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endo.men2b.core.v1PRODUCTION
endo.men2b.core.v1

Multiple endocrine neoplasia type 2B (MEN2B)

endocrinologychronicsyndromepediatricadult
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Care setting:

Encounter flow

12/12 authored

Canonical 12-phase frame with authored status for this dossier.

Current phase

Frame

Detailed

Frame MEN2B as ATA HIGHEST-risk RET syndrome — most aggressive earliest-onset MTC + pheo (~50%) WITHOUT primary hyperparathyroidism; phenotype recognition in a child is the determinant of MTC outcome

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Advance rule
Set
Advance when

MEN2B suspected on phenotype or RET M918T confirmed

Patient inputs (13)

Age dictates thyroidectomy timing — first year of life for ATA highest-risk M918T; infants present with GI/phenotype before MTC is clinically apparent

RET M918T (codon 918, ~95% of MEN2B) defines ATA HIGHEST risk; genotype is the single most consequential input

~50% de novo (paternal origin) — ABSENT family history must NOT lower suspicion; positive history triggers cascade testing

Mucosal neuromas + marfanoid habitus + thickened corneal nerves + alacrima = the recognizable phenotype enabling EARLY diagnosis

Infantile constipation / megacolon / feeding failure is frequently the earliest presenting clue, often before MTC

Primary MTC tumor marker — basal (± stimulated) calcitonin drives surgical urgency and surveillance

Carcinoembryonic antigen — second MTC marker; doubling time prognosticates MTC progression

Pheochromocytoma (~50%, often bilateral) MUST be excluded and treated BEFORE any thyroid/adrenal surgery

Confirm ABSENCE of primary hyperparathyroidism — its presence argues against MEN2B and toward MEN2A (key distinction)

Pheochromocytoma crisis recognition + pre-operative blockade target

Thyroid US ± FNA for MTC staging; central/lateral nodal mapping pre-thyroidectomy

Adrenal cross-sectional imaging localizes pheochromocytoma before adrenalectomy

Tachycardia drives β-blocker timing (only AFTER adequate α-blockade) in pheo

* = hard-required. Engine cannot meaningfully run until these are filled.

Severity triggers (6)

6 need judgement
  • informationallife_threateningmetastatic_mtc_at_presentation_or_infancy
    Distant/metastatic medullary thyroid carcinoma at presentation, including in infancy/early childhood (2015 ATA Wells)
    Trigger could not be auto-evaluated — needs clinician judgement.
  • informationallife_threateningunprepared_pheo_crisis
    Hypertensive / catecholamine crisis from undiagnosed or unblocked pheochromocytoma in a MEN2B patient (2015 ATA Wells; Endocrine Society 2014)
    Trigger could not be auto-evaluated — needs clinician judgement.
  • informationallife_threateningbeta_before_alpha_misuse_in_pheo
    β-blocker started before adequate α-blockade in MEN2B-associated pheochromocytoma (2015 ATA Wells; Endocrine Society 2014)
    Trigger could not be auto-evaluated — needs clinician judgement.
  • informationalseveredelayed_diagnosis_phenotype_missed
    MEN2B phenotype (mucosal neuromas / marfanoid / infantile GI ganglioneuromatosis) present but RET testing/thyroidectomy not yet done in a child (2015 ATA Wells)
    Trigger could not be auto-evaluated — needs clinician judgement.
  • informationalsevereinfant_feeding_failure_or_obstructive_megacolon
    Infantile feeding failure / failure to thrive or obstructive megacolon from intestinal ganglioneuromatosis (2015 ATA Wells)
    Trigger could not be auto-evaluated — needs clinician judgement.
  • informationalsevererising_calcitonin_short_doubling_time
    Post-thyroidectomy biochemical persistence/recurrence — calcitonin/CEA rising with short doubling time (2015 ATA Wells)
    Trigger could not be auto-evaluated — needs clinician judgement.

Workflow calculators

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RISK_STRATIFICATIONoptionalDrives severity classification
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Recommended regimen

MEN2B sequenced pathway — phenotype/RET → pheo FIRST (α then β) → prophylactic total thyroidectomy in first year of life → metastatic MTC RET inhibitor → GI supportive → surveillance
axis: men2b_sequenced_pathwaystep 1 - Step 1 — Phenotype recognition + RET testing + counseling
Selected step "Step 1 — Phenotype recognition + RET testing + counseling" — Mucosal neuromas / marfanoid / infantile GI ganglioneuromatosis OR RET M918T carrier OR MEN2B family
  • RET germline sequencing (codon 918 M918T) + genetic counseling
    first line
    genetic_testing
    triggers: men2b_phenotype, first_degree_relative_men2b
    2015 ATA Wells — M918T (~95% of MEN2B) defines ATA HIGHEST risk; counsel that ~50% are de novo (paternal origin) so absent family history does NOT exclude
  • cascade RET testing of first-degree relatives
    add on
    genetic_testing
    triggers: proband_ret_m918t_positive
    2015 ATA Wells — autosomal dominant; test at-risk relatives to identify carriers needing prophylactic thyroidectomy

outpatient playbook — drug actions (4)

  1. 1. RET test + genetic counseling
    n/a • lab • once
    trigger: Phenotype or family history (2015 ATA Wells)
    M918T = ATA HIGHEST risk; counsel ~50% de novo (2015 ATA Wells)
  2. 2. metanephrine screen
    n/a • lab • before surgery + annual
    trigger: Before ANY surgery (2015 ATA Wells)
    Exclude pheo FIRST (2015 ATA Wells)
  3. 3. phenoxybenzamine if pheo confirmed
    10 mg BID titrate • PO • BID 10–14 d preop
    trigger: Pheo positive (2015 ATA Wells)
    α before β (Endocrine Society 2014)
  4. 4. levothyroxine after thyroidectomy
    weight-based • PO • daily
    trigger: Post total thyroidectomy (2015 ATA Wells)
    Lifelong replacement (2015 ATA Wells)

Auto-drafted A&P note

outpatient

Subjective

- Possible entry pathways: Mucosal neuromas ("bumpy lip"/tongue/eyelid) + marfanoid habitus in a child (2015 ATA Wells); Infantile chronic constipation / megacolon / feeding failure — intestinal ganglioneuromatosis (often earliest clue) (2015 ATA Wells); Elevated calcitonin / CEA or thyroid nodule = medullary thyroid carcinoma (2015 ATA Wells).

Objective

- No vitals, labs, or imaging entered for this encounter.

Assessment

**Multiple endocrine neoplasia type 2B (MEN2B)** (endo.men2b.core.v1).
Phenotype framing: MEN2B vs MEN2A (PHPT + cutaneous lichen amyloidosis / Hirschsprung-associated RET) vs isolated FMTC vs marfanoid connective-tissue mimic (Marfan/MEN1 habitus differential — Marfan has NO mucosal neuromas, normal calcitonin)
Scope: Frame MEN2B as ATA HIGHEST-risk RET syndrome — most aggressive earliest-onset MTC + pheo (~50%) WITHOUT primary hyperparathyroidism; phenotype recognition in a child is the determinant of MTC outcome

No severity triggers fired against current inputs.

Plan

Regimen axis: **MEN2B sequenced pathway — phenotype/RET → pheo FIRST (α then β) → prophylactic total thyroidectomy in first year of life → metastatic MTC RET inhibitor → GI supportive → surveillance** — step "Step 1 — Phenotype recognition + RET testing + counseling".
1. RET germline sequencing (codon 918 M918T) + genetic counseling (genetic_testing, first line) — 2015 ATA Wells — M918T (~95% of MEN2B) defines ATA HIGHEST risk; counsel that ~50% are de novo (paternal origin) so absent family history does NOT exclude
2. cascade RET testing of first-degree relatives (genetic_testing, add on) — 2015 ATA Wells — autosomal dominant; test at-risk relatives to identify carriers needing prophylactic thyroidectomy

Setting playbook (outpatient) — Recognize phenotype, confirm RET M918T, exclude pheo, plan prophylactic total thyroidectomy in the first year of life, cascade-test relatives (2015 ATA Wells)
3. RET test + genetic counseling n/a lab once — Phenotype or family history (2015 ATA Wells) (M918T = ATA HIGHEST risk; counsel ~50% de novo (2015 ATA Wells))
4. metanephrine screen n/a lab before surgery + annual — Before ANY surgery (2015 ATA Wells) (Exclude pheo FIRST (2015 ATA Wells))
5. phenoxybenzamine if pheo confirmed 10 mg BID titrate PO BID 10–14 d preop — Pheo positive (2015 ATA Wells) (α before β (Endocrine Society 2014))
6. levothyroxine after thyroidectomy weight-based PO daily — Post total thyroidectomy (2015 ATA Wells) (Lifelong replacement (2015 ATA Wells))

Non-pharmacologic actions:
- Refer pediatric endocrine surgery for prophylactic total thyroidectomy in the first year of life (2015 ATA Wells)
- Cascade RET testing of first-degree relatives (2015 ATA Wells)
- Pediatric GI referral for ganglioneuromatosis / feeding support (2015 ATA Wells)
- Reproductive counseling — autosomal dominant, PGT/prenatal options

AVOID / contraindication checks:
- Beta blocker NEVER before alpha in pheo (2015 ATA Wells; Endocrine Society 2014)
- No thyroidectomy before pheo excluded and treated (2015 ATA Wells)
- Delaying prophylactic thyroidectomy beyond infancy worsens MTC outcome (2015 ATA Wells)
- Selective RET inhibitor QTc LFT BP monitoring (LIBRETTO 001; ARROW)
- No routine parathyroid resection MEN2B has no primary hyperparathyroidism (2015 ATA Wells)

Monitoring

Regimen monitoring:
- annual calcitonin + CEA with doubling-time tracking (2015 ATA Wells)
- annual fractionated metanephrines for pheochromocytoma (2015 ATA Wells)
- calcium + PTH post-thyroidectomy for surgical hypoparathyroidism (2015 ATA Wells)
- TSH on levothyroxine to age-appropriate target (2015 ATA Wells)
- QTc + LFTs + BP on selpercatinib / pralsetinib (LIBRETTO-001; ARROW)
- pediatric GI follow-up for ganglioneuromatosis (2015 ATA Wells)

Setting (outpatient) monitoring:
- Annual calcitonin + CEA (doubling time) (2015 ATA Wells)
- Annual metanephrines (2015 ATA Wells)
- TSH on levothyroxine; calcium/PTH post-op (2015 ATA Wells)

Follow-up plan: Lifelong endocrine/oncology/genetics; cascade RET testing of at-risk relatives (counsel ~50% de novo); annual calcitonin/CEA/metanephrines; GI follow-up for ganglioneuromatosis; reproductive counseling (autosomal dominant, prenatal/PGT options)
- Close-out criterion: Lifelong surveillance + cascade testing + counseling scheduled

Monitoring phase: Post-thyroidectomy: calcitonin/CEA + lifelong levothyroxine + calcium/PTH for surgical hypoparathyroidism; annual metanephrines for pheo; serial RET-inhibitor toxicity (QTc, LFTs, BP) if on selpercatinib/pralsetinib

Disposition

Current setting: outpatient — Recognize phenotype, confirm RET M918T, exclude pheo, plan prophylactic total thyroidectomy in the first year of life, cascade-test relatives (2015 ATA Wells)

Disposition criteria:
- Continue outpatient if asymptomatic carrier with surveillance + surgery scheduled (2015 ATA Wells)

Escalation triggers (move to higher acuity):
- Pheo crisis / resistant HTN → ED + admit (2015 ATA Wells)
- Metastatic MTC / rapidly rising calcitonin → oncology + admit (LIBRETTO-001)
- Infant feeding failure / obstructive megacolon → admit (2015 ATA Wells)

Earlier-Return Triggers

Return-precaution thresholds (watch for):
- [LIFE_THREATENING] Distant/metastatic medullary thyroid carcinoma at presentation, including in infancy/early childhood (2015 ATA Wells)
- [LIFE_THREATENING] Hypertensive / catecholamine crisis from undiagnosed or unblocked pheochromocytoma in a MEN2B patient (2015 ATA Wells; Endocrine Society 2014)
- [LIFE_THREATENING] β-blocker started before adequate α-blockade in MEN2B-associated pheochromocytoma (2015 ATA Wells; Endocrine Society 2014)

Citations

- 2015 revised ATA Medullary Thyroid Carcinoma Guidelines (Wells); 2021-2025 MEN2B/RET updates (LIBRETTO-001 selpercatinib; ARROW pralsetinib) [PMID:25810047](https://pubmed.ncbi.nlm.nih.gov/25810047/)
- Cited evidence (PMID 32846061) [PMID:32846061](https://pubmed.ncbi.nlm.nih.gov/32846061/)
- Cited evidence (PMID 34118198) [PMID:34118198](https://pubmed.ncbi.nlm.nih.gov/34118198/)
- Cited evidence (PMID 22025146) [PMID:22025146](https://pubmed.ncbi.nlm.nih.gov/22025146/)

Last reconciled with current guidelines: 2026-05-22.
References
  • 2015 revised ATA Medullary Thyroid Carcinoma Guidelines (Wells); 2021-2025 MEN2B/RET updates (LIBRETTO-001 selpercatinib; ARROW pralsetinib) — PMID:25810047
  • Cited evidence (PMID 32846061) — PMID:32846061
  • Cited evidence (PMID 34118198) — PMID:34118198
  • Cited evidence (PMID 22025146) — PMID:22025146