endo.men2a.core.v1

Multiple endocrine neoplasia type 2A (MEN2A)

endocrinologychronicsyndromeadultpediatricoutpatientinpatient

Start encounter →Print handoutPRODUCTION

MEN2A (Sipple syndrome): autosomal-dominant germline RET activating mutation (10q11.2); RET codon-genotype-phenotype sets the ATA risk tier (highest/high/moderate) that, with serial calcitonin, governs the central decision — TIMING of prophylactic total thyroidectomy. Cardinal safety rule: pheochromocytoma must be EXCLUDED and (if present) treated with α-blockade THEN β-blockade and adrenalectomy BEFORE any thyroid/parathyroid surgery, pregnancy or delivery. Advanced/metastatic MTC → selective RET inhibitors (selpercatinib/pralsetinib) preferred over older multikinase agents. Manifest pointer is a placeholder reusing prisma/seed/manifests/endo.pheochromocytoma.v1.ts — a dedicated endo.men2a manifest, problem-package, RxNav RxCUI validation, and Bayesian LRs are deferred (see design brief Open gaps). No rxcui fields are set; non_pharm marks all surgical/genetic/surveillance entries.

Entry points (5)

history
Positive germline RET mutation (proband or cascade-tested relative) (ATA 2015)
positive_ret_germline
history
Family history of MEN2 / MTC / pheochromocytoma (ATA 2015)
family_history_men2_mtc
lab_abnormality
Elevated basal/stimulated calcitonin or CEA (ATA 2015)
elevated_calcitonin
problem_list
Medullary thyroid carcinoma or C-cell hyperplasia on FNA / thyroid nodule (ATA 2015)
mtc_or_thyroid_nodule
problem_list
Bilateral pheochromocytoma or primary hyperparathyroidism in a young patient (ATA 2015)
bilateral_pheo_or_hpt

Required inputs (14)

agerequired
demographic • used at CONTEXT
ATA risk category × age drives prophylactic thyroidectomy timing (highest <5y / by-calcitonin; high by age 5; moderate individualized)
ret_codon_genotyperequired
history • used at CONTEXT
Specific RET codon (e.g., C634, M918T excludes 2A) sets ATA risk tier (highest/high/moderate) and component penetrance
family_pedigreerequired
history • used at CONTEXT
Cascade testing of first-degree relatives; index vs at-risk carrier; de novo vs inherited
calcitoninrequired
lab • used at INITIAL_WORKUP
MTC tumour marker — basal ± stimulated; drives surgical timing and post-op cure/recurrence surveillance + doubling time
cearequired
lab • used at INITIAL_WORKUP
Second MTC marker; rising CEA with stable/falling calcitonin suggests dedifferentiation/progression
plasma_free_metanephrinesrequired
lab • used at INITIAL_WORKUP
Pheochromocytoma must be EXCLUDED before any thyroid/parathyroid surgery, pregnancy or delivery
corrected_calciumrequired
lab • used at INITIAL_WORKUP
Primary hyperparathyroidism component (~20–30%); albumin-corrected calcium screen
pthrequired
lab • used at INITIAL_WORKUP
PTH-dependent hypercalcaemia confirms MEN2A primary hyperparathyroidism (multiglandular)
sbprequired
vital • used at CONTEXT
Pheochromocytoma crisis recognition + preop α/β blockade target
hrrequired
vital • used at CONTEXT
Tachycardia drives β-blocker timing (only AFTER adequate α-blockade)
neck_ultrasound
imaging • used at BRANCHING_WORKUP
Thyroid + central/lateral nodal mapping for MTC extent before thyroidectomy
adrenal_ct_or_mri
imaging • used at BRANCHING_WORKUP
Pheochromocytoma localisation (often bilateral) once metanephrines positive
pregnancy_statusrequired
history • used at CONTEXT
Pheo in pregnancy is life-threatening; alters blockade drug choice and delivery planning
cla_or_hirschsprung
history • used at CONTEXT
MEN2A variant flags — cutaneous lichen amyloidosis (codon 634) / Hirschsprung disease (exon 10, codons 609/611/618/620)

12-phase flow (12)

1FRAME
Establish MEN2A: germline RET activating mutation + ≥1 component (MTC ~100%, pheo ~50%, PHPT ~20–30%); classify proband vs at-risk carrier; distinguish 2A from 2B and MEN1 (ATA 2015)
inputs: ret_codon_genotype
advance: RET status + syndrome scope established
2ENTRY
Trigger: positive germline RET, family history of MEN2/MTC, elevated calcitonin/CEA, MTC on FNA, or bilateral pheo / young-onset PHPT (ATA 2015)
inputs: age
advance: Entry trigger captured
3CONTEXT
RET codon-genotype-phenotype (e.g., C634 high risk; A883F/M918T = 2B not 2A), family pedigree for cascade testing, pregnancy status, MEN2A variant flags (CLA / Hirschsprung) (ATA 2015)
inputs: ret_codon_genotype, family_pedigree, pregnancy_status, cla_or_hirschsprung, sbp, hr
advance: Risk tier assigned; pedigree mapped; variant flags resolved
4RED_FLAGS
Unexcluded/unprepared pheochromocytoma before surgery or delivery; hypertensive crisis / catecholamine cardiomyopathy; hypercalcaemic crisis; rapidly rising calcitonin / metastatic MTC (ATA 2015)
inputs: sbp, hr, plasma_free_metanephrines, corrected_calcium
actions: calc.qsofa, workup.secondary_htn
advance: Life-threatening states screened; pheo cleared or treated FIRST
5INITIAL_WORKUP
Calcitonin (± stimulated), CEA, plasma free metanephrines (exclude pheo BEFORE any surgery), albumin-corrected calcium + PTH, 25-OH-vitamin D, neck ultrasound; germline RET sequencing if not yet done (ATA 2015)
inputs: calcitonin, cea, plasma_free_metanephrines, corrected_calcium, pth
actions: workup.men_screening, panel.tumor, panel.hormone, panel.thyroid, calc.corrected_ca
advance: Three-component biochemical screen complete; RET confirmed
6BRANCHING_WORKUP
Calcitonin high → neck US + cross-sectional staging for MTC; metanephrines positive → adrenal CT/MRI ± functional imaging for (often bilateral) pheo; PTH-dependent hypercalcaemia → parathyroid localisation; cascade RET test of first-degree relatives (ATA 2015)
inputs: neck_ultrasound, adrenal_ct_or_mri
actions: workup.thyroid_nodule, workup.hypercalcemia, workup.adrenal_incidentaloma
advance: Each positive component localised; relatives offered cascade testing
7DIFFERENTIAL
MEN2A vs MEN2B (2B: marfanoid habitus + mucosal neuromas + earliest/most-aggressive MTC, NO PHPT) vs MEN1 (3Ps: parathyroid/pituitary/pancreatic — NO MTC or pheo) vs sporadic MTC/pheo/PHPT vs familial MTC (ATA 2015)
advance: Syndrome confirmed as MEN2A; mimics excluded
8RISK_STRATIFICATION
ATA RET codon-risk category — HIGHEST (MEN2B M918T) / HIGH (C634, A883F) / MODERATE (most other codons) — combined with basal calcitonin governs prophylactic thyroidectomy timing; perioperative pheo risk (ATA 2015)
inputs: ret_codon_genotype, calcitonin
actions: calc.news2
advance: ATA tier + calcitonin-based surgical timing decided
9TREATMENT
SEQUENCE: (1) exclude/treat pheo FIRST — α-blockade then β-blockade then adrenalectomy; (2) prophylactic/therapeutic total thyroidectomy ± central neck dissection by ATA risk + calcitonin (HIGH by age 5 or earlier if calcitonin rises; MODERATE individualized); (3) parathyroidectomy for PHPT; (4) advanced/metastatic MTC → selective RET inhibitor (selpercatinib/pralsetinib); (5) lifelong surveillance (ATA 2015)
inputs: plasma_free_metanephrines, calcitonin, corrected_calcium, sbp, hr
advance: Sequenced operative + medical plan documented (pheo cleared before thyroid/parathyroid surgery)
10DISPOSITION
Outpatient multidisciplinary (endocrinology + endocrine surgery + genetics) for surveillance/prophylaxis; inpatient for perioperative pheo optimisation, thyroidectomy/adrenalectomy/parathyroidectomy, or hypercalcaemic/hypertensive crisis (ATA 2015)
advance: Care setting + multidisciplinary team assigned
11MONITORING
Lifelong biochemical surveillance — calcitonin + CEA (with doubling-time post-thyroidectomy), annual plasma free metanephrines, annual corrected calcium ± PTH; RET-inhibitor toxicity monitoring (BP, QTc, LFTs) when on selpercatinib/pralsetinib (ATA 2015)
inputs: calcitonin, cea, plasma_free_metanephrines, corrected_calcium
actions: panel.tumor, panel.metabolic
advance: Surveillance schedule active; markers trended
12FOLLOWUP
Genetic counselling + cascade RET testing of first-degree relatives; lifelong endo/surgery/genetics follow-up; pre-conception counselling (pheo exclusion before pregnancy); patient education on component surveillance and return precautions (ATA 2015)
advance: Cascade testing + lifelong follow-up + counselling arranged