Pituitary adenoma in MEN1: the third manifestation, and the one that matters most for a growing child
also called MEN1 pituitary tumour · anterior pituitary adenoma MEN1
About a third of people with a faulty menin gene grow a tumour in the pituitary, the gland at the base of the brain that controls growth and puberty. It was the first sign of disease in a third of patients whose MEN1 began before they turned 21.
The same thing, for a scientist
Pituitary tumours occurred in 32% of 258 systematically screened MEN1 carriers with a maximum age-related penetrance of about 40%, third behind parathyroid and enteropancreatic disease [E1]. In the GTE cohort of 160 patients with MEN1 before 21, pituitary adenoma was among the first symptoms in 55 (34%) and 9 (16% of those with an adenoma) were operated before 21 [E2]. This manifestation carries disproportionate weight for a child treated with a menin inhibitor because the anterior pituitary is the control node for growth hormone and gonadotrophins, and growth is already the commonest late effect in infant-leukaemia survivors, affecting 66% in the only infant-specific series - see `concept-growth-endocrine-late-effects-infant-leukemia`. A pituitary hit on top of that baseline would be additive in a domain that is already the most damaged one.
The numbers
| Cohort | Pituitary involvement | Source |
|---|---|---|
| 258 German MEN1 carriers, systematic screening | 32% cumulative; ~40% maximum age-related penetrance | 1 |
| 160 GTE patients with MEN1 before age 21 | pituitary adenoma among first symptoms in 55 (34%); 9 operated before 21 | 2 |
The GTE cohort's overall conclusion applies here: MEN1 lesions occur frequently before 21 but mainly after 10 years of age, with first symptoms before 10 in 22 of 160 (14%) and before 5 in 5 (3%) 2.
Why the pituitary is the axis to prioritise in a treated infant
A child treated for infant leukaemia already carries a heavy growth penalty from chemotherapy alone, independent of radiation. The relevant comparison is not pituitary adenoma - a tumour, which would take years - but anterior pituitary function, which is measurable in months and for which the drug has a direct mechanistic route: menin is a transcriptional cofactor in the anterior pituitary lineage, and the revumenib label independently instructs clinicians to monitor bone growth and development in pediatric patients on the basis of irreversible femoral growth-plate closure in juvenile rats 3.
The cheap tests are IGF-1, and in a child under treatment, serial height velocity and bone age. None of the three registered menin-inhibitor trials collects any of them (see concept-endocrine-endpoint-absence-menin-trial-registries).
The honest caveat: growth-plate closure in a rat is a chondrocyte finding, not a pituitary one, and the two would be distinguished by IGF-1 (low in GH deficiency, normal or high with a primary growth-plate effect). Nobody has published that measurement on drug.
Counter-argument sweep (2026-09-19): what the mouse says, and why it favours reassurance
This entry previously carried the reassuring case only in bite_back, as a plausibility argument. It now has sources, and they are stronger than the argument was.
Menin loss does not disturb pituitary development. Conditional Men1 inactivation in the mouse pituitary and endocrine pancreas leaves both tissues developing normally; prolactinomas appear only from 9 months, and menin loss alone is explicitly reported as not sufficient to initiate pituitary tumorigenesis [counter-evidence to E1]. The endpoint this entry argues matters most in a growing child - anterior pituitary function, not adenoma - is the one the model says is preserved.
Tumorigenesis needs two further things a drug does not supply. In Men1(+/-) mice, pituitary and islet tumours require CDK4: Men1(+/-);Cdk4(-/-) animals developed none, and their pituitaries showed no loss of heterozygosity at Men1, while Men1(+/-) and Men1(+/-);Cdk2(-/-) tumours did [counter-evidence to E1]. Somatic second hit plus proliferative drive. Reversible occupancy of a pocket deletes no allele and drives no cycle.
And the growth-plate warning is not a class finding. Ziftomenib's label, for an adult-only indication, carries no bone-growth, growth-plate or juvenile-animal statement and no endocrine heading at all [counter-evidence to E3]. That is explained by its indication rather than by absence of the effect, but it means the finding has never been reproduced with a second compound and should not be generalised.
Where the concern survives. None of this addresses chronic partial menin inhibition in a child over years, which is what FDA postmarketing requirement 4730-1 contemplates, and none of it measures pituitary hormone output under drug. The residual question is narrower than this entry originally framed it: not whether a menin inhibitor causes a pituitary adenoma - the mouse genetics say that needs LOH and CDK4 - but whether it transiently perturbs the GH/IGF-1 and prolactin axes during the years a child is growing. That is a one-assay question and remains unmeasured.
| organ | anterior pituitary |
|---|---|
| syndrome | multiple endocrine neoplasia type 1 |
| why prioritised in infants | growth is already the commonest late effect in infant-leukaemia survivors, and the revumenib label separately mandates monitoring bone growth in children |
penetrance by source
[
{
"cohort": "258 German MEN1 carriers",
"cumulative_frequency_pct": 32,
"max_age_related_penetrance_pct": 40,
"source": "E1"
},
{
"cohort": "160 GTE patients before age 21",
"first_symptom_pct": 34,
"operated_before_21_n": 9,
"source": "E2"
}
]screening tests
[ "prolactin", "IGF-1", "height velocity", "bone age", "pituitary MRI" ]
- The counter-argument at full strength, and it is now sourced: a pituitary adenoma is a clonal tumour requiring a somatic second hit and CDK4-driven proliferation (PMID 24531709), and conditional menin loss does not disturb normal pituitary development at all (PMID 15060136). The relevant drug-exposure question is pituitary *function*, not tumour formation, and no functional abnormality has been reported.
- The rat growth-plate finding is not evidence of a pituitary effect; growth-plate closure and GH deficiency are different lesions with opposite IGF-1 signatures, and nobody has measured IGF-1 on drug. It is also not a class finding: the ziftomenib label carries no bone-growth or juvenile-animal statement.
- In a child with relapsed KMT2A-rearranged leukaemia the competing risk of death is overwhelming; a possible future pituitary effect is not a reason to withhold treatment, only a reason to measure.
- Honest residual risk: the mouse genetics that make this reassuring all concern tumour initiation over 9-15 months in animals with a germline allele already lost. They say nothing about years of partial pharmacological occupancy in a growing human anterior pituitary, and prolactin and IGF-1 have never been reported on drug.
- Is the juvenile-rat growth-plate finding a chondrocyte-autonomous effect or secondary to the GH/IGF-1 axis? A single IGF-1 measurement in treated children would discriminate, and none is published.
- What fraction of MEN1 pituitary adenomas are prolactinomas, and does that subtype distribution shift with age at onset? The abstracts of both penetrance cohorts aggregate pituitary tumours without subtype.
- Does menin inhibition change prolactin in treated patients? Prolactin is a cheap assay, is abnormal in a substantial fraction of MEN1 pituitary disease, and appears in no menin-inhibitor protocol.
- Does conditional menin loss preserve anterior pituitary HORMONE OUTPUT, not just histology and development? Biondi et al. report normal development (PMID 15060136) but no hormone measurements are given in the abstract; GH, prolactin and the gonadotroph axis under menin loss have not been read back from any model in this entry.
- E1strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paper
Pituitary tumours developed in 32% of 258 systematically screened MEN1 germline mutation carriers, with maximum age-related penetrance of approximately 40%.
Age-related penetrance of endocrine tumours in multiple endocrine neoplasia type 1 (MEN1): a multicentre study of 258 gene carriers · Machens A, Schaaf L, Karges W, Frank-Raue K, Bartsch DK, Rothmund M, Schneyer U, Goretzki P, Raue F, Dralle H · Clin Endocrinol (Oxf) 67:613-22 2007What this evidence cannot show
Read as abstract. The abstract does not break pituitary tumours down by subtype (prolactinoma, somatotroph, non-functioning), and referral-centre ascertainment at mean age 43 means late-onset adenomas are under-counted.
Evidence that argues against this (2)
- The strongest counter to translating MEN1 pituitary penetrance into a paediatric drug concern comes from the mouse model, and it argues twice over for reassurance. Biondi et al. conditionally inactivated Men1 in the pituitary gland and endocrine pancreas and report that **the pituitary gland and pancreas develop normally in the conditional absence of menin** - which is exactly the 'pituitary function in a growing child' endpoint this entry says matters more than tumour formation. They further report that homozygous menin loss is sufficient to cause beta-cell hyperplasia in some islets but **is NOT sufficient to initiate pituitary tumorigenesis**, with prolactinomas appearing only from 9 months and requiring additional genetic events. So in the one system where menin has been removed from the pituitary outright, development was unaffected and menin loss alone did not make a tumour. Biondi CA et al. 2004
- Menin loss is also not the rate-limiting step. In Men1(+/-) mice, pituitary and islet tumorigenesis requires CDK4: Men1(+/-);Cdk4(-/-) mice developed NO tumours, their pituitaries and islets remained hypoplastic, and - critically - their pituitaries showed no loss of heterozygosity at the Men1 locus, whereas Men1(+/-) and Men1(+/-);Cdk2(-/-) tumours did. Pituitary tumorigenesis therefore needs a somatic second hit plus CDK4-driven proliferative drive. Reversible pharmacological occupancy of the menin pocket produces neither: it does not delete the second allele and it does not supply the proliferative signal. This is the mechanistic reason the bite_back argument in this entry is probably right, and it should be stated as sourced biology rather than as a plausibility claim. Gillam MP et al. 2015
- E2strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paper
In the GTE cohort of 160 patients with MEN1 disease before 21 years, pituitary adenoma was among the first symptoms in 55 patients (34%) and 9 underwent pituitary surgery before age 21; first symptoms occurred before 10 years in 22 patients (14%) and before 5 years in 5 (3%).
MEN1 disease occurring before 21 years old: a 160-patient cohort study from the Groupe d etude des Tumeurs Endocrines · Goudet P, Dalac A, Le Bras M, Cardot-Bauters C, Niccoli P, Levy-Bohbot N, et al., Delemer B · J Clin Endocrinol Metab 100:1568-77 2015What this evidence cannot show
Read as abstract. An early-onset-selected cohort: the 14% and 3% figures are proportions of patients who already manifested before 21, not population penetrance at those ages. No unselected cohort reports a first-decade penetrance.
Evidence that argues against this (1)
- Pituitary adenoma as a first symptom in 34% of a screened paediatric carrier cohort is inflated by the same screening effect, and pituitary microadenomas are common incidental findings in the general population on sensitive imaging. Without the imaging protocol and lesion-size threshold the proportion is not interpretable as risk. Journal of Clinical Endocrinology & Metabolism 2015
- E3established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.database
The revumenib prescribing information reports that in 6-7 week old rats treated for 13 weeks, an irreversible increase in femur growth plate closure was observed at exposures approximately 2 times the human exposure at the recommended dose, and directs clinicians to monitor bone growth and development in pediatric patients.
REVUFORJ (revumenib) tablets, for oral use - US full prescribing information (NDA 218944) · Syndax Pharmaceuticals / US FDA · DailyMed / Drugs@FDA (NDA 218944) 2025What this evidence cannot show
Read verbatim from the DailyMed full prescribing information, section 8.4 Animal Data, on 2026-09-18. This is a growth-plate (chondrocyte) finding, not a pituitary one; the label draws no inference about the GH axis. No incidence, no dose-response detail and no measurement of IGF-1 or body length is given in the label.
Evidence that argues against this (1)
- The growth-plate finding is not established as a class property and should not be carried as one. Ziftomenib (KOMZIFTI, NDA 220305, label revised 11/2025) is a second approved menin inhibitor whose prescribing information contains no statement about bone growth, growth plates or juvenile-animal toxicity, no Endocrine disorders heading, and no parathyroid, calcium, phosphate or PTH entry anywhere; its laboratory-abnormality table (N approximately 108-110) lists creatinine increased 45% and alkaline phosphatase increased 41% and nothing bone-specific. The honest reading is that ziftomenib's indication is adult-only, so juvenile animal studies and paediatric growth warnings were not required - which is itself the point: the revumenib growth-plate warning reflects that programme's paediatric development, not a demonstrated class effect, and nothing about it has been replicated with a second compound. Kura Oncology / Kyowa Kirin / US FDA 2025
third most frequent MEN1 manifestation; 32% of screened carriers, ~40% maximum age-related penetrance
a pituitary hit would be additive on a growth axis already damaged in 66% of infant-leukaemia survivors
Counter-evidence (KOMZIFTI label): no bone-growth, growth-plate or juvenile-animal statement and no endocrine heading. The revumenib growth-plate warning reflects that programme's paediatric development, not a replicated class effect.