Primary hyperparathyroidism in MEN1: the first and commonest consequence of losing menin
also called MEN1 pHPT · multiglandular parathyroid hyperplasia · MEN1 hyperparathyroidism
When a person inherits one broken copy of the menin gene, the parathyroid glands in the neck are almost always the first to go wrong, over-producing the hormone that controls blood calcium. It reaches roughly 90% of carriers by late life and it is the earliest thing that shows up.
The same thing, for a scientist
Primary hyperparathyroidism is the index manifestation of MEN1 in most carriers. In 258 German MEN1 carriers with systematic biochemical, hormonal and radiological screening, parathyroid hyperplasia and adenoma developed in 77% - roughly twice the rate of enteropancreatic (49%) and pituitary (32%) tumours and five to sevenfold the rate of adrenal cortical tumours (15%) and carcinoids (10%) - reaching a maximum age-related penetrance of about 90% [E1]. In the 160-patient French GTE cohort of MEN1 disease presenting before 21 years, hyperparathyroidism was the first symptom in 122 of 160 (75%) and the first lesion detected in 90 (56%), with 38 patients (31% of those with pHPT) operated before their 21st birthday [E2]. Crucially for a drug-exposure question, the biochemical abnormality is a raised PTH with hypercalcaemia, and it precedes any tumour that a scan could see. That is the same biochemical axis the revumenib label reports as disturbed in treated patients.
What the numbers actually are, and how they were obtained1 deeper
The Machens multicentre series is the cleanest age-penetrance source because every carrier was screened prospectively rather than presenting symptomatically. Across 258 carriers from six German tertiary centres, mean age 43 at last follow-up 1:
| Organ system | Cumulative frequency in carriers | Maximum age-related penetrance |
|---|---|---|
| Parathyroid (hyperplasia/adenoma) | 77% | ~90% |
| Enteropancreatic | 49% | ~60% |
| Pituitary | 32% | ~40% |
| Adrenal cortical | 15% | ~26% |
| Carcinoid | 10% | ~17% |
The authors stressed the heterogeneity: earliest tumour manifestation ranged from 9 to 25 years depending on tumour type, latest from 68 to 77 years, and time to first diagnosis did not vary much by whether the germline mutation was truncating or in-frame 1. Their own conclusion was that penetrance cannot be predicted individually, so lifelong follow-up is warranted.
The paediatric picture comes from the GTE cohort of 160 patients whose MEN1 disease began before 21 2. Hyperparathyroidism was the first symptom in 75%, and 38 underwent parathyroid surgery before 21. But note what that cohort is: patients ascertained because they manifested young. It bounds what early MEN1 looks like; it does not give a population penetrance at a given age.
Why this manifestation is the right one to watch in a drug-exposed child
Three properties make pHPT the sentinel:
- It is first. In both the adult screening cohort and the paediatric cohort, parathyroid involvement leads 12.
- It is biochemically visible long before it is anatomically visible. A raised intact PTH with a corrected calcium at the top of or above the reference range is the screening test; serum calcium and PTH together cost a few dollars.
- The revumenib label reports exactly this pattern. Intact PTH increased in 34% of 241 treated patients, corrected calcium increased in 15%, and hyperparathyroidism is listed among clinically relevant adverse reactions under Endocrine disorders - see
risk-revumenib-intact-pth-elevation3.
That coincidence is not proof of anything. A raised PTH in a leukaemia patient can be secondary to renal impairment (creatinine rose in 38% on the same label), to phosphate handling, or to vitamin D deficiency. But the prior probability that a menin-pocket ligand disturbs the parathyroid axis is not low, and it is the axis MEN1 hits first.
What loss of menin does in the parathyroid
MEN1 is a classical two-hit tumour suppressor syndrome: a germline inactivating allele plus a somatic second hit in the target cell. Age-related penetrance of MEN1 overall was estimated at >95% by age 30 in the French series of 220 identified gene carriers 4. So the parathyroid tissue of a carrier is menin-haploinsufficient from conception and still takes a decade or more to produce disease. That latency is the single most important quantitative fact for the drug question, and it is the subject of risk-menin-inhibitor-exposure-duration-vs-men1-latency.
| organ | parathyroid |
|---|---|
| syndrome | multiple endocrine neoplasia type 1 |
| earliest reported manifestation years | 9 |
| relevance to menin inhibitors | the axis the revumenib label reports as disturbed (intact PTH up in 34%) |
penetrance by source
[
{
"cohort": "258 German MEN1 carriers, systematic screening",
"cumulative_frequency_pct": 77,
"max_age_related_penetrance_pct": 90,
"source": "E1"
},
{
"cohort": "160 GTE patients with MEN1 before age 21",
"first_symptom_pct": 75,
"first_lesion_pct": 56,
"operated_before_21_n": 38,
"source": "E2"
}
]screening tests
[ "serum corrected calcium", "intact PTH" ]
- The counter-argument at full strength: MEN1 pHPT requires germline haploinsufficiency for a decade or more plus a somatic second hit in a parathyroid clone. Months of reversible pocket occupancy does not create a second hit, and no published case of hyperparathyroidism persisting after menin-inhibitor discontinuation exists.
- A raised PTH in a heavily pretreated leukaemia patient has many causes that have nothing to do with menin, including renal impairment, phosphate shifts and vitamin D deficiency; the label reports raised creatinine in 38% of the same population.
- If the parathyroid signal is real and reversible, it is a monitoring item, not a reason to withhold a drug that produces remissions in children who would otherwise die.
- What is the age-specific hazard of pHPT in MEN1 carriers below age 10? The GTE cohort establishes that first symptoms before 10 occur in 14% of early-onset patients, but no cohort reports a denominator-based penetrance for the first decade.
- Does the raised intact PTH seen on revumenib reflect parathyroid cell biology or renal phosphate handling? Paired PTH, corrected calcium, 25-OH vitamin D, creatinine and phosphate on the same draws would separate these and are not published.
- Is menin-dependent transcription in the parathyroid chief cell driven by the same MBM pocket that menin inhibitors occupy, or by menin functions outside the pocket? No parathyroid CUT&RUN under menin inhibition has been published.
- E1strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paper
In 258 MEN1 germline mutation carriers screened biochemically, hormonally and radiologically at six German centres, parathyroid hyperplasia and adenomas developed in 77% versus 49% for enteropancreatic and 32% for pituitary tumours, with age-related penetrance reaching approximately 90%, 60%, 40%, 26% and 17% for parathyroid, enteropancreatic, pituitary, adrenal cortical and carcinoid tumours respectively; earliest tumour manifestation ranged from 9 to 25 years.
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 (full text not retrieved). Referral-centre carriers, mean age 43 at last follow-up, so the oldest ages are under-represented and the penetrance ceiling is a projection rather than an observed lifetime frequency. Ascertainment is through families known to have MEN1. The abstract does not give confidence intervals or the exact Kaplan-Meier values at each decade.
Evidence that argues against this (1)
- The same paper undercuts any attempt to stratify risk by mutation type: time to first tumour diagnosis did not vary much by whether the MEN1 germline mutation was out-of-frame/truncating or in-frame, and the authors explicitly concluded that tumour penetrance and malignant transformation cannot be predicted individually. Any argument that a given degree of menin disruption maps predictably onto a given tumour risk therefore has no support from the human genetics. Machens A et al. 2007
- E2strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paper
Among 160 patients from the French GTE MEN1 cohort whose disease occurred before 21 years of age, hyperparathyroidism was the first symptom in 122 (75%) and the first lesion in 90 (56%); 38 patients underwent parathyroid surgery before age 21.
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. This is a cohort selected for early onset, so the proportions describe the shape of early MEN1 and not the penetrance of pHPT at a given age in unselected carriers. It is nonetheless the largest paediatric MEN1 series in existence.
Evidence that argues against this (1)
- Hyperparathyroidism being the first symptom in 75% of paediatric MEN1 carriers reflects that it is the easiest manifestation to detect biochemically on routine screening, not that the parathyroid is the most vulnerable tissue. Ordering by first detection orders by assay sensitivity. Journal of Clinical Endocrinology & Metabolism 2015
- E3established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.database
The US prescribing information for REVUFORJ (revumenib) reports intact parathyroid hormone increased in 34% and corrected calcium increased in 15% of the pooled safety population, and lists hyperparathyroidism under Endocrine disorders among clinically relevant adverse reactions occurring in less than 20% of 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 directly from the DailyMed full prescribing information on 2026-09-18; the figures and the Endocrine disorders line were confirmed verbatim in the retrieved document. Pooled safety population N=241 (207 adults, 34 children) mixing KMT2A-r and NPM1m; lab denominators varied 139-240. No grade 3-4 rate is given for PTH. The label does not attribute causality and does not report whether PTH normalised after discontinuation.
Evidence that argues against this (1)
- This is the strongest item in the beat because it is actual human drug data, and it needs the opposite correction from the rest: intact PTH increased in 34% and corrected calcium in 15% are LABORATORY abnormalities on a label, without stated clinical sequelae, baseline adjustment, or attribution. Differentiation syndrome and tumour lysis both perturb calcium independently of any parathyroid effect, and both occur in this population. The signal is real and its mechanism is not established. FDA Drugs@FDA 2024
- E4strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paper
In 220 identified MEN1 gene carriers (167 affected, 53 unaffected) from 84 families and isolated cases, age-related penetrance of MEN1 was estimated at greater than 95% by age 30, and no genotype-phenotype correlation was found.
Germ-line mutation analysis in patients with multiple endocrine neoplasia type 1 and related disorders. · Giraud S, Zhang CX, Serova-Sinilnikova O, Wautot V, Salandre J, Buisson N, et al., Calender A · Am J Hum Genet 63:455-67 1998What this evidence cannot show
Read as abstract. Penetrance here is at the syndrome level, counting any MEN1 manifestation, not pHPT specifically, and is derived from families ascertained through affected probands, which biases upward.
Evidence that argues against this (1)
- A second penetrance estimate from a second germline series does not add independent support for a pharmacological risk; it adds a second measurement of the same germline quantity. Two concordant carrier cohorts make the carrier estimate firmer and leave the extrapolation to drug exposure exactly as weak. American Journal of Human Genetics 1998
germline MEN1 haploinsufficiency plus a somatic second hit in parathyroid chief cells
- supports →The same pocket suppresses JUND: menin inhibition's unmeasured endocrine liability in infants
the parathyroid is the first and commonest MEN1 target, and is the axis the revumenib label reports as disturbed
the syndrome-level curve whose earliest events are overwhelmingly parathyroid
- ← related toIntact PTH rises in 34% of patients on revumenib, and hyperparathyroidism is on the label
the same hormonal axis that MEN1 disrupts first
- ← depends onHypothesis: the PTH rise on menin inhibitors is on-target and exposure-dependent, not renal
the parathyroid is the predicted organ because it is the first and commonest MEN1 target
Normal parathyroid physiology underlying the MEN1 manifestation: menin-dependent TGF-beta restraint of chief-cell proliferation and secretion
Parathyroid-restricted Men1 deletion is sufficient for neoplasia and hypercalcaemia; the gland is a cell-autonomous target