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Multiple Endocrine Neoplasia Type 1 (MEN1) is an inherited endocrine tumor predisposition syndrome. The prevalence is estimated at 1 in 20,000 to 1 in 40,000 and is therefore considered a rare disease (). The syndrome predisposes mutation carriers to develop several endocrine tumors () with a high lifetime incidence of primary hyperparathyroidism (pHPT), pituitary adenomas (PA), and neuroendocrine tumors (NETs) of the pancreas (PanNET) and duodenum (dNET) (). These tumors are considered the cardinal manifestations of the syndrome. Besides these major manifestations, patients with MEN1 are at a higher risk for developing NETs of the thymus, lungs, and stomach. In addition, there is a higher risk for adrenal tumors and a moderate risk for developing breast cancer in women (,). Next to these endocrine manifestations, patients are at risk for developing several non-endocrine lesions of the skin and subcutaneous tumors such as lipomas.

After identification of the causative MEN1 pathogenic variant an intensive lifelong surveillance program follows, preferably starting at childhood because of the high life-time risk for developing tumors (). This follow-up is aimed at early detection of tumors to enable timely interventions in order to prevent complications and metastases of tumors and thereby preventing premature death and improving the quality of the life of patients. In 2001 the first set of clinical practice guidelines was published by Brandi et al. (). Because of paucity of scientific evidence, these guidelines were mainly based on expert opinion. Although more evidence was available, the updated clinical guidelines of Thakker, et al. which were published in 2012 were also written in the absence of robust scientific evidence (). However, publishing the clinical practice guidelines led to more structured care of patients, which facilitated studies of the natural course of the disease and the effect of follow-up and treatment strategies. Therefore, in the last two decades large and sometimes nation-wide MEN1 cohort studies have been initiated which led to new insights into the course of the disease and knowledge about more optimal follow-up and treatment. In 2025 a consensus statement was published by Brandi et al. applying the Delphi method (in a panel of representatives of 22 countries) to address gaps and controversies in screening and surveillance practices for MEN1 and developed an additional 52 clinical recommendations to guide clinicians and patients about approaches for MEN1 management in adults and children ().

The MEN1 gene (OMIM 613733 (gene) and OMIM 131100 (phenotype) ), identified in 1997 (,), consists of 10 exons and is localized on chromosome 11q13. Exon 1, the 5’ region upstream of exon 2 and the 3’ region of exon 10 are non-coding, so there are 9 coding exons (exons 2 through 10). The MEN1 gen encodes the protein menin, a 610 amino-acid nuclear scaffold protein that regulates gene transcription by coordinating chromatin remodeling.

In 2008, Lemos and Thakker published an overview of the 459 different germline mutations reported in the first decade since the discovery of the gene (). In 2016, Concolino et al. identified an additional 208 novel germline variants, of which 76 were reported as Variant of Unknown Significance (VUS) (). Around 40% of all identified variants are frameshift, 25% nonsense, 20% missense, 10% splice-site and the remainder 5% are rarer such as in-frame deletions/insertions and partial or whole gene deletions (). Frameshift, nonsense, and splice-site (L)PVs, which are the majority, predict a loss of function effect that leads to truncated forms of menin (). The variants are scattered throughout the MEN1 gene with no evident hotspots, although some variants are found in apparently unrelated families (). Sequence analysis of the MEN1 gene will reveal most of the (L)PVs. In current practice testing when the diagnosis is suspected will be using the Next Generation Sequencing technique (Whole Exome or Genome sequencing and a panel of genes will be screened). Testing for a known (Likely) Pathogenic variant will usually be by a direct test and Sanger sequencing, although increasingly also for these tests NGS techniques are applied. Since 1-2% of the variants are (partial) deletions of the MEN1 gene (), multiplex ligation-dependent probe amplification (MLPA) or Copy Number Variation (CNV) analysis should also be included in the diagnostic DNA testing ().

Variants in the MEN1 gene found in the diagnostic DNA-laboratory are classified according to the ACMG classification system which categorizes genetic variants into five categories: pathogenic (P), likely pathogenic LP, uncertain significance VUS, likely benign LB, and benign B, based on specific criteria and evidence. Usually (likely) benign variants are not reported. The reporting of a VUS can be considered if there are possibilities for research and re-classification but is not always obvious (). Especially new non-truncating (mostly missense) mutations may be difficult to classify (). The clinical diagnosis is genetically confirmed if a Likely Pathogenic Variant (LPV) or Pathogenic Variant (PV) is found in the germline. In current most applied testing techniques, intronic variants and a germline mosaicism below 10% cannot be excluded. Whole genome sequencing, RNA sequencing and somatic DNA testing can be considered for further evaluation in cases of strong suspicion like a familial clinical diagnosis. See below for differential diagnosis and genetic heterogeneity.

The approximate prevalence of MEN1 has been reported as 1 in 30,000 individuals with no apparent gender bias. MEN1 follows an autosomal dominant pattern of inheritance with >95% penetrance by age 40–50 years (). The major clinical manifestations of MEN1 are primary hyperparathyroidism (pHPT), anterior pituitary adenomas (PA), and NET of the duodenum and pancreas, the so called three P’s. If a patient is diagnosed with MEN1, he or she should be advised to undergo surveillance to detect manifestations and remain under lifelong surveillance in a center of expertise where care is provided by multidisciplinary teams (MDTs) comprising relevant specialists with experience in the diagnosis and treatment of patients with endocrine tumors (). Single center cohorts have identified certain genotypes that are associated with a more aggressive course of the disease (especially related to duodenopancreatic NETs), such as (L)PV in the JUND () or the CHES1 interacting domain () or nonsense/frameshift versus missense variants (), but since none of these associations have been independently validated, genotype cannot be used to individualize surveillance.

Evaluation of 10 Dutch families suggest genetic anticipation (decreased age of disease onset or an increased disease severity in successive generations), a known phenomenon which to date cannot be explained in autosomal dominant inherited disease genes without trinucleotide repeat expansions (“growing genes”) (). Somatic mosaicism with subsequent germline inheritance has been described ().

MEN1 is considered to act as a tumor suppressor gene which is demonstrated by the identification of inactivating mutations, together with loss of heterozygosity (LOH) in MEN1-related tumors. Biochemical, proteomics, genetics, and genomicsapproaches have identified various potential roles, which converge on the regulation of gene expression. Immunohistochemical staining techniques can be used to evaluate the presence of menin protein expression in a tumor, especially a parathyroid adenoma (). The most consistent findings show that menin connects transcription factors including JUND (OMIM 165162 ), NFKB (OMIM 164011 ), and SMAD3 (OMIM 603109 ) and modulates their activities. In the nucleus, menin acts as a scaffold protein to regulate gene transcription by coordinating chromatin remodeling interacting with chromatin regulatory proteins in the MLL1 /MLL2 complex. Menin is implicated in both histone deacetylase and histone methyltransferase activity (HMT), and via the latter it regulates the expression of cyclin-dependent kinase inhibitor (CDKI) and homeobox domain genes (,). While the MEN1 gene functions as a tumor suppressor gene in MEN1, it has an oncogenic role in sporadic breast cancer cells (). Some excellent reviews on the function of the MEN1 gene can be found elsewhere (,,).

Loss of menin in MEN1-associated tissues leads to the disruption of anti-proliferative gene expression programs and to the development of endocrine tumors. Restoration of the epigenetic perturbations or correction of the function of aberrantly expressed genes in the absence of menin hold promise for molecular mechanism-based means to treat or prevent MEN1-related tumors. The fate and function of a cell are determined by its gene expression signature. As menin is a transcriptional regulator, MEN1-related tumorigenesis is likely to be the result of aberrant tumor suppressive gene expression due to the loss of menin. Restoration of the expression of menin target genes in MEN1-affected tissues could therefore have therapeutic consequences. This has been shown in a preclinical study in mice, where MEN1 replacement in pituitary tumors of MEN1 (+/-) mice led to a decrease in proliferation of the pituitary tumors ().

Patients with MEN1 are at risk to develop different endocrine and non-endocrine manifestations. The most important of which are (with approximate lifetime prevalence in parentheses) (, ): Major: Parathyroid hyperplasia, adenomas (>95%). Major: Duodenopancreatic neuroendocrine neoplasias (80%). Miscellaneous: angiofibromas/collegenomas (>50%), lipomas (often), breast cancer 20-30%, meningiomas <10%.

Presently, MEN1 can be diagnosed genetically by identifying the germline heterozygous (likely) pathogenic variant in the MEN1 gene through DNA analysis. According to the guidelines, a diagnosis of MEN1 can also be made on familial grounds in a patient with one of the cardinal MEN1 manifestations and a first-degree family member with MEN1 (). Additionally, a clinical diagnosis can be made in individuals with two of the three major manifestations (). However, with modern-day sensitive DNA testing, the value of the clinical criterion in patients with negative DNA testing is under debate. There is mounting evidence that patients who have clinical MEN1, but negative DNA testing have a different clinical course from patients with positive DNA testing (, ). The same could also be argued for patients with a familial diagnosis with negative DNA testing for the family mutation, as these may have a sporadically occurring endocrine tumor. This subject is discussed in more detail in the paragraph on genetic heterogeneity.

Patients with MEN1 suffer from high morbidity and a decreased life expectancy. In the present day and age, MEN1-related malignancy is the main MEN1-related cause of death, particularly due to duodenopancreatic and thymic NETs (, ). A timely and accurate diagnosis of MEN1 is paramount to improving disease outcomes. This enables early identification of tumor manifestations allowing timely treatment to reduce morbidity and improve survival ().

It is therefore important for clinicians to consider the diagnosis of MEN1 not only in those patients meeting clinical or familial criteria, but also in patients with a suspicious family or personal medical history but not meeting clinical or familial diagnostic criteria. In patients presenting with an endocrine tumor within the MEN1 spectrum, taking a family history of MEN1-related tumors is very important. Additionally, a young age at presentation or multifocality of tumors within a single organ may point to a diagnosis of MEN1. The combination of a major and minor criterion or two minor criteria should also raise suspicion of MEN1. In all these cases of suspected MEN1, the patient should be referred to a clinical geneticist or genetic counselor for counseling and consideration of DNA testing. For patients presenting with sporadically occurring endocrine tumors, de Laat, et al. developed and validated a prediction rule to predict the presence of an MEN1 (L)PV (). In this model, recurrent pHPT, non-recurrent pHPT, dpNETs, PA, NET of the stomach, lung and thymus, a positive family history for a NET and age, predicted the risk of having MEN1. The authors developed a nonogram for clinical practice, allowing the clinician to calculate the risk of MEN1 in patients suspected of MEN1 with sporadically occurring endocrine tumors ().

According to current practice guidelines diagnostic DNA testing for MEN1 should be offered to (): all patients fulfilling the diagnostic criteria of a clinical or familial MEN1 diagnosis. all patients with a pHPT under the age of 30 or multiple (synchronous) parathyroid adenomas under the age of 40 or recurrent parathyroid adenomas. patients with a gastrin-producing NET (irrespective the age of presentation). patients with an apparently solitary PanNET under the age of 40 or multiple PanNETs (patients with two different minor criteria). a patient with an MEN1-related tumor with a positive family history of MEN1-related tumors. Cascade presymptomatic testing in unaffected individuals in families with a (L)PV in the MEN1 gene (special procedures for children).

Data from the DutchMEN Study Group (DMSG) emphasizes the importance of timely genetic testing of family members and prompt clinical screening according to MEN1 guidelines. In a study determining lag time between MEN1 diagnosis in index cases and their non-index family members, they found a median lag time of 3.5 years (range 0-30) years, in which clinically significant manifestations occurred in the non-index family members with MEN1 (). Genetic testing in asymptomatic family members of MEN1 patients is called pre-symptomatic or predictive genetic testing and involves testing the at-risk family members for the familial MEN1 mutation. This is single-site testing, and outcome is whether the family (L)PV is present or absent in this particular family member.

Some studies have reported that between 5% and 10% of patients who fulfill the clinical criteria for MEN1 will not harbor (L)PVs in the coding region or adjacent splice sites. In some of these patients a ((L)PV can be found in the CDKN1A (OMIM 600778 ), CDKN1B (OMIM 116899 ), CDKN2B (OMIM 600431 ) or CDKN2C gene (OMIM 603369 ). (L)PVs in CDKN1B are the cause of the MEN4 syndrome, the latest of the MEN syndromes and most rare, with <50 cases reported in the literature to date (-). Rather than being a separate phenotype, (L)PVs in these genes are more likely to cause a MEN1 phenotype, with pHPT, PA and gastroenteropancreatic NETs as the main features, and are best met with the same guidelines for surveillance, until more is known about the phenotype of this rare syndrome. Recent data have shown that patients with a clinical diagnosis of MEN1, in whom no (likely) pathogenic variant in the MEN1 gene can be found (genotype-negative MEN1/GN-MEN1), and who do not have another known germline mutation, have a different phenotype and clinical course compared to mutation positive patients (, ). Genotype-negative patients develop MEN1 manifestations at higher age, rarely develop a third main MEN1 manifestation, and have a life expectancy comparable with the general population.

Additionally, regarding the individual manifestations, it seems that GN-MEN1 patients have less recurrent or multigland pHPT, less multifocal PanNETs, and more somatotrophinomas and less prolactinomas compared to genotype-positive patients (). Most patients with GN-MEN1 present with the combination of pHPT and PA, followed by pHPT/dpNET and dpNET/PA (). The apparent differences in clinical course suggest that GN-MEN1 patients do not have true MEN1, but another MEN1-like syndrome or sporadic co-incidence of two NETs. In these patients there is usually a negative family history for MEN1-related disease. Although not specified in the current guidelines, these patients may benefit from a separate classification with alternative surveillance recommendations based on the clinical picture, as has been suggested by Pieterman, et al. (). Important baseline considerations for an alternative surveillance are genetic counseling, comprehensive genetic testing based on the personal and family history, and baseline screening to identify any unrecognized manifestations. In these patients, there is generally no cause for surveillance of the first-degree relatives, although these decisions should be individualized and discussed in multidisciplinary teams.

GN-MEN1 patients with a positive family history of clinical MEN1 or a foregut NET and those presenting with all three main MEN1-related tumors, should be followed according to MEN1 guidelines as should their relatives. In these patients, a “false-negative result” of DNA testing should also be considered. This may either be because deletion/duplication analyses are not performed, a sequence variant exists outside of the assayed region, or polymerase chain reaction primer selection led to selective amplification of wild-type DNA (). Additionally, somatic mosaicism or alternative mechanisms of MEN1 gene silencing could lead to inactivation of normal menin (). Depending on the presenting clinical picture and the family history, other hereditary syndromes causing endocrine tumors should also be considered. If pHPT is the primary phenotype, other genes associated with hereditary pHPT are for example CDC73, CASR (AP2S1, GNA11 and RET (MEN2). Germline CDC73 (formerly HRPT2) analysis is recommended in individuals with (suspected) Hyperparathyroidism-Jaw Tumor (HPT-JT) syndrome, familial isolated pHPT, atypical or malignant parathyroid histology, and young individuals with pHPT. These criteria would increase germline CDC73 mutation detection, enabling optimal clinical management of pHPT as well as genetic counseling and surveillance for family members at risk for developing CDC73) ().

If PAs are the primary phenotype, mutations in the AIP gene (OMIM 605555 ) should be considered as these can cause (familial) pituitary adenomas. Predictors of a genetic cause of sporadic pituitary adenomas are young age of diagnosis, and also in AIP pathogenic variants there is an association with gigantism and macroadenomas (). PanNETs can also be seen in neurofibromatosis type 1 (NF1), Von Hippel-Lindau (VHL), and Tuberous Sclerosis Complex (TSC).

Before DNA testing, pretest counseling is of utmost importance. The patient should be informed by genetic counseling about all aspects (medical, psychological, social, and familial implications) of the possible outcome of genetic testing. This should lead to an individual decision whether or not to opt for DNA testing. In case of DNA testing in minors the counseling should be offered to the parents and include the minor if possible (which is obligatory over the age of 12 in the country where the authors practice (the Netherlands) to obtain informed consent for testing. In case of diagnostic testing the patient must be informed about the possible outcomes of the DNA test (finding a (L)PV finding a VUS and not finding (L)PVs) and the implications of these findings for the patient and family members.

In diagnostic DNA testing the MEN1 gene should be analyzed, for which Sanger sequencing can be used, or Next Generation Sequencing (NGS) techniques. To exclude deletions MLPA or CNV analysis must be performed. As mentioned earlier there is genetic heterogeneity and panel DNA diagnostics can be considered. In particular CDKN1A, CDKN1B, CDKN2B, CDKN2C, CDC73 , R ET, CaSR, AP2S1, GNA11 and AIP can be added to the panel using NGS techniques, also to be completed with CNV analysis, depending on the clinical picture. In case of panel testing, the patient must be prepared for the possible findings in the different genes, differentiation of the consequences, and implications of these findings. In case of testing for a familial (likely) pathogenic variant (so-called presymptomatic or predictive DNA testing) presence or absence of the familial mutation can be ascertained, but the differences in expression of the MEN1 syndrome, both within and between families must be emphasized. Also, the social consequences should be explained. In case of future pregnancy, the reproductive options like invasive prenatal diagnostics and Preimplantation Genetic TestingT(PGT should be discussed so the prospective parents can make an informed decision about the desired pregnancy.

The identification of an MEN1 mutation in patients and family members at risk is followed by the advice to remain under lifelong surveillance, with at least annual clinic visits including history, physical examination, biochemical screening, and radiological screening at specific intervals (). This should preferably be carried out in centers of expertise with a dedicated multidisciplinary team well versed in management of patients with MEN1. In MEN1 there are no prophylactic treatments, so the goal of this screening and surveillance program is early detection of MEN1-related tumors to minimize morbidity by hormonal hypersecretion and to prevent malignant NETs by timely intervention. In the absence of known genotype-phenotype correlations and with a heterogeneous clinical course, even within families, the specific mutation or family history cannot solely guide the surveillance program. In the following sections screening and surveillance are discussed within each manifestation.

The current clinical guidelines for MEN1 suggest a first contact of the parents with the (specialized) child-endocrinologist, preferably a member of the expertise center, at the age of 5 years. In shared decision a starting age can be agreed, not later than the age of 10 to start clinical and biochemical screening (of parathyroids and pituitary) every 1-3 years (). Screening of gastrin is not recommended at pediatric age. The earliest reported case of a patient with a clinical MEN1 manifestation is 5 years of age (). For radiologic screening in asymptomatic children, pituitary imaging is suggested from age 15 years onward (every 3-5 years), and abdominal imaging starting at age 10 years (every 1-3 years) and thoracic imaging starting at age 20-25 years (every 1-3years) ().

Primary hyperparathyroidism (pHPT) () is one of the cardinal manifestations of MEN1 and has an almost complete lifetime penetrance (,). It is often the first clinical manifestation of the disease and biochemical (asymptomatic) pHPT can be diagnosed several years before symptoms arise. The reported mean age of pHPT diagnosis in published MEN1 cohorts is in the fourth decade of life (–), with wide ranges. When interpreting these mean ages at diagnosis it is important to realize that these cohorts often span multiple decades, are made up of both index cases and family members and contain patients who did and did not follow prospective screening programs. Although primary hyperparathyroidism can be detected biochemically at a young age in patients with MEN1, its management in children and adolescents requires particular caution. While screening studies have shown that a substantial proportion of pediatric MEN1 patients develop biochemical evidence of pHPT, clinically relevant disease is rarely observed before the age of 10 years (–). In this age group, pHPT is most often mild and asymptomatic at diagnosis, and the long-term consequences of early surgical intervention must be carefully weighed against the risk of early end-organ damage. In contrast to sporadic pHPT, MEN1-related disease is inevitably multiglandular and recurrent, implying that surgery at a young age is likely to be followed by one or more reoperations later in life. Moreover, parathyroidectomy in children and adolescents carries a substantial risk of transient or prolonged hypoparathyroidism, which may have significant implications for growth, bone health, and quality of life. Therefore, current expert consensus recommends an individualized approach to the management of pediatric MEN1-related pHPT, preferably in centers of expertise, taking into account biochemical severity, evidence of skeletal or renal involvement, coexisting MEN1 manifestations, and patient- and family-specific factors. In asymptomatic children without target organ complications, careful observation with structured follow-up may be an appropriate initial strategy ().

Primary hyperparathyroidism in MEN1 is a multiglandular disease, affecting all parathyroid glands, although often asymmetrically and asynchronously. Parathyroid tumors in adults with MEN1 usually represent mono- or oligoclonal proliferations that probably arise independently in each parathyroid gland (). Tumorigenesis is initiated when the remaining normal allele of the MEN1 gene is lost (the second hit), and as this cumulative chance increases with age, normal parathyroid tissue is less often seen with increasing age (). Supernumerary glands (that is, more than four parathyroid glands) are frequently seen in MEN1, with reported ranges between 12-30% (). Parathyroid glands at ectopic locations are also not uncommon in MEN1, especially in the thymus.

The diagnosis of primary hyperparathyroidism can be made when there is hypercalcemia in combination with an elevated or inadequately normal parathyroid hormone (PTH). In patients with MEN1 who follow a prospective screening program from an early age, according to the new guidelines from the age of 10 years, the diagnosis is often made while they are still asymptomatic. Classic objective symptoms of pHPT include polyuria and polydipsia, gastro-intestinal complaints (nausea, abdominal pain, constipation, pancreatitis), (symptomatic) urolithiasis, and decreased bone mineral density (BMD) which can lead to pathological fractures. Non-specific symptoms occurring in pHPT are fatigue, musculoskeletal complaints, neuropsychiatric symptoms such as anxiety, depression, concentration disturbance and sleep-disturbances, and a general decrease in quality of life.

The diagnosis of pHPT in patients with known MEN1 or from a known MEN1 kindred is straightforward. However, pHPT can also be the first clinical clue to an MEN1 diagnosis in a patient or family without prior MEN1 diagnosis or suspected history. The prevalence of pHPT in the general population can be up to 1% (,) and a genetic basis for PHPT occurs in about 10% of all patients with pHPT (,). Considering MEN1 in patients presenting with pHPT is extremely important, because the diagnosis alters the management and prognosis of pHPT, allows screening and surveillance for other endocrine tumors associated with MEN1, and allows for cascade screening within the family to identify MEN1 germline mutations carriers. Important clues to an MEN1 diagnosis in a patient presenting with pHPT are age of onset <30 years, a family history of pHPT or other MEN1-related tumors, a personal history of other MEN1-related tumors, and multiglandular disease or persistent/recurrent pHPT (). Menin immunochemistry can be of added value for diagnosing MEN1 syndrome. Menin loss, particularly if present in multiple parathyroid tumors, is a strong indicator of an underlying MEN1 syndrome. In addition, menin immunohistochemistry can serve as a supplementary pathologic tool for patients with inconclusive genetic testing (). Recurrent pHPT is one of the strongest predictors for the presence of an MEN1 mutation (). Compared to sporadic pHPT, patients with MEN1-related pHPT present at an earlier age, have an almost equal gender distribution compared to female predominance in sporadic pHPT, and present with lower levels of calcium and PTH (,). Even though they have biochemically milder disease, BMD seems to be lower in patients with MEN1-related pHPT and renal involvement similar compared to patient with sporadic pHPT, which may reflect longer standing disease (). MEN1-related pHPT is a multiglandular disease, as already stipulated, while sporadic pHPT is predominantly caused by single-gland adenomas. This also affects recurrence rates which are much higher in MEN1-related pHPT (,). The American Association of Endocrine Surgeons (AAES) guidelines advise genetic counseling for patients younger than 40 years with pHPT and multiglandular disease and to consider this for those with a family history or syndromic manifestations (). The European guidelines slightly differ suggesting genetic testing for MEN1 in patients with pHPT before the age of 40, multiglandular disease, or persistent/recurrent pHPT ().

When comparing, several studies show that patients with MEN1-related pHPT have lower BMD compared to patients with sporadic pHPT (,55,57,61,62), although a Chinese study found no significant difference (). In patients with MEN1-related pHPT, decreased BMD is frequently seen and already present at a young age (–). When measured the 1/3 distal radius seems most affected, so including this location in dual-energy X-ray absorptiometry (DEXA) should be considered in patients with MEN1 (,). Parathyroidectomy improves BMD (,), although there is some evidence that the improvement is less for patients with MEN1 compared to patients with sporadic pHPT (,). A factor contributing to the earlier and more severe bone involvement in MEN1-related pHPT may be the early-onset of the disease thereby also influencing peak bone formation. In addition, other MEN1-related diseases may also contribute to bone loss such as pituitary insufficiency caused by pituitary adenomas or their treatment, hypercortisolism (although infrequent in MEN1), and gastro-intestinal surgery ().

Urolithiasis is also frequently seen and at a young age in patients MEN1-related pHPT (,,). In addition to nephrolithiasis, MEN1 guidelines recognize chronic kidney disease as a relevant long-term complication of MEN1-related pHPT. Evaluation should include renal imaging and assessment of renal function, even in asymptomatic patients, as renal impairment may develop independently of overt stone disease (,,,). It is therefore important to perform Dual-energy X-ray absorptiometry (DEXA) to assess BMD as well as a renal ultrasound and 24-hour urine for calcium excretion to access the risk of urolithiasis in patients with MEN1 diagnosed with pHPT. And if initial observation is chosen, DEXA should be repeated every 1-2 years (,).

In patients with MEN1 and pHPT, the interplay with Zollinger-Ellison Syndrome (ZES; increased gastric acid section due to gastrinomas) is also relevant, as calcium can increase gastrin levels. In a study among 84 patients with MEN1-pHPT and ZES, successful parathyroidectomy resulted in biochemical cure of ZES without any resection of duodenal or pancreatic NETs in 20% of the patients (). In a perspective paper Hackeng and colleagues propose a parathyroid-gut axis arguing that hypercalcemia may promote the gastrin-cell hyperplasia to neoplasia sequence through the calcium-sensing receptor (). The reverse, a more severe form of pHPT among patients with MEN1-ZES has also been suggested, because in the aforementioned study of 84 patients with MEN1-pHPT and ZES, patients had a higher frequency of urolithiasis at presentation, higher serum PTH, and higher recurrences rates after initial subtotal parathyroidectomy compared to the literature ().