ClinVar classifications: Not retrievable in this run because ClinVar/gnomAD tools were not available.
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)
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)
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.
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)
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)
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)
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).
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)
Median age 22; female:male 2:1. (sun2024theclinicalcharacteristics pages 1-2)
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)
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)
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)
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)
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)
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)
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.
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).
These are not established standard-of-care treatments for PPNAD but represent translational directions grounded in mechanistic evidence.
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)
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)
No naturally occurring veterinary/other-species PPNAD analogs were identified in the retrieved evidence.
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)
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)
| Domain | Variable | Numerator/Denominator | Frequency / Value | Notes |
|---|---|---|---|---|
| Cohort | Total patients included | 210/210 | 210 patients | Systematic review cohort size; median age 22 years (Sun et al., Frontiers in Endocrinology, Jun 2024, https://doi.org/10.3389/fendo.2024.1356870) (sun2024theclinicalcharacteristics pages 1-2) |
| Demographics | Female:male ratio | — | 2:1 | Female predominance in pooled cohort; most patients were 10–30 years old (71.88%) (Sun et al., Jun 2024, DOI above) (sun2024theclinicalcharacteristics pages 1-2, sun2024theclinicalcharacteristics pages 4-5) |
| Demographics | Age distribution 10–30 years | — | 71.88% | Majority presented in adolescence/young adulthood (Sun et al., Jun 2024, https://doi.org/10.3389/fendo.2024.1356870) (sun2024theclinicalcharacteristics pages 4-5) |
| Carney complex association | Concurrent Carney complex (CNC) | 66/210 | 31.43% | cPPNAD/CNC subset in pooled review (Sun et al., Jun 2024, DOI above) (sun2024theclinicalcharacteristics pages 1-2, sun2024theclinicalcharacteristics pages 4-5) |
| CNC phenotype | Spotty skin pigmentation among cPPNAD/CNC | 47/66 | 71.21% | Pigmentary findings common in CNC-associated cases; supports PRKAR1A testing consideration (Sun et al., Jun 2024, DOI above) (sun2024theclinicalcharacteristics pages 4-5, sun2024theclinicalcharacteristics pages 12-14) |
| CNC phenotype | Cardiac or cutaneous myxoma among cPPNAD/CNC | 19/66 | 28.79% | Relevant for surveillance due to embolic risk in CNC (Sun et al., Jun 2024, DOI above) (sun2024theclinicalcharacteristics pages 11-12) |
| Major phenotype | Osteoporosis / osteopenia | 33/35 | 94.29% | One of the most frequent reported morbidity features (Sun et al., Jun 2024, https://doi.org/10.3389/fendo.2024.1356870) (sun2024theclinicalcharacteristics pages 1-2, sun2024theclinicalcharacteristics pages 4-5) |
| Major phenotype | Hypertension | 81/120 | 67.50% | Common hypercortisolism-related comorbidity (Sun et al., Jun 2024, DOI above) (sun2024theclinicalcharacteristics pages 4-5) |
| Major phenotype | Weight gain | 71/120 | 59.17% | Typical Cushing syndrome manifestation in pooled cases (Sun et al., Jun 2024, DOI above) (sun2024theclinicalcharacteristics pages 4-5) |
| Diagnostic laboratory | Loss of cortisol circadian rhythm | 70/71 | 98.59% | Strong biochemical hallmark of hypercortisolism (Sun et al., Jun 2024, https://doi.org/10.3389/fendo.2024.1356870) (sun2024theclinicalcharacteristics pages 4-5) |
| Diagnostic laboratory | Low/undetectable ACTH | 77/98 | 78.57% | Consistent with ACTH-independent Cushing syndrome (Sun et al., Jun 2024, DOI above) (sun2024theclinicalcharacteristics pages 4-5) |
| Diagnostic laboratory | Plasma cortisol not suppressed on dexamethasone testing | 31/31 | 100% | Included paradoxical or absent suppression on low-/high-dose dexamethasone/Liddle-type testing (Sun et al., Jun 2024, DOI above) (sun2024theclinicalcharacteristics pages 4-5) |
| Genetics | Patients undergoing genetic testing | 151/210 | 71.90% | Not all published cases had molecular testing (Sun et al., Jun 2024, https://doi.org/10.3389/fendo.2024.1356870) (sun2024theclinicalcharacteristics pages 1-2, sun2024theclinicalcharacteristics pages 12-14) |
| Genetics | Any pathogenic variant detected | 132/151 | 87.42% | High diagnostic yield in tested cases (Sun et al., Jun 2024, DOI above) (sun2024theclinicalcharacteristics pages 1-2, sun2024theclinicalcharacteristics pages 4-5) |
| Genetics | Genes reported in cohort | — | 6 genes | PRKAR1A, PDE11A, PRKACA, CTNNB1, PDE8B, ARMC5 (Sun et al., Jun 2024, DOI above) (sun2024theclinicalcharacteristics pages 1-2, sun2024theclinicalcharacteristics pages 4-5) |
| Genetics | PRKAR1A pathogenic variants | 120/151 | 79.47% | Most common implicated gene in tested patients (Sun et al., Jun 2024, https://doi.org/10.3389/fendo.2024.1356870) (sun2024theclinicalcharacteristics pages 1-2, sun2024theclinicalcharacteristics pages 4-5) |
| Genetics | PDE11A variants | 40/151 | 26.49% | Some patients carried PDE11A along with PRKAR1A (Sun et al., Jun 2024, DOI above) (sun2024theclinicalcharacteristics pages 4-5) |
| Genetics | PRKAR1A + PDE11A co-occurrence | 33/151 | 21.85% | Reported overlap among genetically tested cases (Sun et al., Jun 2024, DOI above) (sun2024theclinicalcharacteristics pages 4-5) |
| Genotype-phenotype | Spotty pigmentation with PRKAR1A variant among evaluable CNC cases | 33/45 | 73.33% | Significant association reported between PRKAR1A and spotty skin pigmentation in CNC with PPNAD (Sun et al., Jun 2024, DOI above) (sun2024theclinicalcharacteristics pages 1-2, sun2024theclinicalcharacteristics pages 4-5) |
| Surgery | Any surgery data available | 122/210 | 58.10% | Surgical approach reported for subset of pooled cases (Sun et al., Jun 2024, https://doi.org/10.3389/fendo.2024.1356870) (sun2024theclinicalcharacteristics pages 4-5) |
| Surgery | Bilateral adrenalectomy | 62/122 | 50.82% | Most common surgical treatment in reported cases (Sun et al., Jun 2024, DOI above) (sun2024theclinicalcharacteristics pages 4-5) |
| Surgery | Unilateral adrenalectomy | 41/122 | 33.61% | Considered in selected patients; review discusses fertility/pregnancy considerations (Sun et al., Jun 2024, DOI above) (sun2024theclinicalcharacteristics pages 4-5, sun2024theclinicalcharacteristics pages 12-14) |
| Surgery | Two-stage bilateral adrenalectomy | 15/122 | 12.30% | Often reflects completion adrenalectomy after initial unilateral approach (Sun et al., Jun 2024, DOI above) (sun2024theclinicalcharacteristics pages 4-5) |
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
(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.
(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.
(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.
(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.
(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.
(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.
(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
(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.
(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.
(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.
(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.
(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.
(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.
(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.
(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.
(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.
(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.