Multiple Endocrine Neoplasia Type 1 Gene Research Articles

A de novo 0.57 Mb microdeletion in chromosome 11q13.1 in a patient with speech problems, autistic traits, dysmorphic features and multiple endocrine neoplasia type 1

We report a 21-year-old patient with speech problems, autistic traits, dysmorphic facial features, broad thumbs with short distal phalanges and a pancreatic gastrinoma.Array-CGH demonstrated a 0.57 Mb de novo deletion in chromosome 11q13.1. The deleted region contains several genes which likely contribute to the patient’s complex phenotype, including the MEN1 gene. The deletion of the MEN1 gene is causing multiple endocrine neoplasia type 1 (MEN1). The neurodevelopmental phenotype of the patient might be associated with the deletion of the genes NRXN2 and PPP2R5B which have been described to be involved in synaptogenesis and dendritic branching. According to our knowledge, we report for the first time a patient with the combination of a neurodevelopmental phenotype and MEN1 caused by a microdeletion on chromosome 11.

Abstract LB-140: Menin-mediated regulation of pancreatic β-cell differentiation factors

Abstract Pancreatic endocrine tumors occur sporadically or in familial multiple tumor syndromes such as MEN1 (Multiple Endocrine Neoplasia type 1). Biallelic loss/inactivation of the MEN1 tumor suppressor gene is only found in 20–30% of sporadic pancreatic endocrine tumors. Therefore, identification of other molecular and genetic causes of pancreatic endocrine tumorigenesis is an area of intense investigation. Because MEN1 is the main gene reported so far that affects pancreatic endocrine tumors, analyzing downstream effects of menin (MEN1 gene encoded protein) could uncover other candidate genes and pathways responsible for pancreatic endocrine tumorigenesis. During the process of endocrine pancreas development, a cascade of transcription factors under tight sequential- and temporal-regulated expression ensures normal organogenesis. Alteration of such developmental and differentiation factors could potentially lead to tumorigenesis. To study cellular transformation related to menin loss in the pancreatic β-cell, we used the mouse pancreatic β-cell line MIN6 as a model system. RNA and protein were isolated from MIN6 cells after menin knockdown or after menin over-expression as well as from their respective controls. Twelve transcription factors associated with β-cell differentiation were analyzed using QRT-PCR and western blot: Hlxb9, Hnf3β, Isl-1, MafA, MafB, NeuroD1, Ngn3, Nkx2.2, Nkx6.1, Pax4, Pax6, and Pdx1. Three different sources of menin siRNAs and four different transfection reagents were tested in time course knockdown experiments. Significant menin knockdown in MIN6 cells was observed with 74.3% ± 15.03% (n=6) knockdown efficiency at 72 hours post-transfection. For transient menin over-expression in MIN6 cells, the transfection efficiency was close to 60% (based on GFP plasmid transfection). Endogenous expression of all factors, except Ngn3, was detectable in MIN6 cells. None of the eleven transcription factors showed significantly altered RNA expression upon menin knockdown or upon menin over-expression. Western blot analyses showed 4–5 factors that were up-regulated upon menin knockdown, and down-regulated upon menin over-expression. Evolutionarily conserved promoter regions of Hlxb9, Isl-1, Nkx6.1, or Pax4 were not regulated upon menin knockdown or upon menin over-expression. These data indicate that menin could regulate some β-cell differentiation factors in a post-transcriptional manner. Mechanism of menin-mediated post-transcriptional regulation and downstream consequences on β-cell transformation and tumorigenesis is under investigation. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr LB-140. doi:10.1158/1538-7445.AM2011-LB-140

Bilateral adrenocortical carcinoma in a patient with multiple endocrine neoplasia type 1 (MEN1) and a novel mutation in the MEN1 gene

The incidence of adrenal involvement in MEN1 syndrome has been reported between 9 and 45%, while the incidence of adrenocortical carcinoma (ACC) in MEN1 patients has been reported between 2.6 and 6%. In the literature data only unilateral development of ACCs in MEN1 patients has been reported. We report a 31 years-old female MEN1-patient, in whom hyperplasia of the parathyroid glands, prolactinoma, non functioning pancreatic endocrine carcinoma and functioning bilateral adrenal carcinomas were diagnosed. Interestingly, a not previously described in the literature data, novel germline mutation (p.E45V) in exon 2 of MEN1 gene, was detected. The association of exon 2 mutation of the MEN1 gene with bilateral adrenal carcinomas in MEN1 syndrome, should be further investigated.

The Menin Tumor Suppressor Protein Is Phosphorylated in Response to DNA Damage

BackgroundMultiple endocrine neoplasia type 1 (MEN1) is a heritable cancer syndrome characterized by tumors of the pituitary, pancreas and parathyroid. Menin, the product of the MEN1 gene, is a tumor suppressor protein that functions in part through the regulation of transcription mediated by interactions with chromatin modifying enzymes.Principal FindingsHere we show menin association with the 5′ regions of DNA damage response genes increases after DNA damage and is correlated with RNA polymerase II association but not with changes in histone methylation. Furthermore, we were able to detect significant levels of menin at the 3′ regions of CDKN1A and GADD45A under conditions of enhanced transcription following DNA damage. We also demonstrate that menin is specifically phosphorylated at Ser394 in response to several forms of DNA damage, Ser487 is dynamically phosphorylated and Ser543 is constitutively phosphorylated. Phosphorylation at these sites however does not influence the ability to interact with histone methyltransferase activity. In contrast, the interaction between menin and RNA polymerase II is influenced by phosphorylation, whereby a phospho-deficient mutant had a higher affinity for the elongating form of RNA polymerase compared to wild type. Additionally, a subset of MEN1-associated missense point mutants, fail to undergo DNA damage dependent phosphorylation.ConclusionTogether, our findings suggest that the menin tumor suppressor protein undergoes DNA damage induced phosphorylation and participates in the DNA damage transcriptional response.

Attenuated expression of menin and p27 Kip1 in an aggressive case of multiple endocrine neoplasia type 1 (MEN1) associated with an atypical prolactinoma and a malignant pancreatic endocrine tumor

Tumors in multiple endocrine neoplasia type 1 (MEN1) are generally benign. Since information on the pathogenesis of MEN1 in malignant cases is limited, we conducted genetic analysis and compared the expression of menin, p27(Kip1)(p27)/CDKN1B and p18(Ink4C)(p18)/CDKN2C with levels in benign cases. We describe the case of a 56 year-old male with an atypical prolactinoma and malignant pancreatic neuroenocrine tumor. At age 50, he had undergone transsphenoidal surgery to remove a prolactinoma. However, the tumor relapsed twice. Histological analysis of the recurrent prolactinoma revealed the presence of prolactin, a high MIB-1 index (32.1 %), p53-positive cells (0.2%), and an unusual association with FSH-positive cells. A few years later, he was also found to have a non-functioning pancreatic tumor with probable metastasis to the extradullar region. The metastatic region tested positive for chromogranin and CD56, and negative for prolactin, with 1.2 % of cells p53-positive. Although genetic analyses of the MEN1, p27, and p18 genes demonstrated no mutation, numbers of menin, p27 and p18 immuno-positive cells were significantly down-regulated in the recurrent prolactinoma, but that of p18 was intact in the metastatic region. Furthermore, MEN1 and p27 mRNA levels of the recurrent prolactinoma were down-regulated, particularly the MEN1 mRNA level, compared to levels in 10 cases of benign prolactinoma, while the p18 mRNA level was similar to that of normal pituitary. The tumor in this case may be a subtype of MEN1 showing more aggressive and malignant features probably induced by low levels of menin and p27.

A case of ACTH-independent macronodular adrenal hyperplasia associated with multiple endocrine neoplasia type 1

Multiple endocrine neoplasia type 1 (MEN1) is an autosomal dominant neoplasia syndrome characterized by the occurrence of tumors in the parathyroid glands, pancreas, and anterior pituitary. Approximately 30-40% of MEN1 patients also have adrenal lesions, such as hyperplasia, benign adenoma, and adrenocortical carcinoma. Most of the cases are hormonally silent. We describe the case of a 60-year-old man with bilateral macronodular adrenal lesions, in addition to parathyroid tumors, multiple insulinomas, and non-functioning pituitary microadenoma. Endocrinological tests revealed subclinical hypercortisolism; midnight cortisol level rose slightly (8.0 µg/dL), although basal plasma ACTH and cortisol levels were within the normal range (19.5 pg/mL and 12.0 µg/dL, respectively). One and 8 mg dexamethasone suppression tests showed cortisol levels of 2.3 and 9.8 µg/dL, respectively. (131)I-adosterol scintigraphy under dexamethasone suppression revealed bilateral adrenal uptake with right-sided predominance. The histological features of the removed right adrenal gland were consistent with ACTH-independent macronodular adrenal hyperplasia (AIMAH): immunoreactivity of 17α-hydroxylase was predominantly observed in the small compact cells, while that of 3β-hydroxysteroid dehydrogenase was exclusively expressed in the large clear cells. The glucose-dependent insulinotropic polypeptide (GIP) receptor was expressed at high levels in compact cells, suggesting that GIP is responsible for the development of AIMAH. Unilateral small adrenal lesions were detected in the patient's 2 children, who also presented with MEN1 symptoms. Genetic abnormalities in the MEN1, p27, and p18 genes were not found, however, the present case may provide a clue to the understanding of the etiology of MEN1 and AIMAH.

Simultaneous double thymic carcinoids: a rare initial manifestation of multiple endocrine neoplasia type 1

A 53-year-old man was referred to our hospital for treatment of two anterior mediastinal tumors. The anterior mediastinal tumors were resected by thymectomy under the probable diagnosis of double thymomas. The final pathological diagnosis was multiple thymic carcinoids. Although 20%-25% of patients with thymic carcinoid have a family history of multiple endocrine neoplasia type 1 (MEN-1), radiographic screening just after the operation did not detect any endocrine tumors. However, the patient had a urinary calculus 4 months 7 months after the operation. Endocrinological examination then revealed mild hypercalcemia, hypophosphatemia, hyperinsulinemia, and hyperprolactinemia. Radiologically, a parathyroid tumor and a pancreatic tumor were found. The patient was referred to a university hospital and a mutation of MEN-1 gene was detected. The diagnosis of MEN-1 was confirmed about 1 year after the operation.

A new mutation in the menin gene causes the multiple endocrine neoplasia type 1 syndrome with adrenocortical carcinoma

Multiple endocrine neoplasia type 1 (MEN1) is an autosomal dominant tumor syndrome that may be caused by mutations in the MEN1 gene on 11q13. Loss of function of the tumor suppressor gene MEN1 leads to synchronous or metachronous appearance of neuroendocrine tumors arising from neuroendocrine cells of the parathyroid and pituitary glands, the duodenum and pancreatic islets, and other endocrine organs such as the adrenal cortex. We here present a patient with MEN1 who developed hyperparathyroidism, multiple well differentiated functionally inactive neuroendocrine tumors of the pancreas and an adrenal carcinoma. We describe a new mutation at codon 443 in the coding region of exon 9 in the MEN1 gene, where a cytosine residue was exchanged for adenosine (TCC > TAC) and, consequently, serine for tyrosine (p.Ser443Tyr; c.1328C > A). [corrected] Also, we provide clinical data that may add to the genotype-phenotype discussion. We conclude that the novel mutation in the MEN1 gene described herein was clinically relevant.

Care for patients with multiple endocrine neoplasia type 1: the current evidence base

Multiple endocrine neoplasia type 1 (MEN1) is a rare disease caused by mutations in the MEN1 gene on chromosome 11. It is characterized by the occurrence of primary hyperparathyroidism (pHPT), duodenopancreatic neuroendocrine tumours (pNET), pituitary tumours (PIT), adrenal adenomas (ADR) and neuroendocrine tumours (NET) of the stomach, bronchus and thymus. MEN1 is a syndrome with high penetrance and high morbidity. Malignant NETs are the most important cause of MEN1-related death. Since 1997 the diagnosis can be made by genetic screening. MEN1 is a complex syndrome and the endocrine manifestations cannot be viewed upon as coinciding sporadic tumours. Differences in epidemiology and pathology between MEN1-related tumours and their sporadic counterparts show that a unique approach is needed. Therefore the care for MEN1 patients should be provided by a centre of expertise. Early genetic diagnosis and periodic screening are important pillars of care. For primary hyperparathyroidism surgery is the most important treatment modality, with a subtotal parathyroid gland resection as the procedure of choice. In neuroendocrine tumours surgery also is the most important treatment modality. Selective tumour enucleation has no place in the surgical treatment of MEN1-related pNETs; the exact procedure depends on the functionality of the tumour. In MEN1-associated pituitary and adrenal adenomas, watchful waiting and medical therapy play more important roles. In the twenty-first century new developments will impact the care for MEN1 patients. These developments should be critically evaluated in clinical research with the ultimate goal of optimizing the care for MEN1 patients on an evidence base.

Familial pituitary adenomas

Pituitary adenomas are benign intracranial neoplasms that present a major clinical concern because of hormonal overproduction or compression symptoms of adjacent structures. Most arise in a sporadic setting with a small percentage developing as a part of familial syndromes such as multiple endocrine neoplasia type 1 ( MEN1), Carney complex (CNC), and the recently described familial isolated pituitary adenomas (FIPA) and MEN-4. While the genetic alterations responsible for the formation of sporadic adenomas remain largely unknown, considerable advances have been made in defining culprit genes in these familial syndromes. Mutations in MEN1 and PRKAR1A genes are found in the majority of MEN1 and CNC patients, respectively. About 15% of FIPA kindreds present with mutations of the aryl hydrocarbon receptor-interacting protein ( AIP) gene. Mutations in the CDKN1B gene, encoding p27 Kip1 were identified in MEN4 cases. Familial tumours appear to differ from their sporadic counterparts not only in genetic basis but also in clinical characteristics. Evidence suggests that, especially in MEN1 and FIPA, they are more aggressive and affect patients at younger age, therefore justifying the importance of early diagnosis. In this review, we summarize the genetic and clinical characteristics of these familial pituitary adenomas.

Ribozyme-mediated compensatory induction of menin-oncosuppressor function in primary fibroblasts from MEN1 patients

Multiple endocrine neoplasia type 1 (MEN1) syndrome is characterized by the occurrence of tumors of parathyroids, neuroendocrine cells of the gastro-enteropancreatic tract and anterior pituitary. MEN1 gene encodes menin-oncosuppressor protein. Loss of heterozygosity at 11q13 is typical of MEN1 tumors. We have analyzed the MEN1 mRNA and menin expression in fibroblasts from normal skin biopsies and from MEN1 patients (two with a frameshift 738del4 (exon 3) mutation, introducing a premature stop codon, and an individual with an R460X (exon 10) nonsense mutation). The expression of full-length menin protein did not differ between MEN1 and normal fibroblasts. Wild-type alleles mRNAs were expressed in MEN1 patients, whereas mutant alleles were partially degraded by nonsense-mediated mRNA decay pathway, suggesting a mechanism of compensation for allelic loss by the up-regulation of wild-type menin expression at a post-transcriptional level. Small-interfering RNA silencing of the wild-type mRNA allele abolished menin compensation, whereas the ribozyme silencing of the MEN1-mutated mRNA allele resulted in strongly enhanced wild-type menin expression. Gel-retardation analysis showed that in vitro-specific RNA-protein complexes bound to MEN1 mRNA. These findings contribute to the understanding of tumorigenesis in MEN1, offering the basis for the development of RNA-based therapies in MEN1 gene mutation carriers.

Characterisation of prostate cancer lesions in heterozygous Men1 mutant mice

BackgroundMutations of the MEN1 gene predispose to multiple endocrine neoplasia type 1 (MEN1) syndrome. Our group and others have shown that Men1 disruption in mice recapitulates MEN1 pathology. Intriguingly, rare lesions in hormone-dependent tissues, such as prostate and mammary glands, were also observed in the Men1 mutant mice.MethodsTo study the occurrence of prostate lesions, we followed a male mouse cohort of 47 Men1+/- mice and 23 age-matched control littermates, starting at 18 months of age, and analysed the prostate glands from the cohort.ResultsSix Men1+/- mice (12.8%) developed prostate cancer, including two adenocarcinomas and four in situ carcinomas, while none of the control mice developed cancerous lesions. The expression of menin encoded by the Men1 gene was found to be drastically reduced in all carcinomas, and partial LOH of the wild-type Men1 allele was detected in three of the five analysed lesions. Using immunostaining for the androgen receptor and p63, a basal epithelial cell marker, we demonstrated that the menin-negative prostate cancer cells did not display p63 expression and that the androgen receptor was expressed but more heterogeneous in these lesions. Furthermore, our data showed that the expression of the cyclin-dependent kinase inhibitor CDKN1B (p27), a Men1 target gene known to be inactivated during prostate cell tumorigenesis, was notably decreased in the prostate cancers that developed in the mutant mice.ConclusionOur work suggests the possible involvement of Men1 inactivation in the tumorigenesis of the prostate gland.

Systematic comparison of sporadic and syndromic pancreatic islet cell tumors

Pancreatic islet cell tumors (ICTs) occur as sporadic neoplasias or as a manifestation of multiple endocrine neoplasia type 1 (MEN1) and von Hippel-Lindau disease (VHL). Molecular classification of ICTs is mandatory for timely diagnosis and surveillance. Systematic comparison of VHL-ICTs and sporadic ICTs has been lacking. Our registry-based approaches used the German NET-Registry with 259 patients with neuroendocrine tumors (NETs), who were primarily diagnosed with NETs, and the German VHL-Registry with 485 molecular genetically confirmed patients who had undergone magnetic resonance imaging or computed tomography of the abdomen. All patients provided blood DNA for testing of the MEN1 and VHL genes for intragenic mutations and large deletions. In the NET-Registry, 9/101 patients (8.9%) with ICTs had germline mutations, 8 in MEN1 and 1 in VHL. In the VHL-Registry, prevalence of NETs was 52/487 (10.6%), and all were ICTs. Interestingly, of those with VHL p.R167W, 47% developed ICTs, compared to 2% of those with p.Y98H. In total, there were 92 truly sporadic, i.e. mutation-negative ICT patients. Comparing these with the 53 VHL-ICT patients, the statistically significant differences were predominance of female gender (P=0.01), multifocal ICTs (P=0.0029), and lower malignancy rate (P<0.001) in VHL-ICTs compared to sporadic cases. VHL was prevalent in <0.5% of NETs, while NETs occur in ∼10% of VHL, virtually exclusively as ICTs, which are rarely the first presentation. Patients with NETs should not be subjected to genetic testing of the VHL gene, unless they have multifocal ICTs, other VHL-associated tumors, and/or a family history for VHL.

MEN1 in pancreatic endocrine tumors: analysis of gene and protein status in 169 sporadic neoplasms reveals alterations in the vast majority of cases

Pancreatic endocrine tumors (PETs) may be part of hereditary multiple endocrine neoplasia type 1 (MEN1) syndrome. While MEN1 gene mutation is the only ascertained genetic anomaly described in PETs, no data exist on the cellular localization of MEN1-encoded protein, menin, in normal pancreas and PETs. A total of 169 PETs were used to assess the i) MEN1 gene mutational status in 100 clinically sporadic PETs by direct DNA sequencing, ii) immunohistochemical expression of menin in normal pancreas and 140 PETs, including 71 cases screened for gene mutations, and iii) correlation of these findings with clinical-pathological parameters. Twenty-seven PETs showed mutations that were somatic in 25 patients and revealed to be germline in 2 patients. Menin immunostaining showed strong nuclear and very faint cytoplasmic signal in normal islet cells, whereas it displayed abnormal location and expression levels in 80% of tumors. PETs harboring MEN1 truncating mutations lacked nuclear protein, and most PETs with MEN1 missense mutations showed a strong cytoplasmic positivity for menin. Menin was also misplaced in a significant number of cases lacking MEN1 mutations. In conclusion, the vast majority of PETs showed qualitative and/or quantitative alterations in menin localization. In 30% of cases, this was associated with MEN1 mutations affecting sequences involved in nuclear localization or protein-protein interaction. In cases lacking MEN1 mutations, the alteration of one of the menin interactors may have prevented its proper localization, as suggested by recent data showing that menin protein shuttles between the nucleus and cytoplasm and also affects the subcellular localization of its interactors.

Multiple endocrine neoplasia type 1 (MEN1)

Multiple Endocrine Neoplasia type 1 (MEN1) is an autosomal-dominant disorder characterised by the occurrence of tumours of the parathyroids, pancreas and anterior pituitary. The MEN1 gene, consists of 10 exons that encode a 610-amino acid protein referred to as Menin. Menin is predominantly a nuclear protein that has roles in transcriptional regulation, genome stability, cell division and proliferation. Germ-line mutations usually result in MEN1 or occasionally in an allelic variant referred to as Familial Isolated Hyperparathyroidism (FIHP). MEN1 tumours frequently have loss of heterozygosity (LOH) of the MEN1 locus, which is consistent with a tumour suppressor role of MEN1. Furthermore, somatic abnormalities of MEN1 have been reported in MEN1 and non-MEN1 endocrine tumours. To date, over 1300 mutations have been reported, and the majority (>70%) of these are predicted to lead to truncated forms of Menin. The mutations are scattered throughout the >9 kb genomic sequence of the MEN1 gene. Four, which consist of c.249_252delGTCT (deletion at codons 83-84), c.1546_1547insC (insertion at codon 516), c.1378C>T (Arg460Ter) and c.628_631delACAG (deletion at codons 210-211) have been reported to occur frequently in 4.5%, 2.7%, 2.6% and 2.5% of families, respectively. However, a comparison of the clinical features in patients and their families with the same mutations reveals an absence of phenotype-genotype correlations. The majority of MEN1 mutations are likely to disrupt the interactions of Menin with other proteins and thereby alter critical events in cell cycle regulation and proliferation.

Clinical and molecular genetics of parathyroid neoplasms

Primary hyperparathyroidism (HPT) results from the excessive secretion of parathyroid hormone from parathyroid tumours. While most HPT is sporadic, it is associated with a familial syndrome in a minority of cases. The study of these syndromes has helped define the pathophysiology of both familial and sporadic parathyroid neoplasms. Investigation of kindred with multiple endocrine neoplasia type 1 (MEN1) and the hyperparathyroidism-jaw tumour syndrome (HPT-JT) led to the discovery of the tumour suppressor genes MEN1 and HRPT2. We now recognise that somatic mutations in MEN1 and HRPT2 tumour suppressor genes are frequent events in sporadic parathyroid adenomas and carcinomas, respectively. Parathyroid tumours in the MEN2A syndrome result from mutational activation of the RET oncogene. The CCND1/PRAD1 oncogene was discovered by analysis of sporadic parathyroid tumours. Studies of familial isolated HPT and analysis of chromosomal loss and gain in parathyroid tumours suggest that other genes relevant to parathyroid neoplasia await identification.

A novel mutation of the MEN1 gene in a Chinese kindred with multiple endocrine neoplasia type 1

Germline mutations in the MEN1 gene are well documented as the genetic cause of multiple endocrine neoplasia type 1 (MEN1). In this study, we performed genetic analysis by direct MEN1 gene mutation analysis on a Chinese MEN1 family. The two patients in this family were diagnosed as MEN1 by the typical clinical findings of parathyroidoma, insulinoma and pituitary adenoma. The coding sequences, including 9 coding exons and exon/intron boundaries of the MEN1 gene were amplified by polymerase chain reaction (PCR) and subjected to direct sequencing. Sequence analysis showed a same novel insertion mutation in exon 3 (c.433_434ins CTTC) in both patients, resulting in an open reading frames shift and produced a premature termination codon. None of the other family members had this insert mutation. In conclusion, we add a new mutation of MEN1 gene in Chinese patients with MEN1, and it would be useful for the diagnosis of the disease.

A Case of Familial Isolated Primary Hyperparathyroidism with a Novel Gene Mutation

Familial isolated primary hyperparathyroidism (FIHP) is an autosomal dominant disorder that is characterized by an early stage of either multiple endocrine neoplasia type 1 (MEN1) or hyperparathyroidism-jaw tumor (HPT-JT) syndrome. We report here on a case of a 42-years old woman who was diagnosed with papillary thyroid cancer and primary hyperparathyroidism. Her younger brother also had primary hyperparathyroidism. On the genetic analysis, they were both proven to have a novel frameshift mutation in the MEN1 gene (exon 10). (

Néoplasies endocriniennes multiples, aspects génétiques

Multiple endocrine neoplasia type 1 (MEN1) and type 2 (MEN2) are major genetic disorders carrying a high risk of endocrine tumor development. The mutated genes were identified in 1993 (MEN2-RET) and 1997 (MEN1), enabling genetic testing and functional studies. Genetic analysis has led to new clinical and therapeutic strategies for MEN1/2 patients, and has improved our understanding of the pathways underlying the development of such tumors, which occur in an autosomal dominant manner and with high penetrance. The MEN1 gene encodes menin, a protein involved in many cell functions, such as transcription, genome stability, cell cycling and apoptosis. The MEN1 gene has 10 exons, and its exhaustive analysis in MEN1 patients helps guide their management. MEN2 is related to activating missense mutations in the RET protooncogene, which encodes a tyrosine kinase receptor (TKR). RET activation occurs upon autodimerization induced by the binding of specific ligands belonging to glial cell-derived neurotrophic factor-like family (GFL) proteins, regulated by coreceptors. The position of missense mutations--in the extracellular or intracellular TK domains--influences the aggressiveness of the most frequent malignancy, medullary thyroid carcinoma, establishing a genotype-phenotype correlation. We also briefly describe the genetic basis of three other inherited states predisposing individuals to endocrine tumors, namely Carney's syndrome, hyperparathyroidism type 2 (HRPT2) and familial isolated pituitary adenoma (FIPA), which are related to inactivating mutations in the PRKAR1-alpha, HRPT2 and AIP genes, respectively.

Primary Hyperparathyroidism in Patients with Multiple Endocrine Neoplasia Type 1

Primary hyperparathyroidism may occur as a part of an inherited syndrome in a combination with pancreatic endocrine tumours and/or pituitary adenoma, which is classified as Multiple Endocrine Neoplasia type 1 (MEN-1). This syndrome is caused by a germline mutation in MEN-1 gene encoding a tumour-suppressor protein, menin. Primary hyperparathyroidism is the most frequent clinical presentation of MEN-1, which usually appears in the second decade of life as an asymptomatic hypercalcemia and progresses through the next decades. The most frequent clinical presentation of MEN-1-associated primary hyperparathyroidism is bone demineralisation and recurrent kidney stones rarely followed by chronic kidney disease. The aim of this paper is to present the pathomechanism, screening procedures, diagnosis, and management of primary hyperparathyroidism in the MEN-1 syndrome. It also summarises the recent advances in the pharmacological therapy with a new group of drugs—calcimimetics.