MEN1 Gene Mutation Research Articles

A Novel Germline Mutation ofMEN1Gene in a Young-aged Multiple Insulinoma with Hyperparathyroidism

A Novel Germline Mutation of<i>MEN1</i>Gene in a Young-aged Multiple Insulinoma with Hyperparathyroidism

Genetic analysis of a patient with coexisting acromegaly, thyroid papillary carcinoma and subcutaneous fibroma.

The aim of the present study was to analyze the MEN1 and gsα gene mutations in a Chinese patient with growth hormone-producing pituitary tumors causing acromegaly, papillary thyroid carcinoma and subcutaneous fibroma. Genomic DNA was isolated from the patient and 10 healthy controls, and prepared for polymerase chain reaction (PCR) analysis. Numerous pairs of primers were designed to amplify exons 1–10 of the MEN1 gene and exons 8 and 9 of the gsα gene, and the PCR products were sequenced to detect mutations. In the study patient, a heterozygous G→A mutation was detected at nucleotide 7848 within exon 10 of the MEN1 gene; the missense mutation caused the substitution of alanine with threonine at amino acid 541 (A541T) in the menin protein. In addition, a G→A mutation at nucleotide 7997 within exon 10 of the MEN1 gene was identified; the mutation was synonymous, therefore, the proline at amino acid 590 of the menin protein (P590P) did not change. No other mutations were observed in exons 8 and 9 of the gsα gene, therefore, the G7848A mutation within exon 10 of the MEN1 gene may represent the molecular pathology underlying pituitary somatotroph adenomas and papillary thyroid carcinoma. Furthermore, the pituitary adenomas, thyroid carcinoma and subcutaneous fibroma of the present patient may be considered as early manifestations of multiple endocrinologic neoplasia syndrome 1 as opposed to pure endocrine tumors, however, a long-term follow-up study is required to clarify this.

Multiple endocrine neoplasia (MEN)

Multiple endocrine neoplasia (MEN) types 1 and 2 are hereditary cancer syndromes. They are characterized by the occurrence of many benign and malignant tumor types. Carriers of a MEN1 or RET gene mutation can be identified before manifestation of the disease. Family screening allows the early diagnosis and therapy of gene carriers. Early thyroidectomy in young patients with MEN2 results in a high cure rate of medullary thyroid carcinoma (MTC). Treatment with tyrosine kinase inhibitors (TKI), such as vadetanib and cabozantinib, represents an important new therapeutic option for patients with progressive metastatic MTC. Neuroendocrine tumors (MEN1) are treated surgically and progressive disease is treated with somatostatin or everolimus. The most important imaging methods for monitoring of MTC are sonography of the neck and upper abdomen and computed tomography (CT) of the lungs. In cases of MEN1 metastases can be localized by DOTATOC positron emission tomography CT (PET/CT). Using these methods up to 70 % of tumors and metastases can be detected, depending on the localization, size and endocrine activity. Follow-up investigations with CT is an important tool for monitoring changes in tumor mass which are important criteria for decisions concerning TKI therapy. Together with the doubling time of tumor markers, tumor progression monitored by imaging methods or response evaluation criteria In solid tumors (RECIST) are prognostic factors and provide indications for initiating systemic therapy (e.g. Patients with MEN syndromes should be treated in specialized centers because of the complexity and rarity.

Multiple endocrine neoplasia type 1: a case report and review of the literature

Abstract Multiple endocrine neoplasia syndrome, type 1 (MEN1) is an underdiagnosed autosomal dominant inherited cancer predisposition syndrome with inter- and intrafamilial variability without a known genotype-phenotype correlation. Disease is caused by mutations in the MEN1 gene located on chromosome 11, but other genes (CDKN1B, AIP) and mechanisms might be involved too. We performed retrospective case series study of MEN1 syndrome patient and his family and present our experience of management of genetically confirmed 9 MEN1 syndrome large family members from Lithuania with novel MEN1 gene mutation (MEN1 exon 6 — c. 879delT (p.Pro293Profs*76)) and delineate its clinical phenotype. At present the diagnosis of MEN1 syndrome must be established by direct mutation testing. MEN1 syndrome patients, their relatives and patients suspected of MEN1 are eligible for mutation testing. Patients with MEN1 have a shorter life expectancy than the general population. MEN1 patients and mutation carriers should be subjected to periodic screening in order to detect manifestations in an early stage. Early genetic diagnosis and subsequent periodic screening is associated with less morbidity and mortality at follow-up. Our study confirmed the absence of genotype-phenotype correlation and showed high intrafamilial clinical expression variability of the MEN1 syndrome.

Familial Cushing syndrome due to thymic carcinoids in a multiple endocrine neoplasia type 1 kindred

The objective of this study is to present a familial Cushing syndrome (CS) caused by multiple endocrine neoplasia type 1 (MEN-1)-associated thymic carcinoid. Immunohistochemistry, gene sequencing, loss of heterozygosity analysis, and Western blot were used to determine the expression of ACTH in MEN-1-related thymic tumors, MEN1 gene mutation, the pattern and extent of allelic deletion, and the expression of Menin in MEN-1-associated tumors, respectively. Tumor cells from thymus ectopic-secreted ACTH. A deletion involving the MEN1 gene locus was confirmed. The expression of Menin in MEN-1-associated tumors declined. To conclude, we presented an unusual kindred of MEN-1, which pointed out the significance of making screening of MEN-1 for both male and female patients with CS and thymic carcinoid.

Concurrent Type 2 Diabetes and Multiple Endocrine Neoplasia Type 1 With a Novel MEN1 Gene Mutation

Concurrent Type 2 Diabetes and Multiple Endocrine Neoplasia Type 1 With a Novel MEN1 Gene Mutation

Abstract A185: Menin functions as a gatekeeper of the proliferative MAPK arm of K-Ras signaling.

Abstract Activating mutations of the prototypical oncogene KRAS drive proliferation in all pancreatic ductal adenocarcimomas, but have never been found in pancreatic endocrine tumors, which more commonly inactivate tumor suppressors such as MEN1, the gene mutated in the autosomal dominant cancer syndrome Multiple Endocrine Neoplasia type 1, showing that outcomes of K-Ras signaling depend on cellular context. We have shown that K-Ras does not promote but instead strongly suppresses endocrine cell growth and that this paradoxical activity derives from the Men1 gene product Menin. We have proposed a model in which K-Ras activates both the pro-proliferative MAPK pathway, and the anti-proliferative RASSF1 pathway. In tissues susceptible to MEN1 gene mutation, Menin normally prevents the MAPK effector pathway from driving proliferation while leaving the inhibitory RASSF1 effector pathway intact. In this model, loss of Menin causes proliferation due to removal of the block in MAPK-driven proliferation downstream of K-Ras, while loss of K-Ras signaling increases proliferation by decreasing the unopposed RASSF1 activity in susceptible cells. To test this model, we assessed the effect of various inhibitors of the K-Ras pathway on beta cell proliferation in cultured mouse islets. We found that treatment with a combination of farnesyl- and geranyl-geranyl-transferase inhibitors, which block K-Ras signaling, stimulated beta cell proliferation; but blocking MAPK signaling with an inhibitor of Mek1/2 had no effect on proliferation rate. However, in beta-cells with reduced Men1 gene dosage, both K-Ras and Mek1/2 inhibition reduced the increased basal replication rate, consistent with our model that Menin specifically blocks pro-proliferative outputs of the MAPK arm of K-Ras signaling. Remarkably, complete loss of Men1 created a synthetic lethal interaction with Mek1/2 inhibition. Our study suggests that inhibitors of the Raf/MEK/ERK pathway offer a rational therapy for tumors with germline or somatic MEN1 mutations. Citation Information: Mol Cancer Ther 2013;12(11 Suppl):A185. Citation Format: Chester Chamberlain, Michael German. Menin functions as a gatekeeper of the proliferative MAPK arm of K-Ras signaling. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr A185.

The Genetics of Neuroendocrine Tumors

Neuroendocrine tumors (NETs) present a wide spectrum of malignant diseases from rather benign to very malignant variants. The majority of these tumors are sporadic, but there are several familial (inherited) syndromes to consider, such as multiple endocrine neoplasia type 1 and type 2 (MEN-1 and MEN-2), von Hippel-Lindau syndrome (VHL), tuberosclerosis, and neurofibromatosis syndromes. The MEN-1 gene is mutated not only in MEN-1 families, but a recent study shows that more than 40% of sporadic pancreatic NETs (PNETs) harbor MEN-1 gene mutations. The same study reported that ATRX/DAXX genes are mutated in a significant number of tumors, as are genes encoding components of the mammalian target of rapamycin (mTOR) signal transduction pathway. These findings have implications for the new therapies that have been approved for the treatment of PNETs, such as the tyrosine kinase inhibitor sunitinib, as well the mTOR inhibitor everolimus. Small intestinal NETs show a less varied mutational pattern in that the majority of genetic alterations are found on chromosome 18. There seem to be no differences between the sporadic and the familiar type of small intestinal NETs (carcinoids). A wide range of genetic alterations have been described for the different subtypes of NETs, but the mechanisms underlying tumor development are essentially unknown except for MEN-2, in which an activating mutation of the RET proto-oncogene drives tumor progression and affords a direct genotype/phenotype correlation. Genome-wide screening of different types of NETs can now be performed for a reasonable price and is likely to generate new insights into the tumor biology and carcinogenesis in various subtypes of NETs.

Pancreatic Neuroendocrine Tumor Presenting as a Cushing’s Syndrome Associated with Hypertension

A young female was evaluated in the emergency department (ED) for persistent headache and fatigue one week after being started on antihypertensive therapy with poor response. Her medications were Amlodipine 10 mg daily, Hydrochlorothiazide 25 mg daily, Atenolol 100 mg daily and Hydralazine 50 mg three times daily. Further evaluation revealed cushingoid appearance, her blood pressure was 171/100 mmHg despite compliance with multiple antihypertensive therapy. Her clinical manisfestation prompted the evaluation for secondary causes of hypertension with laboratory evidence of hypokalemia, hyperglycemia, hypercortisolism with high ACTH that did not respond to low and high dose dexamethasone suppression. A splice mutation in MEN 1gene was found with the eventual diagnosis of metastatic pancreatic neuroendocrine tumor. Her turbulent course unravels how complex medical problems continue to masquerade as general medical ailments.

Functioning glucagonoma associated with primary hyperparathyroidism: multiple endocrine neoplasia type 1 or incidental association?

BackgroundDiagnosis of multiple endocrine neoplasia type 1 (MEN1) is commonly based on clinical criteria, and confirmed by genetic testing. In patients without known MEN1-related germline mutations, the possibility of a casual association between two or more endocrine tumors cannot be excluded and subsequent management may be difficult to plan. We describe a very uncommon case of functioning glucagonoma associated with primary hyperparathyroidism (pHPT) in which genetic testing failed to detect germline mutations of MEN-1 and other known genes responsible for MEN1.Case presentationThe patient, a 65-year old woman, had been suffering for more than 1 year from weakness, progressive weight loss, angular cheilitis, glossitis and, more recently, skin rashes on the perineum, perioral skin and groin folds. After multidisciplinary investigations, functioning glucagonoma and asymptomatic pHPT were diagnosed and, since family history was negative, sporadic MEN1 was suspected. However, genetic testing revealed neither MEN-1 nor other gene mutations responsible for rarer cases of MEN1 (CDKN1B/p27 and other cyclin-dependent kinase inhibitor genes CDKN1A/p15, CDKN2C/p18, CDKN2B/p21). The patient underwent distal splenopancreatectomy and at the 4-month follow-up she showed complete remission of symptoms. Six months later, a thyroid nodule, suspected to be a malignant neoplasia, and two hyperfunctioning parathyroid glands were detected respectively by ultrasound with fine needle aspiration cytology and 99mTc-sestamibi scan with SPECT acquisition. Total thyroidectomy was performed, whereas selective parathyroidectomy was preferred to a more extensive procedure because the diagnosis of MEN1 was not supported by genetic analysis and intraoperative intact parathyroid hormone had revealed “adenoma-like” kinetics after the second parathyroid resection. Thirty-nine and 25 months after respectively the first and the second operation, the patient is well and shows no signs or symptoms of recurrence.ConclusionsDespite well-defined diagnostic criteria and guidelines, diagnosis of MEN1 can still be challenging. When diagnosis is doubtful, appropriate management may be difficult to establish.

MEN1 gene mutations with different phenotypic presentations in two families: Is it a time to grade MEN1 mutations as high-risk and low-risk?

1540 Background: MEN1 syndrome results from MEN1 gene mutations and is characterized by primary hyperparathyroidism (PHPT), pancreatic endocrine tumors (PET), pituitary adenomas, thymic and other tumors. About 600 different mutations have been reported on Human Gene Mutation Database and 30 of them presented as Familial Isolated Hyperparathyroidism (FIHP); however, no genotype-phenotype correlations have been identified. Methods: We characterized 2 independent families with newly diagnosed MEN1. Mutation analyses were performed in Dept of Genetics Yale University. Diagnostic tests, surgical treatment were implemented. Results: Family 1 has 21 members. 5 presented with early onset of PHPT and no other tumors. 3 ½ parathyroidectomies were performed. A proband had direct sequencing that showed a mutation in Exon 7, consisting of single base insertion in codon 319 (TAC to TTAC)(c1065_1066insT). There were no deaths in the family. Family 2 has 20 members. 7 were tested and showed a mutation in Exon 2, consisting of single base deletion in codon 103 (CTG to _TG)(c417delC). One 1st generation member died from PET at age 79, three 3rd generation members had multifocal metatstatic malignant gastrinomas (ages 32, 39, 41). The proband had total pancreatectomy at age 32. Five members had PHPT, angiofibromas. Three 2nd generation members had thymic carcinomas (ages 20, 54, 60). Conclusions: Phenotypic presentation of MEN1 syndrome may vary with the same mutation suggesting a lack of genotype-phenotype correlation and the effect of modifying factors. On the other hand, these two families—one with a mutation predicted to truncate the menin protein close to its terminus and the other with a truncating mutation early in the coding sequence—have dramatically different severity of the syndrome. Our findings suggest that the exon 7 mutation has a milder effect on protein function resulting in FIHP. The management may be heavily influenced by the predicted clinical phenotype, we are proposing the development of a grading system for MEN1 gene mutations as low-risk and high-risk and to attempt to identify other modifying genetic and environmental factors to improve screening and timing for surgery.

Mutation analysis in two Chinese families with multiple endocrine neoplasia type 1

This study aimed at identifing mutations in two Chinese genealogies with MEN1. Three members of two Chinese families with MEN1 were enrolled in this study, and all of the coding regions and adjacent sequences of the MEN1 gene were amplified and sequenced. A recurrent mutation of heterozygous change T>A at IVS 4+1 was found in family I, and a novel insGAGGTGG mutation (c.703-709dup7bp) resulted in a frameshift (p.A237Gfsx13) in family II. We are able to add a new mutation of MEN1 gene in Chinese patients with MEN1 that will be useful for the diagnosis and treatment of the disease.

MEN1 and pituitary adenomas

MEN1 gene mutations predispose carriers to pituitary tumors. Molecular pathways involved in the development of these tumors seem different to what is known in sporadic tumors. Clinical studies showed that all types of adenomas can be found with a predominance of prolactinoma and macroadenoma compared to a control population. These MEN1 tumors seem more aggressive, invasive and resistant to treatment requiring a very careful long-life follow-up. Occurrence of these tumors can be described in the pediatric population and it can be the first and only manifestation of MEN1 for some years asking the question of the systematic screening for MEN1 gene mutation in pediatric population with pituitary adenoma.

Carcinoma of Two Parathyroid Glands Caused by a Novel MEN1 Gene Mutation – a Rare Feature of the MEN 1 Syndrome

Multiple endocrine neoplasia type 1 (MEN 1) is a rare syndrome inherited in an autosomal dominant pattern, characterized by combinations of tumors of the parathyroid glands, pituitary gland, and pancreatic islet cells and more rare tumors of endocrine organs and nonendocrine tissues. Germline mutations in the MEN1 gene are responsible for the MEN 1 syndrome, leading to an inactive form of menin protein. Benign lesions of the parathyroid glands are characteristic in patients with the MEN 1 syndrome; however, patients can develop parathyroid carcinomas very rarely. This report presents a clinical case of the MEN 1 syndrome: a 39-year-old woman underwent surgery for carcinoma of two parathyroid glands as well as was treated for pituitary prolactinoma, which caused infertility, and malignant insulinoma; the patient had multiple subcutaneous lipomas as well. Genetic analysis revealed a novel germline mutation in the MEN1 gene - a nucleotide insertion at codon 43 in exon 2 (c.129insA), which caused the occurrence of the MEN1 syndrome. The clinical case of the MEN 1 syndrome presented here is relevant in gathering the data on etiopathogenesis of not only MEN 1 syndrome, but an extremely rare pathology - parathyroid carcinoma - as well.

A new frameshift MEN1 gene mutation associated with familial malignant insulinomas

MEN-1 is an autosomal dominant familial cancer syndrome characterized by involvement of parathyroid, enteropancreatic endocrine tissues and the anterior pituitary gland. Malignant insulinomas are rare, and therefore, there are few data regarding their clinical presentation and long-term prognosis. In this report we present a large family with malignant insulinoma and hyperparathyroidism with MEN-1 gene mutation analysis. A large family (three generations) with several members affected were evaluated for clinical and biochemical characteristic of MEN-1 syndrome. Genetic analysis for MEN1 gene was carried out in all family members using PCR amplification of coding regions followed by direct sequencing. In three brothers that presented with hypoglycemia, insulinoma was confirmed and two were malignant according to pathology and surgery report. Two of them had hyperparathyroidism too. Mutation screening revealed the presence of a two nucleotide deletion in the exon 2 (c199_200del2). In the current study, the deletion happens early in the sequence, and obviously results in a non-functional gene product. However, it will be helpful to further examine somatic mutations and other genetic markers for a more precise study of genotype-phenotype correlation.

Atypical carcinoid of thymus associated with multiple endocrine neoplasia syndrome type 1

Thymic carcinoid associated with multiple endocrine neoplasia syndrome type 1 (MEN-1) is a rare tumor. We report a case of MEN-1-related thymic carcinoid. The patient reported herein had already been diagnosed with MEN-1 and was found to have a mediastinal mass. She underwent thymectomy with partial resection of the left innominate vein and lung. Histological examination revealed atypical carcinoid with infiltration. MEN-1 gene mutation was detected by employing the direct nucleotide sequencing method. Postoperative 2-fluoro-2-deoxyglucose positron emission tomography showed probable multiple metastases in the vertebrae and myocardium. However, she has been alive and asymptomatic for 2 years postoperatively. MEN-1-related thymic carcinoid is often insidious with a poor prognosis. We suggest chest computed tomography scan or magnetic resonance imaging for MEN-1 patients and serological or genetic screening for patients with thymic carcinoid to screen for MEN-1.

A novel germline CDKN1B mutation causing multiple endocrine tumors: clinical, genetic and functional characterization

Multiple endocrine neoplasia (MEN) syndromes are characterized by tumors involving two or more endocrine glands. Two MEN syndromes have long been known: MEN1 and MEN2, caused by germline mutations in MEN1 or RET, respectively. Recently, mutations in CDKN1B, encoding the cyclin-dependent kinase (Cdk) inhibitor p27, were identified in patients having a MEN1-like phenotype but no MEN1 gene mutations. Currently, the molecular mechanisms mediating the role of p27 in tumor predisposition are ill defined. We here report a novel germline missense variant in CDKN1B (c.678C>T, p.P69L) found in a patient with multiple endocrine tumors. We previously reported a nonsense p27 mutation (c.692G>A, p.W76X) in two patients with MEN1-like phenotype. Functional assays were used to characterize p27P69L and p27W76X in vitro. We show that p27P69L is expressed at reduced level and is impaired in both binding to Cdk2 and inhibiting cell growth. p27W76X, which is mislocalized to the cytoplasm, can no longer efficiently bind Cyclins-Cdks, nor inhibit cell growth or induce apoptosis. In the patient's tumor tissues, p27P69L associates with reduced/absent p27 expression and in one tumor with loss-of-heterozygosity. Our results extend previous findings of CDKN1B mutations in patients with MEN1-related states and support the hypothesis of a tumor suppressor role for p27 in neuroendocrine cells. © 2010 Wiley-Liss, Inc.

The role of germline AIP, MEN1, PRKAR1A, CDKN1B and CDKN2C mutations in causing pituitary adenomas in a large cohort of children, adolescents, and patients with genetic syndromes

The prevalence of germline mutations in MEN1, AIP, PRKAR1A, CDKN1B and CDKN2CI is unknown among pediatric patients with pituitary adenomas (PA). In this study, we screened children with PA for mutations in these genes; somatic GNAS mutations were also studied in a limited number of growth hormone (GH) or prolactin (PRL)-secreting PA. We studied 74 and 6 patients with either isolated Cushing disease (CD) or GH- or PRL-secreting PA, respectively. We also screened four pediatric patients with CD, and four with GH/PRL-secreting tumors who had some syndromic features. There was one AIP mutation (p.Lys103Arg) among 74 CD patients. Two MEN1 mutations that occurred in patients with recurrent or difficult-to-treat disease were found among patients with CD. There was one MEN1 and three AIP mutations (p.Gln307ProfsX104, p.Pro114fsX, p.Lys241X) among pediatric patients with isolated GH- or PRL-secreting PA and one additional MEN1 mutation in a patient with positive family history. There were no mutations in the PRKAR1A, CDKN1B, CDKN2C or GNAS genes. Thus, germline AIP or MEN1 gene mutations are frequent among pediatric patients with GH- or PRL-secreting PA but are significantly rarer in pediatric CD; PRKAR1A mutations are not present in PA outside of Carney complex.

Should Routine Analysis of the MEN1 Gene be Performed in all Patients with Primary Hyperparathyroidism Under 40 Years of Age?

Familial hyperparathyroidism, especially Multiple Endocrine Neoplasia Type 1, is more likely to present with primary hyperparathyroidism (1 degrees HPT) at a young age, mandating bilateral exploration of the parathyroid glands. However, the majority of young patients will not be gene carriers or have a family history. Recent evidence suggests that young adults under 40, in whom there is no suspicion of family history, can be managed with the same pre- and perioperative strategy as used for sporadic primary HPT of any age. Our aim was to evaluate the prevalence of mutations in the MEN1 gene in young adults under 40 who present with apparent sporadic 1 degrees HPT. A retrospective review was undertaken of all patients who underwent surgery for 1 degrees HPT between 1993 and 2004. From a total of 1253 patients, 87 (6.2%) were under the age of 40. Thirty-three patients provided informed consent to a detailed personal and family history, physical examination, and genetic analysis of the MEN1 gene. Twelve patients were subsequently excluded as they were known gene carriers prior to surgery (10 MEN1 and 2 MEN2A patients). Twenty-one patients underwent genetic analysis. Of the 21 patients who consented to genetic analysis, the mean age was 30.8 years (range = 18-39 years with 43% younger than 30). These patients had no suspicious family or personal histories suggestive of a MEN phenotype. Fifteen patients presented with symptomatic hypercalcemia. All 21 patients underwent parathyroid surgery by conventional cervicotomy (12) or endoscopic parathyroidectomy in cases (9) where the parathyroid gland was localized preoperatively. Nineteen patients (91%) had uniglandular disease. Surgical cure was achieved in all patients. Of the 21 patients, only one patient (4.7%) was found to have a MEN1 gene mutation (exon 3, at codon 190, c;680_681delGGinsC). This patient was found to have double adenomas at surgery with subsequent histological confirmation. The overall prevalence of MEN1 mutation in all patients under 40 was 13%. Although young age is often the only criterion to suspect MEN1, our results do not support routine MEN1 analysis in patients under 40. We propose that these patients be managed with the same preoperative and surgical approach as those presenting with sporadic 1 degrees HPT of any age.

Detection of the mutation of MEN1 gene in a pedigree with multiple endocrine neoplasia type 1

Objective To dectect the mutation of the MEN1 gene in a pedigree with multiple endocrine neoplasia type 1 (MEN 1).Methods Twelve family members were recruited to this study.Peripheral blood was collected and total genomic DNA was prepared for PCR.PCR products of all 10 exons in MEN1 gene were purified and a direct gene sequence analysis was performed.Subclone sequencing was performed to identify the heterozygosity.Results A one base pair of insertion (1649_1650insC) in exon 10 of MEN1 gene,resulting in a frameshift mutation of codon 514,was detected in a patient with parathyroid hyperplasia diagnosed by pathology.Genetic screening identified the same mutation in other 2 family members and the results of clinical detection were consistent with the diagnostic criteria of MEN1.Conclusions A Chinese family with a new heterozygous mutation (1649_1650insC) in the MEN1 gene,which was not reported previously,is herein described.With genetic screening,it is possible to diagnose the disease at an earlier stage. Key words: Multiple endocrine neoplasia，type 1; Parathyroid hyperplasia; Pituitary neoplasms; MEN1 gene; Mutation