The label says monitor bone growth in children. Not one paper has asked what menin does in a growth plate
also called menin chondrocyte gap · growth plate menin absence · revumenib growth plate mechanism unknown
Revumenib's label warns that young rats' thigh-bone growth plates closed early and permanently, and tells doctors to watch children's growth. Nobody has ever published a study of what menin does in the cells that make a growth plate work.
The same thing, for a scientist
A documented absence, verified rather than assumed. The REVUFORJ label reports irreversible increased femur growth-plate closure in 6-7-week-old rats dosed for 13 weeks at approximately 2x the human AUC, and instructs prescribers to monitor bone growth and development in paediatric patients [E1]. A raw eutils search on 2026-09-19 for `(menin OR Men1)[Title/Abstract] AND (growth plate OR chondrocyte OR epiphys*)[Title/Abstract]` returns **2 records**, both about acromegaly and gigantism - i.e. pituitary growth-hormone excess, not chondrocyte menin. A second search for any menin-inhibitor term with growth plate, chondrocyte, bone mass, osteoblast or puberty returns **0 records**. The only chondrocyte-adjacent datum in the entire menin literature is incidental: menin knockdown in BMP-2-treated multipotential mesenchymal cells left chondrogenic markers (Alcian blue, type IX collagen) unaffected while abolishing osteogenic commitment [E2].
The searches, so they can be re-run
Run against NCBI eutils esearch on 2026-09-19, with [Title/Abstract] tags (the PubMed MCP tool ANDs keywords and was not used):
| Query | Count |
|---|---|
menin inhibitor[Title/Abstract] | 118 |
menin[Title/Abstract] AND parathyroid[Title/Abstract] | 167 |
(menin OR Men1) AND (growth plate OR chondrocyte OR epiphys*) | 2 (both acromegaly/gigantism) |
(menin inhibitor OR menin-MLL inhibitor OR revumenib OR ziftomenib) AND (growth plate OR chondrocyte OR bone mass OR osteoblast OR puberty) | 0 |
(menin inhibitor OR MI-503 OR MI-463 OR MI-2 OR revumenib OR ziftomenib) AND (parathyroid OR PTH OR hypercalcemia) | 0 |
The first two lines are the controls: both halves of each intersection have substantial literatures, so the zeros are not a query artefact.
Why this particular hole is the worst one
Of every finding in the menin-inhibitor safety package, growth-plate closure is:
- the only one that is explicitly paediatric in the label's own instruction;
- irreversible in the animal study;
- landing on a population in which growth is already the commonest late effect, at 66% in the only infant-leukaemia-specific survivor cohort (see
concept-growth-endocrine-late-effects-infant-leukemia); - and the only one with no mechanistic literature whatsoever.
So the graph's most concrete paediatric harm is also its least understood. The closest mechanistic neighbours - menin in the osteoblast lineage, menin in cranial neural crest - are both about bone-forming and skeletal patterning cells, not about the chondrocyte column that drives longitudinal growth.
What would fill it
- Immunostain menin in a juvenile growth plate across the resting, proliferative and hypertrophic zones. One slide, one antibody, one afternoon.
- Re-read the revumenib juvenile rat study slides for zone-specific changes - the sponsor holds them and the label summary does not describe them.
- Treat primary chondrocytes or a metatarsal explant culture with revumenib across the clinically achieved concentration range and measure column height and hypertrophic differentiation.
None requires a new animal study, and the first two require no new experiment at all.
| absence verified | true |
|---|---|
| search date | 2026-09-19 |
| method | NCBI eutils esearch with [Title/Abstract] tags, not the PubMed MCP tool |
| library check | scripts/check-absence-vs-library.py --min-overlap 2 run 2026-09-19; no existing graph entry carries a growth-plate or chondrocyte menin citation |
controls
{
"menin inhibitor": 118,
"menin AND parathyroid": 167
}results — the numbers behind the chart
{
"menin/Men1 AND growth plate/chondrocyte/epiphys*": 2,
"menin inhibitor AND skeletal terms": 0,
"menin inhibitor AND parathyroid terms": 0
}- The most concrete paediatric harm in the entire menin-inhibitor package has no mechanism, no human measurement and no literature, so it cannot be predicted, monitored mechanistically or mitigated.
- Because growth-plate closure is irreversible, the beat's general reversibility argument - partial, short, competitive occupancy - does not apply to it at all.
- If the effect is secondary to the mineral axis rather than direct, then the PTH and phosphate abnormalities on the label are not merely laboratory curiosities but the proximate cause of a permanent skeletal injury.
- Is menin expressed in the growth-plate chondrocyte at all, and in which zone?
- Did the juvenile rat study record zone-specific histology, and will FDA release the review that describes it?
- Is the growth-plate finding a direct chondrocyte effect, a secondary consequence of the disturbed PTH-phosphate-calcium axis, or a systemic consequence of altered IGF-1 - none of which has been distinguished?
- E1established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.database
The REVUFORJ label reports irreversible increased femur growth-plate closure in juvenile rats at ~2x human AUC and instructs monitoring of bone growth and development in paediatric patients.
REVUFORJ (revumenib) tablets, for oral use - US Prescribing Information (SPL version 5, published 20 Feb 2026) · Syndax Pharmaceuticals, Inc. · DailyMed / FDA Structured Product Label, setid 6eb3cdbc-0e74-477d-82d6-3bb172d3f63f 2026What this evidence cannot show
Label summary only; no incidence, severity, zone-level histology or mechanism is given, and the primary study report is not public.
Evidence that argues against this (1)
- The ziftomenib label reports no growth-plate finding and states that paediatric safety and effectiveness have not been established, so the finding is currently single-compound and may be compound-specific rather than class-wide. Kura Oncology et al. 2025
- E2weak confidence 2 of 5: Preliminary, small, indirect, or not yet peer reviewed.paper
Menin knockdown in BMP-2-treated multipotential mesenchymal cells abolished osteogenic commitment but left chondrogenic markers unaffected.
Inactivation of menin, the product of the multiple endocrine neoplasia type 1 gene, inhibits the commitment of multipotential mesenchymal stem cells into the osteoblast lineage. · Sowa H, Kaji H, Canaff L, Hendy GN, Tsukamoto T, Yamaguchi T, et al. · Journal of Biological Chemistry 2003What this evidence cannot show
An incidental negative control in a 2003 osteoblast paper, in an immortalised mesenchymal line under BMP-2, not in growth-plate chondrocytes and not with a menin inhibitor; a negative in this system is very weak evidence about the growth plate.
Evidence that argues against this (1)
- Menin is required in cranial neural crest for palatogenesis and rib patterning, so menin clearly does have skeletal developmental roles beyond the osteoblast; a null in one in-vitro chondrogenesis assay does not close the question. Engleka KA et al. 2007
Verified absence: 2 records for menin/Men1 with growth plate/chondrocyte/epiphysis (both acromegaly), 0 for any menin inhibitor with skeletal terms, against 118 for 'menin inhibitor' as a control
The reversibility argument does not reach the growth plate: closure is irreversible in the animal study, so a short reversible exposure hitting an irreversible developmental window is not reversible in the sense that entry assumes
- ← depends onHypothesis: the same drug is protective in the islet and harmful in the parathyroid and the growth plate
The skeletal arm has a toxicology finding and no mechanism; this is the weakest leg of the hypothesis and is flagged as such