12-phase flow (12)

1. 1FRAME
   Establish whether MEN1 diagnostic criteria are met — (1) ≥2 of 3 main tumors, (2) 1 main tumor + first-degree relative with MEN1, or (3) germline MEN1 mutation; distinguish clinical vs genetically-confirmed vs at-risk carrier (Thakker JCEM 2012)
   inputs: germline_men1_mutation, family_history_men1
   advance: MEN1 status classified — confirmed (clinical or genetic), at-risk carrier, or differential
2. 2ENTRY
   Capture trigger — affected relative / known mutation (cascade), early or multiglandular pHPT, multi-organ endocrine tumors, Zollinger-Ellison, or fasting neuroglycopenia (Thakker JCEM 2012)
   inputs: family_history_men1
   advance: Entry trigger captured
3. 3CONTEXT
   Age and youngest age of onset, full three-generation pedigree, smoking status (thymic-carcinoid risk), pregnancy status, PPI / thiazide / lithium use confounding screens, prior endocrine surgery (Thakker JCEM 2012)
   inputs: age, family_history_men1, smoking_status, pregnancy_status, current_meds
   advance: Pedigree, confounders, and risk modifiers documented
4. 4RED_FLAGS
   Screen MEN1 emergencies — hypercalcemic crisis (Ca >14 / AKI / AMS), neuroglycopenic insulinoma episode, complicated Zollinger-Ellison (perforation / GI bleed), pituitary apoplexy or chiasmal compression, aggressive/invasive thymic carcinoid (Thakker JCEM 2012)
   inputs: serum_calcium_corrected, fasting_glucose_insulin_proinsulin
   actions: calc.corrected_ca, workup.hypercalcemia
   advance: Acute MEN1 emergencies screened and stabilized if present
5. 5INITIAL_WORKUP
   Annual MEN1 biochemical screen — corrected calcium + intact PTH, fasting gastrin, fasting glucose/insulin/C-peptide/proinsulin, prolactin, IGF-1, chromogranin A; plus germline MEN1 sequencing/MLPA if not done (Thakker JCEM 2012 surveillance program)
   inputs: serum_calcium_corrected, pth_intact, fasting_gastrin, fasting_glucose_insulin_proinsulin, prolactin, igf1, chromogranin_a
   actions: workup.men_screening, panel.hormone, panel.metabolic, panel.tumor
   advance: Full annual biochemical panel resulted; genetic testing initiated/known
6. 6BRANCHING_WORKUP
   Finding-directed imaging — pituitary MRI (prolactin/IGF-1 abnormal or periodic), pancreas MRI/CT ± EUS (gastrin/insulin abnormal or periodic), chest CT/MRI for thymic carcinoid, neck localization + adrenal CT for incidentaloma; functional somatostatin-receptor PET for NET staging (Thakker JCEM 2012; ENETS)
   inputs: pituitary_mri, pancreas_ct_mri_eus, thymic_chest_imaging
   actions: panel.glucose_a1c, workup.adrenal_incidentaloma
   advance: Localizing imaging completed for each abnormal axis
7. 7DIFFERENTIAL
   Resolve MEN1 vs MEN2A/2B (no MTC or pheochromocytoma in MEN1; RET vs MEN1 gene), MEN4 (CDKN1B), familial isolated hyperparathyroidism, hyperparathyroidism-jaw-tumor (CDC73), familial hypocalciuric hypercalcemia, sporadic single-gland adenoma, and non-syndromic pNET/prolactinoma (Thakker JCEM 2012)
   advance: Syndrome confirmed and phenocopies excluded
8. 8RISK_STRATIFICATION
   Stratify by organ burden and aggressiveness — pHPT meeting surgical criteria, gastrinoma/ZES severity, insulinoma neuroglycopenia, pNET size/grade and metastatic risk, thymic carcinoid (mortality), pituitary macroadenoma mass effect; mutation-genotype/family-phenotype context (Thakker JCEM 2012)
   inputs: serum_calcium_corrected, fasting_gastrin
   actions: calc.corrected_ca
   advance: Per-organ risk tier assigned; surgical vs medical pathway selected
9. 9TREATMENT
   Organ-directed, MEN1-aware therapy — multiglandular subtotal/total parathyroidectomy + parathyroid cryopreservation for pHPT; high-dose PPI first-line for gastrinoma (surgery controversial / multifocal); enucleation/resection for insulinoma; cabergoline for prolactinoma, transsphenoidal/medical per pituitary subtype; thymic/pancreatic NET resection by size/grade; somatostatin analogue for unresectable functional NET (Thakker JCEM 2012; ENETS)
   inputs: serum_calcium_corrected, fasting_gastrin, prolactin
   advance: Per-organ treatment plan documented and sequenced
10. 10DISPOSITION
    Predominantly outpatient multidisciplinary care (endocrinology + endocrine surgery + genetics ± GI/neurosurgery/oncology); inpatient for surgery, hypercalcemic crisis, insulinoma admission, or complicated ZES (Thakker JCEM 2012)
    advance: Care setting and multidisciplinary referrals secured
11. 11MONITORING
    Lifelong surveillance — annual calcium/PTH, gastrin, fasting glucose/insulin/proinsulin, prolactin, IGF-1, chromogranin A; periodic pituitary MRI (~3-yearly), pancreas MRI/CT ± EUS (1-3-yearly), chest imaging for thymic carcinoid (1-2-yearly); post-parathyroidectomy hungry-bone and recurrence watch (Thakker JCEM 2012 surveillance schedule)
    inputs: serum_calcium_corrected, fasting_gastrin, prolactin
    actions: workup.men_screening, panel.hormone
    advance: Lifelong surveillance schedule established and documented
12. 12FOLLOWUP
    Cascade genetic testing + counseling for at-risk first-degree relatives (offer from ~5-10 y of age depending on earliest familial tumor), patient education, smoking cessation (thymic risk), pregnancy planning, and lifelong MEN1-center follow-up (Thakker JCEM 2012)
    advance: Cascade screening offered, counseling and follow-up booked