Confirmed germline pathogenic / likely-pathogenic variant in CDKN1B (p27/Kip1) — Multiple...

Deterministic view of the source YAML entity. Clinical authority remains with the cited source IDs and reviewer sign-off state.

ID	`RF-MEN4-CONFIRMED-CARRIER`
Type	Red flag
Status	reviewed 2026-05-20 \| pending_clinical_signoff
Diseases	`DIS-GI-NET` `DIS-PNET`
Sources	`SRC-NCCN-NET-2025`

Red Flag Origin

Definition	Confirmed germline pathogenic / likely-pathogenic variant in CDKN1B (p27/Kip1) — Multiple Endocrine Neoplasia type 4 (MEN4). Patient has had germline CDKN1B testing returned positive; the pedigree-suspicion question is settled. MEN4 is a more recently characterized (Pellegata et al. 2006) MEN1-like syndrome — autosomal dominant inheritance with overlapping but generally less penetrant tumor spectrum than classical MEN1. Tumor distribution: primary hyperparathyroidism (most common manifestation, ~80% in series), pituitary adenoma (~30-40%, often somatotrophs / corticotrophs), GEP-NET (pancreatic + duodenal + gastric — gastrinoma less common than in MEN1), adrenocortical tumors (modest), bronchial / thymic NET (rare but reported), reproductive-tract neuroendocrine tumors. MEN4 has later age-of-onset than MEN1 and less aggressive natural history in published series, but registry data are e...
Clinical direction	investigate
Category	other

Trigger Logic

{
  "any_of": [
    {
      "finding": "germline_cdkn1b_pathogenic_variant_confirmed",
      "value": true
    }
  ],
  "type": "lab_value"
}

Notes

Wave O confirmed-carrier surveillance pathway — MEN4 / CDKN1B. Fires on documented germline CDKN1B pathogenic variant positivity in an asymptomatic individual. Engine routes to PreventionPlan recommending: (a) IND-MEN4-CARRIER-SURVEILLANCE (standard) — MEN1-like multi-organ screening adapted for MEN4 lower penetrance + later onset: annual PTH + ionized Ca + prolactin + IGF-1 + chromogranin-A starting from late childhood / adolescence (age 10-15) — later than MEN1 (age 5); pituitary MRI q3-5y from age 15 (longer interval than MEN1 q3y); abdominal MRI q1-2y from age 20 for GEP-NET surveillance. (b) IND-MEN4-CARRIER-INTENSIFIED (aggressive) — standard PLUS MEN1-equivalent surveillance intervals (rather than MEN4- adjusted longer intervals) for high-risk pedigrees + intensified gastrinoma / Zollinger-Ellison surveillance + earlier-threshold parathyroidectomy decision-making. STUB pending two-Clinical-Co-Lead signoff per CHARTER §6.1 dev-mode exemption. Source-set TODO: MEN4-specific surveillance source — Pellegata et al. PNAS 2006; ENETS / ESE MEN1 / MEN4 management consensus papers; Frederiksen et al. JCEM 2019 (CDKN1B variant spectrum review) — Wave O authoring backlog new SRC entit...

Confirmed germline pathogenic / likely-pathogenic variant in CDKN1B (p27/Kip1) — Multiple...

Red Flag Origin

Trigger Logic

Notes

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Indications