CDH23-associated pituitary adenoma 5

Genetic MONDO:0054601 Pathograph 5 Show in embeddings browser familial isolated pituitary adenoma

Pituitary adenoma 5, multiple types (PITA5) is modeled as a provisional genetic susceptibility association rather than a complete causal mechanism. Reported germline CDH23 variants are associated with familial and sporadic pituitary adenoma, and a proposed cell-adhesion effect is plausible, but the causal bridge from CDH23 function to pituitary lineage proliferation or hormone excess remains a knowledge gap.

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Mappings

MONDO

MONDO:0054601 pituitary adenoma 5, multiple types

MONDO:0054601 is the gene-specific MONDO term for PITA5, has synonym PITA5, xrefs OMIM:617540 and DOID:0112008, and carries the CDH23 gene relationship.

Discussions and Knowledge Gaps

What is the causal mechanism linking germline CDH23 variants to pituitary adenoma formation, and which pituitary cell lineage or signaling pathway is affected?

KNOWLEDGE GAP OPEN gap_cdh23_pituitary_adenoma_mechanism

Attached to

pathophysiology#Germline CDH23 variant association pathophysiology#Predicted impaired CDH23-mediated cell adhesion pathophysiology#Pituitary adenoma susceptibility with unresolved mechanism

The CDH23 literature supports a genetic association and a predicted cadherin-domain adhesion effect, but it does not yet establish a mechanistic chain from CDH23 function to pituitary endocrine-lineage proliferation, hormone excess, or adenoma initiation. This should remain a knowledge gap rather than being forced into the AIP/GPR101/GNAS cAMP module or the USP8 corticotroph EGFR/POMC module.

Show evidence (1 reference)

PMID:28413019 SUPPORT Human Clinical

"Therefore, mutations in CDH23 are linked with familial and sporadic PA and could play important roles in the pathogenesis of PA."

The association is reported, but the wording and available evidence leave the causal mechanism unresolved.

⚙

Pathophysiology

Germline CDH23 variant association

Heterozygous germline CDH23 missense variants are associated with familial and sporadic pituitary adenoma in the reported cohort.

CDH23 hgnc:13733

Genetic context CDH23 hgnc:13733 variant_origin: GERMLINE allelic_event: MISSENSE_VARIANT functional_impact_category: UNKNOWN

Reported CDH23 variants are germline missense variants; the disease mechanism and penetrance are unresolved.

pituitary gland UBERON:0000007

Downstream

Predicted impaired CDH23-mediated cell adhesion The reported missense variant is predicted to impair CDH23-mediated cell-cell adhesion.

Show evidence (2 references)

PMID:28413019 SUPPORT Human Clinical

"identified cosegregation of the PA phenotype with the heterozygous missense mutation c.4136G>T (p.Arg1379Leu) in cadherin-related 23 (CDH23)."

This supports familial segregation for one reported heterozygous CDH23 missense variant.

PMID:28413019 SUPPORT Human Clinical

"33% of the families with familial PA (4/12) and 12% of individuals with sporadic PA (15/125) harbored functional CDH23 variants."

This supports recurrence of CDH23 variants in familial and sporadic PA cohorts.

Predicted impaired CDH23-mediated cell adhesion

A proposed proximal effect of CDH23 variants is altered cadherin-mediated cell-cell adhesion, but this is a prediction and not yet a validated pituitary tumorigenesis mechanism.

CDH23 hgnc:13733 ↓ DECREASED

cell adhesion GO:0007155 ↓ DECREASED

Downstream

Pituitary adenoma susceptibility with unresolved mechanism The mechanistic path from altered CDH23 adhesion to pituitary adenoma formation is not established.

Show evidence (1 reference)

PMID:28413019 SUPPORT Computational

"This mutation causes an amino acid substitution in the calcium-binding motif of the extracellular cadherin (EC) domains of CDH23 and is predicted to impair cell-cell adhesion."

This supports the proposed adhesion defect but also indicates that the functional effect is predicted rather than established experimentally in pituitary cells.

Pituitary adenoma susceptibility with unresolved mechanism

CDH23 variants are associated with pituitary adenoma risk, but the specific pituitary cell type, signaling route, and tumorigenic intermediate states remain unresolved.

pituitary gland UBERON:0000007

Downstream

Pituitary adenoma The provisional CDH23-associated susceptibility state manifests clinically as familial or sporadic pituitary adenoma, while the causal intermediates remain unresolved.

Show evidence (1 reference)

PMID:28413019 SUPPORT Human Clinical

"Therefore, mutations in CDH23 are linked with familial and sporadic PA and could play important roles in the pathogenesis of PA."

This supports pituitary adenoma association while leaving the mechanism unresolved.

⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.

●

Phenotypes

Pituitary adenoma HP:0002893

Show evidence (1 reference)

PMID:28413019 SUPPORT Human Clinical

"Therefore, mutations in CDH23 are linked with familial and sporadic PA and could play important roles in the pathogenesis of PA."

This anchors the associated phenotype to pituitary adenoma while leaving the mechanism provisional.

🧬

Genetic Associations

CDH23 (Germline CDH23 variants have been reported as risk-associated variants in familial and sporadic pituitary adenoma cohorts, but the mechanism is not yet established to the same level as AIP, GPR101, GNAS, or USP8.)

Gene: CDH23 hgnc:13733 relationship_type: RISK_FACTOR variant_origin: GERMLINE

Show evidence (1 reference)

PMID:28413019 SUPPORT Human Clinical

"Therefore, mutations in CDH23 are linked with familial and sporadic PA and could play important roles in the pathogenesis of PA."

This supports CDH23 as an associated germline risk gene while the wording remains less definitive than a fully established causal mechanism.

{ }

Source YAML

click to show

name: CDH23-associated pituitary adenoma 5
creation_date: "2026-06-03T00:00:00Z"
category: Genetic
categories:
- Endocrine Neoplasia
- Genetic Susceptibility
parents:
- familial isolated pituitary adenoma
disease_term:
  preferred_term: pituitary adenoma 5, multiple types
  term:
    id: MONDO:0054601
    label: pituitary adenoma 5, multiple types
synonyms:
- Pituitary adenoma 5
- PITA5
- pituitary adenoma 5, multiple types
- CDH23-associated familial pituitary adenoma
- CDH23-associated sporadic pituitary adenoma
mappings:
  mondo_mappings:
  - term:
      id: MONDO:0054601
      label: pituitary adenoma 5, multiple types
    mapping_predicate: skos:exactMatch
    mapping_source: MONDO
    mapping_justification: >-
      MONDO:0054601 is the gene-specific MONDO term for PITA5, has synonym
      PITA5, xrefs OMIM:617540 and DOID:0112008, and carries the CDH23
      gene relationship.
description: >-
  Pituitary adenoma 5, multiple types (PITA5) is modeled as a provisional genetic
  susceptibility association rather than a complete causal mechanism. Reported
  germline CDH23 variants are associated with familial and sporadic pituitary
  adenoma, and a proposed cell-adhesion effect is plausible, but the causal
  bridge from CDH23 function to pituitary lineage proliferation or hormone
  excess remains a knowledge gap.
references:
- reference: PMID:28413019
  title: "Germline Mutations in CDH23, Encoding Cadherin-Related 23, Are Associated with Both Familial and Sporadic Pituitary Adenomas."
  findings:
  - statement: >-
      Germline CDH23 variants were reported in familial and sporadic pituitary
      adenoma cohorts, with a predicted cell-cell adhesion effect for at least
      one segregating missense variant.
genetic:
- name: CDH23
  gene_term:
    preferred_term: CDH23
    term:
      id: hgnc:13733
      label: CDH23
  relationship_type: RISK_FACTOR
  variant_origin: GERMLINE
  association: >-
    Germline CDH23 variants have been reported as risk-associated variants in
    familial and sporadic pituitary adenoma cohorts, but the mechanism is not
    yet established to the same level as AIP, GPR101, GNAS, or USP8.
  evidence:
  - reference: PMID:28413019
    reference_title: "Germline Mutations in CDH23, Encoding Cadherin-Related 23, Are Associated with Both Familial and Sporadic Pituitary Adenomas."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Therefore, mutations in CDH23 are linked with familial and sporadic PA
      and could play important roles in the pathogenesis of PA.
    explanation: >-
      This supports CDH23 as an associated germline risk gene while the wording
      remains less definitive than a fully established causal mechanism.
pathophysiology:
- name: Germline CDH23 variant association
  description: >-
    Heterozygous germline CDH23 missense variants are associated with familial
    and sporadic pituitary adenoma in the reported cohort.
  role: trigger
  mechanism_confidence: PROVISIONAL
  gene:
    preferred_term: CDH23
    term:
      id: hgnc:13733
      label: CDH23
  genetic_context:
    gene:
      preferred_term: CDH23
      term:
        id: hgnc:13733
        label: CDH23
    variant_origin: GERMLINE
    allelic_events:
    - MISSENSE_VARIANT
    functional_impact_category: UNKNOWN
    description: >-
      Reported CDH23 variants are germline missense variants; the disease
      mechanism and penetrance are unresolved.
  locations:
  - preferred_term: pituitary gland
    term:
      id: UBERON:0000007
      label: pituitary gland
  evidence:
  - reference: PMID:28413019
    reference_title: "Germline Mutations in CDH23, Encoding Cadherin-Related 23, Are Associated with Both Familial and Sporadic Pituitary Adenomas."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      identified cosegregation of the PA phenotype with the heterozygous
      missense mutation c.4136G>T (p.Arg1379Leu) in cadherin-related 23
      (CDH23).
    explanation: >-
      This supports familial segregation for one reported heterozygous CDH23
      missense variant.
  - reference: PMID:28413019
    reference_title: "Germline Mutations in CDH23, Encoding Cadherin-Related 23, Are Associated with Both Familial and Sporadic Pituitary Adenomas."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      33% of the families with familial PA (4/12) and 12% of individuals with
      sporadic PA (15/125) harbored functional CDH23 variants.
    explanation: >-
      This supports recurrence of CDH23 variants in familial and sporadic PA
      cohorts.
  downstream:
  - target: Predicted impaired CDH23-mediated cell adhesion
    description: >-
      The reported missense variant is predicted to impair CDH23-mediated
      cell-cell adhesion.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES

- name: Predicted impaired CDH23-mediated cell adhesion
  description: >-
    A proposed proximal effect of CDH23 variants is altered cadherin-mediated
    cell-cell adhesion, but this is a prediction and not yet a validated
    pituitary tumorigenesis mechanism.
  role: provisional_effector
  mechanism_confidence: HYPOTHETICAL
  gene:
    preferred_term: CDH23
    modifier: DECREASED
    term:
      id: hgnc:13733
      label: CDH23
  biological_processes:
  - preferred_term: cell adhesion
    modifier: DECREASED
    term:
      id: GO:0007155
      label: cell adhesion
  evidence:
  - reference: PMID:28413019
    reference_title: "Germline Mutations in CDH23, Encoding Cadherin-Related 23, Are Associated with Both Familial and Sporadic Pituitary Adenomas."
    supports: SUPPORT
    evidence_source: COMPUTATIONAL
    snippet: >-
      This mutation causes an amino acid substitution in the calcium-binding
      motif of the extracellular cadherin (EC) domains of CDH23 and is
      predicted to impair cell-cell adhesion.
    explanation: >-
      This supports the proposed adhesion defect but also indicates that the
      functional effect is predicted rather than established experimentally in
      pituitary cells.
  downstream:
  - target: Pituitary adenoma susceptibility with unresolved mechanism
    description: >-
      The mechanistic path from altered CDH23 adhesion to pituitary adenoma
      formation is not established.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES

- name: Pituitary adenoma susceptibility with unresolved mechanism
  description: >-
    CDH23 variants are associated with pituitary adenoma risk, but the specific
    pituitary cell type, signaling route, and tumorigenic intermediate states
    remain unresolved.
  role: consequence
  mechanism_confidence: PROVISIONAL
  locations:
  - preferred_term: pituitary gland
    term:
      id: UBERON:0000007
      label: pituitary gland
  evidence:
  - reference: PMID:28413019
    reference_title: "Germline Mutations in CDH23, Encoding Cadherin-Related 23, Are Associated with Both Familial and Sporadic Pituitary Adenomas."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Therefore, mutations in CDH23 are linked with familial and sporadic PA
      and could play important roles in the pathogenesis of PA.
    explanation: >-
      This supports pituitary adenoma association while leaving the mechanism
      unresolved.
  downstream:
  - target: Pituitary adenoma
    description: >-
      The provisional CDH23-associated susceptibility state manifests clinically
      as familial or sporadic pituitary adenoma, while the causal intermediates
      remain unresolved.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:28413019
      reference_title: "Germline Mutations in CDH23, Encoding Cadherin-Related 23, Are Associated with Both Familial and Sporadic Pituitary Adenomas."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Therefore, mutations in CDH23 are linked with familial and sporadic PA
        and could play important roles in the pathogenesis of PA.
      explanation: >-
        This supports the link from CDH23-associated susceptibility to pituitary
        adenoma while preserving the unresolved-mechanism qualification.
phenotypes:
- name: Pituitary adenoma
  phenotype_term:
    preferred_term: Pituitary adenoma
    term:
      id: HP:0002893
      label: Pituitary adenoma
  evidence:
  - reference: PMID:28413019
    reference_title: "Germline Mutations in CDH23, Encoding Cadherin-Related 23, Are Associated with Both Familial and Sporadic Pituitary Adenomas."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Therefore, mutations in CDH23 are linked with familial and sporadic PA
      and could play important roles in the pathogenesis of PA.
    explanation: >-
      This anchors the associated phenotype to pituitary adenoma while leaving
      the mechanism provisional.
discussions:
- discussion_id: gap_cdh23_pituitary_adenoma_mechanism
  prompt: >-
    What is the causal mechanism linking germline CDH23 variants to pituitary
    adenoma formation, and which pituitary cell lineage or signaling pathway is
    affected?
  kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - pathophysiology#Germline CDH23 variant association
  - pathophysiology#Predicted impaired CDH23-mediated cell adhesion
  - pathophysiology#Pituitary adenoma susceptibility with unresolved mechanism
  rationale: >-
    The CDH23 literature supports a genetic association and a predicted
    cadherin-domain adhesion effect, but it does not yet establish a mechanistic
    chain from CDH23 function to pituitary endocrine-lineage proliferation,
    hormone excess, or adenoma initiation. This should remain a knowledge gap
    rather than being forced into the AIP/GPR101/GNAS cAMP module or the USP8
    corticotroph EGFR/POMC module.
  evidence:
  - reference: PMID:28413019
    reference_title: "Germline Mutations in CDH23, Encoding Cadherin-Related 23, Are Associated with Both Familial and Sporadic Pituitary Adenomas."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Therefore, mutations in CDH23 are linked with familial and sporadic PA
      and could play important roles in the pathogenesis of PA.
    explanation: >-
      The association is reported, but the wording and available evidence leave
      the causal mechanism unresolved.

📚

References & Deep Research

References

PMID:28413019

Germline Mutations in CDH23, Encoding Cadherin-Related 23, Are Associated with Both Familial and Sporadic Pituitary Adenomas.

1 finding

Germline CDH23 variants were reported in familial and sporadic pituitary adenoma cohorts, with a predicted cell-cell adhesion effect for at least one segregating missense variant.

Deep Research

Falcon ▸

Disease Characteristics Research Template

Edison Scientific Literature 35 citations 2026-06-03T16:58:50.036808

Question: You are an expert researcher providing comprehensive, well-cited information.

Provide detailed information focusing on: 1. Key concepts and definitions with current understanding 2. Recent developments and latest research (prioritize 2023-2024 sources) 3. Current applications and real-world implementations 4. Expert opinions and analysis from authoritative sources 5. Relevant statistics and data from recent studies

Format as a comprehensive research report with proper citations. Include URLs and publication dates where available. Always prioritize recent, authoritative sources and provide specific citations for all major claims.

Disease Characteristics Research Template

Target Disease

Disease Name: CDH23-associated pituitary adenoma 5
MONDO ID: (if available)
Category: Genetic

Research Objectives

Please provide a comprehensive research report on CDH23-associated pituitary adenoma 5 covering all of the disease characteristics listed below. This report will be used to populate a disease knowledge base entry. Be thorough and cite primary literature (PMID preferred) for all claims.

For each section, suggested databases/resources are listed. These are the first places you should search for information on each topic.

1. Disease Information

Search first: OMIM, Orphanet, ICD-10/ICD-11, MeSH, PubMed

What is the disease? Provide a concise overview.
What are the key identifiers? (OMIM, Orphanet, ICD-10/ICD-11, MeSH, Mondo)
What are the common synonyms and alternative names?
Is the information derived from individual patients (e.g., EHR) or aggregated disease-level resources?

2. Etiology

Disease Causal Factors: What are the primary causes? (genetic, environmental, infectious, mechanistic)
Risk Factors:

Search first: PubMed, Cochrane Library, UpToDate, clinical guidelines, ClinVar, ClinGen, GWAS Catalog, PheGenI, CTD, CDC, WHO, epidemiological databases
Genetic risk factors (causal variants, susceptibility loci, modifier genes)
Environmental risk factors (toxins, lifestyle, occupational exposures, age, sex, family history)
Protective Factors:

Search first: PubMed, Cochrane Library, clinical trial databases, GWAS Catalog, gnomAD, WHO, CDC, nutrition databases
Genetic protective factors (protective variants, modifier alleles)
Environmental protective factors (diet, lifestyle, exposures that reduce risk)
Gene-Environment Interactions: How do genetic and environmental factors interact to influence disease?

Search first: CTD, PubMed, PheGenI, GxE databases

3. Phenotypes

Search first: HPO (Human Phenotype Ontology), OMIM, Orphanet, PubMed, clinicaltrials.gov, MedDRA, SNOMED CT, DECIPHER, LOINC

For each phenotype, provide: - Phenotype type: symptoms, clinical signs, physical manifestations, behavioral changes, or laboratory abnormalities

For symptoms/signs: HPO, OMIM, Orphanet, PubMed For behavioral changes: HPO, DSM, RDoC (Research Domain Criteria), PubMed For laboratory abnormalities: LOINC, SNOMED CT, LabTests Online, PubMed - Phenotype characteristics: Search first: OMIM, Orphanet, HPO, PubMed - Age of symptom onset (neonatal, childhood, adult-onset, late-onset) - Symptom severity (mild, moderate, severe, variable) - Symptom progression (stable, progressive, episodic, fluctuating) - Frequency among affected individuals (percentage or qualitative) - Quality of life impact: Effects on daily functioning and well-being (per-phenotype when possible) Search first: EQ-5D database, SF-36, WHO QOL databases, PubMed - Suggest HPO (Human Phenotype Ontology) terms for each phenotype

4. Genetic/Molecular Information

Causal Genes: Gene mutations or chromosomal abnormalities responsible for disease (gene symbols, OMIM IDs)

Search first: OMIM, ClinVar, HGMD, Ensembl, NCBI Gene
Pathogenic Variants:
Affected genes (gene symbols, HGNC IDs) > Search first: OMIM, NCBI Gene, Ensembl, HGNC, UniProt, GeneCards
Variant classification (pathogenic, likely pathogenic, VUS per ACMG/AMP guidelines) > Search first: ClinVar, ClinGen, ACMG/AMP guidelines, VarSome
Variant type/class (missense, frameshift, nonsense, splice-site, structural)
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Somatic vs germline origin > Search first: COSMIC (somatic), ClinVar, ICGC, TCGA
Functional consequences (loss of function, gain of function, dominant negative)
Modifier Genes: Genes that modify disease severity or expression
Epigenetic Information: DNA methylation, histone modifications, chromatin changes affecting disease

Search first: ENCODE, Roadmap Epigenomics, MethBase, DiseaseMeth
Chromosomal Abnormalities: Large-scale genetic changes (aneuploidy, translocations, inversions)

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5. Environmental Information

Environmental Factors: Non-genetic contributing factors (toxins, radiation, pollution, occupational exposure)

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Lifestyle Factors: Behavioral factors (smoking, diet, exercise, alcohol consumption)

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Infectious Agents: If applicable, pathogens causing or triggering disease (bacteria, viruses, fungi, parasites)

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6. Mechanism / Pathophysiology

Molecular Pathways: Specific signaling cascades or biochemical pathways involved (Wnt, MAPK, mTOR, PI3K-AKT, etc.)

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Cellular Processes: Cell-level mechanisms (apoptosis, autophagy, cell cycle dysregulation, inflammation, etc.)

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Protein Dysfunction: How protein structure or function is altered (misfolding, aggregation, loss of function, gain of function)

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Metabolic Changes: Alterations in metabolic processes (energy metabolism, lipid metabolism, amino acid metabolism)

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Immune System Involvement: Role of immune response (autoimmunity, immunodeficiency, chronic inflammation)

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Tissue Damage Mechanisms: How tissues/ are injured (oxidative stress, ischemia, fibrosis, necrosis)

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Biochemical Abnormalities: Specific molecular defects (enzyme deficiencies, receptor dysfunction, ion channel defects)

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Epigenetic Changes: DNA methylation, histone modifications affecting gene expression in disease

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Molecular Profiling (if available):
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Proteomics findings > Search first: PRIDE, ProteomeXchange, Human Protein Atlas, STRING, BioGRID
Metabolomics signatures > Search first: MetaboLights, Metabolomics Workbench, HMDB, METLIN
Lipidomics alterations > Search first: LIPID MAPS, SwissLipids, LipidHome, Metabolomics Workbench
Genomic structural features > Search first: UCSC Genome Browser, Ensembl, NCBI, dbVar, DGV
Advanced Technologies (if applicable):
Single-cell analysis findings (cell-type specific mechanisms, cellular heterogeneity) > Search first: Human Cell Atlas, Single Cell Portal, GEO, CELLxGENE
Spatial transcriptomics findings > Search first: GEO, Spatial Research, Vizgen, 10x Genomics data
Multi-omics integration results > Search first: TCGA, ICGC, cBioPortal, LinkedOmics, PubMed
Functional genomics screens (CRISPR, RNAi) > Search first: DepMap, GenomeRNAi, PubMed, BioGRID ORCS

For each mechanism, describe: - The causal chain from initial trigger to clinical manifestation - Which mechanisms are upstream vs downstream - What cell types and biological processes are involved - Suggest GO terms for biological processes and CL terms for cell types

7. Anatomical Structures Affected

Organ Level:
Primary organs directly affected
Secondary organ involvement (complications, secondary effects)
Body systems involved (cardiovascular, nervous, digestive, respiratory, endocrine, etc.)

Search first: Uberon, FMA (Foundational Model of Anatomy), OMIM, HPO, ICD-11, MeSH, SNOMED CT
Tissue and Cell Level:
Specific tissue types affected (epithelial, connective, muscle, nervous)
Specific cell populations targeted (with Cell Ontology terms)

Search first: Uberon, Human Protein Atlas, Cell Ontology, Human Cell Atlas, CellMarker, PanglaoDB
Subcellular Level:
Cellular compartments involved (mitochondria, nucleus, ER, lysosomes) (with GO Cellular Component terms)

Search first: Gene Ontology (Cellular Component), UniProt, Human Protein Atlas
Localization:
Specific anatomical sites (with UBERON terms) > Search first: FMA, Uberon, NeuroNames (for brain), SNOMED CT
Lateralization (unilateral, bilateral, asymmetric) > Search first: HPO, clinical literature, imaging databases

8. Temporal Development

Onset:
Typical age of onset (congenital, pediatric, adult, geriatric)
Onset pattern (acute, subacute, chronic, insidious)

Search first: OMIM, Orphanet, HPO, PubMed
Progression:
Disease stages (early, intermediate, advanced, end-stage) > Search first: Cancer Staging Manual (AJCC), WHO classifications, PubMed
Progression rate (rapid, slow, variable)
Disease course pattern (episodic, relapsing-remitting, progressive, stable)
Disease duration (self-limited, chronic lifelong)

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Patterns:
Remission patterns (spontaneous, treatment-induced) > Search first: Clinical trial databases, disease registries, PubMed
Critical periods (time windows of vulnerability or opportunity for intervention) > Search first: PubMed, developmental biology databases, clinical guidelines

9. Inheritance and Population

Epidemiology:
Prevalence (cases per 100,000 at given time)
Incidence (new cases per 100,000 per year)

Search first: Orphanet, CDC, WHO, GBD (Global Burden of Disease), national registries, SEER, disease registries
For Genetic Etiology:
Inheritance pattern (AD, AR, X-linked, mitochondrial, multifactorial, polygenic) > Search first: OMIM, Orphanet, ClinVar, GTR (Genetic Testing Registry)
Penetrance (complete, incomplete, age-dependent) > Search first: ClinVar, OMIM, PubMed, ClinGen
Expressivity (variable, consistent) > Search first: OMIM, ClinVar, PubMed
Genetic anticipation (increasing severity in successive generations) > Search first: OMIM, PubMed (especially for repeat expansion disorders)
Germline mosaicism > Search first: ClinVar, OMIM, genetic counseling literature, PubMed
Founder effects (population-specific mutations) > Search first: gnomAD, population genetics databases, PubMed
Consanguinity role > Search first: OMIM, population studies, genetic counseling resources
Carrier frequency > Search first: gnomAD, carrier screening databases, GeneReviews, GTR
Population Demographics:
Affected populations (ethnic or demographic groups with higher prevalence) > Search first: gnomAD, 1000 Genomes, PAGE Study, PubMed, population registries
Geographic distribution (endemic areas, regional variation) > Search first: WHO, CDC, GBD, Orphanet, geographic epidemiology databases
Geographic distribution of specific variants
Sex ratio (male:female) > Search first: Disease registries, OMIM, PubMed, epidemiological databases
Age distribution of affected individuals > Search first: CDC, disease registries, SEER, Orphanet

10. Diagnostics

Clinical Tests:
Laboratory tests (blood, urine, tissue chemistry, specific enzyme assays) > Search first: LOINC, LabTests Online, PubMed
Biomarkers (proteins, metabolites, genetic markers, circulating biomarkers) > Search first: FDA Biomarker List, BEST (Biomarkers, EndpointS, and other Tools), PubMed
Imaging studies (X-ray, CT, MRI, PET, ultrasound) > Search first: RadLex, DICOM, Radiopaedia, imaging databases
Functional tests (pulmonary function, cardiac stress tests) > Search first: LOINC, clinical guidelines, PubMed
Electrophysiology (EEG, EMG, ECG, nerve conduction studies) > Search first: LOINC, clinical neurophysiology databases, PubMed
Biopsy findings (histopathology, immunohistochemistry) > Search first: SNOMED CT, College of American Pathologists resources, PubMed
Pathology findings (microscopic examination) > Search first: SNOMED CT, Digital Pathology databases, PubMed
Genetic Testing:

Search first: GTR (Genetic Testing Registry), GeneReviews, ClinGen
Overview of recommended genetic testing approach
Whole genome sequencing (WGS) utility > Search first: GTR, ClinVar, GEL (Genomics England), gnomAD
Whole exome sequencing (WES) utility > Search first: GTR, ClinVar, OMIM, GeneMatcher
Gene panels (which panels, which genes) > Search first: GTR, ClinVar, laboratory-specific databases
Single gene testing > Search first: GTR, ClinVar, OMIM, GeneReviews
Chromosomal microarray (CMA) > Search first: DECIPHER, ClinVar, dbVar, ECARUCA
Karyotyping > Search first: Chromosome Abnormality Database, ClinVar, cytogenetics resources
FISH > Search first: ClinVar, cytogenetics databases, PubMed
Mitochondrial DNA testing > Search first: MITOMAP, MSeqDR, ClinVar, GTR
Repeat expansion testing > Search first: GTR, ClinVar, repeat expansion databases, PubMed
Omics-Based Diagnostics (if applicable):
RNA sequencing / transcriptomics > Search first: GEO, ArrayExpress, GTEx, RNA-seq databases
Proteomics > Search first: PRIDE, ProteomeXchange, FDA Biomarker database
Metabolomics > Search first: MetaboLights, Metabolomics Workbench, HMDB
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For each treatment, suggest MAXO (Medical Action Ontology) terms where applicable.

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15. Model Organisms

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Model limitations (aspects of human disease not captured) > Search first: Model organism databases, PubMed, review articles
Applications:
Research applications (what aspects of disease can be studied) > Search first: Model organism databases, PubMed
Resources:
Model databases > Search first: MGI, RGD, ZFIN, FlyBase, WormBase, IMSR, EMMA, MMRRC

Citation Requirements

Cite primary literature (PMID preferred) for all mechanistic and clinical claims
Prioritize recent reviews and landmark papers
Include direct quotes from abstracts where possible to support key statements
Distinguish evidence source types: human clinical, model organism, in vitro, computational

Output Format

Structure your response as a comprehensive narrative organized by the sections above. For each section, provide: - Factual content with specific details (numbers, percentages, gene names, variant nomenclature) - Ontology term suggestions (HPO, GO, CL, UBERON, CHEBI, MAXO, MONDO) where applicable - Evidence citations with PMIDs - Direct quotes from abstracts to support key claims - Clear indication when information is not available or not applicable for this disease

This report will be used to populate a disease knowledge base entry with: - Pathophysiology descriptions with causal chains - Gene/protein annotations (HGNC, GO terms) - Phenotype associations (HP terms) with frequencies - Cell type involvement (CL terms) - Anatomical locations (UBERON terms) - Chemical entities (CHEBI terms) - Treatment annotations (MAXO terms) - Evidence items with PMIDs and exact abstract quotes - Epidemiology, prognosis, diagnostic, and prevention information - Animal model descriptions with phenotype recapitulation details

Comprehensive Disease Research Report: CDH23-associated pituitary adenoma 5 (genetic predisposition to PitNET/PA)

Target disease

Disease name: CDH23-associated pituitary adenoma 5 (often discussed as germline CDH23–associated predisposition to pituitary adenoma / pituitary neuroendocrine tumor (PitNET)) (zhang2017germlinemutationsin pages 1-2) Category: Genetic (germline predisposition) (zhang2017germlinemutationsin pages 1-2)

1. Disease information

1.1 Concise overview

“CDH23-associated pituitary adenoma 5” refers to pituitary adenoma/PitNET susceptibility associated with germline variants in CDH23 (cadherin-related 23), initially reported through familial segregation and case-control enrichment analyses and subsequently observed in additional sequencing cohorts. (zhang2017germlinemutationsin pages 1-2)

Pituitary adenomas are now commonly referred to as pituitary neuroendocrine tumours (PitNETs) in the WHO nomenclature. (sousa2023pituitarytumoursmolecular pages 1-2, sousa2023pituitarytumoursmolecular pages 2-4)

1.2 Key identifiers

MONDO / OMIM / Orphanet / MeSH / ICD-10/11: Not retrievable with available tools in this run; OpenTargets did not map “CDH23-associated pituitary adenoma 5” to a disease identifier. (tool error noted in history; disease-specific ID not available)

1.3 Synonyms / alternative names (used in literature)

Pituitary adenoma; pituitary neuroendocrine tumour (PitNET) (sousa2023pituitarytumoursmolecular pages 1-2, sousa2023pituitarytumoursmolecular pages 2-4)
Familial isolated pituitary adenoma (FIPA) context when familial aggregation occurs (zhang2017germlinemutationsin pages 1-2)

1.4 Evidence source types

Aggregated cohort-level human genetics: family-based WES + case-control screening and association testing (zhang2017germlinemutationsin pages 1-2)
Human sequencing cohorts (apparently sporadic PA): WES/panel studies reporting rare CDH23 variants (alzahrani2024germlinevariantsin pages 4-5, gaspar2024germlinemutationsin pages 1-6, gaspar2024germlinemutationsin pages 6-9)
Experimental disease modeling: patient-derived iPSC → pituitary organoids for corticotroph PitNET/Cushing’s disease modeling (chakrabarti2023or2005generationof pages 1-1)
Guideline-level sources (for diagnostics/treatment): prolactinoma/pediatric pituitary adenoma guidance (korbonits2024consensusguidelinefor pages 2-3, cozzi2023italianguidelinesfor pages 1-2)

2. Etiology

2.1 Disease causal factors

Primary causal factor: germline CDH23 variation associated with pituitary adenoma susceptibility.

In the discovery report, WES in a pituitary adenoma family identified a heterozygous CDH23 missense variant c.4136G>T (p.Arg1379Leu) that cosegregated with disease. (zhang2017germlinemutationsin pages 1-2)
In extended screening, functional CDH23 variants were enriched in cases vs controls (familial and sporadic cohorts). (zhang2017germlinemutationsin pages 1-2)

2.2 Risk factors

Genetic risk factors

CDH23: case enrichment and family segregation support CDH23 as a pituitary adenoma predisposition gene. (zhang2017germlinemutationsin pages 1-2)
Discovery study screening: functional CDH23 variants in 33% of familial PA families (4/12) and 12% of sporadic PA individuals (15/125) vs 0.8% of controls (2/260); gene-based association p reported as 5.54×10⁻⁷. (zhang2017germlinemutationsin pages 1-2)
Subsequent cohorts continued to identify rare germline CDH23 variants in apparently sporadic pituitary adenomas and in young-onset macroadenomas (variant examples summarized in artifacts below). (alzahrani2024germlinevariantsin pages 4-5, gaspar2024germlinemutationsin pages 6-9)

Environmental / lifestyle risk factors

No CDH23-specific environmental or lifestyle risk factors were identified in the retrieved evidence; pituitary adenomas are typically considered primarily driven by genetic/epigenetic mechanisms with subtype-specific biology. (sousa2023pituitarytumoursmolecular pages 1-2, sousa2023pituitarytumoursmolecular pages 2-4)

2.3 Protective factors

No CDH23-specific protective factors were identified in the retrieved evidence.

2.4 Gene–environment interactions

No CDH23-specific gene–environment interaction evidence was identified in the retrieved sources.

3. Phenotypes

CDH23-associated pituitary adenoma susceptibility spans multiple pituitary tumor lineages/subtypes (GH, ACTH, PRL, and nonfunctioning tumors reported across cohorts/case reports). (zhang2017germlinemutationsin pages 1-2, ertorer2025arylhydrocarbonreceptor pages 7-7, alzahrani2024germlinevariantsin pages 4-5, albasri2026anovelgermline pages 1-2)

A phenotype-to-HPO mapping based strictly on extracted evidence is provided here:

Clinical feature / phenotype	Suggested HPO term(s)	Typical laboratory / imaging findings supported by evidence	Reported tumor subtype / context	Evidence
Acromegaly / GH excess	HP:0001510 Acromegaly; HP:0000829 Growth hormone excess	High GH or IGF-1 reported in affected carriers; one 48-year-old man with CDH23 p.E302D had an acromegaly–prolactinoma macroadenoma	GH-secreting pituitary adenoma; mixed acromegaly–prolactinoma macroadenoma	(zhang2017germlinemutationsin pages 1-2, alzahrani2024germlinevariantsin pages 4-5)
Cushing disease / ACTH excess	HP:0000846 Hypercortisolism; HP:0011748 Increased circulating ACTH level	ACTH-secreting corticotroph PitNETs reported; CDH23-mutant patient-derived iPSC organoids showed corticotroph-like trajectories and tumor behavior; a Turkish FIPA family with CDH23 p.Ala765Val included an ACTH-secreting adenoma	Corticotroph PitNET / ACTH-secreting pituitary adenoma	(ertorer2025arylhydrocarbonreceptor pages 7-7, chakrabarti2023or2005generationof pages 1-1)
Prolactinoma / hyperprolactinemia with hypogonadism	HP:0002904 Hyperprolactinemia; HP:0000824 Hypogonadotropic hypogonadism; HP:0008245 Central hypothyroidism	Ultra-giant prolactinoma case: prolactin 277,500 ng/mL; extensive sellar, supra/parasellar, skull-base and nasopharyngeal involvement; associated mild central hypothyroidism and hypogonadotropic hypogonadism; marked clinical/radiologic response to low-dose cabergoline	Prolactinoma, specifically ultra-giant prolactinoma	(albasri2026anovelgermline pages 1-2)
Nonfunctioning macroadenoma	HP:0000818 Abnormality of the endocrine system; HP:0000505 Visual impairment (possible mass effect, when present)	CDH23 p.A366T identified in a 22-year-old woman with a nonfunctioning macroadenoma; by definition, nonfunctioning tumors lack a hypersecretory hormonal syndrome in the excerpt	Nonfunctioning pituitary macroadenoma	(alzahrani2024germlinevariantsin pages 4-5)
Macroadenoma / large invasive tumor burden	HP:0001085 Macroadenoma; HP:0012813 Pituitary mass	Macroadenomas were reported in sporadic CDH23-variant carriers; giant prolactinomas are defined as pituitary adenomas ≥4 cm with plasma prolactin >1000 ng/mL; invasive extension into skull base/nasopharynx described in one CDH23 case	Macroadenoma; giant/ultra-giant prolactinoma	(alzahrani2024germlinevariantsin pages 4-5, albasri2026anovelgermline pages 1-2)
Invasiveness / extensive local extension	HP:0033690 Invasive neoplasm; HP:0012813 Pituitary mass	In the discovery study, non-CDH23 cases were noted to have larger, more invasive tumors; later CDH23-associated prolactinoma case showed extensive infiltrative sellar/suprasellar/parasellar and skull-base disease	Invasive PitNET behavior reported across familial/sporadic contexts; especially giant prolactinoma	(zhang2017germlinemutationsin pages 1-2, albasri2026anovelgermline pages 1-2)
Possible reduced/age-dependent penetrance	HP:0003829 Variable expressivity (suggested); HP:0003677 Slow progression (suggested disease predisposition context)	Two family members carrying the segregating CDH23 variant were phenotypically unaffected but were younger than 30 years, suggesting incomplete or age-dependent penetrance rather than absence of risk	Familial CDH23-associated pituitary adenoma predisposition	(zhang2017germlinemutationsin pages 1-2)

Table: This table maps the main clinically reported manifestations of CDH23-associated pituitary adenoma/PitNET cases to suggested HPO terms, alongside the supporting lab and imaging findings. It is useful for structuring phenotype annotations in a disease knowledge base while keeping each row tied to published evidence.

Penetrance/expressivity: In the original segregating family, two mutation carriers were phenotypically unaffected but <30 years old, supporting incomplete and/or age-dependent penetrance. (zhang2017germlinemutationsin pages 1-2)

Quality-of-life impacts (general, tumor-subtype dependent) include endocrine morbidity (e.g., acromegaly, Cushing disease, hypogonadism) and mass effects (e.g., visual impairment) consistent with pituitary adenomas, but CDH23-specific QoL quantitative data were not found in the retrieved sources. (korbonits2024consensusguidelinefor pages 2-3, korbonits2024consensusguidelinefor pages 1-2)

4. Genetic / molecular information

4.1 Causal gene

CDH23 (cadherin-related 23), a cadherin-superfamily member involved in calcium-dependent cell–cell adhesion. (shen2019insightsintopituitary pages 5-6, zhang2017germlinemutationsin pages 1-2)

4.2 Pathogenic/implicated variants (examples)

Across studies, implicated variants are mainly heterozygous missense germline changes; evidence strength varies by cohort and classification method.

Discovery family segregating variant: c.4136G>T (p.Arg1379Leu). (zhang2017germlinemutationsin pages 1-2)
Apparently sporadic cohort: c.906G>C (p.E302D); c.1096G>A (p.A366T) (reclassified by authors’ in-silico approach as likely pathogenic). (alzahrani2024germlinevariantsin pages 4-5, alzahrani2024germlinevariantsin pages 1-2)
Young-onset macroadenoma panel: p.Glu2520Lys (heterozygous; single case in 225). (gaspar2024germlinemutationsin pages 6-9)
Additional familial report: p.Ala765Val in an affected sib-pair with ACTH-secreting adenoma. (ertorer2025arylhydrocarbonreceptor pages 7-7)
Single-case ultra-giant prolactinoma: NM_022124.6:c.2621C>A (p.Ala874Asp). (albasri2026anovelgermline pages 1-2)

A structured variant summary is provided here:

Publication year	Study	Study type / cohort	CDH23 germline variant(s)	Phenotype / tumor subtype	Key statistics	URL / DOI	Citation
2017	Zhang et al.	Discovery family by WES plus follow-up screening of 12 familial PA kindreds, 125 sporadic PA cases, and 260 controls	c.4136G>T (p.Arg1379Leu) segregating in one family; additional functional germline CDH23 variants reported across screened cohorts	Familial isolated pituitary adenoma; reported phenotypes included GH-secreting PA with acromegaly/high GH or IGF-1 and nonfunctioning PA	Functional CDH23 variants in 4/12 familial kindreds (33%), 15/125 sporadic cases (12%), and 2/260 controls (0.8%); gene-based association p=5.54×10^-7	https://doi.org/10.1016/j.ajhg.2017.03.011	(zhang2017germlinemutationsin pages 1-2, zhang2017germlinemutationsin media 44e0f3aa)
2024	Alzahrani et al.	WES of 134 apparently sporadic pituitary adenomas	c.906G>C (p.E302D); c.1096G>A (p.A366T)	p.E302D: acromegaly-prolactinoma macroadenoma in a 48-year-old man; p.A366T: nonfunctioning macroadenoma in a 22-year-old woman	2 CDH23 variants among 134 sporadic PA patients; study estimated likely pathogenic germline variants in PA-associated genes in ~6.7% overall; CDH23 variants were ACMG VUS/benign but AlphaMissense-likely pathogenic	https://doi.org/10.1210/jendso/bvae085	(alzahrani2024germlinevariantsin pages 4-5, alzahrani2024germlinevariantsin pages 1-2)
2024	Gaspar et al.	Multigene panel analysis of 225 young-onset sporadic pituitary macroadenomas	p.Glu2520Lys (protein reported; cDNA not provided in excerpt)	Pituitary macroadenoma; subtype not specified in excerpt	1/225 patients (~0.4%) carried a CDH23 P/LP variant; overall P/LP yield 16/225 (7.1%); authors described this as independent confirmation of CDH23 involvement	https://doi.org/10.1101/2024.06.02.24308129	(gaspar2024germlinemutationsin pages 1-6, gaspar2024germlinemutationsin pages 6-9)
2023	Chakrabarti et al.	Patient-derived iPSC / PitNET organoid modeling from a CD patient with CDH23 mutation	Specific variant not given in abstract excerpt	Corticotroph PitNET / Cushing's disease model	No cohort frequency reported; organoids showed dysregulated cell cycle/proliferation, E2F upregulation, increased CD44/xCT antioxidant signaling, and skewing toward corticotroph/NOTCH trajectories	https://doi.org/10.1210/jendso/bvad114.1314	(chakrabarti2023or2005generationof pages 1-1)
2025	Ertorer et al.	WES of 20 Turkish FIPA cases from 12 families	p.Ala765Val	Familial isolated pituitary adenoma; affected sib-pair including an ACTH-secreting adenoma	CDH23 variant identified in 1/20 FIPA cases/families reported in this cohort (5% as summarized in excerpt)	https://doi.org/10.1038/s41598-025-08610-1	(ertorer2025arylhydrocarbonreceptor pages 7-7)
2026	Albasri et al.	Single-case WES report	NM_022124.6:c.2621C>A (p.Ala874Asp)	Ultra-giant prolactinoma with extensive skull-base/nasopharyngeal invasion	Single case; giant prolactinomas occur in ~1–5% of prolactinomas; marked clinical/radiologic response to low-dose cabergoline reported	https://doi.org/10.1186/s13023-025-04161-w	(albasri2026anovelgermline pages 1-2)

Table: This table summarizes the key reported germline CDH23 variants linked to pituitary adenomas/PitNETs, including discovery and follow-up cohorts, tumor phenotypes, and available frequency statistics. It is useful for quickly comparing the strength and scope of evidence across studies.

4.3 Somatic vs germline

The association emphasized here is germline (inherited) variants; for the cases summarized, CDH23 variants were reported from blood DNA germline analyses (WES/panels/case report). (zhang2017germlinemutationsin pages 1-2, alzahrani2024germlinevariantsin pages 4-5, gaspar2024germlinemutationsin pages 6-9, albasri2026anovelgermline pages 1-2)

4.4 Functional consequence (current understanding)

CDH23 is described as a calcium-dependent cell–cell adhesion glycoprotein. (shen2019insightsintopituitary pages 5-6)

The discovery segregating variant affected an amino acid in the calcium-binding motif of extracellular cadherin (EC) domains and was predicted to impair adhesion, suggesting a plausible tumor-susceptibility mechanism via altered adhesion/microenvironmental interactions. (zhang2017germlinemutationsin pages 1-2)

4.5 Modifier genes / epigenetics / chromosomal abnormalities

No CDH23-specific modifier genes or epigenetic signatures were identified in the retrieved evidence.

5. Environmental information

No CDH23-specific environmental, lifestyle, or infectious contributors were identified in the retrieved sources.

6. Mechanism / pathophysiology

6.1 Proposed causal chain (evidence-supported components)

Germline CDH23 missense variation (often in EC-domain regions affecting calcium-binding motifs) may alter CDH23 structure and cell–cell adhesion properties. (zhang2017germlinemutationsin pages 1-2, shen2019insightsintopituitary pages 5-6)
Altered adhesion and/or downstream cellular programs may increase susceptibility to pituitary tumor formation; in the discovery study, CDH23 variants were enriched in cases and the family variant cosegregated with disease. (zhang2017germlinemutationsin pages 1-2)
In experimental modeling of Cushing’s disease, CDH23-mutant patient-derived iPSC pituitary organoids showed tumor-like behavior and transcriptomic features consistent with pituitary tumorigenesis, including dysregulated cell cycle / increased proliferation markers, E2F family upregulation, increased CD44/xCT (SLC7A11) antioxidant system, and altered Wnt/NOTCH+ stem-like lineage trajectories with terminal enrichment for corticotroph markers and NOTCH signaling. (chakrabarti2023or2005generationof pages 1-1)

6.2 Pathways and processes (suggested ontology mappings)

Biological process (GO) suggestions (based on reported mechanisms): * Cell–cell adhesion (e.g., GO:0098609 cell-cell adhesion) (supported conceptually by cadherin function) (shen2019insightsintopituitary pages 5-6, zhang2017germlinemutationsin pages 1-2) * Cell cycle regulation / proliferation (e.g., GO:0007049 cell cycle) (chakrabarti2023or2005generationof pages 1-1) * Notch signaling pathway (e.g., GO:0007219 Notch signaling pathway) (chakrabarti2023or2005generationof pages 1-1) * Wnt signaling pathway (e.g., GO:0016055 Wnt signaling pathway) (chakrabarti2023or2005generationof pages 1-1) * Response to oxidative stress / cystine-glutamate transport system involvement (conceptual mapping to SLC7A11/xCT) (chakrabarti2023or2005generationof pages 1-1)

Cell type (CL) suggestions (based on reported tumor lineage in modeling and clinical phenotypes): * Corticotroph (ACTH-secreting pituitary cell) (chakrabarti2023or2005generationof pages 1-1) * Somatotroph (GH-secreting pituitary cell) (zhang2017germlinemutationsin pages 1-2) * Lactotroph (prolactin-secreting pituitary cell) (albasri2026anovelgermline pages 1-2)

6.3 Molecular profiling

Single-cell transcriptomic findings were reported for CDH23-mutant iPSC-derived organoid models (see above). (chakrabarti2023or2005generationof pages 1-1)

7. Anatomical structures affected

7.1 Primary organ

Pituitary gland (anterior pituitary); lesions are pituitary adenomas/PitNETs. (sousa2023pituitarytumoursmolecular pages 1-2, sousa2023pituitarytumoursmolecular pages 2-4)

7.2 Localization / extension

Macroadenomas and invasive phenotypes are represented among CDH23-associated cases, including an ultra-giant prolactinoma with extensive skull base/nasopharyngeal involvement. (albasri2026anovelgermline pages 1-2)

UBERON suggestions: * UBERON:0000007 pituitary gland (conceptual mapping; not directly provided in evidence text)

8. Temporal development

Age of onset: Variable; evidence includes young-onset macroadenoma cohorts and adult cases. (gaspar2024germlinemutationsin pages 6-9, alzahrani2024germlinevariantsin pages 4-5)

Progression/course: Tumor subtype-dependent; one source describes pituitary adenoma recurrence after resection generally occurring within 1–5 years and reports a 10-year recurrence estimate of 7–12% in pituitary adenomas overall (not CDH23-specific). (chang2021geneticandepigenetic pages 1-2)

9. Inheritance and population

9.1 Inheritance pattern

The discovery family finding and subsequent familial reports are consistent with autosomal dominant predisposition with incomplete/age-dependent penetrance, as carriers may be unaffected at younger ages. (zhang2017germlinemutationsin pages 1-2)

9.2 Epidemiology and population statistics

General pituitary tumor epidemiology (context): * Prevalence of clinically relevant pituitary adenomas: ~1 in 1000. (sousa2023pituitarytumoursmolecular pages 1-2) * Familial pituitary tumors: ~5% of pituitary adenoma cases. (sousa2023pituitarytumoursmolecular pages 1-2, sousa2023pituitarytumoursmolecular pages 2-4)

Prolactinoma epidemiology (context): * Prolactinomas account for ~50% of pituitary adenomas; guideline gives prevalence ~50/100,000 and incidence 3–5/100,000/year. (cozzi2023italianguidelinesfor pages 1-2) * Giant prolactinomas occur in ~1–5% of prolactinomas. (albasri2026anovelgermline pages 1-2)

CDH23-associated pituitary adenoma 5 (direct estimates): True population prevalence is unknown; available evidence is from selected cohorts. * Discovery study reported functional CDH23 variants in 4/12 familial kindreds and 15/125 sporadic cases, versus 2/260 controls. (zhang2017germlinemutationsin pages 1-2) * A young-onset sporadic macroadenoma panel study reported 1 CDH23 P/LP case in 225 (~0.4%). (gaspar2024germlinemutationsin pages 6-9)

10. Diagnostics

CDH23-specific diagnostic criteria are not established; diagnosis follows standard pituitary adenoma subtype workups plus consideration of germline testing in selected patients.

Key guideline-based diagnostic points: * PRL testing pitfalls: macroprolactin screening and “hook effect” dilution testing in large lesions; hook effect reported in ~5% of macroprolactinomas in the cited pediatric consensus excerpt. (korbonits2024consensusguidelinefor pages 2-3, cozzi2023italianguidelinesfor pages 2-3) * Imaging: MRI is central to classify micro/macroadenoma and assess invasion. (cozzi2023italianguidelinesfor pages 1-2) * Hormone panels: IGF-1 in suspected mixed secretion; evaluation of confounders (thyroid, renal/hepatic disease, medications) in interpreting prolactin. (korbonits2024consensusguidelinefor pages 2-3, korbonits2024consensusguidelinefor pages 1-2)

Genetic testing implementation: Young-onset disease and family history are repeatedly emphasized as determinants of germline variant detection; multigene panels/WES have been used to identify CDH23 variants. (gaspar2024germlinemutationsin pages 1-6, gaspar2024germlinemutationsin pages 6-9, zhang2017germlinemutationsin pages 1-2)

A structured diagnostics and treatment summary (with MAXO suggestions) is provided here:

Domain	Test / intervention	What to do / when to use	Key details / outcome statistics	Suggested MAXO term(s)	Evidence
Diagnostics	Serum prolactin (PRL) assay	First-line biochemical test when prolactinoma is suspected; confirm hyperprolactinemia with careful sampling	Basal PRL should be measured with attention to assay conditions; prolactinomas account for ~50% of pituitary adenomas, with prevalence ~50/100,000 and incidence 3–5/100,000/year in the cited guideline context (cozzi2023italianguidelinesfor pages 1-2)	MAXO:0000001 clinical test; MAXO:0000408 hormone measurement	(cozzi2023italianguidelinesfor pages 1-2, korbonits2024consensusguidelinefor pages 1-2)
Diagnostics	Macroprolactin assessment	Check when PRL is only mildly elevated or incidentally high to avoid misclassification	Polyethylene glycol precipitation is recommended; recovery <40% suggests macroprolactin predominance, >60% suggests true monomeric hyperprolactinemia (cozzi2023italianguidelinesfor pages 2-3)	MAXO:0000001 clinical test; MAXO:0000408 hormone measurement	(cozzi2023italianguidelinesfor pages 2-3, korbonits2024consensusguidelinefor pages 2-3)
Diagnostics	Hook effect / assay dilution	Use serial dilutions for large pituitary lesions with only modest PRL elevation	The high-dose hook effect can mask severe hyperprolactinemia and is reported in ~5% of macroprolactinomas in the pediatric consensus excerpt (korbonits2024consensusguidelinefor pages 2-3)	MAXO:0000001 clinical test	(korbonits2024consensusguidelinefor pages 2-3, cozzi2023italianguidelinesfor pages 2-3)
Diagnostics	MRI of sellar region	Standard imaging to define pituitary lesion size, invasion, optic apparatus compression, and treatment planning	Macroadenoma versus microadenoma classification and invasive extension are central for management; CDH23-associated cases reported macroadenoma and giant invasive phenotypes (alzahrani2024germlinevariantsin pages 4-5, albasri2026anovelgermline pages 1-2)	MAXO:0000376 magnetic resonance imaging	(alzahrani2024germlinevariantsin pages 4-5, albasri2026anovelgermline pages 1-2, cozzi2023italianguidelinesfor pages 1-2)
Diagnostics	Hormone panel: GH/IGF-1	Use when acromegaly or mixed somatotroph disease is suspected	CDH23-associated cases include GH excess/acromegaly and acromegaly–prolactinoma macroadenoma; elevated GH or IGF-1 was reported in affected carriers (zhang2017germlinemutationsin pages 1-2, alzahrani2024germlinevariantsin pages 4-5)	MAXO:0000408 hormone measurement	(zhang2017germlinemutationsin pages 1-2, alzahrani2024germlinevariantsin pages 4-5)
Diagnostics	Hormone panel: ACTH/cortisol	Use when Cushing disease/corticotroph PitNET is suspected	CDH23-associated disease spectrum includes ACTH-secreting adenoma/Cushing disease models; organoid data support corticotroph lineage skewing (ertorer2025arylhydrocarbonreceptor pages 7-7, chakrabarti2023or2005generationof pages 1-1)	MAXO:0000408 hormone measurement	(ertorer2025arylhydrocarbonreceptor pages 7-7, chakrabarti2023or2005generationof pages 1-1)
Diagnostics	Broader endocrine workup	Assess thyroid, gonadal, renal/hepatic confounders and pituitary function	Guideline excerpts recommend excluding severe hypothyroidism, renal/hepatic disease, medications, and assessing related pituitary axes; IGF-1 should be measured to exclude mixed GH secretion in prolactinoma workup (korbonits2024consensusguidelinefor pages 2-3, korbonits2024consensusguidelinefor pages 1-2)	MAXO:0000001 clinical test; MAXO:0000408 hormone measurement	(korbonits2024consensusguidelinefor pages 2-3, korbonits2024consensusguidelinefor pages 1-2)
Genetic evaluation	Germline testing trigger: young onset	Consider germline testing in young-onset pituitary adenoma/macroadenoma	Young age at diagnosis is repeatedly highlighted as a major determinant of germline variant detection; 7.1% of 225 young-onset sporadic macroadenoma patients carried pathogenic/likely pathogenic variants overall in one panel study, including one CDH23 case (~0.4%) (gaspar2024germlinemutationsin pages 1-6, gaspar2024germlinemutationsin pages 6-9)	MAXO:0000127 genetic testing	(gaspar2024germlinemutationsin pages 1-6, gaspar2024germlinemutationsin pages 6-9, sousa2023pituitarytumoursmolecular pages 1-2)
Genetic evaluation	Germline testing trigger: family history / FIPA	Strongly consider testing when pituitary adenoma clusters in a family or syndromic features are present	Familial pituitary tumors account for ~5% of all pituitary adenoma cases; CDH23 emerged as an FIPA/predisposition candidate from familial segregation and enrichment studies (sousa2023pituitarytumoursmolecular pages 1-2, zhang2017germlinemutationsin pages 1-2)	MAXO:0000127 genetic testing; MAXO:0000055 genetic counseling	(sousa2023pituitarytumoursmolecular pages 1-2, zhang2017germlinemutationsin pages 1-2, shen2019insightsintopituitary pages 1-3)
Genetic evaluation	Testing approach	Prefer multigene panel or exome sequencing rather than single-gene testing in unclear hereditary cases	Studies identifying CDH23 in familial and sporadic PAs used WES or multigene panels; recent cohorts continue to recover rare CDH23 variants among broader PA predisposition genes (zhang2017germlinemutationsin pages 1-2, alzahrani2024germlinevariantsin pages 1-2, gaspar2024germlinemutationsin pages 1-6)	MAXO:0000127 genetic testing	(zhang2017germlinemutationsin pages 1-2, alzahrani2024germlinevariantsin pages 1-2, gaspar2024germlinemutationsin pages 1-6)
Treatment	Cabergoline	First-line dopamine agonist for prolactinomas and hyperprolactinemic tumors	2023 Italian guideline recommends cabergoline over bromocriptine as first choice; adult/pediatric guideline data report median PRL normalization 68% (range 40–100%), tumor shrinkage 62% (20–100%), visual field improvement 67% (33–100%), menses normalization 78%, fertility improvement 53%, galactorrhea resolution 86% (cozzi2023italianguidelinesfor pages 7-9, korbonits2024consensusguidelinefor pages 2-3)	MAXO:0001298 dopamine agonist therapy; MAXO:0000745 cabergoline administration	(cozzi2023italianguidelinesfor pages 7-9, korbonits2024consensusguidelinefor pages 2-3, cozzi2023italianguidelinesfor pages 1-2)
Treatment	Bromocriptine	Alternative dopamine agonist when cabergoline is not tolerated or unsuitable	Less favored because of poorer tolerability and multiple daily dosing; guideline recommends bromocriptine mainly as an alternative for cabergoline-intolerant patients not eligible for surgery (cozzi2023italianguidelinesfor pages 2-3, cozzi2023italianguidelinesfor pages 1-2)	MAXO:0001298 dopamine agonist therapy; MAXO:0000746 bromocriptine administration	(cozzi2023italianguidelinesfor pages 2-3, cozzi2023italianguidelinesfor pages 1-2)
Treatment	Transsphenoidal pituitary surgery	Use for DA resistance/intolerance, lack of neuro-ophthalmologic improvement, recurrence/escape, patient preference, or non-prolactinoma subtypes where surgery is standard	Italian guideline recommends resection when no significant neuro-ophthalmologic improvement occurs within 2 weeks of cabergoline, with DA resistance/intolerance, treatment escape, or unwillingness for chronic DA therapy; pediatric consensus excerpt notes adult remission rates of ~30–50% in prolactinoma surgery (cozzi2023italianguidelinesfor pages 1-2, korbonits2024consensusguidelinefor pages 2-3)	MAXO:0000437 transsphenoidal surgery	(cozzi2023italianguidelinesfor pages 1-2, korbonits2024consensusguidelinefor pages 2-3, chang2021geneticandepigenetic pages 1-2)
Treatment	Radiotherapy	Consider for residual, recurrent, or progressive tumors, especially in multimodal management	Used after surgery/medical therapy failure or for progressive disease; contemporary reviews describe radiotherapy as an option for residual, recurrent, or progressive tumors (cozzi2023italianguidelinesfor pages 1-2)	MAXO:0000014 radiotherapy	(cozzi2023italianguidelinesfor pages 1-2)
Treatment	Temozolomide	Reserve for aggressive pituitary tumors/carcinomas or refractory disease in multidisciplinary care	In guideline synthesis, temozolomide produced tumor shrinkage in 73.5% and PRL reduction in 75%, but PRL normalization only in 8.3%; progression occurred in ~20.6% (cozzi2023italianguidelinesfor pages 6-7)	MAXO:0000063 chemotherapy; MAXO:0000754 temozolomide administration	(cozzi2023italianguidelinesfor pages 6-7, cozzi2023italianguidelinesfor pages 1-2)
Monitoring	Long-term follow-up	Continue endocrine, imaging, and genetic follow-up because penetrance may be incomplete/age-dependent	In the discovery family, two CDH23 variant carriers were unaffected but under age 30, suggesting possible age-dependent penetrance; long-term surveillance is therefore reasonable in predisposed families (zhang2017germlinemutationsin pages 1-2)	MAXO:0000011 follow-up evaluation; MAXO:0000055 genetic counseling	(zhang2017germlinemutationsin pages 1-2)

Table: This table summarizes clinically relevant diagnostic and treatment actions for suspected CDH23-associated pituitary adenoma predisposition, using disease-specific genetic evidence plus modern prolactinoma/pituitary adenoma guidelines. It is useful for translating the literature into structured knowledge-base actions, including testing triggers, assay pitfalls, therapies, and outcome benchmarks.

11. Outcome / prognosis

CDH23-specific prognostic statistics are not established.

Contextual outcomes from guidelines and related pituitary tumor literature: * Dopamine agonists (adult-derived ranges cited in pediatric consensus) normalize prolactin in median 68% and cause tumor shrinkage in 62%, with visual field improvement in 67% (ranges in guideline). (korbonits2024consensusguidelinefor pages 2-3) * In a single-center series of prolactinomas with visual impairment, cabergoline improved visual impairment in 16/18 (88.9%), with 2/18 (11.1%) requiring surgery (not CDH23-specific). (zhang2017germlinemutationsin media 22b51610) * For aggressive/resistant prolactinomas, guideline synthesis reports temozolomide-associated tumor shrinkage 73.5% and PRL reduction 75%, but PRL normalization 8.3%, with progression ~20.6% (not CDH23-specific). (cozzi2023italianguidelinesfor pages 6-7)

Case-level outcome example: * An ultra-giant prolactinoma with germline CDH23 p.Ala874Asp showed “marked clinical and radiologic response to low-dose cabergoline.” (albasri2026anovelgermline pages 1-2)

12. Treatment

No CDH23-genotype–specific therapy exists; treatment is tumor-subtype driven.

Prolactinoma-first line: dopamine agonists, especially cabergoline (recommended as first-choice pharmacotherapy in a 2023 national guideline). (cozzi2023italianguidelinesfor pages 7-9, cozzi2023italianguidelinesfor pages 1-2)

Surgery: transsphenoidal resection for DA failure/intolerance or urgent neuro-ophthalmologic concerns; Italian guideline lists specific indications including lack of neuro-ophthalmologic improvement within 2 weeks of cabergoline, DA resistance/intolerance, escape, or patient preference. (cozzi2023italianguidelinesfor pages 1-2)

Other modalities: radiotherapy and temozolomide for refractory/aggressive disease in multidisciplinary settings. (cozzi2023italianguidelinesfor pages 6-7, cozzi2023italianguidelinesfor pages 1-2)

Outcome statistics for DA therapy and DA withdrawal: guideline synthesis notes high on-treatment PRL normalization rates (~88% overall across observational studies) but lower sustained remission after DA discontinuation (~32% overall; microP 52%, macroP 28%). (cozzi2023italianguidelinesfor pages 6-7)

MAXO term suggestions for major interventions are included in artifact-02. (cozzi2023italianguidelinesfor pages 6-7, cozzi2023italianguidelinesfor pages 1-2)

13. Prevention

No primary prevention is established. Practical prevention is secondary prevention in predisposed families: early recognition of symptoms, biochemical screening, and MRI when clinically indicated, plus genetic counseling/testing in families with clustering or in young-onset cases. (gaspar2024germlinemutationsin pages 6-9, zhang2017germlinemutationsin pages 1-2)

14. Other species / natural disease

No evidence for naturally occurring CDH23-associated pituitary adenoma predisposition in non-human species was identified in the retrieved sources.

15. Model organisms / model systems

A human experimental model relevant to CDH23-associated pituitary tumorigenesis has been reported: * Patient-derived iPSCs carrying CDH23 mutation differentiated into pituitary organoids to model corticotroph PitNET/Cushing’s disease pathogenesis; single-cell transcriptomics showed dysregulated proliferation/cell cycle (E2F), increased CD44/xCT(SLC7A11), and Wnt/NOTCH/corticotroph-enriched trajectories. (chakrabarti2023or2005generationof pages 1-1)

Visual evidence from primary literature

Zhang et al. 2017 includes figures showing the family pedigree and segregation of the CDH23 variant and the case-control screening summary for functional CDH23 variants. (zhang2017germlinemutationsin media 44e0f3aa, zhang2017germlinemutationsin media 22b51610)

Notes on evidence gaps and interpretation

The term “CDH23-associated pituitary adenoma 5” appears to represent a gene-defined predisposition entity rather than a well-curated disease entry across major ontologies; a MONDO/OMIM/Orphanet identifier could not be confirmed with the available tools in this run.
Some later cohort studies classify CDH23 variants as VUS by ACMG but “likely pathogenic” by additional in-silico tools; clinical interpretation should therefore follow expert variant curation standards and family segregation/tumor correlation where possible. (alzahrani2024germlinevariantsin pages 4-5, alzahrani2024germlinevariantsin pages 1-2)

References

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(cozzi2023italianguidelinesfor pages 1-2): Renato Cozzi, Renata Simona Auriemma, Ernesto De Menis, Felice Esposito, Emanuele Ferrante, Giuseppe Iatì, Diego Mazzatenta, Maurizio Poggi, Roberta Rudà, Fabio Tortora, Fabio Cruciani, Zuzana Mitrova, Rosella Saulle, Simona Vecchi, Michele Basile, Paolo Cappabianca, Agostino Paoletta, Enrico Papini, Agnese Persichetti, Irene Samperi, Alessandro Scoppola, Alessandro Bozzao, Marco Caputo, Francesco Doglietto, Francesco Ferraù, Andrea Gerardo Lania, Stefano Laureti, Stefano Lello, Davide Locatelli, Pietro Maffei, Giuseppe Minniti, Alessandro Peri, Chiara Ruini, Fabio Settanni, Antonio Silvani, Nadia Veronese, Franco Grimaldi, and Roberto Attanasio. Italian guidelines for the management of prolactinomas. Endocrine, Metabolic & Immune Disorders - Drug Targets, 23:1459-1479, Oct 2023. URL: https://doi.org/10.2174/1871530323666230511104045, doi:10.2174/1871530323666230511104045. This article has 23 citations.
(ertorer2025arylhydrocarbonreceptor pages 7-7): M. Eda Ertorer, Feyza N. Tuncer, Sema Ciftci, Seher Tanrikulu, Ozlem Soyluk Selcukbiricik, Ömercan Topaloğlu, Mehtap Evran, Pinar Kadioglu, Sevcan Aydin, Bulent Can, Canan Sehit, Zafer Pekkolay, Guzide Gonca Oruk, Berrin Cetinarslan, and Sema Yarman. Aryl hydrocarbon receptor interacting protein and syndromic gene variants detected in turkish isolated pituitary adenoma families by whole exome sequencing. Scientific Reports, Jul 2025. URL: https://doi.org/10.1038/s41598-025-08610-1, doi:10.1038/s41598-025-08610-1. This article has 5 citations and is from a peer-reviewed journal.
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(shen2019insightsintopituitary pages 5-6): Angeline Jia Jia Shen, James King, Hamish Scott, Peter Colman, and Christopher J Yates. Insights into pituitary tumorigenesis: from sanger sequencing to next-generation sequencing and beyond. Expert Review of Endocrinology & Metabolism, 14:399-418, Nov 2019. URL: https://doi.org/10.1080/17446651.2019.1689120, doi:10.1080/17446651.2019.1689120. This article has 18 citations and is from a peer-reviewed journal.
(alzahrani2024germlinevariantsin pages 1-2): Ali S Alzahrani, Abdulghani Bin Nafisah, Meshael Alswailem, Balgees Alghamdi, Burair Alsaihati, Hussain Aljafar, Batoul Baz, Hindi Alhindi, Yosra Moria, Muhammad Imran Butt, Abdulrahman Ghiatheddin Alkabbani, Omalkhaire M Alshaikh, Anhar Alnassar, Ahmed Bin Afeef, Reem AlQuraa, Rawan Alsuhaibani, Omar Alhadlaq, Fayha Abothenain, and Yasser A Altwaijry. Germline variants in sporadic pituitary adenomas. Journal of the Endocrine Society, Apr 2024. URL: https://doi.org/10.1210/jendso/bvae085, doi:10.1210/jendso/bvae085. This article has 14 citations and is from a peer-reviewed journal.
(zhang2017germlinemutationsin media 44e0f3aa): Qilin Zhang, Cheng Peng, Jianping Song, Yichao Zhang, Jianhua Chen, Zhijian Song, Xuefei Shou, Zengyi Ma, Hong Peng, Xuemin Jian, Wenqiang He, Zhao Ye, Zhiqiang Li, Yongfei Wang, Hongying Ye, Zhaoyun Zhang, Ming Shen, Feng Tang, Hong Chen, Zhifeng Shi, Chunjui Chen, Zhengyuan Chen, Yue Shen, Ye Wang, Shaoyong Lu, Jian Zhang, Yiming Li, Shiqi Li, Ying Mao, Liangfu Zhou, Hai Yan, Yongyong Shi, Chuanxin Huang, and Yao Zhao. Germline mutations in cdh23, encoding cadherin-related 23, are associated with both familial and sporadic pituitary adenomas. American journal of human genetics, 100 5:817-823, May 2017. URL: https://doi.org/10.1016/j.ajhg.2017.03.011, doi:10.1016/j.ajhg.2017.03.011. This article has 83 citations and is from a highest quality peer-reviewed journal.
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(cozzi2023italianguidelinesfor pages 2-3): Renato Cozzi, Renata Simona Auriemma, Ernesto De Menis, Felice Esposito, Emanuele Ferrante, Giuseppe Iatì, Diego Mazzatenta, Maurizio Poggi, Roberta Rudà, Fabio Tortora, Fabio Cruciani, Zuzana Mitrova, Rosella Saulle, Simona Vecchi, Michele Basile, Paolo Cappabianca, Agostino Paoletta, Enrico Papini, Agnese Persichetti, Irene Samperi, Alessandro Scoppola, Alessandro Bozzao, Marco Caputo, Francesco Doglietto, Francesco Ferraù, Andrea Gerardo Lania, Stefano Laureti, Stefano Lello, Davide Locatelli, Pietro Maffei, Giuseppe Minniti, Alessandro Peri, Chiara Ruini, Fabio Settanni, Antonio Silvani, Nadia Veronese, Franco Grimaldi, and Roberto Attanasio. Italian guidelines for the management of prolactinomas. Endocrine, Metabolic & Immune Disorders - Drug Targets, 23:1459-1479, Oct 2023. URL: https://doi.org/10.2174/1871530323666230511104045, doi:10.2174/1871530323666230511104045. This article has 23 citations.
(shen2019insightsintopituitary pages 1-3): Angeline Jia Jia Shen, James King, Hamish Scott, Peter Colman, and Christopher J Yates. Insights into pituitary tumorigenesis: from sanger sequencing to next-generation sequencing and beyond. Expert Review of Endocrinology & Metabolism, 14:399-418, Nov 2019. URL: https://doi.org/10.1080/17446651.2019.1689120, doi:10.1080/17446651.2019.1689120. This article has 18 citations and is from a peer-reviewed journal.
(cozzi2023italianguidelinesfor pages 7-9): Renato Cozzi, Renata Simona Auriemma, Ernesto De Menis, Felice Esposito, Emanuele Ferrante, Giuseppe Iatì, Diego Mazzatenta, Maurizio Poggi, Roberta Rudà, Fabio Tortora, Fabio Cruciani, Zuzana Mitrova, Rosella Saulle, Simona Vecchi, Michele Basile, Paolo Cappabianca, Agostino Paoletta, Enrico Papini, Agnese Persichetti, Irene Samperi, Alessandro Scoppola, Alessandro Bozzao, Marco Caputo, Francesco Doglietto, Francesco Ferraù, Andrea Gerardo Lania, Stefano Laureti, Stefano Lello, Davide Locatelli, Pietro Maffei, Giuseppe Minniti, Alessandro Peri, Chiara Ruini, Fabio Settanni, Antonio Silvani, Nadia Veronese, Franco Grimaldi, and Roberto Attanasio. Italian guidelines for the management of prolactinomas. Endocrine, Metabolic & Immune Disorders - Drug Targets, 23:1459-1479, Oct 2023. URL: https://doi.org/10.2174/1871530323666230511104045, doi:10.2174/1871530323666230511104045. This article has 23 citations.
(cozzi2023italianguidelinesfor pages 6-7): Renato Cozzi, Renata Simona Auriemma, Ernesto De Menis, Felice Esposito, Emanuele Ferrante, Giuseppe Iatì, Diego Mazzatenta, Maurizio Poggi, Roberta Rudà, Fabio Tortora, Fabio Cruciani, Zuzana Mitrova, Rosella Saulle, Simona Vecchi, Michele Basile, Paolo Cappabianca, Agostino Paoletta, Enrico Papini, Agnese Persichetti, Irene Samperi, Alessandro Scoppola, Alessandro Bozzao, Marco Caputo, Francesco Doglietto, Francesco Ferraù, Andrea Gerardo Lania, Stefano Laureti, Stefano Lello, Davide Locatelli, Pietro Maffei, Giuseppe Minniti, Alessandro Peri, Chiara Ruini, Fabio Settanni, Antonio Silvani, Nadia Veronese, Franco Grimaldi, and Roberto Attanasio. Italian guidelines for the management of prolactinomas. Endocrine, Metabolic & Immune Disorders - Drug Targets, 23:1459-1479, Oct 2023. URL: https://doi.org/10.2174/1871530323666230511104045, doi:10.2174/1871530323666230511104045. This article has 23 citations.
(zhang2017germlinemutationsin media 22b51610): Qilin Zhang, Cheng Peng, Jianping Song, Yichao Zhang, Jianhua Chen, Zhijian Song, Xuefei Shou, Zengyi Ma, Hong Peng, Xuemin Jian, Wenqiang He, Zhao Ye, Zhiqiang Li, Yongfei Wang, Hongying Ye, Zhaoyun Zhang, Ming Shen, Feng Tang, Hong Chen, Zhifeng Shi, Chunjui Chen, Zhengyuan Chen, Yue Shen, Ye Wang, Shaoyong Lu, Jian Zhang, Yiming Li, Shiqi Li, Ying Mao, Liangfu Zhou, Hai Yan, Yongyong Shi, Chuanxin Huang, and Yao Zhao. Germline mutations in cdh23, encoding cadherin-related 23, are associated with both familial and sporadic pituitary adenomas. American journal of human genetics, 100 5:817-823, May 2017. URL: https://doi.org/10.1016/j.ajhg.2017.03.011, doi:10.1016/j.ajhg.2017.03.011. This article has 83 citations and is from a highest quality peer-reviewed journal.

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1. Disease Information

2. Etiology

3. Phenotypes

4. Genetic/Molecular Information

5. Environmental Information

6. Mechanism / Pathophysiology

7. Anatomical Structures Affected

8. Temporal Development

9. Inheritance and Population

10. Diagnostics

11. Outcome/Prognosis

12. Treatment

13. Prevention

14. Other Species / Natural Disease

15. Model Organisms

Citation Requirements

Output Format

Comprehensive Disease Research Report: CDH23-associated pituitary adenoma 5 (genetic predisposition to PitNET/PA)

Target disease

1. Disease information

1.1 Concise overview

1.2 Key identifiers

1.3 Synonyms / alternative names (used in literature)

1.4 Evidence source types

2. Etiology

2.1 Disease causal factors

2.2 Risk factors

Genetic risk factors

Environmental / lifestyle risk factors

2.3 Protective factors

2.4 Gene–environment interactions

3. Phenotypes

4. Genetic / molecular information

4.1 Causal gene

4.2 Pathogenic/implicated variants (examples)

4.3 Somatic vs germline

4.4 Functional consequence (current understanding)

4.5 Modifier genes / epigenetics / chromosomal abnormalities

5. Environmental information

6. Mechanism / pathophysiology

6.1 Proposed causal chain (evidence-supported components)

6.2 Pathways and processes (suggested ontology mappings)

6.3 Molecular profiling

7. Anatomical structures affected

7.1 Primary organ

7.2 Localization / extension

8. Temporal development

9. Inheritance and population

9.1 Inheritance pattern

9.2 Epidemiology and population statistics

10. Diagnostics

11. Outcome / prognosis

12. Treatment

13. Prevention

14. Other species / natural disease

15. Model organisms / model systems

Visual evidence from primary literature

Notes on evidence gaps and interpretation

Artifacts