Review article
Multiple endocrine neoplasia type 1

https://doi.org/10.1016/j.ejim.2007.08.004Get rights and content

Abstract

The co-occurrence of parathyroid hyperplasia with pancreatic endocrine tumours and/or pituitary adenoma is classified as Multiple Endocrine Neoplasia type 1 (MEN-1) and is caused by a germ-line mutation in MEN-1 gene encoding a tumour suppressor protein, menin. This review presents clinical expressions, diagnosis and management of the MEN-1 syndrome. Properties and mechanisms of menin functions are also reviewed.

Introduction

Multiple endocrine neoplasia type 1 (MEN-1) is a rare congenital disease but its genetic background offers a unique opportunity to understand a pathway of tumour genesis that may be common also for some sporadic tumours.

The classic clinical manifestation of MEN-1 is a composition of parathyroid hyperplasia, pancreatic endocrine tumour and pituitary adenoma [1]. Some patients, however, do not present all three tumours during their life span. Therefore, the definition of MEN-1 is the coincidence of at least two of the above mentioned tumours [1]. A diagnosis of familial MEN-1 requires, besides that, first-degree relative with at least one of the three tumours [1].

Section snippets

Clinical expressions of MEN-1

Primary hyperparathyroidism is the most common clinical expression in affected patients, present in more than 90% of cases (Table 1). Multi-nodular hyperplasia of parathyroid glands is the most frequent, however solitary tumours (usually diagnosed as adenomas) are also seen. Interestingly, parathyroid carcinoma is less frequent than in sporadic cases of primary hyperparathyroidism. The onset age for MEN-1 associated parathyroid adenomas is about 25 years [2] in contrast to sporadic cases

MEN-1 gene function

The MEN-1 gene is located at chromosome 11q13, spans 9.8 kb with 10 exons, and encodes a 610-amino-acid protein named menin [16]. Menin is an abundantly expressed 67-kDa protein which is located primarily in the nucleus [17] and is able to bind to DNA independently of the sequence [18]. It was co-localized with telomers in meiotic, but not in somatic cells [19]. Menin may bind directly or indirectly to the transcription, DNA processing or DNA repair factors and cytoskeleton-associated proteins

Diagnosis of tumours in MEN-1

It is recommended that the carriers of MEN-1 mutation should be screened biochemically every 1–3 years for hyperparathyroidism, prolactinoma, gastrinoma, insulinoma and other enteropancreatic tumours. Clinical manifestation is mostly mild for a long period of time and lack of regular screening may result in numerous complications [45].

Until recently total serum calcium concentration alone seemed satisfactory as a screening test for hyperparathyroidism in MEN-1 [46]. This was partly because

Treatment of tumours in MEN-1

Multiplicity of tumours is the main feature in MEN-1 and occurs as multiple tumours within one tissue as well as multiple tissues affected with tumourogenesis. Due to this, characteristic recurrence of tumours is common even after sub-total removal of a tissue. Nevertheless, MEN-1 related tumours are mostly subjected to surgical treatment.

In contrast to single gland resection in sporadic cases of primary hyperparathyroidism, total parathyroidectomy and thymectomy with autotransplantation of

Learning points

• Carriers of MEN-1 mutations require a thorough follow-up by an experienced endocrinologist.

• MEN-1 germ-line testing should be considered in both affected and unaffected relatives in a MEN-1 family. However, unlike the RET test in MEN-2, the positive result does not implicate intervention to prevent or cure malignancy.

References (63)

  • BensonL et al.

    Hyperparathyroidism presenting as the first lesion in multiple endocrine neoplasia type 1

    Am J Med

    (1987)
  • MarxSJ

    Multiple endocrine neoplasia type 1

  • BrandiML et al.

    Guidelines for diagnosis and therapy of MEN type 1 and type 2

    J Clin Endocrinol Metab

    (2001)
  • TrumpD et al.

    Clinical studies of multiple endocrine neoplasia type 1 (MEN1)

    QJM

    (1996)
  • HeathH et al.

    Primary hyperparathyroidism. Incidence, morbidity, and potential economic impact in a community

    N Engl J Med

    (1980)
  • GeerdinkEA et al.

    Do patients with multiple endocrine neoplasia syndrome type 1 benefit from periodical screening?

    Eur J Endocrinol

    (2003)
  • NortonJA et al.

    Surgery to cure the Zollinger–Ellison syndrome

    N Engl J Med

    (1999)
  • CorbettaS et al.

    Multiple endocrine neoplasia type 1 in patients with recognized pituitary tumours of different types

    Clin Endocrinol (Oxf)

    (1997)
  • YoshimotoK et al.

    Clinical characteristics in multiple endocrine neoplasia type 1 in Japan: a review of 106 patients

    Nippon Naibunpi Gakkai Zasshi

    (1991)
  • GodwinJD

    Carcinoid tumors. An analysis of 2,837 cases

    Cancer

    (1975)
  • SkogseidB et al.

    Clinical and genetic features of adrenocortical lesions in multiple endocrine neoplasia type 1

    J Clin Endocrinol Metab

    (1992)
  • BerdjisCC

    Pluriglandular syndrome. II. Multiple endocrine adenomas in man. A report of five cases and a review of literature

    Ophthalmologica

    (1962)
  • BrandiML et al.

    Familial multiple endocrine neoplasia type I: a new look at pathophysiology

    Endocr Rev

    (1987)
  • VasenHF et al.

    Screening of families predisposed to cancer development in The Netherlands

    Anticancer Res

    (1990)
  • UchinoS et al.

    Screening of the Men1 gene and discovery of germ-line and somatic mutations in apparently sporadic parathyroid tumors

    Cancer Res

    (2000)
  • ChandrasekharappaSC et al.

    Positional cloning of the gene for multiple endocrine neoplasia-type 1

    Science

    (1997)
  • GuruSC et al.

    Menin, the product of the MEN-1 gene, is a nuclear protein

    Proc Natl Acad Sci USA

    (1998)
  • SuphapeetipornK et al.

    MEN1 tumor-suppressor protein localizes to telomeres during meiosis

    Genes Chromosomes Cancer

    (2002)
  • SukhodoletsKE et al.

    The 32-kilodalton subunit of replication protein A interacts with menin, the product of the MEN-1 tumor suppressor gene

    Mol Cell Biol

    (2003)
  • SchneppRW et al.

    Mutation of tumor suppressor gene MEN-1 acutely enhances proliferation of pancreatic islet cells

    Cancer Res

    (2006)
  • KimYS et al.

    Stable overexpression of MEN-1 suppresses tumorigenicity of RAS

    Oncogene

    (1999)

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