ABSTRACT

Multiple Endocrine Neoplasia Type 1 (MEN1) is a rare autosomal dominantly inherited endocrine tumor predisposition syndrome, caused by (likely) pathogenic variants ((L)PV) in the MEN1 gene. The three major manifestations are primary hyperparathyroidism (pHPT), pituitary adenomas (PA), and neuroendocrine tumors (NETs) of the pancreas (PanNET) and duodenum. Other manifestations are NETs of thymus, lung, and stomach, adrenal tumors, and an increased breast cancer risk in women. Malignant NETs are the most important cause of disease-related mortality, mainly non-functioning (NF), PanNETs, gastrinomas, and thymus NETs. Timely recognition of MEN1, referral for genetic testing, and subsequent cascade genetic testing is essential. In patients with a clinical diagnosis of MEN1 syndrome without a genetic confirmation, the clinical course is different and there is no reason for surveillance of family members. MEN1-related pHPT (penetrance >95%) is a multiglandular disease and recurrence after initial operation is to be expected. The initial operation recommended  by most experts and guidelines is a bilateral cervical exploration, identifying all four parathyroid glands and performing a subtotal parathyroidectomy. Prolactinomas are the most prevalent PA in MEN1, followed by non-functioning (NF) PAs. Treatment and treatment results do not differ from sporadic PAs. Life-time penetrance of duodenopancreatic NETs is >80%. NF-PanNETs are most frequent, followed by gastrinomas and insulinomas. Surgical resection is the mainstay of treatment and is indicated in (1) non-gastrinoma functional PanNETs and (2) NF-PanNETs >2cm or with progression during follow-up. No consensus exists on the surgical treatment of MEN1-related gastrinoma. MEN1- related duodenopancreatic NETs (dpNETs) are currently detected at earlier stages and more indolent small dpNETs are seen. The main challenge is to identify patients at risk for an aggressive disease course. Thymic NETs (2-8%) occur predominantly in males and have a poor prognosis. Bronchopulmonary NETs are more frequent than previously thought, occur in both sexes and are usually indolent - although cases with a deviant progressive course occur. Adrenal tumors are mostly indolent NF adenomas, but adrenocortical carcinomas and pheochromocytomas have been described. Women with MEN1 have an increased (RR 2.8) risk of breast cancer, at a younger age than the general population. Given the complexity of the disease, it is strongly advised that patients, whenever possible, be followed and treated in centers of expertise. For complete coverage of all related areas of Endocrinology, please visit our on-line FREE web-text, WWW.ENDOTEXT.ORG.

INTRODUCTION

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 (1). The syndrome predisposes mutation carriers to develop several endocrine tumors (Figure 1) with a high lifetime incidence of primary hyperparathyroidism (pHPT), pituitary adenomas (PA), and neuroendocrine tumors (NETs) of the pancreas (PanNET) and duodenum (dNET) (2). 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 (3,4). Next to these endocrine manifestations, patients are at risk for developing several non-endocrine lesions of the skin and subcutaneous tumors such as lipomas.

Figure1.

Manifestations of MEN1. NET neuroendocrine tumor. Figure created by JM de Laat.

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 (2). 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. (5). 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 (6). 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 (2).

GENETICS

The MEN1 gene (OMIM 613733 (gene) and OMIM 131100 (phenotype)), identified in 1997 (1,7), 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 (8). In 2016, Concolino et al. identified an additional 208 novel germline variants, of which 76 were reported as Variant of Unknown Significance (VUS) (9). 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 (10). Frameshift, nonsense, and splice-site (L)PVs, which are the majority, predict a loss of function effect that leads to truncated forms of menin (8). The variants are scattered throughout the MEN1 gene with no evident hotspots, although some variants are found in apparently unrelated families (11). 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 (8), multiplex ligation-dependent probe amplification (MLPA) or Copy Number Variation (CNV) analysis should also be included in the diagnostic DNA testing (2).

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 (12). Especially new non-truncating (mostly missense) mutations may be difficult to classify (13).

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.

DIAGNOSIS AND GENETIC TESTING

PRIMARY HYPERPARATHYROIDISM

Primary hyperparathyroidism (pHPT) (Figure 1) is one of the cardinal manifestations of MEN1 and has an almost complete lifetime penetrance (25,38). 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 (39–45), 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 (46–49). 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 (2).

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 (50). 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 (51). Supernumerary glands (that is, more than four parathyroid glands) are frequently seen in MEN1, with reported ranges between 12-30% (52). 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% (53,54) and a genetic basis for PHPT occurs in about 10% of all patients with pHPT (55,56). 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 (30). 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 (19). Recurrent pHPT is one of the strongest predictors for the presence of an MEN1 mutation (30). 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 (57,58). 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 (57). 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 (58,59). 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 (59). 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 (60).

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 (63). In patients with MEN1-related pHPT, decreased BMD is frequently seen and already present at a young age (64–66). 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 (64,66). Parathyroidectomy improves BMD (61,67), although there is some evidence that the improvement is less for patients with MEN1 compared to patients with sporadic pHPT (55,61). 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 (68).

Urolithiasis is also frequently seen and at a young age in patients MEN1-related pHPT (57,64,66). 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 (2,65,69,70).

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 (2,71).

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 (73). 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 (73). 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 (72).

PITUITARY ADENOMAS

Pituitary adenomas (PAs) are one of the three cardinal features associated with MEN1 and part of the so-called ‘three Ps’ (Figure 1). PAs are in general benign lesions and do not seem to negatively affect survival in patients with MEN1 (28,98), although cases of mortality due to PAs have been reported (27). However, they can cause significant morbidity due to mass effect on the optic chiasm or hormone secretion leading to functional symptoms or hormone deficiency.

As in other main manifestations of MEN1, loss of heterozygosity (LOH) at the MEN1 locus has been demonstrated in pituitary adenomas in patients with MEN1, confirming the role of MEN1 in the pathogenesis of these tumors (99–102). However, in contrast to PanNETs, the role of MEN1/menin in tumorigenesis of sporadic PAs seems to be limited. Although initially, before the identification of the MEN1 gene, 19-33% of sporadic PAs showed allelic loss on chromosome 11 (103,104), subsequent studies investigating LOH, somatic mutations, and messenger mRNA expression found limited involvement of MEN1 in sporadic PAs (105–109).

As the prevalence of clinically relevant PAs is 68-98/100,000 in the general population and in general <3% of patients with a PA will have MEN1, the question is when to think of MEN1 in a patient presenting with a PA. To complicate things further, PAs are often the (sole) first clinical manifestation of the MEN1 syndrome (9-23%) (110–114). Obviously, MEN1 should be considered in a patient with a family history of MEN1-related tumors or presenting with other MEN1-related tumors. For patients with apparently sporadic PAs (no suspicious family history or syndromic features), a systematic review has shown that MEN1 mutation analysis is recommended in patients ≤ 30 years, although this was a weak recommendation based on low quality of evidence (36).

DUODENOPANCREATIC NEUROENDOCRINE TUMORS AND GASTRIC NETs

THORACIC NEUROENDOCRINE TUMORS

ADRENAL TUMORS

Adrenal involvement (Figure 1) is frequently seen in patients with MEN1 and is considered to be part of the syndrome though not one of the cardinal manifestations. Mice with heterozygous inactivation of the Men1 gene develop adrenocortical lesions to a greater proportion than Men1 wild-type controls (234,235) and the adrenal tumors show loss of heterogeneity (LOH) and loss of menin staining. In humans with MEN1, LOH is rarely seen in benign adrenocortical tumors (236-238). It has been hypothesized that the development of adrenal tumors in MEN1 might be related to PanNETs and hyperinsulinemia, because in some cohorts an association was seen between the occurrence of PanNETs, hyperinsulinemia, and adrenal lesions. However, in the largest series to date, no difference was found in the prevalence of main MEN1 manifestations between those with and without adrenal lesions (238).

In retrospective cohorts studying adrenal involvement in MEN1 the reported prevalence greatly differs from 20-73% (237-247). Prevalence in part differs by the way adrenal lesions are defined (i.e. also including hyperplasia) and the manner of diagnosis, with prevalence being the highest (73%) in an EUS study (n=49) including all adrenal lesions from ‘plump’ adrenals to adenomas (242). In the series (n=27) with the second-highest prevalence (63%) all CT scans were re-read with the purpose of classifying adrenal lesions and every adrenocortical lesion >5 mm was considered a nodule (246). The largest series to date from the French GTE (n=715) has the lowest prevalence of 20.4% (238). Adrenal lesions are rarely the reason for an MEN1 diagnosis or the first manifestation of the disease and are most frequently diagnosed asymptomatically by screening/surveillance imaging during follow-up or at the time of initial comprehensive imaging after the diagnosis of MEN1 is made (238,244). Mean age of diagnosis is usually in the fifth decade, but ranges vary widely (238,244,245,247).

The French GTE series compared MEN1-related adrenal lesions to a cohort of sporadic incidentalomas (n=144) and found that adrenal lesions in patients with MEN1 were diagnosed at a younger age and were similar in size and in prevalence of bilateral lesions (238).

CUTANEOUS AND OTHER LESIONS

Facial angiofibromas and collagenomas are the main skin lesions in MEN1 (Figure 1) (263,264). Frequencies vary significantly since large multi-institutional studies with thorough dermatologic examination are missing but a prevalence of 85% for angiofibromas and 70% for collagenomas by the age of 40 have been described (265). Multiple angiofibromas and collagenomas are present in 77–81% of the MEN1 patients (263). Primarily angiofibromas are seen in patients with MEN1 (263,266). An odds ratio of 6.6 (95% CI, 1.09–40.43) for cutaneous lesions in MEN1 in 29 patients with MEN1 in comparison with their non- affected family members is described (266). Angiofibromas and collagenomas prevalence rates are increasing with age. In most cases, no treatment is needed, but for cosmetic reasons a dermatologist can be consulted.

These findings are further supported by the allelic loss of the MEN1 gene in six angiofibromas, three collagenomas, and one lipoma, suggesting that loss of function of the wild-type MEN1 gene product plays a role in the development of these skin lesions in patients with MEN1 (267). Melanomas and other skin lesions are also described in the MEN1 population, but not with significant prevalences.

Lipomas (Figure 1) are reported in 17-34% of patients with MEN1 (263,264,266). Loss of heterozygosity of the MEN1 gene is described in MEN1-related lipomas (99,267,268) and may also play a role in sporadic lipomas (268). Menin seems to be an important factor for adipogenesis and contributes to lipoma development (269,270).

A case of a novel MEN1 gene mutation with a recurrent sarcoma addresses the need for cautiousness of (atypical) skin lesions in patients with MEN1 (271).

Besides cutaneous lesions, there are other non-endocrine manifestations of MEN1. Leiomyomas are smooth muscle tumors with a described prevalence of ~10% in MEN1 patients, but the true prevalence remains unknown in absence of systematic evaluation (265).

Given the benign nature of these cutaneous and smooth muscle tumors, routine surveillance is not advised. Meningiomas have been proposed as well as non-endocrine manifestations of MEN1 syndrome. However, the high incidence of meningiomas in the general population in combination with regular imaging of the brain in MEN1 patients and the lack of strong evidence on the loss of MEN1 function in meningioma pathogenesis question this correlation. Screening for meningiomas is not recommended.

BREAST CANCER AND MEN1

A higher incidence of breast cancer (Figure 1) was found in four independent MEN1 cohorts in the Netherlands, France, Tasmania, and the United States. In the Dutch cohort a relative risk of 2.83 was found, which was significantly higher than in the general Dutch population (3). The median age for breast cancer was 45 years, which is approximately 15 years younger than the general Dutch population. The increased risk for breast cancer for MEN1 carriers was not associated with other breast cancer risk factors or a familial breast cancer risk. Considering the younger age of breast cancer occurrence and an earlier age of breast cancer, the authors suggest that surveillance should be considered. Breast cancer surveillance from the age of 40 is initiated in the Dutch MEN1 cohort (2). After the latter publication, several cases of early breast cancer in MEN1 patients were reported (272-276).

These epidemiological findings are supported by basic research. Loss-of-function Men1 mouse models have shown an increased incidence of both in situ and invasive mammary cancer (277). Menin, the tumor suppressor protein encoded by MEN1, is co-localized with the estrogen receptor (ER) alpha in breast cancer cells. In this manner, menin functions as a direct activator of ERα (278). In sporadic ER-positive breast cancer, menin seems to have a proliferative role, which is in contrast with breast cancer in MEN1 carriers, in whom LOH of the MEN1 gene could be found (3,279). Studies have shown that reduced menin staining is associated with ER-negative breast cancer and in ER-positive breast cancer with larger tumors, higher grade tumors, and luminal subtype tumors. These provide further evidence that there is an important role of menin in ERα regulation and breast cancer formation (280).

The causality between MEN1 and the development of breast cancer and the need for earlier breast cancer screening in women with MEN1 are still under debate (265). The current guidelines have not incorporated recommendations for earlier breast cancer screening in women with MEN1 (2). Future epidemiological and translational studies are warranted to establish conclusive evidence.

PSYCHOSOCIAL ASPECTS

The first study on health-related quality of life (QoL) was published in 2003, which showed that psychosocial outcomes such as anxiety, depression, intrusion, and avoidance are not altered by the hospital or home setting. A higher burden of MEN related disease led to more depression. Compared to the population-based norm values, patients with MEN1 scored lower for General Health and Social Functioning according to the SF-36 (281).

Postoperatively, quality of life (QOL) scores did not differ after pancreaticoduodenal surgery in MEN1 patients in comparison with the general population. Financial difficulties caused by the treatment were significantly worse in MEN1 patients (282). Financial burden seems to be associated with having MEN1. The degree of financial burden has a linear relationship with worse health-related QOL. Patients were three times more likely to be unemployed in comparison with the US population (283).

The largest QOL-related study showed that employment status was the most consistent predictor for QOL. The health-related QOL according to the SF-36 was significantly lower for patients with MEN1 on all subscales except for the physical functioning scale. Patients who are aware of their PA and PanNET have worse QOL scores in comparison with patients who are not aware of having these tumors (284). The degree of fear of disease recurrence is high in patients with MEN1. This fear is negatively associated with health-related QOL and is higher in patients who consider themselves at high risk for developing a MEN1-related tumor. More MEN1-related manifestations lead to more fear of disease occurrence (285). In comparison with other chronic diseases MEN1 scores worse regarding anxiety, depression, and fatigue (286).

QOL did not overly differ from the general population in the Italian cohort (287,288) and patients were more optimistic than in the Swedish cohort (281). This could be due to cultural differences, population selection, and awareness of the disease and its implications.

In the first study on QoL in 77 children with MEN (5-18 years) and 26 healthy siblings (8-29 years) children with MEN1 and MEN2A reported QoL comparable to siblings and healthy Dutch norms. Children with MEN2B showed lower physical QoL. Moreover, children with MEN1 and MEN2B who have clinical MEN-related manifestations, have significantly lower physical, social, and school functioning scores than those without clinical manifestations (289).

The high response rates regarding participation in QoL related studies in the MEN population illustrates the motivation of patients to participate in research and care about their wellbeing 281,284,289).

CONCLUSION

In conclusion, in the past decades there have been great advances in the understanding of the natural course of MEN1-related tumors, which have had direct consequences on clinical care. In the coming decade one of the main research objectives will be the identification of individual predictors of disease course, which can guide personalized treatment and surveillance. Increasing international collaborations will enable prospective studies. Given the complexity of the disease, it is strongly advised that patients, whenever possible, be followed and treated in centers of expertise. If this is not feasible, consultation with a center of expertise should be considered.

ACKNOWLEDGEMENTS

We would like to acknowledge the contributions of Carolina R.C. Pieterman MD, PhD, Endocrinologist, Department of Endocrine Oncology, University Medical Center Utrecht, Utrecht, the Netherlands to earlier versions of this chapter.

REFERENCES

1.

Chandrasekharappa. SC, Guru S, Manickam P, Olufemi S, Collins FS, Emmert-Buck MR, et al. Positional cloning of the gene for MEN1. Science (1979). 1997 Apr;276(5311):404–7. [PubMed: 9103196]

2.

Brandi ML, Pieterman CRC, English KA, Lines KE, Shariq OA, Marini F, et al. Multiple endocrine neoplasia type 1 (MEN1): recommendations and guidelines for best practice. The Lancet Diabetes and Endocrinology. Elsevier Ltd; 2025. p. 699–721. doi: PubMed PMID: 40523372.10.1016/S2213-8587(25)00119-6 [PubMed: 40523372] [CrossRef]

3.

Dreijerink KMA, Goudet P, Burgess JR, Valk GD. Breast-Cancer Predisposition in Multiple Endocrine Neoplasia Type 1. New England Journal of Medicine. 2014 Aug 7;371(6):583–4. doi:.10.1056/nejmc1406028 [PMC free article: PMC4243053] [PubMed: 25099597] [CrossRef]

4.

Van Leeuwaarde RS, Dreijerink KM, Ausems MG, Beijers HJ, Dekkers OM, De Herder WW, et al. MEN1-dependent breast cancer: Indication for early screening? Results from the Dutch MEN1 study group. Journal of Clinical Endocrinology and Metabolism. 2017 Jun 1;102(6):2083–90. doi:.10.1210/jc.2016-3690 [PubMed: 28323962] [CrossRef]

5.

Brandi ML, Gagel RF, Angeli A, Bilezikian JP, Beck-Peccoz P, Bordi C, et al. Guidelines for Diagnosis and Therapy of MEN Type 1 and Type 2. Journal of Clinical Endocrinology and Metabolism [Internet]. 2001;86:5658–71. Available from: https://academic​.oup​.com/jcem/article/86/12/5658/2849111 [PubMed: 11739416]

6.

Thakker R V., Newey PJ, Walls G V., Bilezikian J, Dralle H, Ebeling PR, et al. Clinical practice guidelines for multiple endocrine neoplasia type 1 (MEN1). Journal of Clinical Endocrinology and Metabolism. 2012. p. 2990–3011. doi:.10.1210/jc.2012-1230 [PubMed: 22723327] [CrossRef]

7.

Lemmens I, M Van de Ven WJ, Kas K, Zhang CX, Giraud S, Wautot V, et al. Identification of the multiple endocrine neoplasia type 1 (MEN1) gene The European Consortium on MEN1. Human Molecular Genetics. Oxford University Press; 1997. Report. [PubMed: 9215690]

8.

Lemos MC, Thakker R V. Multiple endocrine neoplasia type 1 (MEN1): Analysis of 1336 mutations reported in the first decade following identification of the gene. Hum Mutat. 2008 Jan;29(1):22–32. doi:.10.1002/humu.20605 [PubMed: 17879353] [CrossRef]

9.

Concolino P, Costella A, Capoluongo E. Multiple endocrine neoplasia type 1 (MEN1): An update of 208 new germline variants reported in the last nine years. Cancer Genet. 2016 Jan 1;209(1–2):36–41. doi:.10.1016/j.cancergen.2015.12.002 [PubMed: 26767918] [CrossRef]

10.

Kooblall KG, Boon H, Cranston T, Stevenson M, Pagnamenta AT, Rogers A, et al. Multiple Endocrine Neoplasia Type 1 (MEN1) 5′UTR Deletion, in MEN1 Family, Decreases Menin Expression. Journal of Bone and Mineral Research. 2021 Jan 1;36(1):100–9. doi:.10.1002/jbmr.4156 [PubMed: 32780883] [CrossRef]

11.

Agarwal SK. The future: genetics advances in MEN1 therapeutic approaches and management strategies. Endocrine-related cancer. 2017. p. T119–34. doi:.10.1530/ERC-17-0199 [PMC free article: PMC5679100] [PubMed: 28899949] [CrossRef]

12.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, et al. Standards and guidelines for the interpretation of sequence variants: A joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genetics in Medicine. 2015 May 8;17(5):405–24. doi:.10.1038/gim.2015.30 [PMC free article: PMC4544753] [PubMed: 25741868] [CrossRef]

13.

Romanet P, Odou MF, North MO, Saveanu A, Coppin L, Pasmant E, et al. Proposition of adjustments to the ACMG-AMP framework for the interpretation of MEN1 missense variants. Hum Mutat. 2019 Jun 1;40(6):661–74. doi:.10.1002/humu.23746 [PubMed: 30869828] [CrossRef]

14.

Thevenon J, Bourredjem A, Faivre L, Cardot-bauters C, Calender A, Murat A, et al. Higher risk of death among men1 patients with mutations in the jund interacting domain: A groupe d’étude des tumeurs endocrines (GTE) cohort study. Hum Mol Genet. 2013 May;22(10):1940–8. doi:.10.1093/hmg/ddt039 [PubMed: 23376981] [CrossRef]

15.

Bartsch DK, Slater EP, Albers M, Knoop R, Chaloupka B, Lopez CL, et al. Higher risk of aggressive pancreatic neuroendocrine tumors in MEN1 patients with men1 mutations affecting the CHES1 interacting MENIN domain. Journal of Clinical Endocrinology and Metabolism. 2014 Nov 1;99(11):E2387–91. doi:.10.1210/jc.2013-4432 [PubMed: 25210877] [CrossRef]

16.

Klein Haneveld MJ, Van Treijen MJC, Pieterman CRC, Dekkers OM, Van De Ven A, De Herder WW, et al. Initiating Pancreatic Neuroendocrine Tumor (pNET) Screening in Young MEN1 Patients: Results from the DutchMEN Study Group. Journal of Clinical Endocrinology and Metabolism. 2021 Dec 1;106(12):3515–25. doi:.10.1210/clinem/dgab569 [PubMed: 34333645] [CrossRef]

17.

Van Den Broek MFM, Van Nesselrooij BPM, Pieterman CRC, Stuart AAV, Van De Ven AC, De Herder WW, et al. Clues for genetic anticipation in multiple endocrine neoplasia type 1. Journal of Clinical Endocrinology and Metabolism. 2020 Jul 1;105(7). doi:.10.1210/clinem/dgaa257 [PubMed: 32396602] [CrossRef]

18.

Beijers HJBH, Stikkelbroeck NML, Mensenkamp AR, Pfundt R, Van Der Luijt RB, Timmers HJLM, et al. Germline and somatic mosaicism in a family with multiple endocrine neoplasia type 1 (MEN1) syndrome. Eur J Endocrinol. 2019 Feb 1;180(2):K15–9. doi:.10.1530/EJE-18-0778 [PubMed: 30481156] [CrossRef]

19.

Vera A, Verschuur D, Kok ASM, Morsink FHM, De Leng WWJ, Van Den Broek MFM, et al. Diagnostic Utility of Menin Immunohistochemistry in Patients With Multiple Endocrine Neoplasia Type 1 Syndrome. American journal of Surgical Pathology [Internet]. 2023 Jul;47:785–91. Available from: http://links​.lww.com/PAS/B546; [PMC free article: PMC10270278] [PubMed: 37199453]

20.

Dreijerink KMA, Timmers HTM, Brown M. Twenty years of menin: emerging opportunities for restoration of transcriptional regulation in MEN1. Endocrine-related cancer. 2017. p. T135–45. doi:.10.1530/ERC-17-0281 [PMC free article: PMC5609455] [PubMed: 28811299] [CrossRef]

21.

Canaff L, Vanbellinghen JF, Kaji H, Goltzman D, Hendy GN. Impaired transforming growth factor-β (TGF-β) transcriptional activity and cell proliferation control of a menin in-frame deletion mutant associated with Multiple Endocrine Neoplasia type 1 (MEN1). Journal of Biological Chemistry. 2012 Mar 9;287(11):8584–97. doi:.10.1074/jbc.M112.341958 [PMC free article: PMC3318699] [PubMed: 22275377] [CrossRef]

22.

Iyer S, Agarwal SK. Epigenetic regulation in the tumorigenesis of MEN1-associated endocrine cell types. Journal of Molecular Endocrinology. BioScientifica Ltd.; 2018. p. R13–24. doi: PubMed PMID: 29615472.10.1530/JME-18-0050 [PMC free article: PMC5966343] [PubMed: 29615472] [CrossRef]

23.

Pieterman C, Vriens M, Dreijerink K, van der Luijt R, Valk G. Care for patients with multiple endocrine neoplasia type 1: the current evidence base. Fam Cancer. 2011;10(1):157–71. [PubMed: 21061174]

24.

Van Leeuwaarde RS, De Laat JM, Pieterman CRC, Dreijerink K, Vriens MR, Valk GD. The future: Medical advances in MEN1 therapeutic approaches and management strategies. Endocr Relat Cancer. 2017;24(10):T179–93. doi:.10.1530/ERC-17-0225 [PubMed: 28768698] [CrossRef]

25.

de Laat JM, van der Luijt RB, Pieterman CRC, Oostveen MP, Hermus AR, Dekkers OM, et al. MEN1 redefined, a clinical comparison of mutation-positive and mutation-negative patients. BMC Med. 2016 Nov 15;14(1). doi:.10.1186/s12916-016-0708-1 [PMC free article: PMC5109674] [PubMed: 27842554] [CrossRef]

26.

Pieterman CRC, Hyde SM, Wu SY, Landry JP, Chiang YJ, Christakis I, et al. Understanding the clinical course of genotype-negative MEN1 patients can inform management strategies. In: Surgery (United States). Mosby Inc.; 2021. p. 175–84. doi: PubMed PMID: 32703679.10.1016/j.surg.2020.04.067 [PMC free article: PMC7856683] [PubMed: 32703679] [CrossRef]

27.

Geerdink EA, Van Der Luijt RB, Lips CJ. Do patients with multiple endocrine neoplasia syndrome type 1 benefit from periodical screening? Eur J Endocrinol [Internet]. 2003;149:577–82. Available from: https://academic​.oup​.com/ejendo/article/149/6/577/6753400 [PubMed: 14641000]

28.

Goudet P, Murat A, Binquet C, Cardot-Bauters C, Costa A, Ruszniewski P, et al. Risk factors and causes of death in men1 disease. a gte (groupe d’etude des tumeurs endocrines) cohort study among 758 patients. World J Surg. 2010 Feb;34(2):249–55. doi:.10.1007/s00268-009-0290-1 [PubMed: 19949948] [CrossRef]

29.

De Laat JM, Van Leeuwaarde RS, Valk GD. The importance of an early and accurate MEN1 diagnosis. Frontiers in Endocrinology. Frontiers Media S.A.; 2018. doi:10.3389/fendo.2018.00533 [PMC free article: PMC6141626] [PubMed: 30254610] [CrossRef]

30.

De Laat JM, Tham E, Pieterman CRC, Vriens MR, Dorresteijn JAN, Bots ML, et al. Predicting the risk of multiple endocrine neoplasia type 1 for patients with commonly occurring endocrine tumors. Eur J Endocrinol. 2012 Aug;167(2):181–7. doi:.10.1530/EJE-12-0210 [PubMed: 22581216] [CrossRef]

31.

Van Leeuwaarde RS, Van Nesselrooij BPM, Hermus AR, Dekkers OM, De Herder WW, Van Der Horst-Schrivers AN, et al. Impact of delay in diagnosis in outcomes in MEN1: Results from the Dutch MEN1 study group. Journal of Clinical Endocrinology and Metabolism. 2016 Mar 1;101(3):1159–65. doi:.10.1210/jc.2015-3766 [PubMed: 26751192] [CrossRef]

32.

Alrezk R, Hannah-Shmouni F, Stratakis CA. MEN4 and CDKN1B mutations: The latest of the MEN syndromes. Endocrine-Related Cancer. BioScientifica Ltd.; 2017. p. T195–208. doi: PubMed PMID: 28824003.10.1530/ERC-17-0243 [PMC free article: PMC5623937] [PubMed: 28824003] [CrossRef]

33.

Frederiksen A, Rossing M, Hermann P, Ejersted C, Thakker R V., Frost M. Clinical Features of Multiple Endocrine Neoplasia Type 4: Novel Pathogenic Variant and Review of Published Cases. Journal of Clinical Endocrinology and Metabolism. 2019 Apr 11;104(9):3637–46. doi:.10.1210/jc.2019-00082 [PMC free article: PMC6637788] [PubMed: 30990521] [CrossRef]

34.

Georgitsi M, Raitila A, Karhu A, Van Der Luijt RB, Aalfs CM, Sane T, et al. Brief report: Germline CDKN1B/p27Kip1 mutation in multiple endocrine neoplasia. Journal of Clinical Endocrinology and Metabolism. 2007;92(8):3321–5. doi:.10.1210/jc.2006-2843 [PubMed: 17519308] [CrossRef]

35.

Van Der Tuin K, Tops CMJ, Adank MA, Cobben JM, Hamdy NAT, Jongmans MC, et al. CDC73-related disorders: Clinical manifestations and case detection in primary hyperparathyroidism. Journal of Clinical Endocrinology and Metabolism. 2017;102(12):4534–40. doi:.10.1210/jc.2017-01249 [PubMed: 29040582] [CrossRef]

36.

van den Broek MFM, van Nesselrooij BPM, Verrijn Stuart AA, van Leeuwaarde RS, Valk GD. Clinical Relevance of Genetic Analysis in Patients With Pituitary Adenomas: A Systematic Review. Frontiers in Endocrinology. Frontiers Media S.A.; 2019. doi:.10.3389/fendo.2019.0083737 [PMC free article: PMC6914701] [PubMed: 31920960] [CrossRef]

37.

Stratakis CA, Schussheim D, Freedman S, Keil M, Pack S, Agarwal S, et al. Pituitary macroadenoma in a 5-year-old: an early expression of multiple endocrine neoplasia type 1. J Clin Endocrinol Metab [Internet]. 2000 Dec;85(12). Available from: https://academic​.oup​.com/jcem/article/85/12/4776/2856086 [PubMed: 11134142]

38.

Romanet P, Mohamed A, Giraud S, Odou MF, North MO, Pertuit M, et al. UMD-MEN1 Database: An Overview of the 370 MEN1 Variants Present in 1676 Patients from the French Population. Journal of Clinical Endocrinology and Metabolism. 2018 Dec 28;104(3):753–64. doi:.10.1210/jc.2018-01170 [PubMed: 30339208] [CrossRef]

39.

Goudet P, Cougard P, Vergès B, Murat A, Carnaille B, Calender A, et al. Hyperparathyroidism in multiple endocrine neoplasia type I: Surgical trends and results of a 256-patient series from Groupe d’Etude des Néoplasies Endocriniennes Multiples Study Group. World J Surg. 2001;25(7):886–90. doi:.10.1007/s00268-001-0046-z [PubMed: 11572029] [CrossRef]

40.

Pieterman CRC, Schreinemakers JMJ, Koppeschaar HPF, Vriens MR, Rinkes IHMB, Zonnenberg BA, et al. Multiple endocrine neoplasia type 1 (MEN1): Its manifestations and effect of genetic screening on clinical outcome. Clin Endocrinol (Oxf). 2009 Apr;70(4):575–81. doi:.10.1111/j.1365-2265.2008.03324.x [PubMed: 18616711] [CrossRef]

41.

Marini F, Giusti F, Brandi ML. Multiple endocrine neoplasia type 1: Extensive analysis of a large database of Florentine patients. Orphanet J Rare Dis. 2018 Nov 14;13(1). doi:.10.1186/s13023-018-0938-8 [PMC free article: PMC6237029] [PubMed: 30428914] [CrossRef]

42.

Giusti F, Cianferotti L, Boaretto F, Cetani F, Cioppi F, Colao A, et al. Multiple endocrine neoplasia syndrome type 1: institution, management, and data analysis of a nationwide multicenter patient database. Endocrine. 2017 Nov 1;58(2):349–59. doi:.10.1007/s12020-017-1234-4 [PubMed: 28132167] [CrossRef]

43.

Sakurai A, Suzuki S, Kosugi S, Okamoto T, Uchino S, Miya A, et al. Multiple endocrine neoplasia type 1 in Japan: Establishment and analysis of a multicentre database. Clin Endocrinol (Oxf). 2012 Apr;76(4):533–9. doi:.10.1111/j.1365-2265.2011.04227.x [PubMed: 21950691] [CrossRef]

44.

Soczomski P, Jurecka-Lubieniecka B, Rogozik N, Tukiendorf A, Jarząb B, Bednarczuk T. Multiple endocrine neoplasia type 1 in Poland: A two-centre experience. Endokrynol Pol. 2019;70(5):385–91. doi:.10.5603/EP.a2019.0031 [PubMed: 31274185] [CrossRef]

45.

Waldmann J, Fendrich V, Habbe N, Bartsch DK, Slater EP, Kann PH, et al. Screening of patients with multiple endocrine neoplasia type 1 (MEN-1): A critical analysis of its value. World J Surg. 2009 Jun;33(6):1208–18. doi:.10.1007/s00268-009-9983-8 [PubMed: 19350320] [CrossRef]

46.

Herath M, Parameswaran V, Thompson M, Williams M, Burgess J. Paediatric and young adult manifestations and outcomes of multiple endocrine neoplasia type 1. Clin Endocrinol (Oxf). 2019 Nov 1;91(5):633–8. doi:.10.1111/cen.14067 [PubMed: 31348545] [CrossRef]

47.

Goudet P, Dalac A, Le Bras M, Cardot-Bauters C, Niccoli P, Lévy-Bohbot N, et al. MEN1 disease occurring before 21 years old: A 160-patient cohort study from the Groupe d’étude des Tumeurs Endocrines. Journal of Clinical Endocrinology and Metabolism. 2015 Apr 1;100(4):1568–77. doi:.10.1210/jc.2014-3659 [PubMed: 25594862] [CrossRef]

48.

Shariq OA, Lines KE, English KA, Jafar-Mohammadi B, Prentice P, Casey R, et al. Multiple endocrine neoplasia type 1 in children and adolescents: Clinical features and treatment outcomes. In: Surgery (United States). Elsevier Inc.; 2022. p. 77–87. doi: PubMed PMID: 34183184.10.1016/j.surg.2021.04.041 [PubMed: 34183184] [CrossRef]

49.

Vannucci L, Marini F, Giusti F, Ciuffi S, Tonelli F, Brandi ML. MEN1 in children and adolescents: Data from patients of a regional referral center for hereditary endocrine tumors. Endocrine. 2018 Feb 1;59(2):438–48. doi:.10.1007/s12020-017-1322-5 [PubMed: 28530019] [CrossRef]

50.

Marx SJ, Lourenço DM. Questions and controversies about parathyroid pathophysiology in children with multiple endocrine neoplasia type 1. Front Endocrinol (Lausanne). 2018 Jul 17;9(JUL). doi:10.3389/fendo.2018.00359 [PMC free article: PMC6057055] [PubMed: 30065698] [CrossRef]

51.

Doherty GM, Lairmore TC, DeBenedetti MK. Multiple endocrine neoplasia type 1 parathyroid adenoma development over time. World Journal of Surgery. 2004. p. 1139–42. doi:.10.1007/s00268-004-7560-8 [PubMed: 15490065] [CrossRef]

52.

d’Alessandro A, Montenegro F de M, Brandao L, Lourenco Jr DM, Toledo S de A, Cordeiro A. Supernumerary parathyroid glands in hyperparathyroidism associated with multiple endocrine neoplasia type 1. Rev Assoc Med Bras. 2012 May;58(3):323–7. [PubMed: 22735224]

53.

Yeh MW, Ituarte PHG, Zhou HC, Nishimoto S, In-Lu Amy Liu, Harari A, et al. Incidence and prevalence of primary hyperparathyroidism in a racially mixed population. Journal of Clinical Endocrinology and Metabolism. 2013 Mar;98(3):1122–9. doi:.10.1210/jc.2012-4022 [PMC free article: PMC3590475] [PubMed: 23418315] [CrossRef]

54.

Press DM, Siperstein AE, Berber E, Shin JJ, Metzger R, Jin J, et al. The prevalence of undiagnosed and unrecognized primary hyperparathyroidism: A population-based analysis from the electronic medical record. Surgery (United States). 2013 Dec;154(6):1232–8. doi:.10.1016/j.surg.2013.06.051 [PubMed: 24383100] [CrossRef]

55.

Gheorghe AM, Stanciu M, Lebada IC, Nistor C, Carsote M. An Updated Perspective of the Clinical Features and Parathyroidectomy Impact in Primary Hyperparathyroidism Amid Multiple Endocrine Neoplasia Type 1 (MEN1): Focus on Bone Health. Journal of Clinical Medicine. Multidisciplinary Digital Publishing Institute (MDPI); 2025. doi:10.3390/jcm14093113 [PMC free article: PMC12072311] [PubMed: 40364143] [CrossRef]

56.

Minisola S, Arnold A, Belaya Z, Brandi ML, Clarke BL, Hannan FM, et al. Epidemiology, Pathophysiology, and Genetics of Primary Hyperparathyroidism. Journal of Bone and Mineral Research. John Wiley and Sons Inc; 2022. p. 2315–29. doi: PubMed PMID: 36245271. doi: PubMed PMID: 22581216.10.1002/jbmr.4665 [PMC free article: PMC10092691] [PubMed: 36245271] [CrossRef]

57.

Eller-Vainicher C, Chiodini I, Battista C, Viti R, Mascia ML, Massironi S, et al. Sporadic and MEN1-related primary hyperparathyroidism: Differences in clinical expression and severity. Journal of Bone and Mineral Research. 2009 Aug;24(8):1404–10. doi:.10.1359/jbmr.090304 [PubMed: 19309299] [CrossRef]

58.

Twigt BA, Scholten A, Valk GD, Rinkes IHMB, Vriens MR. Differences between sporadic and MEN related primary hyperparathyroidism; Clinical expression, preoperative workup, operative strategy and follow-up. Orphanet J Rare Dis. 2013;8(1). doi:.10.1186/1750-1172-8-50 [PMC free article: PMC3623824] [PubMed: 23547958] [CrossRef]

59.

Wilhelm SM, Wang TS, Ruan DT, Lee JA, Asa SL, Duh QY, et al. The American association of endocrine surgeons guidelines for definitive management of primary hyperparathyroidism. JAMA Surg. 2016 Oct 1;151(10):959–68. doi:.10.1001/jamasurg.2016.2310 [PubMed: 27532368] [CrossRef]

60.

Iacobone M, Carnaille B, Palazzo FF, Vriens M. Hereditary hyperparathyroidism—a consensus report of the European Society of Endocrine Surgeons (ESES). Langenbeck’s Archives of Surgery. Springer Verlag; 2015. p. 867–86. doi: PubMed PMID: 26450137.10.1007/s00423-015-1342-7 [PubMed: 26450137] [CrossRef]

61.

Silva AM, Vodopivec D, Christakis I, Lyons G, Wei Q, Waguespack SG, et al. Operative intervention for primary hyperparathyroidism offers greater bone recovery in patients with sporadic disease than in those with multiple endocrine neoplasia type 1–related hyperparathyroidism. In: Surgery (United States). Mosby Inc.; 2017. p. 107–15. doi: PubMed PMID: 27842919.10.1016/j.surg.2016.06.065 [PubMed: 27842919] [CrossRef]

62.

Wang W, Nie M, Jiang Y, Li M, Meng X, Xing X, et al. Impaired geometry, volumetric density, and microstructure of cortical and trabecular bone assessed by HR-pQCT in both sporadic and MEN1-related primary hyperparathyroidism. Osteoporosis International. 2020 Jan 1;31(1):165–73. doi:.10.1007/s00198-019-05186-1 [PubMed: 31642976] [CrossRef]

63.

Kong J, Wang O, Nie M, Shi J, Hu Y, Jiang Y, et al. Clinical and genetic analysis of multiple endocrine neoplasia type 1-related primary hyperparathyroidism in Chinese. PLoS One. 2016 Nov 1;11(11). doi:.10.1371/journal.pone.0166634 [PMC free article: PMC5112846] [PubMed: 27846313] [CrossRef]

64.

Lourenço DM, Coutinho FL, Toledo RA, Montenegro FL, Correia-Deur JE, Toledo SP. Early-onset, progressive, frequent, extensive, and severe bone mineral and renal complications in multiple endocrine neoplasia type 1-associated primary hyperparathyroidism. Journal of Bone and Mineral Research. 2010 Nov;25(11):2382–91. doi:.10.1002/jbmr.125 [PubMed: 20499354] [CrossRef]

65.

Burgess JR, David R, Greenaway TM, Parameswaran; V, Shepherd JJ. Osteoporosis in Multiple Endocrine Neoplasia Type 1 Severity, Clinical Significance, Relationship to Primary Hyperparathyroidism, and Response to Parathyroidectomy. Archives of Surgery. 1999 Oct;134(10):1119–23. [PubMed: 10522858]

66.

Lourenço DM, Toledo RA, Mackowiak II, Coutinho FL, Cavalcanti MG, Correia-Deur JEM, et al. Multiple endocrine neoplasia type 1 in Brazil: MEN1 founding mutation, clinical features, and bone mineral density profile. Eur J Endocrinol. 2008 Sep;159(3):259–74. doi:.10.1530/EJE-08-0153 [PubMed: 18524795] [CrossRef]

67.

Coutinho FL, Lourenço DM, Toledo RA, Montenegro FLM, Correia-Deur JEM, Toledo SPA. Bone mineral density analysis in patients with primary hyperparathyroidism associated with multiple endocrine neoplasia type 1 after total parathyroidectomy. Clin Endocrinol (Oxf). 2010 Apr;72(4):462–8. doi:.10.1111/j.1365-2265.2009.03672.x [PubMed: 19650788] [CrossRef]

68.

Kann PH, Bartsch D, Langer P, Waldmann J, Hadji P, Pfützner A, et al. Peripheral bonemineral density in correlation to disease-related predisposing conditions in patients withmultiple endocrine neoplasia type 1. J Endocrinol Invest. 2012 Jun;35(6):573–9. doi:.10.3275/7880 [PubMed: 21791969] [CrossRef]

69.

Green P, Zagzag J, Patel D, Weinstein LS, Simonds WF, Blau J, et al. High prevalence of chronic kidney disease in patients with multiple endocrine neoplasia type 1 and improved kidney function after parathyroidectomy. Surgery (United States). 2019 Jan 1;165(1):124–8. doi:.10.1016/j.surg.2018.04.064 [PMC free article: PMC8191379] [PubMed: 30414705] [CrossRef]

70.

English KA, Pieterman CRC, Marini F, Lines KE, Cuny T, Saulle R, et al. Treatments for MEN1-associated endocrine tumours: three systematic reviews and a meta-analysis. Lancet Diabetes Endocrinol. 2025 Aug 1;13(8):685–98. doi:.10.1016/S2213-8587(25)00118-4 [PubMed: 40523371] [CrossRef]

71.

Bilezikian JP, Khan AA, Silverberg SJ, Fuleihan GEH, Marcocci C, Minisola S, et al. Evaluation and Management of Primary Hyperparathyroidism: Summary Statement and Guidelines from the Fifth International Workshop. Journal of Bone and Mineral Research. John Wiley and Sons Inc; 2022. p. 2293–314. doi: PubMed PMID: 36245251.10.1002/jbmr.4677 [PubMed: 36245251] [CrossRef]

72.

Norton JA, Venzon DJ, Berna MJ, Alexander HR, Fraker DL, Libutti SK, et al. Prospective study of surgery for primary hyperparathyroidism (HPT) in multiple endocrine neoplasia-type 1 and zollinger-ellison syndrome long-term outcome of a more virulent form of HPT. Ann Surg. 2008 Mar;247(3):501–10. doi:.10.1097/SLA.0b013e31815efda5 [PMC free article: PMC2717476] [PubMed: 18376196] [CrossRef]

73.

Hackeng WM, Dreijerink KMA, Offerhaus GJA, Brosens LAA. A parathyroid–gut axis: Hypercalcemia and the pathogenesis of gastrinoma in multiple endocrine neoplasia 1. Molecular Cancer Research. American Association for Cancer Research Inc.; 2021. p. 946–9. doi: PubMed PMID: 33771883.10.1158/1541-7786.MCR-21-0073 [PubMed: 33771883] [CrossRef]

74.

Nobecourt PF, Zagzag J, Asare EA, Perrier ND. Intraoperative Decision-Making and Technical Aspects of Parathyroidectomy in Young Patients With MEN1 Related Hyperparathyroidism. Frontiers in Endocrinology. Frontiers Media S.A.; 2018. doi:10.3389/fendo.2018.00618 [PMC free article: PMC6232704] [PubMed: 30459713] [CrossRef]

75.

Iacobone M, Scerrino G, Palazzo FF. Parathyroid surgery: an evidence-based volume—outcomes analysis: European Society of Endocrine Surgeons (ESES) positional statement. Langenbeck’s Archives of Surgery. Springer; 2019. p. 919–27. doi: PubMed PMID: 31595330.10.1007/s00423-019-01823-9 [PubMed: 31595330] [CrossRef]

76.

Rajan S, Gracie D, Aspinall S. Does Surgeon Volume Impact Morbidity Following Parathyroidectomy? A Study of 16,140 Parathyroidectomies from the UK Registry of Endocrine and Thyroid Surgery (UKRETS) Database. World J Surg. 2023 May 1;47(5):1221–30. doi:.10.1007/s00268-022-06863-9 [PubMed: 36593341] [CrossRef]

77.

Nastos C, Papaconstantinou D, Kofopoulos-Lymperis E, Peppa M, Pikoulis A, Lykoudis P, et al. Optimal extent of initial parathyroid resection in patients with multiple endocrine neoplasia syndrome type 1: A meta-analysis. Surgery (United States). Mosby Inc.; 2021. p. 302–10. doi: PubMed PMID: 33008613.10.1016/j.surg.2020.08.021 [PubMed: 33008613] [CrossRef]

78.

Schreinemakers JMJ, Pieterman CRC, Scholten A, Vriens MR, Valk GD, Borel Rinkes IHM. The optimal surgical treatment for primary hyperparathyroidism in MEN1 patients: A systematic review. World Journal of Surgery. 2011. p. 1993–2005. doi: PubMed PMID: 21713580.79.10.1007/s00268-011-1068-9 [PubMed: 21713580] [CrossRef]

79.

Manoharan J, Albers MB, Bollmann C, Maurer E, Mintziras I, Wächter S, et al. Single gland excision for MEN1-associated primary hyperparathyroidism. Clin Endocrinol (Oxf). 2020 Jan 1;92(1):63–70. doi:.10.1111/cen.14112 [PubMed: 31626728] [CrossRef]

80.

Kluijfhout WP, Beninato T, Drake FT, Vriens MR, Gosnell J, Shen WT, et al. Unilateral Clearance for Primary Hyperparathyroidism in Selected Patients with Multiple Endocrine Neoplasia Type 1. World J Surg. 2016 Dec 1;40(12):2964–9. doi:.10.1007/s00268-016-3624-9 [PMC free article: PMC5104782] [PubMed: 27402205] [CrossRef]

81.

Montenegro FL de M, Brescia MDG, Lourenco Jr DM, Arap SS, d’Alessandro AF, Filho G de BES, et al. Could the Less-Than Subtotal Parathyroidectomy Be an Option for Treating Young Patients With Multiple Endocrine Neoplasia Type 1-Related Hyperparathyroidism? Front Endocrinol (Lausanne). 2019 Mar;123:123. [PMC free article: PMC6417394] [PubMed: 30899245]

82.

Choi HR, Choi SH, Choi SM, Kim JK, Lee CR, Kang SW, et al. Benefit of diverse surgical approach on short-term outcomes of MEN1-related hyperparathyroidism. Sci Rep. 2020 Dec 1;10(1). doi:.10.1038/s41598-020-67424-5 [PMC free article: PMC7326992] [PubMed: 32606444] [CrossRef]

83.

Boucher A, Delabie J, Lussey-Lepoutre C, Haissaguerre M, Ouvrard E, Lavinia V, et al. Performance of [18F]fluorocholine PET/CT in MEN1-related primary hyperparathyroidism before initial surgery or for persistent/recurrent disease. Eur J Nucl Med Mol Imaging. 2024 Apr 1;51(5):1349–60. doi:.10.1007/s00259-023-06537-1 [PubMed: 38057652] [CrossRef]

84.

Shariq OA, Abrantes VB, Lu LY, Tebben PJ, Foster TM, Dy BM, et al. Primary hyperparathyroidism in patients with multiple endocrine neoplasia type 1: Impact of genotype and surgical approach on long-term postoperative outcomes. Surgery (United States). 2024 Jan 1;175(1):8–16. doi:.10.1016/j.surg.2023.05.044 [PubMed: 37891063] [CrossRef]

85.

Palazzo FF. Invited Commentary: Less than Subtotal Parathyroidectomy for Multiple Endocrine Neoplasia Type 1 Primary Hyperparathyroidism: A Systematic Review and Meta-Analysis. World Journal of Surgery. Springer Science and Business Media Deutschland GmbH; 2022. p. 2676–7. doi: PubMed PMID: 36042033.10.1007/s00268-022-06707-6 [PMC free article: PMC9529694] [PubMed: 36042033] [CrossRef]

86.

Keutgen XM, Nilubol N, Agarwal S, Welch J, Cochran C, Marx SJ, et al. Reoperative Surgery in Patients with Multiple Endocrine Neoplasia Type 1 Associated Primary Hyperparathyroidism. Ann Surg Oncol. 2016 Dec 1;23:701–7. doi:.10.1245/s10434-016-5467-x [PMC free article: PMC6415766] [PubMed: 27464610] [CrossRef]

87.

Bjornsdottir S, Ing S, Mitchell DM, Sikjaer T, Underbjerg L, Hassan-Smith Z, et al. Epidemiology and Financial Burden of Adult Chronic Hypoparathyroidism. Journal of Bone and Mineral Research. 2022 Dec 1;37(12):2602–14. doi:.10.1002/jbmr.4675 [PMC free article: PMC10087725] [PubMed: 36054571] [CrossRef]

88.

Fyrsten E, Norlén O, Hessman O, Stålberg P, Hellman P. Long-Term Surveillance of Treated Hyperparathyroidism for Multiple Endocrine Neoplasia Type 1: Recurrence or Hypoparathyroidism? World J Surg. 2016 Mar 1;40(3):615–21. doi:.10.1007/s00268-015-3297-9 [PubMed: 26541865] [CrossRef]

89.

Pieterman CRC, Van Hulsteijn LT, Den Heijer M, Van Der Luijt RB, Bonenkamp JJ, Hermus ARMM, et al. Primary hyperparathyroidism in MEN1 patients: A cohort study with longterm follow-up on preferred surgical procedure and the relation with genotype. Annals of Surgery. 2012. p. 1171–8. doi:.10.1097/SLA.0b013e31824c5145 [PubMed: 22470073] [CrossRef]

90.

Clarke BL, Khan AA, Rubin MR, Schwarz P, Vokes T, Shoback DM, et al. Efficacy and Safety of TransCon PTH in Adults With Hypoparathyroidism: 52-Week Results From the Phase 3 PaTHway Trial. Journal of Clinical Endocrinology and Metabolism. 2025 Apr 1;110(4):951–60. doi:.10.1210/clinem/dgae693 [PMC free article: PMC11913112] [PubMed: 39376010] [CrossRef]

91.

Rubin M, Palermo A, Vokes T, Khan AA, Schwarz P, Cetani F, et al. Patient-reported outcomes in palopegteriparatide-treated adults with hypoparathyroidism: PaTH Forward trial extension. J Clin Endocrinol Metab. 2025 Dec 9. doi:10.1210/clinem/dgaf653 [PMC free article: PMC13017087] [PubMed: 41365829] [CrossRef]

92.

Filopanti M, Verga U, Ermetici F, Olgiati L, Eller-Vainicher C, Corbetta S, et al. MEN1-related hyperparathyroidism: Response to cinacalcet and its relationship with the calcium-sensing receptor gene variant Arg990Gly. Eur J Endocrinol. 2012 Aug;167(2):157–64. doi:.10.1530/EJE-12-0117 [PubMed: 22577108] [CrossRef]

93.

Giusti F, Cianferotti L, Gronchi G, Cioppi F, Masi L, Faggiano A, et al. Cinacalcet therapy in patients affected by primary hyperparathyroidism associated to Multiple Endocrine Neoplasia Syndrome type 1 (MEN1). Endocrine. 2016 Jun 1;52(3):495–506. doi:.10.1007/s12020-015-0696-5 [PubMed: 26224587] [CrossRef]

94.

Moyes VJ, Monson JP, Chew SL. Clinical use of cinacalcet in MEN1 hyperparathyroidism. Int J Endocrinol. 2010;2010. doi:10.1155/2010/906163 [PMC free article: PMC2877200] [PubMed: 20585352] [CrossRef]

95.

Geslot A, Vialon M, Caron P, Grunenwald S, Vezzosi D. New therapies for patients with multiple endocrine neoplasia type 1. Annales d’Endocrinologie. Elsevier Masson s.r.l.; 2021. p. 112–20. doi: PubMed PMID: 33839123.10.1016/j.ando.2021.03.005 [PubMed: 33839123] [CrossRef]

96.

Singh Ospina N, Thompson GB, Lee RA, Reading CC, Young WF. Safety and Efficacy of Percutaneous Parathyroid Ethanol Ablation in Patients with Recurrent Primary Hyperparathyroidism and Multiple Endocrine Neoplasia Type 1. J Clin Endocrinol Metab. 2015 Jan;100(1):E87–90. doi:10.1210/jc.2014-3255 [PubMed: 25337928] [CrossRef]

97.

Song A, Yang Y, Liu S, Nie M, Jiang Y, Li M, et al. Prevalence of Parathyroid Carcinoma and Atypical Parathyroid Neoplasms in 153 Patients With Multiple Endocrine Neoplasia Type 1: Case Series and Literature Review. Front Endocrinol (Lausanne). 2020 Sep 30;11. doi:10.3389/fendo.2020.557050 [PMC free article: PMC7556219] [PubMed: 33101196] [CrossRef]

98.

Ito T, Igarashi H, Uehara H, Berna MJ, Jensen RT. Causes of death and prognostic factors in multiple endocrine neoplasia type 1: A prospective study:Comparison of 106 men1/zollinger-ellison syndrome patients with 1613 literature men1 patients with or without pancreatic endocrine tumors. Medicine (United States). 2013 May;92(3):135–81. doi:.10.1097/MD.0b013e3182954af1 [PMC free article: PMC3727638] [PubMed: 23645327] [CrossRef]

99.

Dong Q, Debelenko L V, Chandrasekharappa SC, Emmert-Buck MR, Zhuang Z, Guru SC, et al. Loss of Heterozygosity at 11q13: Analysis of Pituitary Tumors, Lung Carcinoids, Lipomas, and Other Uncommon Tumors in Subjects with Familial Multiple Endocrine Neoplasia Type 1. J Clin Endocrinol Metab. 1997;82(5):416–20. doi:.10.1210/jcem.82.5.3944 [PubMed: 9141526] [CrossRef]

100.

Thakker R V. The molecular genetics of the multiple endocrine neoplasia syndromes. Clinical Endocrinology. 1993. p. 1–14. doi:.10.1111/j.1365-2265.1993.tb00964.x [PubMed: 8094647] [CrossRef]

101.

Weil RJ, Huang S, Boni R, Lubensky IA, Pack S, Marx SJ, et al. 11q13 Allelic Loss in Pituitary Tumors in Patients with Multiple Endocrine Neoplasia Syndrome Type 1. Clinical cancer research [Internet]. 1998 Jul;4:1673–8. Available from: http://aacrjournals​.org​/clincancerres/article-pdf​/2070256/1673.pdf [PubMed: 9676841]

102.

Yoshimoto. Allele loss on chromosome 11 in a pituitary tumor from a MEN1 patient. Japanese Journal of Cancer Research. 1991 Aug;82:886–9. [PMC free article: PMC5918587] [PubMed: 1680115]

103.

Thakker R V., Pook MA, Wooding C, Boscaro M, Scanarini M, Clayton RN. Association of somatotrophinomas with loss of alleles on chromosome 11 and with gsp mutations. Journal of Clinical Investigation. 1993;91(6):2815–21. doi:.10.1172/jci116524 [PMC free article: PMC443349] [PubMed: 8514889] [CrossRef]

104.

Boggild M, Jenkinson S, Pistorello M, Boscaro M, Scanarini M, McTernan P, et al. Molecular genetic studies of sporadic pituitary tumors. Journal of Clinical Endocrinology and Metabolism. 1994 Feb;78(2):387–92. [PubMed: 8106627]

105.

Asa SL, Somers K, Ezzat S. The MEN-1 Gene Is Rarely Down-Regulated in Pituitary Adenomas. Journal of Clinical Endocrinology and Metabolism [Internet]. 1998;83(9):3210–2. Available from: https://academic​.oup​.com/jcem/article/83/9/3210/2865439 [PubMed: 9745428]

106.

Farrell W, Simpson D, Bicknell J, Margay J, Kyrodimou E, Thakker R, et al. Sequence analysis and transcript expression of the MEN1gene in sporadic pituitary tumours. Br J Cancer. 1999 Apr;80(1–2):44–50. [PMC free article: PMC2363023] [PubMed: 10389976]

107.

Prezant TR, Levine J, Melmed S. Molecular characterization of the men1 tumor suppressor gene in sporadic pituitary adenomas. Journal of Clinical Endocrinology and Metabolism. 1998;83(4):1388–91. [PubMed: 9543172]

108.

Tanaka C, Kimura T, Yang P, Moritani M, Yamaoka T, Yamada S, et al. Analysis of Loss of Heterozygosity on Chromosome 11 and Infrequent Inactivation of the MEN1 Gene in Sporadic Pituitary Adenomas. Journal of Clinical Endocrinology and Metabolism [Internet]. 1998 Aug;83(8):2631–4. Available from: https://academic​.oup​.com/jcem/article/83/8/2631/2660422 [PubMed: 9709923]

109.

Zhuang Z, Ezzat S, Vortmeyer A, Weil R, Oldfield E, Park W, et al. Mutations of the MEN1 tumor suppressor gene in pituitary tumors. Cancer Res. 1997 Dec;57(24):5446–51. [PubMed: 9407947]

110.

Verges B, Boureille O, Goudet P, Murat A, Beckers A, Genevie‘ G, et al. Pituitary Disease in MEN Type 1 (MEN1): Data from the France-Belgium MEN1 Multicenter Study. Journal of Clinical Endocrinology and Metabolism [Internet]. 2002;87(2):457–66. Available from: http://rockefeller1​.univ-lyon1​.fr/GENEM/new/database.html [PubMed: 11836268]

111.

De Laat JM, Dekkers OM, Pieterman CRC, Kluijfhout WP, Hermus AR, Pereira AM, et al. Long-term natural course of pituitary tumors in patients with MEN1: Results from the Dutch MEN1 study group (DMSG). Journal of Clinical Endocrinology and Metabolism. 2015 Sep 1;100(9):3288–96. doi:.10.1210/JC.2015-2015 [PubMed: 26126205] [CrossRef]

112.

Wu Y, Gao L, Guo X, Wang Z, Lian W, Deng K, et al. Pituitary adenomas in patients with multiple endocrine neoplasia type 1: a single-center experience in China. Pituitary. 2019 Apr 15;22(2):113–23. doi:.10.1007/s11102-019-00939-x [PubMed: 30637623] [CrossRef]

113.

Cohen-Cohen S, Brown DA, Himes BT, Wheeler LP, Ruff MW, Major BT, et al. Pituitary adenomas in the setting of multiple endocrine neoplasia type 1: A single-institution experience. J Neurosurg. 2021 Apr 1;134(4):1132–8. doi:.10.3171/2020.1.JNS193538 [PubMed: 32244213] [CrossRef]

114.

Valdés N, Romero A, Diego E, Calatayud M, Lamas C, Araujo-Castro M, et al. Long term outcomes of pituitary adenomas in Multiple Endocrine Neoplasia type 1: a nationwide study. Front Endocrinol (Lausanne). 2024;15. doi:.10.3389/fendo.2024.1427821 [PMC free article: PMC11493648] [PubMed: 39439563] [CrossRef]

115.

Ballard H, Fame B, Hartsock R. Familial multiple endocrine adenoma-peptic ulcer complex. Medicine (Baltimore). 1964 Jul;43:481–516. [PubMed: 14183520]

116.

Trouillas J, Labat-Moleur oise, Sturm N, Kujas M, Marie-Franc J, Heymann oise, et al. Pituitary Tumors and Hyperplasia in Multiple Endocrine Neoplasia Type 1 Syndrome (MEN1): A Case-Control Study in a Series of 77 Patients Versus 2509 Non-MEN1 Patients. american journal of Surgical Pathology. 2008 Apr;32(4):534–43. [PubMed: 18300794]

117.

Le Bras M, Leclerc H, Rousseau O, Goudet P, Cuny T, Castinetti F, et al. Pituitary adenoma in patients with multiple endocrine neoplasia type 1: a cohort study. Eur J Endocrinol. 2021 Nov 26;185(6):863–73. doi:.10.1530/EJE-21-0630 [PubMed: 34636744] [CrossRef]

118.

Omotosho YB, Vikram NU, Wright EC, Dola V, Abbas W, Tora R, et al. Radiological Surveillance for Pituitary Adenomas in Multiple Endocrine Neoplasia Type 1: A Longitudinal Cohort Study. J Clin Endocrinol Metab. 2026 Jan 7. doi:10.1210/clinem/dgaf704 [PMC free article: PMC13183421] [PubMed: 41498210] [CrossRef]

119.

Valdés N, Romero-Lluch AR, Diego E, Calatayud M, Lamas C, Araujo-Castro M, et al. Risk Factors Pituitary Adenomas Development in Multiple Endocrine Neoplasia Type 1: A Nationwide Study of 240 Cases. J Clin Endocrinol Metab. 2025 Sep 8. doi:10.1210/clinem/dgaf497 [PubMed: 40921719] [CrossRef]

120.

Manoharan J, Raue F, Lopez CL, Albers MB, Bollmann C, Fendrich V, et al. Is Routine Screening of Young Asymptomatic MEN1 Patients Necessary? World J Surg. 2017 Aug 1;41(8):2026–32. doi:.10.1007/s00268-017-3992-9 [PubMed: 28321559] [CrossRef]

121.

Makri A, Bonella MB, Keil MF, Hernandez-Ramirez L, Paluch G, Tirosh A, et al. Children with MEN1 gene mutations may present first (and at a young age) with Cushing disease. Clin Endocrinol (Oxf). 2018 Oct 1;89(4):437–43. doi:.10.1111/cen.13796 [PMC free article: PMC6341462] [PubMed: 29927501] [CrossRef]

122.

Raverot G, Burman P, Abreu AP, Heaney AP, Van Hulsteijn L, Lin AL, et al. Revised European Society of Endocrinology Clinical Practice Guideline for the management of aggressive pituitary tumours and pituitary carcinomas. European Journal of Endocrinology. Oxford University Press; 2025. p. R45–78. doi: PubMed PMID: 40506054.10.1093/ejendo/lvaf100 [PubMed: 40506054] [CrossRef]

123.

Fleseriu M, Gurnell M, McCormack A, Fukuoka H, Glezer A, Langlois F, et al. Pituitary incidentaloma: a Pituitary Society international consensus guideline statement. Nature Reviews Endocrinology. Nature Research; 2025. p. 638–55. doi: PubMed PMID: 40555795.10.1038/s41574-025-01134-8 [PubMed: 40555795] [CrossRef]

124.

Fleseriu M, Auchus R, Bancos I, Ben-Shlomo A, Bertherat J, Biermasz NR, et al. Consensus on diagnosis and management of Cushing’s disease: a guideline update. The Lancet Diabetes and Endocrinology. Elsevier Ltd; 2021. p. 847–75. doi: PubMed PMID: 34687601.10.1016/S2213-8587(21)00235-7 [PMC free article: PMC8743006] [PubMed: 34687601] [CrossRef]

125.

Melmed S, Casanueva FF, Hoffman AR, Kleinberg DL, Montori VM, Schlechte JA, et al. Diagnosis and treatment of hyperprolactinemia: An endocrine society clinical practice guideline. Journal of Clinical Endocrinology and Metabolism. 2011. p. 273–88. doi:.10.1210/jc.2010-1692 [PubMed: 21296991] [CrossRef]

126.

Freda PU, Beckers AM, Katznelson L, Molitch ME, Montori VM, Post KD, et al. Pituitary incidentaloma: An endocrine society clinical practice guideline. Journal of Clinical Endocrinology and Metabolism. 2011 Apr;96(4):894–904. doi:.10.1210/jc.2010-1048 [PMC free article: PMC5393422] [PubMed: 21474686] [CrossRef]

127.

Katznelson L, Laws ER, Melmed S, Molitch ME, Murad MH, Utz A, et al. Acromegaly: An endocrine society clinical practice guideline. Journal of Clinical Endocrinology and Metabolism. Endocrine Society; 2014. p. 3933–51. doi: PubMed PMID: 25356808.10.1210/jc.2014-2700 [PubMed: 25356808] [CrossRef]

128.

Incandela F, Feraco P, Putortì V, Geraci L, Salvaggio G, Sarno C, et al. Malignancy course of pituitary adenoma in MEN1 syndrome: Clinical-Neuroradiological signs. Eur J Radiol Open. 2020 Jan 1;7. doi:10.1016/j.ejro.2020.100242 [PMC free article: PMC7365899] [PubMed: 32695849] [CrossRef]

129.

Philippon M, Morange I, Barrie M, Barlier A, Taieb D, Dufour H, et al. Long-term control of a MEN1 prolactin secreting pituitary carcinoma after temozolomide treatment. Ann Endocrinol (Paris). 2012 Jun;73(3):225–9. doi:.10.1016/j.ando.2012.03.001 [PubMed: 22520146] [CrossRef]

130.

Gordon M, Varma D, McLean C, Bittar R, Burgess J, Topliss D. Metastatic prolactinoma presenting as a cervical spinal cord tumour in multiple endocrine neoplasia type one (MEN-1). Clin Endocrinol (Oxf). 2007 Jan;66(1):150–2. doi:.10.1111/j.1365-2265.2006.02686.x [PubMed: 17201817] [CrossRef]

131.

Benito M, Asa SL, LiVolsi VA, West VA, Snyder PJ. Gonadotroph tumor associated with multiple endocrine neoplasia type 1. In: Journal of Clinical Endocrinology and Metabolism. 2005. p. 570–4. doi: PubMed PMID: 15522929.10.1210/jc.2004-1373 [PubMed: 15522929] [CrossRef]

132.

Scheithauer BW, Kovacs K, Nose V, Lombardero M, Osamura YR, Lloyd R V., et al. Multiple endocrine neoplasia type 1-associated thyrotropin-producing pituitary carcinoma: report of a probable de novo example. Hum Pathol. 2009 Feb;40(2):270–8. doi:.10.1016/j.humpath.2008.06.013 [PubMed: 18755492] [CrossRef]

133.

Morokuma H, Ando T, Hayashida T, Horie I, Inoshita N, Murata F, et al. A Case of Nonfunctioning Pituitary Carcinoma That Responded to Temozolomide Treatment. Case Rep Endocrinol. 2012;2012:1–5. doi:10.1155/2012/645914 [PMC free article: PMC3472534] [PubMed: 23091742] [CrossRef]

134.

Huang W, Molitch ME. Management of nonfunctioning pituitary adenomas (NFAs): observation. Pituitary. Springer New York LLC; 2018. p. 162–7. doi:.10.1007/s11102-017-0856-0 [PubMed: 29280025] [CrossRef]

135.

Triponez F, Dosseh D, Goudet P, Cougard P, Bauters C, Murat A, et al. Epidemiology data on 108 MEN 1 patients from the GTE with isolated nonfunctioning tumors of the pancreas. Ann Surg. 2006 Feb;243(2):265–72. doi:.10.1097/01.sla.0000197715.96762.68 [PMC free article: PMC1448903] [PubMed: 16432361] [CrossRef]

136.

Vinault S, Mariet AS, Le Bras M, Mirallié E, Cardot-Bauters C, Pattou F, et al. Metastatic Potential and Survival of Duodenal and Pancreatic Tumors in Multiple Endocrine Neoplasia Type 1: A GTE and AFCE Cohort Study (Groupe d’étude des Tumeurs Endocrines and Association Francophone de Chirurgie Endocrinienne). Ann Surg. 2020 Dec 1;272(6):1094–101. doi:.10.1097/SLA.0000000000003162 [PubMed: 30585820] [CrossRef]

137.

Pipeleers-Marichal M, Somers G, Willems G, Foulis A, Imrie C, Bishop A, et al. Gastrinomas in the duodenums of patients with multiple endocrine neoplasia type 1 and the zollinger-ellison syndrome. New England Journal of Medicine. 1990;322(11):723–7. [PubMed: 1968616]

138.

Lévy-Bohbot N, Merle C, Goudet P, Delemer B, Calender A, Jolly D, et al. Prevalence, characteristics and prognosis of MEN 1-associated glucagonomas, VIPomas, and somatostatinomas: Study from the GTE (Groupe des Tumeurs Endocrines) registry. Gastroenterol Clin Biol. 2004;28(11):1075–81. doi:.10.1016/S0399-8320(04)95184-6 [PubMed: 15657529] [CrossRef]

139.

Borson-Chazot F, Garby L, Raverot G, Claustrat F, Raverot V, Sassolas G. Acromegaly induced by ectopic secretion of GHRH: A review 30 years after GHRH discovery. Ann Endocrinol (Paris). 2012 Dec;73(6):497–502. doi:.10.1016/j.ando.2012.09.004 [PubMed: 23122576] [CrossRef]

140.

Milanesi A, Yu R, Geller SA, Burton D, Deftos LJ, Wolin EM. Concurrent Primary Hyperparathyroidism and Humoral Hypercalcemia of Malignancy in a Patient With Multiple Endocrine Neoplasia Type 1. Pancreas [Internet]. 2011 May;40(4):634–7. Available from: www​.pancreasjournal.com [PubMed: 21483254]

141.

Klöppel G, Anlauf M, Perren A, Sipos B. Hyperplasia to neoplasia sequence of duodenal and pancreatic neuroendocrine diseases and pseudohyperplasia of the PP-cells in the pancreas. Endocr Pathol. 2014;25(2):181–5. doi:.10.1007/s12022-014-9317-8 [PubMed: 24718881] [CrossRef]

142.

Anlauf M, Perren A, Henopp T, Rudolph T, Garbrecht N, Schmitt A, et al. Allelic deletion of the MEN1 gene in duodenal gastrin and somatostatin cell neoplasms and their precursor lesions. Gut. 2007 May;56(5):637–44. doi:.10.1136/gut.2006.108910 [PMC free article: PMC1942169] [PubMed: 17135306] [CrossRef]

143.

van Beek DJ, Nell S, Verkooijen HM, Borel Rinkes IHM, Valk GD, Vriens MR, et al. Surgery for multiple endocrine neoplasia type 1-related insulinoma: long-term outcomes in a large international cohort. British Journal of Surgery. 2020 Oct 1;107(11):1489–99. doi:.10.1002/bjs.11632 [PMC free article: PMC7540387] [PubMed: 32352164] [CrossRef]

144.

Gibril F, Schumann M, Pace A, Jensen RT. Multiple Endocrine Neoplasia Type 1 and Zollinger-Ellison Syndrome: A Prospective Study of 107 Cases and Comparison with 1009 Cases from the Literature. Medicine. 2004 Jan;83(1):43–83. doi:.10.1097/01.md.0000112297.72510.32 [PubMed: 14747767] [CrossRef]

145.

van Beek DJ, Nell S, Pieterman CRC, de Herder WW, van de Ven AC, Dekkers OM, et al. Prognostic factors and survival in MEN1 patients with gastrinomas: Results from the DutchMEN study group (DMSG). J Surg Oncol. 2019 Nov 1;120(6):966–75. doi:.10.1002/jso.25667 [PMC free article: PMC6852496] [PubMed: 31401809] [CrossRef]

146.

Jensen R, Ito T. Gastrinoma. In: Feingold K, Adler R, Ahmed S, Anawalt B, Blackman M, Chrousos G, et al., editors. Endotext [Internet]. South Dartmouth (MA).: MDText.com, Inc. Copyright © 2000-2021; 2000.

147.

Hampel H, Bennett RL, Buchanan A, Pearlman R, Wiesner GL. A practice guideline from the American College of Medical Genetics and Genomics and the National Society of Genetic Counselors: Referral indications for cancer predisposition assessment. Genetics in Medicine. Nature Publishing Group; 2015. p. 70–87. doi: PubMed PMID: 25394175.10.1038/gim.2014.147 [PubMed: 25394175] [CrossRef]

148.

Norton JA, Alexander HR, Fraker DL, Venzon DJ, Gibril F, Jensen RT. Comparison of Surgical Results in Patients With Advanced and Limited Disease With Multiple Endocrine Neoplasia Type 1 and Zollinger-Ellison Syndrome. ANNALS OF SURGERY. 2001. Report. [PMC free article: PMC1422073] [PubMed: 11573043]

149.

Conemans E, Nell S, Pieterman C, de Herder W, Dekkers O, Hermus A, et al. Prognostic factors for survival of MEN1 patients with duodenopancreatic tumors metastatic to the liver: results from the DMSG. Endocrine Practice. 2017 Jun;23(6):641–8. [PubMed: 28225311]

150.

Giudici F, Cavalli T, Giusti F, Gronchi G, Batignani G, Tonelli F, et al. Natural History of MEN1 GEP-NET: Single-Center Experience After a Long Follow-Up. World J Surg. 2017 Sep 1;41(9):2312–23. doi:.10.1007/s00268-017-4019-2 [PubMed: 28429092] [CrossRef]

151.

Christakis I, Qiu W, Hyde SM, Cote GJ, Grubbs EG, Perrier ND, et al. Genotype-phenotype pancreatic neuroendocrine tumor relationship in multiple endocrine neoplasia type 1 patients: A 23-year experience at a single institution. Surgery (United States). 2018 Jan 1;163(1):212–7. doi:.10.1016/j.surg.2017.04.044 [PubMed: 29122330] [CrossRef]

152.

Nagtegaal ID, Odze RD, Klimstra D, Paradis V, Rugge M, Schirmacher P, et al. The 2019 WHO classification of tumours of the digestive system. Histopathology. Blackwell Publishing Ltd; 2020. p. 182–8. doi: PubMed PMID: 31433515.10.1111/his.13975 [PMC free article: PMC7003895] [PubMed: 31433515] [CrossRef]

153.

Amin M, Edge S, Greene F, Byrd D, Brookland R, Washington M. AJCC Cancer Staging Manual. 8th ed. In. New York: Springer International Publishing; 2017. p. 407–19.

154.

van Treijen MJC, van Beek DJ, van Leeuwaarde RS, Vriens MR, Valk GD. Diagnosing nonfunctional pancreatic NETs in MEN1: The evidence base. J Endocr Soc. 2018;2(9):1067–88. doi:10.1210/JS.2018-00087 [PMC free article: PMC6125714] [PubMed: 30202829] [CrossRef]

155.

Sadowski SM, Pieterman CRC, Perrier ND, Triponez F, Valk GD. Prognostic factors for the outcome of nonfunctioning pancreatic neuroendocrine tumors in MEN1: A systematic review of literature. Endocrine-Related Cancer. BioScientifica Ltd.; 2020. p. R145–61. doi: PubMed PMID: 32229700.10.1530/ERC-19-0372 [PMC free article: PMC7304521] [PubMed: 32229700] [CrossRef]

156.

Partelli S, Tamburrino D, Lopez C, Albers M, Milanetto AC, Pasquali C, et al. Active Surveillance versus Surgery of Nonfunctioning Pancreatic Neuroendocrine Neoplasms ≤2 cm in MEN1 Patients. Neuroendocrinology. 2016 Sep 1;103(6):779–86. doi:.10.1159/000443613 [PubMed: 26731608] [CrossRef]

157.

Nell S, Verkooijen HM, Pieterman CRC, De Herder WW, Hermus AR, Dekkers OM, et al. Management of MEN1 Related Nonfunctioning Pancreatic NETs: A Shifting Paradigm: Results from the DutchMEN1 Study Group. Ann Surg. 2018 Jun 1;267(6):1155–60. doi:.10.1097/SLA.0000000000002183 [PubMed: 28257328] [CrossRef]

158.

Triponez F, Goudet P, Dosseh D, Cougard P, Bauters C, Murat A, et al. Is surgery beneficial for MEN1 patients with small (≤2 cm), nonfunctioning pancreaticoduodenal endocrine tumor? An analysis of 65 patients from the GTE. World J Surg. 2006 May;30(5):654–62. doi:.10.1007/s00268-005-0354-9 [PubMed: 16680582] [CrossRef]

159.

Pieterman CRC, De Laat JM, Twisk JWR, Van Leeuwaarde RS, De Herder WW, Dreijerink KMA, et al. Long-term natural course of small nonfunctional pancreatic neuroendocrine tumors in MEN1-results from the Dutch MEN1 study group. Journal of Clinical Endocrinology and Metabolism. 2017 Oct 1;102(10):3795–805. doi:.10.1210/jc.2017-00372 [PubMed: 28938468] [CrossRef]

160.

Hackeng WM, Brosens LAA, Kim JY, O’Sullivan R, Sung YN, Liu TC, et al. Non-functional pancreatic neuroendocrine tumours: ATRX/DAXX and alternative lengthening of telomeres (ALT) are prognostically independent from ARX/PDX1 expression and tumour size. Gut. 2022 May 1;71(5):961–73. doi:.10.1136/gutjnl-2020-322595 [PMC free article: PMC8511349] [PubMed: 33849943] [CrossRef]

161.

Cejas P, Drier Y, Dreijerink KMA, Brosens LAA, Deshpande V, Epstein CB, et al. Enhancer signatures stratify and predict outcomes of non-functional pancreatic neuroendocrine tumors. Nat Med. 2019 Aug 1;25(8):1264–9. doi:.10.1038/s41591-019-0493-4 [PMC free article: PMC6919319] [PubMed: 31263286] [CrossRef]

162.

Chan CS, Laddha S V., Lewis PW, Koletsky MS, Robzyk K, Da Silva E, et al. ATRX, DAXX or MEN1 mutant pancreatic neuroendocrine tumors are a distinct alpha-cell signature subgroup. Nat Commun. 2018 Dec 1;9(1). doi:.10.1038/s41467-018-06498-2 [PMC free article: PMC6185985] [PubMed: 30315258] [CrossRef]

163.

Ghosh R, Akbulut D, Simonds WF, Weinstein LS, Sadowski SM, Blau JE, et al. MEN1-Related Neuroendocrine Tumors Show c-MET Overexpression. J Endocr Soc. 2025 Oct 1;9(10). doi:10.1210/jendso/bvaf147 [PMC free article: PMC12464676] [PubMed: 41018051] [CrossRef]

164.

Fahrmann JF, Wasylishen AR, Pieterman CRC, Irajizad E, Vykoukal J, Murage E, et al. A Blood-based Polyamine Signature Associated with MEN1 Duodenopancreatic Neuroendocrine Tumor Progression. Journal of Clinical Endocrinology and Metabolism. 2021 Dec 1;106(12):E4969–80. doi:.10.1210/clinem/dgab554 [PMC free article: PMC8864750] [PubMed: 34318891] [CrossRef]

165.

Niederle B, Selberherr A, Bartsch DK, Brandi ML, Doherty GM, Falconi M, et al. Multiple Endocrine Neoplasia Type 1 and the Pancreas: Diagnosis and Treatment of Functioning and Non-Functioning Pancreatic and Duodenal Neuroendocrine Neoplasia within the MEN1 Syndrome - An International Consensus Statement. Neuroendocrinology. 2021;111(7):609–30. doi:.10.1159/000511791 [PubMed: 32971521] [CrossRef]

166.

Metz DC, Cadiot G, Poitras P, Ito T, Jensen RT. Diagnosis of Zollinger–Ellison Syndrome in the Era of Ppis, Faulty Gastrin Assays, Sensitive Imaging and Limited Access to Acid Secretory Testing. Int J Endocr Oncol. 2017 Nov;4(4):167–85. doi:.10.2217/ije-2017-0018 [PMC free article: PMC5757869] [PubMed: 29326808] [CrossRef]

167.

Singh Ospina N, Donegan D, Rodriguez-Gutierrez R, Al-Hilli Z, Young WF. Assessing for Multiple Endocrine Neoplasia Type 1 in Patients Evaluated for Zollinger-Ellison Syndrome—Clues to a Safer Diagnostic Process. American Journal of Medicine. 2017 May 1;130(5):603–5. doi:.10.1016/j.amjmed.2016.11.035 [PubMed: 28011308] [CrossRef]

168.

Hofland J, Falconi M, Christ E, Castaño JP, Faggiano A, Lamarca A, et al. European Neuroendocrine Tumor Society 2023 guidance paper for functioning pancreatic neuroendocrine tumour syndromes. J Neuroendocrinol. 2023 Aug 1;35(8). doi:.10.1111/jne.13318 [PubMed: 37578384] [CrossRef]

169.

Albers MB, Manoharan J, Bartsch DK. Contemporary surgical management of the Zollinger-Ellison syndrome in multiple endocrine neoplasia type 1. Best Practice and Research: Clinical Endocrinology and Metabolism. Bailliere Tindall Ltd; 2019. doi: PubMed PMID: 31521501.10.1016/j.beem.2019.101318 [PubMed: 31521501] [CrossRef]

170.

Hackeng WM, Van Beek DJ, Kok ASM, Van Emst M, Morsink FHM, Van Treijen MJC, et al. Metastatic Patterns of Duodenopancreatic Neuroendocrine Tumors in Patients With Multiple Endocrine Neoplasia Type 1. Am J Surg Pathol [Internet]. 2022. Report. Available from: www​.ajsp.com|159 [PubMed: 34560682]

171.

Gibril F, Venzon D, Ojeaburu J, Bashir S, Jensen R. Prospective study of the natural history of gastrinoma in patients with MEN1: definition of an aggressive and a nonaggressive form. Journal of Clinical Endocrinology and Metabolism. 2001 Nov;86(11):5282–93. [PubMed: 11701693]

172.

Panzuto F, Ramage J, Pritchard DM, van Velthuysen MLF, Schrader J, Begum N, et al. European Neuroendocrine Tumor Society (ENETS) 2023 guidance paper for gastroduodenal neuroendocrine tumours (NETs) G1–G3. J Neuroendocrinol. 2023 Aug 1;35(8). doi:.10.1111/jne.13306 [PubMed: 37401795] [CrossRef]

173.

Endall R, Thompson M, Parameswaran V, Burgess J. The Relationship of Gastrinoma in MEN 1 to Helicobacter pylori infection. Journal of Clinical Endocrinology and Metabolism. 2020 Jan 8;105(3). doi:.10.1210/clinem/dgaa004 [PubMed: 31919513] [CrossRef]

174.

Cryer PE, Axelrod L, Grossman AB, Heller SR, Montori VM, Seaquist ER, et al. Evaluation and management of adult hypoglycemic disorders: An endocrine society clinical practice guideline. Journal of Clinical Endocrinology and Metabolism. 2009;94(3):709–28. doi:10.1210/jc.2008-1410 [PubMed: 19088155] [CrossRef]

175.

Bartsch DK, Albers M, Knoop R, Kann PH, Fendrich V, Waldmann J. Enucleation and limited pancreatic resection provide long-term cure for insulinoma in multiple endocrine neoplasia type 1. Neuroendocrinology. 2014;98(4):290–8. doi:.10.1159/000357779 [PubMed: 24356648] [CrossRef]

176.

Vezzosi D, Cardot-Bauters C, Bouscaren N, Lebras M, Bertholon-Grégoire M, Niccoli P, et al. Long-term results of the surgical management of insulinoma patients with MEN1: A Groupe d’étude des Tumeurs Endocrines (GTE) retrospective study. Eur J Endocrinol. 2015 Mar 1;172(3):309–19. doi:.10.1530/EJE-14-0878 [PubMed: 25538206] [CrossRef]

177.

Tonelli F, Giudici F, Nesi G, Batignani G, Brandi ML. Operation for insulinomas in multiple endocrine neoplasia type 1: When pancreatoduodenectomy is appropriate. Surgery (United States). 2017 Mar 1;161(3):727–34. doi:.10.1016/j.surg.2016.09.017 [PubMed: 27863775] [CrossRef]

178.

Antwi K, Nicolas G, Fani M, Heye T, Pattou F, Grossman A, et al. Ga-Exendin-4 PET/CT Detects Insulinomas in Patients with Endogenous Hyperinsulinemic Hypoglycemia in MEN-1. Journal of Clinical Endocrinology and Metabolism. 2019 Aug 13;104(12):5843–52. doi:.10.1210/jc.2018-02754 [PubMed: 31298706] [CrossRef]

179.

Shah R, Garg R, Majmundar M, Purandare N, Malhotra G, Patil V, et al. Exendin-4-based imaging in insulinoma localization: Systematic review and meta-analysis. Clin Endocrinol (Oxf). 2021 Aug 1;95(2):354–64. doi:.10.1111/cen.14406 [PubMed: 33386617] [CrossRef]

180.

van Beek DJ, Nell S, Verkooijen HM, Borel Rinkes IHM, Valk GD, Vriens MR, et al. Prognosis after surgery for multiple endocrine neoplasia type 1-related pancreatic neuroendocrine tumors: Functionality matters. Surgery (United States). 2021 Apr 1;169(4):963–73. doi:.10.1016/j.surg.2020.09.037 [PMC free article: PMC9263962] [PubMed: 33220975] [CrossRef]

181.

Dasari BVM, Al-Shakhshir S, Pawlik TM, Shah T, Marudanayagam R, Sutcliffe RP, et al. Outcomes of Surgical and Endoscopic Resection of Duodenal Neuroendocrine Tumours (NETs): a Systematic Review of the Literature. Journal of Gastrointestinal Surgery. Springer New York LLC; 2018. p. 1652–8. doi:.10.1007/s11605-018-3825-7 [PubMed: 29869091] [CrossRef]

182.

Rimbaş M, Horumbă M, Rizzatti G, Crinò SF, Gasbarrini A, Costamagna G, et al. Interventional endoscopic ultrasound for pancreatic neuroendocrine neoplasms. Digestive Endoscopy. Blackwell Publishing; 2020. p. 1031–41. doi: PubMed PMID: 31995848.10.1111/den.13635 [PubMed: 31995848] [CrossRef]

183.

Caplin ME, Pavel M, Ćwikła JB, Phan AT, Raderer M, Sedláčková E, et al. Lanreotide in Metastatic Enteropancreatic Neuroendocrine Tumors. New England Journal of Medicine. 2014 Jul 17;371(3):224–33. doi:.10.1056/nejmoa1316158 [PubMed: 25014687] [CrossRef]

184.

Caplin ME, Pavel M, Ćwikła JB, Phan AT, Raderer M, Sedláčkova E, et al. Anti-tumour effects of lanreotide for pancreatic and intestinal neuroendocrine tumours: The CLARINET open-label extension study. Endocr Relat Cancer. 2016 Mar 1;23(3):191–9. doi:.10.1530/ERC-15-0490 [PMC free article: PMC4740728] [PubMed: 26743120] [CrossRef]

185.

Ramundo V, Del Prete M, Marotta V, Marciello F, Camera L, Napolitano V, et al. Impact of long-acting octreotide in patients with early-stage MEN1-related duodeno-pancreatic neuroendocrine tumours. Clin Endocrinol (Oxf). 2014;80(6):850–5. doi:.10.1111/cen.12411 [PubMed: 24443791] [CrossRef]

186.

Cioppi F, Cianferotti L, Masi L, Giusti F, Brandi ML. The LARO-MEN1 study: a longitudinal clinical experience with octreotide Long-Acting Release in patients with Multiple Endocrine Neoplasia type 1 Syndrome. Clinical Cases in Mineral & Bone Metabolism. 2017 May;(2):123–30. [PMC free article: PMC5726195] [PubMed: 29263719]

187.

Faggiano A, Modica R, Lo Calzo F, Camera L, Napolitano V, Altieri B, et al. Lanreotide Therapy vs Active Surveillance in MEN1-Related Pancreatic Neuroendocrine Tumors < 2 Centimeters. Journal of Clinical Endocrinology and Metabolism. 2019 Sep 12;105(1). doi:.10.1210/clinem/dgz007 [PubMed: 31586182] [CrossRef]

188.

Pieterman CRC, Sadowski SM, Maxwell JE, Katz MHG, Lines KE, Heaphy CM, et al. Hereditary endocrine tumours: Current state-of-the-art and research opportunities: MEN1-related pancreatic NETs: Identification of unmet clinical needs and future directives. Endocrine-Related Cancer. BioScientifica Ltd.; 2020. p. T9–25. doi: PubMed PMID: 32069215.10.1530/ERC-19-0441 [PubMed: 32069215] [CrossRef]

189.

Pavel M, O’Toole D, Costa F, Capdevila J, Gross D, Kianmanesh R, et al. ENETS consensus guidelines update for the management of distant metastatic disease of intestinal, pancreatic, bronchial neuroendocrine neoplasms (NEN) and NEN of unknown primary site. In: Neuroendocrinology. S. Karger AG; 2016. p. 172–85. doi: PubMed PMID: 26731013.10.1159/000443167 [PubMed: 26731013] [CrossRef]

190.

Yao JC, Shah MH, Lombard Bohas C, Wolin EM, Cutsem V, Hobday TJ, et al. Everolimus for Advanced Pancreatic Neuroendocrine Tumors. N Engl J Med. 2011. Report. [PMC free article: PMC4208619] [PubMed: 21306238]

191.

Raymond E, Dahan L, Raoul JL, Bang YJ, Borbath I, Lombard-Bohas C, et al. Sunitinib Malate for the Treatment of Pancreatic Neuroendocrine Tumors. n engl j med [Internet]. 2011. Report. Available from: http://ctep​.cancer.gov​/protocolDevelopment/ [PubMed: 21306237]

192.

Strosberg J, El-Haddad G, Wolin E, Hendifar A, Yao J, Chasen B, et al. Phase 3 Trial of 177 Lu-Dotatate for Midgut Neuroendocrine Tumors . New England Journal of Medicine. 2017 Jan 12;376(2):125–35. doi:.10.1056/nejmoa1607427 [PMC free article: PMC5895095] [PubMed: 28076709] [CrossRef]

193.

Frost M, Lines KE, Thakker R V. Current and emerging therapies for PNETS in patients with or without MEN1. Nature Reviews Endocrinology. Nature Publishing Group; 2018. p. 216–27. doi: PubMed PMID: 29449689.10.1038/nrendo.2018.3 [PMC free article: PMC6538535] [PubMed: 29449689] [CrossRef]

194.

Debelenko L, Emmert-Buck M, Zhuang Z, Epshteyn E, Moskaluk C, Jensen R, et al. The multiple endocrine neoplasia type I gene locus is involved in the pathogenesis of type II gastric carcinoids. Gastroenterology. 1997 Sep;113(3):773–81. [PubMed: 9287968]

195.

Lee L, Ramos-Alvarez I, Ito T, Jensen RT. Insights into effects/risks of chronic hypergastrinemia and lifelong ppi treatment in man based on studies of patients with zollinger–ellison syndrome. Int J Mol Sci. 2019 Oct 2;20(20). doi:.10.3390/ijms20205128 [PMC free article: PMC6829234] [PubMed: 31623145] [CrossRef]

196.

Manoharan J, Anlauf M, Albers MB, Denzer UW, Mintziras I, Wächter S, et al. Gastric enterochromaffin-like cell changes in multiple endocrine neoplasia type 1. Clin Endocrinol (Oxf). 2021 Sep 1;95(3):439–46. doi:.10.1111/cen.14430 [PubMed: 33506527] [CrossRef]

197.

Richards ML, Gauger P, Thompson NW, Giordano TJ. Regression of type II gastric carcinoids in multiple endocrine neoplasia type 1 patients with Zollinger-Ellison syndrome after surgical excision of all gastrinomas. World J Surg. 2004;28(7):652–8. doi:.10.1007/s00268-004-7345-0 [PubMed: 15383867] [CrossRef]

198.

Klöppel G, Anlauf M, Perren A. Endocrine precursor lesions of gastroenteropancreatic neuroendocrine tumors. In: Endocrine Pathology. 2007. p. 150–5. doi: PubMed PMID: 18058264.10.1007/s12022-007-0025-5 [PubMed: 18058264] [CrossRef]

199.

Berna MJ, Annibale B, Marignani M, Luong TV, Corleto V, Pace A, et al. A prospective study of gastric carcinoids and enterochromaffin-like cell changes in multiple endocrine neoplasia type 1 and Zollinger-Ellison syndrome: Identification of risk factors. Journal of Clinical Endocrinology and Metabolism. 2008;93(5):1582–91. doi:.10.1210/jc.2007-2279 [PMC free article: PMC2386679] [PubMed: 18270260] [CrossRef]

200.

Tomassetti P, Migliori M, Caletti G, Fusaroli P, Corinaldesi R, Gullo L. Treatment of type II gastric carcinoid tumors with somatostatin analogues. New England Journal of Medicine. 2000 Aug;343(8):551. [PubMed: 10954763]

201.

Bordi C, Falchetti A, Azzoni C, D’Adda T, Canaverse G, Guariglia A, et al. Aggressive forms of gastric neuroendocrine tumors in multiple endocrine neoplasia type I. American Journal of Surgical Pathology. 1997 Sep;21(9):1075–82. [PubMed: 9298884]

202.

Norton JA, Melcher ML, Gibril F, Jensen RT. Gastric carcinoid tumors in multiple endocrine neoplasia-1 patients with Zollinger-Ellison syndrome can be symptomatic, demonstrate aggressive growth, and require surgical treatment. Surgery. 2004;136(6):1267–74. doi:10.1016/j.surg.2004.06.057 [PubMed: 15657586] [CrossRef]

203.

Gao Y, Li R, Wu L, Yang H, Mao J, Zhao W. Thymoma in multiple endocrine neoplasia type 1: a case report and systematic review. Endocrine. 2023 Nov 1;82(2):442–9. doi:.10.1007/s12020-023-03440-5 [PubMed: 37668926] [CrossRef]

204.

Mandl A, Welch JM, Kapoor G, Parekh VI, Schrump DS, Ripley RT, et al. Two distinct classes of thymic tumors in patients with MEN1 show LOH at the MEN1 locus. Endocr Relat Cancer. 2021;28(11):L15–9. doi:.10.1530/ERC-21-0226 [PMC free article: PMC8558845] [PubMed: 34515662] [CrossRef]

205.

Volante M, Mete O, Pelosi G, Roden AC, Speel EJM, Uccella S. Molecular Pathology of Well-Differentiated Pulmonary and Thymic Neuroendocrine Tumors: What Do Pathologists Need to Know? Endocrine Pathology. Springer; 2021. p. 154–68. doi: PubMed PMID: 33641055.10.1007/s12022-021-09668-z [PMC free article: PMC7960615] [PubMed: 33641055] [CrossRef]

206.

Teh B, McArdle John, Pheng Chan S, Menon J, Hartley L, Pullan P, et al. Clinicopathologic studies of thymic carcinoids in Multiple Endocrine Neoplasia Type 1. Medicine (United States). 1997 Jan;76(1):21–9. [PubMed: 9064485]

207.

Ye L, Wang W, Ospina NS, Jiang L, Christakis I, Lu J, et al. Clinical features and prognosis of thymic neuroendocrine tumours associated with multiple endocrine neoplasia type 1: A single-centre study, systematic review and meta-analysis. Clin Endocrinol (Oxf). 2017 Dec 1;87(6):706–16. doi:.10.1111/cen.13480 [PubMed: 28940393] [CrossRef]

208.

Singh Ospina N, Thompson GB, C. Nichols F, D. Cassivi S, Young WF. Thymic and Bronchial Carcinoid Tumors in Multiple Endocrine Neoplasia Type 1: The Mayo Clinic Experience from 1977 to 2013. Horm Cancer. 2015 Jun 13;6(5–6):247–53. doi:.10.1007/s12672-015-0228-z [PMC free article: PMC10355915] [PubMed: 26070346] [CrossRef]

209.

Sakurai A, Imai T, Kikumori T, Horiuchi K, Okamoto T, Uchino S, et al. Thymic neuroendocrine tumour in multiple endocrine neoplasia type 1: Female patients are not rare exceptions. Clin Endocrinol (Oxf). 2013 Feb;78(2):248–54. doi:.10.1111/j.1365-2265.2012.04467.x [PubMed: 22690831] [CrossRef]

210.

Goudet P, Murat A, Cardot-Bauters C, Emy P, Baudin E, Du Boullay Choplin H, et al. Thymic neuroendocrine tumors in multiple endocrine neoplasia type 1: A comparative study on 21 cases among a series of 761 MEN1 from the GTE (Groupe des Tumeurs Endocrines). World J Surg. 2009;33(6):1197–207. doi:.10.1007/s00268-009-9980-y [PubMed: 19294466] [CrossRef]

211.

Gibril F, Chen YJ, Schrump DS, Vortmeyer A, Zhuang Z, Lubensky IA, et al. Prospective study of thymic carcinoids in patients with multiple endocrine neoplasia type 1. Journal of Clinical Endocrinology and Metabolism. 2003 Mar 1;88(3):1066–81. doi:.10.1210/jc.2002-021314 [PubMed: 12629087] [CrossRef]

212.

Ferolla P, Falchetti A, Filosso P, Tomassetti P, Tamburrano G, Avenia N, et al. Thymic neuroendocrine carcinoma (carcinoid) in multiple endocrine neoplasia type 1 syndrome: The Italian series. Journal of Clinical Endocrinology and Metabolism. 2005 May;90(5):2603–9. doi:.10.1210/jc.2004-1155 [PubMed: 15713725] [CrossRef]

213.

De Laat JM, Pieterman CR, Van Den Broek MF, Twisk JW, Hermus AR, Dekkers OM, et al. Natural course and survival of neuroendocrine tumors of thymus and lung in MEN1 patients. Journal of Clinical Endocrinology and Metabolism. 2014 Sep 1;99(9):3325–33. doi:.10.1210/jc.2014-1560 [PubMed: 24915123] [CrossRef]

214.

Christakis I, Qiu W, Silva Figueroa AM, Hyde S, Cote GJ, Busaidy NL, et al. Clinical Features, Treatments, and Outcomes of Patients with Thymic Carcinoids and Multiple Endocrine Neoplasia Type 1 Syndrome at MD Anderson Cancer Center. Horm Cancer. 2016 Aug 1;7(4):279–87. doi:.10.1007/s12672-016-0269-y [PMC free article: PMC10355947] [PubMed: 27311764] [CrossRef]

215.

Yliaska I, Tokola H, Ebeling T, Kuismin O, Ukkola O, Koivikko ML, et al. Thymic neuroendocrine tumors in patients with multiple endocrine neoplasia type 1. Endocrine. 2022 Sep 1;77(3):527–37. doi:.10.1007/s12020-022-03099-4 [PMC free article: PMC9385812] [PubMed: 35696052] [CrossRef]

216.

Lim LC, Tan MH, Eng C, Teh BT, Rajasoorya RC. Thymic carcinoid in multiple endocrine neoplasia 1: Genotype-phenotype correlation and prevention. J Intern Med. 2006 Apr;259(4):428–32. doi:.10.1111/j.1365-2796.2006.01619.x [PubMed: 16594911] [CrossRef]

217.

Baudin E, Caplin M, Garcia-Carbonero R, Fazio N, Ferolla P, Filosso PL, et al. Lung and thymic carcinoids: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Annals of Oncology. 2021 Apr;32(4):439–51. doi:10.1016/j.annonc [PubMed: 33482246] [CrossRef]

218.

De Jong MC, Parameswaran R. Revisiting the Evidence for Routine Transcervical Thymectomy for the Prevention of Thymic Carcinoid Tumours in MEN-1 Patients. Oncology (Switzerland). S. Karger AG; 2022. p. 696–700. doi: PubMed PMID: 36103839.10.1159/000526775 [PubMed: 36103839] [CrossRef]

219.

Van Den Broek MFM, De Laat JM, Van Leeuwaarde RS, Van De Ven AC, De Herder WW, Dekkers OM, et al. The Management of Neuroendocrine Tumors of the Lung in MEN1: Results from the Dutch MEN1 Study Group. Journal of Clinical Endocrinology and Metabolism. 2021 Feb 1;106(2):E1014–27. doi:.10.1210/clinem/dgaa800 [PubMed: 33135721] [CrossRef]

220.

Sachithanandan N, Harle RA, Burgess JR. Bronchopulmonary carcinoid in multiple endocrine neoplasia type 1. Cancer. 2005. p. 509–15. doi:.10.1002/cncr.20825 [PubMed: 15611976] [CrossRef]

221.

Lecomte P, Binquet C, Le Bras M, Tabarin A, Cardot-Bauters C, Borson-Chazot F, et al. Histologically Proven Bronchial Neuroendocrine Tumors in MEN1: A GTE 51-Case Cohort Study. World J Surg. 2018 Jan 1;42(1):143–52. doi:.10.1007/s00268-017-4135-z [PubMed: 28785839] [CrossRef]

222.

Bartsch DK, Albers MB, Lopez CL, Apitzsch JC, Walthers EM, Fink L, et al. Bronchopulmonary Neuroendocrine Neoplasms and Their Precursor Lesions in Multiple Endocrine Neoplasia Type 1. Neuroendocrinology. 2016 May 1;103(3–4):240–7. doi:.10.1159/000435921 [PubMed: 26113081] [CrossRef]

223.

van den Broek MFM, Levy S, Buikhuisen WA, Dijke K, Hartemink KJ, van Leeuwaarde RS, et al. Well-Differentiated Bronchopulmonary Neuroendocrine Tumors: More Than One Entity. Journal of Thoracic Oncology. 2021 Nov 1;16(11):1810–20. doi:.10.1016/j.jtho.2021.07.020 [PubMed: 34352379] [CrossRef]

224.

Sadowski SM, Cadiot G, Dansin E, Goudet P, Triponez F. The future: surgical advances in MEN1 therapeutic approaches and management strategies. Endocrine-related cancer. 2017. p. T243–60. doi:.10.1530/ERC-17-0285 [PubMed: 28811298] [CrossRef]

225.

Koumarianou A, Filosso PL, Bodei L, Castano JP, Fernandez-Cuesta L, Deroose CM, et al. Clinical management of typical and atypical carcinoids/neuroendocrine tumors in ENETS centres of excellence (CoE): Survey from the ENETS lung NET task force. J Neuroendocrinol. 2024 Aug 1;36(8). doi:.10.1111/jne.13412 [PubMed: 38754956] [CrossRef]

226.

Cieszanowski A, Lisowska A, Dabrowska M, Korczynski P, Zukowska M, Grudzinski IP, et al. MR imaging of pulmonary nodules: Detection rate and accuracy of size estimation in comparison to computed tomography. PLoS One. 2016 Jun 1;11(6). doi:.10.1371/journal.pone.0156272 [PMC free article: PMC4892605] [PubMed: 27258047] [CrossRef]

227.

Sim AJ, Kaza E, Singer L, Rosenberg SA. A review of the role of MRI in diagnosis and treatment of early stage lung cancer. Clinical and Translational Radiation Oncology. Elsevier Ireland Ltd; 2020. p. 16–22. doi:10.1016/j.ctro.2020.06.002 [PMC free article: PMC7306507] [PubMed: 32596518] [CrossRef]

228.

Sadowski SM, Millo C, Cottle-Delisle C, Merkel R, Yang LA, Herscovitch P, et al. Results of 68Gallium-DOTATATE PET/CT Scanning in Patients with Multiple Endocrine Neoplasia Type 1. J Am Coll Surg. 2015 Aug 1;221(2):509–17. doi:.10.1016/j.jamcollsurg.2015.04.005 [PMC free article: PMC4515773] [PubMed: 26206648] [CrossRef]

229.

Lastoria S, Marciello F, Faggiano A, Aloj L, Caracò C, Aurilio M, et al. Role of 68Ga-DOTATATE PET/CT in patients with multiple endocrine neoplasia type 1 (MEN1). Endocrine. 2016 Jun 1;52(3):488–94. doi:.10.1007/s12020-015-0702-y [PubMed: 26242621] [CrossRef]

230.

Froeling V, Elgeti F, Maurer MH, Scheurig-Muenkler C, Beck A, Kroencke TJ, et al. Impact of Ga-68 DOTATOC PET/CT on the diagnosis and treatment of patients with multiple endocrine neoplasia. Ann Nucl Med. 2012 Nov;26(9):738–43. doi:.10.1007/s12149-012-0634-z [PubMed: 22865406] [CrossRef]

231.

Albers MB, Librizzi D, Lopez CL, Manoharan J, Apitzsch JC, Slater EP, et al. Limited Value of Ga-68-DOTATOC-PET-CT in Routine Screening of Patients with Multiple Endocrine Neoplasia Type 1. World J Surg. 2017 Jun 1;41(6):1521–7. doi:.10.1007/s00268-017-3907-9 [PubMed: 28138732] [CrossRef]

232.

Gao J, Liu C, Zhou J, Pan Y, Zhang Y. The lesion detection rate of Ga-68 DOTATATE PET/MR in multiple endocrine neoplasia type 1. J Med Imaging Radiat Oncol. 2024 Apr 1;68(3):250–6. doi:.10.1111/1754-9485.13641 [PubMed: 38563291] [CrossRef]

233.

Singh R, Goel SA, Singh JS, John DR, Suthar PP. Multiple Endocrine Neoplasia Type 1 (MEN1) Syndrome Clinical Presentation and the Role of Newer Functional Imaging in the Diagnosis and Management: A Case Report. Cureus. 2025 Feb 24. doi:10.7759/cureus.79580 [PMC free article: PMC11944600] [PubMed: 40144450] [CrossRef]

234.

Harding B, Lemos MC, Reed AAC, Walls G V., Jeyabalan J, Bowl MR, et al. Multiple endocrine neoplasia type 1 knockout mice develop parathyroid, pancreatic, pituitary and adrenal tumours with hypercalcaemia, hypophosphataemia and hypercorticosteronaemia. Endocr Relat Cancer. 2009 Dec;16(4):1313–27. doi:.10.1677/ERC-09-0082 [PMC free article: PMC4439740] [PubMed: 19620250] [CrossRef]

235.

Loffler KA, Biondi CA, Gartside M, Waring P, Stark M, Serewko-Auret MM, et al. Broad tumor spectrum in a mouse model of multiple endocrine neoplasia type 1. Int J Cancer. 2007 Jan 15;120(2):259–67. doi:.10.1002/ijc.22288 [PubMed: 17044021] [CrossRef]

236.

Ludwig L, Schleithoff L, Kessler H, Wagner PK, Boehm B 0, Karges W. Loss of Wild-Type MEND Gene Expression in Multiple Endocrine Neoplasia Type 1-Associated Parathyroid Adenoma. Endocrine Journal. 1999. Report. [PubMed: 10580746]

237.

Skogseid B, Larsson C, Lindgren P, Kvanta E, Rastad J, Theodorsson E, et al. Clinical and genetic features of adrenocortical lesions in multiple endocrine neoplasia type 1. Journal of Clinical Endocrinology and Metabolism. 1992;75(1):76–81. [PubMed: 1352309]

238.

Gatta-Cherifi B, Chabre O, Murat A, Niccoli P, Cardot-Bauters C, Rohmer V, et al. Adrenal involvement in MEN1. Analysis of 715 cases from the Groupe d’étude des Tumeurs Endocrines database. Eur J Endocrinol. 2012 Feb;166(2):269–79. doi:.10.1530/EJE-11-0679 [PubMed: 22084155] [CrossRef]

239.

Barzon L, Pasquali C, Grigoletto C, Pedrazzoli S, Boscaro M, Fallo F. Multiple endocrine neoplasia type 1 and adrenal lesions. Journal of Urology. 2001;166(1):24–7. [PubMed: 11435815]

240.

Burgess J, Harle R, Tucker P, Parameswaran V, Davies P, Greenaway T, et al. Adrenal lesions in a large kindred with multiple endocrine neoplasia type 1. Archives of Surgery. 1996 Jul;131(7):699–702. [PubMed: 8678766]

241.

Langer P, Cupisti K, Bartsch DK, Nies C, Goretzki PE, Rothmund M, et al. Adrenal involvement in multiple endocrine neoplasia type 1. In: World Journal of Surgery. 2002. p. 891–6. doi: PubMed PMID: 12016472.10.1007/s00268-002-6492-4 [PubMed: 12016472] [CrossRef]

242.

Schaefer S, Shipotko M, Meyer S, Ivan D, Klose KJ, Waldmann J, et al. Natural course of small adrenal lesions in multiple endocrine neoplasia type 1: An endoscopic ultrasound imaging study. Eur J Endocrinol. 2008 May;158(5):699–704. doi:.10.1530/EJE-07-0635 [PubMed: 18426829] [CrossRef]

243.

Skogseid B, Rastad J, Gobl A, Larsson C, Backlin K, Juhlin C, et al. Adrenal lesion in multiple endocrine neoplasia type 1. Surgery. 1995 Dec;118(6):1077–82. [PubMed: 7491526]

244.

Ventura M, Melo M, Carrilho F. Outcome and long-term follow-up of adrenal lesions in multiple endocrine neoplasia type 1. Arch Endocrinol Metab. 2019 Sep 1;63(5):516–23. doi:.10.20945/2359-3997000000170 [PMC free article: PMC10522267] [PubMed: 31482957] [CrossRef]

245.

Waldmann J, Bartsch DK, Kann PH, Fendrich V, Rothmund M, Langer P. Adrenal involvement in multiple endocrine neoplasia type 1: Results of 7 years prospective screening. Langenbecks Arch Surg. 2007 Jul;392(4):437–43. doi:.10.1007/s00423-006-0124-7 [PubMed: 17235589] [CrossRef]

246.

Whitley SA, Moyes VJ, Park KM, Brooke AM, Grossman AB, Chew SL, et al. The appearance of the adrenal glands on computed tomography in multiple endocrine neoplasia type 1. Eur J Endocrinol. 2008 Dec;159(6):819–24. doi:.10.1530/EJE-08-0516 [PubMed: 18827064] [CrossRef]

247.

Clemente-Gutierrez U, Pieterman CRC, Lui MS, Yamashita TS, Tame-Elorduy A, Huang BL, et al. Beyond the three P’s: adrenal involvement in MEN1. Endocr Relat Cancer. 2024 Feb 1;31(2). doi:.10.1530/ERC-23-0162 [PMC free article: PMC10854230] [PubMed: 38108666] [CrossRef]

248.

Tepede AA, Welch J, Lee M, Mandl A, Agarwal SK, Nilubol N, et al. 18F-FDOPA PET/CT accurately identifies MEN1-associated pheochromocytoma. Endocrinol Diabetes Metab Case Rep. 2020 Jan 1;2020(1). doi:.10.1530/EDM-19-0156 [PMC free article: PMC7077596] [PubMed: 32130200] [CrossRef]

249.

Dénes J, Swords F, Rattenberry E, Stals K, Owens M, Cranston T, et al. Heterogeneous genetic background of the association of pheochromocytoma/paraganglioma and pituitary adenoma: Results from a large patient cohort. Journal of Clinical Endocrinology and Metabolism. 2015 Mar 1;100(3):E531–41. doi:.10.1210/jc.2014-3399 [PMC free article: PMC4333031] [PubMed: 25494863] [CrossRef]

250.

Asa SL, Mohamed A. Menin Loss in Pheochromocytoma of Multiple Endocrine Neoplasia Type 1. Endocr Pathol. 2023 Mar 1;34(1):156–8. doi:.10.1007/s12022-022-09744-y [PubMed: 36520343] [CrossRef]

251.

Wang W, Han R, Ye L, Xie J, Tao B, Sun F, et al. Adrenocortical carcinoma in patients with MEN1: A kindred report and review of the literature. Endocr Connect. 2019;8(3):230–8. doi:10.1530/EC-18-0526 [PMC free article: PMC6391906] [PubMed: 30721134] [CrossRef]

252.

Febrero B, Ríos A, Rodríguez JM. Aggressive adrenal carcinoma in a young patient with Multiple Endocrine Neoplasia 1 syndrome. Med Clin (Barc). 2017 Nov;149(10):463. [PubMed: 28625514]

253.

Griniatsos JE, Dimitriou N, Zilos A, Sakellariou S, Evangelou K, Kamakari S, et al. Bilateral adrenocortical carcinoma in a patient with multiple endocrine neoplasia type 1 (MEN1) and a novel mutation in the MEN1 gene. World J Surg Oncol. 2011 Jan 25;9. doi:.10.1186/1477-7819-9-6 [PMC free article: PMC3039620] [PubMed: 21266030] [CrossRef]

254.

Haase M, Anlauf M, Schott M, Schinner S, Kaminsky E, Scherbaum WA, et al. A new mutation in the menin gene causes the multiple endocrine neoplasia type 1 syndrome with adrenocortical carcinoma. Endocrine. 2011;39(2):153–9. doi:.10.1007/s12020-010-9424-3 [PubMed: 21069576] [CrossRef]

255.

Harada K, Yasuda M, Hasegawa K, Yamazaki Y, Sasano H, Otsuka F. A novel case of myxoid variant of adrenocortical carcinoma in a patient with multiple endocrine neoplasia type 1. Endocr J. 2019;66(8):739–44. [PubMed: 31118348]

256.

Kharb S, Pandit A, Gundgurthi A, Garg M, Brar K, Kannan N, et al. Hidden diagnosis of multiple endocrine neoplasia-1 unraveled during workup of virilization caused by adrenocortical carcinoma. Indian J Endocrinol Metab. 2013;17(3):514. doi:10.4103/2230-8210.111672 [PMC free article: PMC3712387] [PubMed: 23869313] [CrossRef]

257.

Ohara N, Kaneko M, Ikeda M, Ishizaki F, Suzuki K, Maruyama R, et al. Lung adenocarcinoma and adrenocortical carcinoma in a patient with multiple endocrine neoplasia type 1. Respir Med Case Rep. 2017;20:77–81. doi:10.1016/j.rmcr.2016.12.002 [PMC free article: PMC5219631] [PubMed: 28070481] [CrossRef]

258.

Green D, Richards K, Doyle B, Thompson C, Hill A, O’reilly MW, et al. Extra-adrenal adrenocortical cancer associated with multiple endocrine neoplasia type 1. Endocrinol Diabetes Metab Case Rep. 2024 Oct 1;2024(4). doi:10.1530/EDM-23-0068 [PMC free article: PMC11623281] [PubMed: 39608104] [CrossRef]

259.

Yang M, Li S, Zhong XW. Multiple Endocrine Neoplasia Type 1 With Adrenal Cortical Adrenocortical Carcinoma: A 25-Year Follow-Up and Family Report. JCEM Case Reports. 2025 Feb 10;3(3). doi:10.1210/jcemcr/luae248 [PMC free article: PMC11808802] [PubMed: 39935491] [CrossRef]

260.

Howarth S, Macfarlane J, Palma A, Stokes VJ, Challis B, Ang JE, et al. Bilateral and recurrent adrenocortical carcinoma in MEN1: a case report and review of the literature. Endocrine Oncology. 2025 Jan 1;5(1). doi:10.1530/EO-25-0067 [PMC free article: PMC12552834] [PubMed: 41141223] [CrossRef]

261.

Assié G, Letouzé E, Fassnacht M, Jouinot A, Luscap W, Barreau O, et al. Integrated genomic characterization of adrenocortical carcinoma. Nat Genet. 2014;46(6):607–12. doi:.10.1038/ng.2953 [PubMed: 24747642] [CrossRef]

262.

Fassnacht M, Tsagarakis S, Terzolo M, Tabarin A, Sahdev A, Newell-Price J, et al. European Society of Endocrinology clinical practice guidelines on the management of adrenal incidentalomas, in collaboration with the European Network for the Study of Adrenal Tumors. Eur J Endocrinol. 2023 Jul 1;189(1):G1–42. doi:.10.1093/ejendo/lvad066 [PubMed: 37318239] [CrossRef]

263.

Asgharian B, Turner ML, Gibril F, Entsuah LK, Serrano J, Jensen RT. Cutaneous tumors in patients with multiple endocrine neoplasm type 1 (MEN1) and gastrinomas: Prospective study of frequency and development of criteria with high sensitivity and specificity for MEN1. Journal of Clinical Endocrinology and Metabolism. 2004 Nov;89(11):5328–36. doi:.10.1210/jc.2004-0218 [PubMed: 15531478] [CrossRef]

264.

Darling TN, Skarulis MC, Steinberg SM, Marx SJ, Spiegel AM, Turner M. Multiple facial angiofibromas and collagenomas in patients with multiple endocrine neoplasia type 1. Arch Dermatol Res. 1997 Jul;133(7):853–7. [PubMed: 9236523]

265.

Waguespack SG. Beyond the “3 Ps”: A critical appraisal of the non-endocrine manifestations of multiple endocrine neoplasia type 1. Front Endocrinol (Lausanne). 2022 Oct 17;13. doi:10.3389/fendo.2022.1029041 [PMC free article: PMC9618614] [PubMed: 36325452] [CrossRef]

266.

Vidal A, Iglesias MJ, Fernández B, Fonseca E, Cordido F. Cutaneous lesions associated to multiple endocrine neoplasia syndrome type 1. Journal of the European Academy of Dermatology and Venereology. 2008 Jul;22(7):835–8. doi:.10.1111/j.1468-3083.2008.02578.x [PubMed: 18435740] [CrossRef]

267.

Pack S, Turner ML, Zhuang Z, Vortmeyer AO, Böni R, Skarulis M, et al. Cutaneous Tumors in Patients with Multiple Endocrine Neoplasia Type 1 Show Allelic Deletion of the MEN1 Gene. Journal of Investigative Dermatology. 1998 Apr;110(4):438–40. [PubMed: 9540988]

268.

Vortmeyer AO, Böni R, Pak E, Pack S, Zhuang Z. Multiple Endocrine Neoplasia 1 Gene Alterations in MEN1-Associated and Sporadic Lipomas. J Natl Cancer Inst [Internet]. 1998 Mar;90(5):398–9. Available from: https://academic​.oup​.com/jnci/article/90/5/398/979539 [PubMed: 9498491]

269.

Dreijerink KMA, Varier RA, van Beekum O, Jeninga EH, Höppener JWM, Lips CJM, et al. The Multiple Endocrine Neoplasia Type 1 (MEN1) Tumor Suppressor Regulates Peroxisome Proliferator-Activated Receptor γ-Dependent Adipocyte Differentiation. Mol Cell Biol. 2009 Sep 1;29(18):5060–9. doi:.10.1128/mcb.01001-08 [PMC free article: PMC2738285] [PubMed: 19596783] [CrossRef]

270.

Parekh VI, Modali SD, Desai SS, Agarwal SK. Consequence of Menin Deficiency in Mouse Adipocytes Derived by in Vitro Differentiation. Int J Endocrinol. 2015;2015. doi:10.1155/2015/149826 [PMC free article: PMC4503551] [PubMed: 26229531] [CrossRef]

271.

Radman M, Milicevic T. A novel mutation of the MEN1 gene in a patient with multiple endocrine neoplasia type 1 and recurrent fibromyxoid sarcoma- A case report. BMC Med Genet. 2020 Sep 29;21(1). doi:.10.1186/s12881-020-01129-4 [PMC free article: PMC7526371] [PubMed: 32993530] [CrossRef]

272.

Cheah SK, Bisambar CR, Pitfield D, Giger O, Ten Hoopen R, Martin JE, et al. Breast cancer in multiple endocrine neoplasia type 1 (Men1). Endocrinol Diabetes Metab Case Rep. 2021 Jan 1;2021(1). doi:10.1530/EDM-20-0196 [PMC free article: PMC8115436] [PubMed: 33960322] [CrossRef]

273.

Jeong YJ, Oh HK, Bong JG. Multiple endocrine neoplasia type 1 associated with breast cancer: A case report and review of the literature. Oncol Lett. 2014;8(1):230–4. doi:10.3892/ol.2014.2144 [PMC free article: PMC4063580] [PubMed: 24959251] [CrossRef]

274.

Kim SH, Park JH. Adrenal incidentaloma, breast cancer and unrecognized multiple endocrine neoplasia type 1. Acta Endocrinol (Copenh). 2019 Oct 1;15(4):513–7. doi:10.4183/aeb.2019.513 [PMC free article: PMC7200108] [PubMed: 32377250] [CrossRef]

275.

Maria BC, Quadros AC, Alves N, Coutinho J. Incidental finding of MEN-1 syndrome during staging and follow-up of breast carcinoma. BMJ Case Rep. 2020 Dec 21;13(12). doi:.10.1136/bcr-2020-238784 [PMC free article: PMC7754650] [PubMed: 33370954] [CrossRef]

276.

Deguidi G, Mirandola S, Nottegar A, Tsvetkova V, Bianchi B, Pellini F. Axillary Hibernoma in woman with Lobular breast cancer and MEN1 syndrome: A case report. Int J Surg Case Rep. 2020 Jan 1;77:834–8. doi:10.1016/j.ijscr.2020.11.073 [PMC free article: PMC7721659] [PubMed: 33395907] [CrossRef]

277.

Seigne C, Auret M, Treilleux I, Bonnavion R, Assade F, Carreira C, et al. High incidence of mammary intraepithelial neoplasia development in Men1 -disrupted murine mammary glands. Journal of Pathology. 2013 Mar;229(4):546–58. doi:.10.1002/path.4146 [PubMed: 23180448] [CrossRef]

278.

Imachi H, Murao K, Dobashi H, Bhuyan MM, Cao X, Kontani K, et al. Menin, a product of the MENI gene, binds to estrogen receptor to enhance its activity in breast cancer cells: Possibility of a novel predictive factor for tamoxifen resistance. Breast Cancer Res Treat. 2010 Jul;122(2):395–407. doi:.10.1007/s10549-009-0581-0 [PubMed: 19847644] [CrossRef]

279.

Dreijerink KMA, Groner AC, Vos ESM, Font-Tello A, Gu L, Chi D, et al. Enhancer-Mediated Oncogenic Function of the Menin Tumor Suppressor in Breast Cancer. Cell Rep. 2017 Mar 7;18(10):2359–72. doi:.10.1016/j.celrep.2017.02.025 [PMC free article: PMC5609449] [PubMed: 28273452] [CrossRef]

280.

Teinturier R, Abou Ziki R, Kassem L, Luo Y, Malbeteau L, Gherardi S, et al. Reduced menin expression leads to decreased ERα expression and is correlated with the occurrence of human luminal B-like and ER-negative breast cancer subtypes. Breast Cancer Res Treat. 2021 Dec 1;190(3):389–401. doi:.10.1007/s10549-021-06339-9 [PMC free article: PMC8558183] [PubMed: 34561764] [CrossRef]

281.

Berglund G, Lidén A, Hansson MG, Öberg K, Sjöden PO, Nordin K. Quality of life in patients with multiple endocrine neoplasia type 1 (MEN1) . Fam Cancer. 2003;1(2):27–33. [PubMed: 14574164]

282.

You YN, Thompson GB, Young WF, Larson D, Farley DR, Richards M, et al. Pancreatoduodenal surgery in patients with multiple endocrine neoplasia type 1: Operative outcomes, long-term function, and quality of life. Surgery. 2007;142(6):829-836.e1. doi:.10.1016/j.surg.2007.09.010 [PubMed: 18063064] [CrossRef]

283.

Peipert BJ, Goswami S, Helenowski I, Yount SE, Sturgeon C. Financial burden is associated with worse health-related quality of life in adults with multiple endocrine neoplasia type 1. Surgery (United States). 2017 Dec 1;162(6):1278–85. doi:.10.1016/j.surg.2017.07.010 [PubMed: 28923697] [CrossRef]

284.

Van Leeuwaarde RS, Pieterman CRC, May AM, Dekkers OM, Van Der Horst-Schrivers AN, Hermus AR, et al. Health-Related Quality of Life in Patients with Multiple Endocrine Neoplasia Type 1. Neuroendocrinology. 2021 Feb 1;111(3):288–95. doi:.10.1159/000508374 [PubMed: 32365349] [CrossRef]

285.

Van Leeuwaarde RS, Pieterman CRC, Bleiker EMA, Dekkers OM, Van Der Horst-Schrivers AN, Hermus AR, et al. High Fear of Disease Occurrence Is Associated with Low Quality of Life in Patients with Multiple Endocrine Neoplasia Type 1: Results from the Dutch MEN1 Study Group. Journal of Clinical Endocrinology and Metabolism. 2018 Jun 1;103(6):2354–61. doi:.10.1210/jc.2018-00259 [PubMed: 29618015] [CrossRef]

286.

Peipert BJ, Goswami S, Yount SE, Sturgeon C. Health-related quality of life in MEN1 patients compared with other chronic conditions and the United States general population. Surgery (United States). 2018 Jan 1;163(1):205–11. doi:.10.1016/j.surg.2017.04.030 [PubMed: 29128174] [CrossRef]

287.

Marini F, Giusti F, Tonelli F, Brandi ML. Management impact: effects on quality of life and prognosis in MEN1. Endocrine-related cancer. 2017. p. T227–42. doi:.10.1530/ERC-17-0203 [PubMed: 28733468] [CrossRef]

288.

Giusti F, Cioppi F, Fossi C, Marini F, Masi L, Tonelli F, et al. Quality of life in Italian patients with Multiple endocrine neoplasia type 1 (MEN 1): results of an extensive survey. Orphanet J Rare Dis. 2021 Dec 1;16(1). doi:.10.1186/s13023-020-01650-y [PMC free article: PMC7788910] [PubMed: 33407684] [CrossRef]

289.

Zwerus D, Verrijn Stuart AA, van Santen HM, Valk GD, de Bruin C, Sas TCJ, et al. Health-related quality of life in children with multiple endocrine neoplasia (MEN) and their siblings. J Clin Endocrinol Metab. 2026 Mar 4. doi:10.1210/clinem/dgag094 [PMC free article: PMC13368371] [PubMed: 41779164] [CrossRef]