Multiple Endocrine Neoplasia Syndrome Type Research Articles

Management of hereditary medullary thyroid carcinoma.

Hereditary medullary thyroid carcinoma (MTC) represents up to one-third of MTC cases and includes multiple endocrine neoplasia syndrome type 2A (and its variant familial MTC) and 2B. The aim of this paper is to provide an overview of the disease focusing on the management of hereditary MTC patients, who have already developed tumor, as well as discuss the recommended approach for asymptomatic family members carrying the same mutation. A PubMed search was performed to review recent literature on diagnosis, genetic testing, and surgical and medical management of hereditary MTC. The wide use of genetic testing for RET mutations has markedly influenced the course of hereditary MTC. Prophylactic thyroidectomy of RET carriers at an early age eliminates the risk of developing MTC later in life. Pre-operative staging is a strong prognostic factor in patients, who have developed MTC. The use of recently approved tyrosine kinase inhibitors (vandetanib, cabozantinib) holds promising results for the treatment of unresectable, locally advanced, and progressive metastatic MTC. Genetic testing of the RET gene is a powerful tool in the diagnosis and prognosis of MTC. Ongoing research is expected to add novel treatment options for patients with advanced, progressive disease.

Clinical case of rare neuroendocrine tumor of pancreas - proinsulinoma

Proinsulinoma is very rare neuroendocrine tumor of pancreas with proinsulin activity. Today there is no data about its true prevalence and occurrence within the syndrome of Multiple Endocrine Neoplasia (MEN) type 1. We have found no one clinical cases of the disease in available domestic literature, but only few clinical cases in foreign literature. Actually the management of patients with proinsulinoma is unknown, because such clinical guidelines are absent. Therefore, it is essential to describe particularly every new case of this neuroendocrine tumor in order to obtain sufficient data about proinsulinoma, because it is unclear whether the following management of such patients is correct or not. The clinical case of patient with proinsulinoma is described in the article. Atypical clinical presentation of hypoglycemia is reported. All stages of diagnostic research with main errors, the disputed key issues of follow up are discussed in detail, especially differential diagnosis of hypoglycemia in real clinical practice, screening of syndrome of MEN type 1 and the protocol of further observation.

MEN1 syndrome: an anusual case

Multiple endocrine neoplasia type 1 (MEN1) is a rare autosomal dominant endocrine disorder and is characterised by the concurrent appearance of adenomas of the parathyroid glands, neuroendocrine-enteropancreatic tumours, and pituitary adenomas, as well as other types of less frequent tumours, such as adrenal cortical tumours, carcinoid tumours, lipomas, etc. Two different forms, familial and sporadic, have been described. The gene responsible, MEN1, consists of 10 exons encoding a 610-amino acid protein known as menin. The MEN1 syndrome is caused by inactivating mutations in MEN1 tumour suppressor gene. The combination of clinical and genetic investigation helps in the diagnosis. Genetic testing has been advocated to identify MEN1 carriers of the MEN1 families for the purpose of earlier detection of tumours. We present a patient with traditionally described manifestations of MEN1 (a parathyroid hyperplasia associated with a pancreatic neuroendocrine tumour and a gastrinoma), but with a negative genetic test for the MEN1 mutation.

The development of rapid and accurate screening test for RET hotspot somatic and germline mutations in MEN2 syndromes

Medullary thyroid carcinoma (MTC) is a rare endocrine malignancy with distinctive features separating it from other thyroid cancers. Cancer may be sporadic or occur as a consequence of the hereditary syndrome called multiple endocrine neoplasia type 2 (MEN2) with three distinct phenotypes in MEN2A, MEN2B and FMTC. Each variant of MEN2 results from different RET gene mutations, with a good genotype–phenotype correlation. The goal of the study was to develop a fast and accurate screening method for a reliable detection of hot-spot RET germline and sporadic tumor mutations. From a cohort of 191 patients with MTC and their relatives, 38 tested positive and 31 tested negative for a germline or somatic tumor RET mutation were selected. A positive HRM mutation pattern was detected in all mutation-positive patients and altogether the method was able to clearly differentiate between twenty different genotypes. A novel germline variant p.Ala639Thr was detected in MTC patient, which was determined to be likely benign. Analytical specificity was determined to be 98.6% and a sensitivity threshold was determined to be 30%. The fast and accurate HRM method reduces the turnaround time providing fast and important information, especially when targeted anti-tyrosine kinase therapy on tumor samples is considered. Overall, we developed a high-throughput, accurate and cost-effective approach for the detection of RET germline and sporadic tumor mutations.

Abstract 4994: RET isoforms differentially contribute to focal adhesion formation

Abstract RET is a receptor tyrosine kinase crucial for the development of the kidney, and some neuroendocrine tissues. RET activation by its ligand, glial cell-line derived neurotrophic factor (GDNF), results in autophosphorylation of several key tyrosine kinase residues in the intracellular region, which allow binding of adaptor and signalling proteins, and consequently activation of various cellular processes, including survival, proliferation and migration. RET has two major protein isoforms, called RET9 and RET51 after the number of unique amino acids at the C-terminus, generated by alternative splicing. Although the RET isoforms are highly conserved across species, and both isoforms are normally co-expressed, they have major molecular and functional differences, including different transforming abilities, and trafficking properties. RET is implicated in several human diseases. Gain-of-function RET mutations result in the cancer syndrome multiple endocrine neoplasia type 2, that affects neuroendocrine tissues, somatic RET rearrangements are found in papillary thyroid carcinoma, and lung adenocarcinoma, and aberrant wild-type RET activation occurs in many cancers, including breast and pancreatic cancer. Focal adhesion protein complexes are involved in interactions of cells with the extracellular matrix, and are crucial for controlling cancer-related processes, including cell migration and invasion. The contributions of RET isoforms to the processes of focal adhesion formation and dynamics have not yet been investigated. To explore the roles of RET isoforms in focal adhesion formation, we used total internal resonance fluorescence (TIRF) microscopy to assess localization of various focal adhesion proteins, including paxillin, vinculin and zyxin in response to GDNF in a cell-based model system. Our results suggest that RET51 promotes more early (ie. paxillin) and late (ie. zyxin) stage focal adhesion formation than does RET9. Additionally, we demonstrate that the kinase dead form of RET51 results in a decrease of the number of focal adhesions compared to RET51 wild-type, suggesting that the increase in focal adhesion formation in the presence of RET51 is phosphorylation-dependent. Inhibition of SRC and FAK led to a reduction in focal adhesion formation, indicating that these pathways play roles in this process. Ongoing studies are investigating the focal adhesion dynamics of the RET isoforms and further characterizing the molecular differences underlying the ability of RET51 to induce greater focal adhesion formation than RET9. Citation Format: Piriya Yoganathan, Eric Lian, Lois M. Mulligan. RET isoforms differentially contribute to focal adhesion formation. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4994. doi:10.1158/1538-7445.AM2015-4994

Abstract 4990: The RET receptor Y791F variant activates the kinase but diminishes ligand responsiveness

Abstract The RET receptor tyrosine kinase is essential for normal development of the kidneys and enteric nervous system, and is also implicated in several human pathologies. Gain-of-function mutations in RET are associated with the familial cancer syndrome multiple endocrine neoplasia type 2 (MEN 2), where single amino acid substitutions lead to constitutive RET activation in the absence of its ligands of the glial cell line-derived neurotrophic factor (GDNF) family. Conversely, loss-of-function RET mutations are associated with Hirschsprung disease, a congenital abnormality of the enteric nervous system. Previous studies have identified a specific substitution variant of a phenylalanine for tyrosine at amino acid 791 in the RET kinase domain in both cancer and Hirschsprung disease patients. Thus, the functional implications of this variant and its contributions to these diverse phenotypes are not clear. Here, we have explored the role of MEN 2-associated RET mutations in RET-mediated cell invasion and migration. We showed that GDNF-stimulation promotes RET-mediated cell migration and that a GDNF-chemotactic gradient significantly increased invasion of cells expressing wild type RET or a MEN2B (M918T) mutant RET form. However, we found that a GDNF gradient did not enhance invasion of cells expressing RET-Y791F. Consistent with this, we showed that MEN 2-associated RET mutants M918T and Y791F were phosphorylated in the absence of GDNF and stimulated downstream signaling pathways. GDNF treatment further increased phosphorylation of the RET-M918T but not RET-Y791F proteins, suggesting that RET-Y791F has reduced responsiveness to GDNF ligand. Our results suggest that despite constitutive activation of RET signaling, cells expressing the Y791F variant may possess a diminished capacity to recognize and respond to GDNF in the cell microenvironment. This may be linked to a disturbance in the directional migration of cells expressing the mutant receptor thus contributing to the phenotypic variability observed. Citation Format: Andrew Fetz, Mathieu J.F. Crupi, Eric Lian, Brandy D. Hyndman, Lois M. Mulligan. The RET receptor Y791F variant activates the kinase but diminishes ligand responsiveness. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4990. doi:10.1158/1538-7445.AM2015-4990

Operative Failure Rate and Documentation of Family History in Young Patients Undergoing Focused Parathyroidectomy for Primary Hyperparathyroidism

Primary hyperparathyroidism in multiple endocrine neoplasia type I usually affects all parathyroid glands, making focused parathyroidectomy (FP) inappropriate. The risk of previously undiagnosed multiple endocrine neoplasia type I in a younger patient with primary hyperparathyroidism is higher than in an older patient. We hypothesized that FP may lead to a higher failure rate in younger versus older patients. A retrospective review was performed of a single-institution database of patients who underwent parathyroidectomy for primary hyperparathyroidism. Routine statistical analysis was performed, including Fisher's exact test. A total of 635 patients were included. Operative failure occurred in 7/55 (13%) younger patients and 21/580 (4%) older patients (P = 0.007). In conclusion, operative failure occurred in a statistically significantly higher percentage of younger versus older patients undergoing FP. This is partly explained by undiagnosed multiple endocrine neoplasia syndrome type I in the younger patient group. Endocrine surgeons must make every effort to preoperatively identify multiple endocrine neoplasia syndrome type I in the younger patient population.

Large Malignant Pheochromocytoma: About Three Cases

Introduction : Malignant pheochromocytomas are rare tumors which carry a poor prognosis and their clinical presentation is variable. Malignancy is defined by the presence of local invasion and/or metastases. In this report, we describe three cases of large malignant pheochromocytomas. Cases Presentation : The three cases have presented abdominal masses. Two patients complained of hypochondrium pain, and the third one was asymptomatic. One of the patients experienced sweating for 2 years, while the two others had no symptoms suggesting the hyper secretion of catecholamines. Urinalysis revealed elevation of daily urinary excretion of catecholamine metabolites in two cases and the computed tomography (CT) revealed large adrenal masses in the three cases. The malignancy was confirmed by the presence of multiple liver, lung and bone metastases. Surgery was performed in one case, but the tumor resection was impossible because the mass was adherent to great vessels. Calcitonin, intact parathormone (PTH) and calcium were normal in the 3 cases, which ruled out multiple endocrine neoplasia syndrome type 2. Otherwise, there was no sign suggesting phacomatosis. Two patients died before starting therapy, while in the third case the treatment considered was surgery and chemotherapy regimen of cyclophosphamide, dacarbazine and vincristine (CVD). Follow-up, showed a progression of tumor size with no significant improvement of metastatic disease. Conclusion : Malignant pheochromocytomas are particularly rare and aggressive tumors. Despite advances in diagnosis and treatment of malignant pheochromocytomas, their management is still a real dilemma, especially in our context because of the lack of diagnostic tools such as genetic analysis and the cost of therapy.

Palisaded encapsulated neuroma

Palisaded encapsulated neuroma (PEN) is a benign cutaneous or mucosal neural tumor which, usually, presents as a solitary, firm, asymptomatic, papule or nodule showing striking predilection for the face. It occurs commonly in middle age, and there is no sex predilection. Oral PEN are not common, and these lesions must be distinguished from other peripheral nerve sheath tumors such as the neurofibroma, neurilemma (schwannoma), and traumatic neuroma. The major challenge in dealing with lesions of PEN is to avoid the misdiagnosis of neural tumors that may be associated with systemic syndromes such as neurofibromatosis and multiple endocrine neoplasia syndrome type 2B. Here, we present a case of benign PEN of the gingiva in the left anterior mandibular region, laying importance on immunohistochemical staining in diagnosing such lesions.

Hereditary Medullary Thyroid Cancer Genotype-Phenotype Correlation.

During the last two decades, there has been a marked expansion of our knowledge of both the basic and clinical aspects of multiple endocrine neoplasia type 2 (MEN2). There are two clinically distinct types of MEN2 syndrome, termed MEN2A and MEN2B. Within MEN2A, there are four variants: (i) classical MEN2A, represented by the uniform presence of MTC and the less frequent occurrence of pheochromocytoma, or primary hyperparathyroidism, or both; (ii) MEN2A with cutaneous lichen amyloidosis; (iii) MEN2A with Hirschsprung's disease; and (iv) familial medullary thyroid carcinoma (FMTC), i.e., families or individuals with only MTC. MEN2B is associated with MTC, pheochromocytoma, and mucosal neuromas. Hereditary MTC is caused by autosomal dominant gain of function mutations in the RET proto-oncogene. Specific RET mutations may suggest a predilection toward a particular phenotype and clinical course with a strong genotype-phenotype correlation. Based upon these genotype-phenotype correlations, RET mutations are now stratified into three risk levels, i.e., highest, high, and moderate risk, based on the penetrance and aggressiveness of the MTC. Children in the highest risk category should undergo thyroidectomy in their first year of life, and perhaps even in their first months of life. Children in the high-risk category should have ultrasound of the neck and calcitonin (CTN) measurement performed prior to thyroidectomy. Thyroidectomy should typically be performed at the age of 5 or earlier, depending on the presence of elevated serum CTN levels. However, heterogeneity in disease expression and progression within these groups varies considerably. To personalize disease management, the decision regarding the age of prophylactic thyroidectomy is no longer based upon genotype alone but is currently driven by additional clinical data, the most important being serum CTN levels; specifically, the decision to perform thyroidectomy should err on the safe side if the CTN level is elevated but below 30pg/ml, especially in the moderate risk group. Personalized management also includes decisions about the best age to begin biochemical screening for pheochromocytoma and primary hyperparathyroidism.

Genetic test in multiple endocrine neoplasia type 1 syndrome: An evolving story.

Multiple endocrine neoplasia type 1 (MEN1) is an autosomal dominant inherited tumour syndrome expressing various endocrine and non-endocrine lesions and tumours. Since the identification of the causative gene, the oncosuppressor gene MEN1, in 1997, genetic testing has revealed an important approach for the early and differential diagnosis of the disease. The finding of a MEN1 mutation in a patient has important clinical implications for relatives since it allows very early disease diagnosis and identification of carriers, even before biochemical and/or clinical manifestation, permitting their inclusion in a specific program of surveillance and subsequent praecox therapy. Currently, genetic testing for MEN1 consists principally of the sequencing of coding regions and intron-exon junctions of the MEN1 gene. However, the recent acquisition of novel high throughput technologies will allow the design of innovative, accurate, complete and rapid genetic diagnosis. These new tools are able to increase the strength of the analysis and almost completely eliminate the possibility of false negative results. This review aims to give an overview on genetic testing of MEN1 syndrome, reporting the positive aspects of performing the analysis and the future perspectives for improving the performance of the test, as well as its application in clinical practice.

PTCH 1 staining of pancreatic neuroendocrine tumor (PNET) samples from patients with and without multiple endocrine neoplasia (MEN-1) syndrome reveals a potential therapeutic target

Pancreatic neuroendocrine tumors (PNETs) are rare, indolent tumors that may occur sporadically or develop in association with well-recognized hereditary syndromes, particularly multiple endocrine neoplasia type 1 (MEN-1). We previously demonstrated that the hedgehog (HH) signaling pathway was aberrantly up-regulated in a mouse model that phenocopies the human MEN-1 syndrome, Men1l/l;RipCre, and that inhibition of this pathway suppresses MEN-1 tumor cell proliferation. We hypothesized that the HH signaling pathway is similarly upregulated in human PNETs. We performed immunohistochemical (IHC) staining for PTCH1 in human fresh and archival PNET specimens to examine whether human sporadic and MEN-1-associated PNETs revealed similar abnormalities as in our mouse model and correlated the results with clinical and demographic factors of the study cohort. PTCH1 staining was positive in 12 of 22 PNET patients (55%). Four of 5 MEN-1 patients stained for PTCH1 (p = 0.32 as compared with sporadic disease patients). Nine of 16 patients with metastatic disease stained for PTCH1 as compared with zero of 3 with localized disease only (p = 0.21). No demographic or clinical features appeared to be predictive of PTCH 1 positivity and PTCH 1 positivity per se was not predictive of clinical outcome. PTCH1, a marker of HH pathway up regulation, is detectable in both primary and metastatic tumors in more than 50% of PNET patients. Although no clinical or demographic factors predict PTCH1 positivity and PTCH1 positivity does not predict clinical outcome, the frequency of expression alone indicates that perturbation of this pathway with agents such as Vismodegib, an inhibitor of Smoothened (SMO), should be examined in future clinical trials.

Imaging diagnostic standard in multiple endocrine neoplasia (MEN)

Background Among all hereditary cancer syndromes MEN Type 1 and 2 are characterized by the concurrent but independent appearance of benign as well as malignant tumours. Neoplasias of parathyroid glands, pancreas, pituitary gland as well as neuroendocrine tumours of the stomach and intestinal wall are typical for MEN 1. Medullary thyroid carcinomas together with parathyroid adenomas and phaeochromocytomas are hallmarks of MEN 2. This presentation gives an overview about the multitude of imaging techniques that are inevitable for diagnostics and long-term follow up in MEN patients beyond molecular genetic and laboratory methods. Methods

Demographic, clinical, and genetic characteristics of patients with medullary thyroid cancer in the past 16 years in Castilla-La Mancha

Objective Medullary thyroid cancer is a rare tumor that is more aggressive and has a worse prognosis than differentiated thyroid cancer. The purpose of this study was to report the demographic, clinical, and genetic characteristics of patients seen in the health care system of the community of Castilla-La Mancha over a 16-year period. Patients and methods Data were collected through a review of patients' medical records. Results The medical records of 58 patients (mean age at diagnosis, 51 years; range, 6-82 years; 63.8% women) were reviewed. Prevalence rate was 2.84 cases per 100,000 inhabitants, with a high variability between areas (range, 0-5.4 cases per 100,000 inhabitants). Familial cases accounted for 34.5% of all medullary thyroid cancers, and the most common mutation was C634Y. The condition was most commonly diagnosed following palpation of a cervical lump (70.6%). At diagnosis, 56 of 58 patients underwent ultrasound and 8 of 58 patients were tested for serum calcitonin. Tumor multicentricity was reported in 59 and 50% of patients with multiple endocrine neoplasia syndrome type 2A and 2B, respectively, and in no sporadic cases. Fifty-two percent of patients had an advanced stage (iii or iv) at diagnosis. Median follow-up was 36 months (interquartile range, 14-210); 11 patients were lost to follow-up. Conclusions In Castilla-La Mancha, medullary thyroid cancer is diagnosed by cervical ultrasound, rather than calcitonin assay. There is a high prevalence of both familial and sporadic medullary thyroid cancer, and a significant variability in the type of proto-oncogen rearranged during transfection mutation as compared to the rest of the Spanish population.

Menin-mediated regulation of miRNA biogenesis uncovers the IRS2 pathway as a target for regulating pancreatic beta cells.

Menin, a protein encoded by the MEN1 gene, is mutated in patients with multiple endocrine neoplasia type 1 (MEN1). Menin acts as a tumor suppressor in endocrine organs while it is also required for transformation of a subgroup of leukemia. The recently solved crystal structure of menin with different binding partners reveals that menin is a key scaffold protein that cross-talks with various partners, including transcription factors, to regulate gene transcription. Our recent findings unravel a previously undiscovered mechanism for menin-mediated control of gene expression via processing of certain microRNA's, thus adding to the plethora of ways in which menin regulates gene expression. By interacting with ARS2, an RNA binding protein, menin facilitates the processing of pri-let 7a and pri-miR155 to pre-let 7a and pre-miR155 respectively. Consistently, excision of the Men1 gene results in upregulation of IRS2, a let-7a target. As IRS2 is known to mediate both insulin signaling and insulin-induced cell proliferation, and let-7a targets include oncogenes like RAS and HMGA2, a deeper understanding of the menin-ARS2 complex in regulating miRNA biogenesis will yield further insights into the pathogenesis of the MEN1 syndrome and other menin-associated malignancies.

Association between the p27 rs2066827 variant and tumor multiplicity in patients harboring MEN1 germline mutations.

To date, no evidence of robust genotype-phenotype correlation or disease modifiers for multiple endocrine neoplasia type 1 (MEN1) syndrome has been described, leaving the highly variable clinical presentation of patients unaccounted for. As the CDKN1B (p27) gene causes MEN4 syndrome and it is transcriptionally regulated by the product of the MEN1 gene (menin), we sought to analyze whether p27 influences the phenotype of MEN1-mutated patients. The cohort consisted of 100 patients carrying germline MEN1 gene mutations and 855 population-matched control individuals. Genotyping of the coding p27 c.326T>G (V109G) variant was performed by sequencing and restriction site digestion, and the genotypes were associated with clinical parameters by calculating odds ratios (ORs) and their 95% CIs using logistic regression. There were significant differences in p27 V109G allele frequencies between controls and MEN1-mutated patients (OR=2.55, P=0.019, CI=1.013-5.76). Among patients who are ≥30 years old carrying truncating MEN1 mutations, the T allele was strongly associated with susceptibility to tumors in multiple glands (three to four glands affected vs one to two glands affected; OR=18.33; P=0.002, CI=2.88-16.41). This finding remained significant after the Bonferroni's multiple testing correction, indicating a robust association. No correlations were observed with the development of MEN1-related tumors such as hyperparathyroidism, pituitary adenomas, and enteropancreatic and adrenocortical tumors. Our study suggests that the p27 tumor suppressor gene acts as a disease modifier for the MEN1 syndrome associated with MEN1 germline mutations. If confirmed in independent patient cohorts, this finding could facilitate the management of this clinically complex disease.

Multiple endocrine neoplasia type 1 associated with breast cancer: A case report and review of the literature.

Multiple endocrine neoplasia type 1 (MEN1) is a cancer predisposition syndrome that includes a combination of endocrine and non-endocrine tumors. The present study reports a rare case of MEN1 associated with breast cancer with the MEN1 gene mutation. A 45-year-old female was diagnosed with breast cancer subsequent to presenting with a right breast mass. Pre-operative radiological studies indicated right breast cancer with a suspicious metastatic nodule of the lung. Further studies demonstrated bilateral thyroid nodules, a neuroendocrine tumor of the pancreas, paraganglioma, a left adrenal adenoma, gallstones, uterine subserosal myoma and pituitary macroadenoma. Laboratory examinations revealed hypercalcemia, hypophosphatemia and an increased intact parathyroid hormone level. The workup for the suspected MEN syndrome revealed an increased basal plasma level of insulin-like growth factor-1, prolactin and calcitonin, and an increased 24-h urinary free cortisol level. The patient underwent surgical removal of the breast cancer and the tumors of the pancreas, adrenal gland, thyroid and parathyroid glands, uterus, anterior mediastinum and lung. The pathological diagnosis of the resected breast was of invasive ductal carcinoma. Otherwise the pathological diagnosis was of calcitonin-producing pancreatic endocrine carcinoma, adrenal cortical adenoma, bilateral papillary thyroid carcinomas, parathyroid adenomas, uterine leiomyoma with adenomyosis, a thymic carcinoid tumor and lung hamatoma. Gene analysis was performed to determine the association between gene mutations and the development of tumors in this patient, and a germ-line MEN1 gene mutation was consequently detected. It could be assumed that MEN1 syndrome may have possibly predisposed the present patient to breast cancer. However, additional observations and further studies are required to demonstrate this association.

Demografía, características clínicas y genéticas de pacientes con carcinoma medular de tiroides en los últimos 16 años en Castilla-La Mancha

ObjectiveMedullary thyroid cancer is a rare tumor that is more aggressive and has a worse prognosis than differentiated thyroid cancer. The purpose of this study was to report the demographic, clinical, and genetic characteristics of patients seen in the health care system of the community of Castilla-La Mancha over a 16-year period. Patients and methodsData were collected through a review of patients’ medical records. ResultsThe medical records of 58 patients (mean age at diagnosis, 51 years; range, 6-82 years; 63.8% women) were reviewed. Prevalence rate was 2.84 cases per 100,000 inhabitants, with a high variability between areas (range, 0-5.4 cases per 100,000 inhabitants). Familial cases accounted for 34.5% of all medullary thyroid cancers, and the most common mutation was C634Y. The condition was most commonly diagnosed following palpation of a cervical lump (70.6%). At diagnosis, 56 of 58 patients underwent ultrasound and 8 of 58 patients were tested for serum calcitonin. Tumor multicentricity was reported in 59 and 50% of patients with multiple endocrine neoplasia syndrome type 2A and 2B, respectively, and in no sporadic cases. Fifty-two percent of patients had an advanced stage (iii or iv) at diagnosis. Median follow-up was 36 months (interquartile range, 14-210); 11 patients were lost to follow-up. ConclusionsIn Castilla-La Mancha, medullary thyroid cancer is diagnosed by cervical ultrasound, rather than calcitonin assay. There is a high prevalence of both familial and sporadic medullary thyroid cancer, and a significant variability in the type of proto-oncogen rearranged during transfection mutation as compared to the rest of the Spanish population.

Deletion of exons 1–3 of the MEN1 gene in a large Italian family causes the loss of menin expression

Multiple endocrine neoplasia type 1 (MEN1) syndrome is an autosomal dominant disease, characterized by parathyroid adenomas, endocrine gastroenteropancreatic tumors and pituitary adenomas, due to inactivating mutations of the MEN1 gene (chromosome 11q13). MEN1 mutations are mainly represented by nonsense, deletions/insertions, splice site or missense mutations that can be detected by direct sequencing of genomic DNA. However, MEN1 patients with large heterozygous deletions may escape classical genetic screening and may be misidentified as phenocopies, thereby hindering proper clinical surveillance. We employed a real-time polymerase chain reaction application, the TaqMan copy number variation assay, to evaluate a family in which we failed to identify an MEN1 mutation by direct sequencing, despite a clear clinical diagnosis of MEN1 syndrome. Using the TaqMan copy number variation assay we identified a large deletion of the MEN1 gene involving exons 1 and 2, in three affected family members, but not in the other nine family members that were to date clinically unaffected. The same genetic alteration was not found in a group of ten unaffected subjects, without family history of endocrine tumors. The MEN1 deletion was further confirmed by multiplex ligation-dependent probe amplification, which showed the deletion extended from exon 1 to exon 3. This new approach allowed us to correctly genetically diagnose three clinical MEN1 patients that were previously considered as MEN1 phenocopies. More importantly, we excluded the presence of genetic alterations in the unaffected family members. These results underline the importance of using a variety of available biotechnology approaches when pursuing a genetic diagnosis in a clinically suggestive setting of inherited endocrine cancer.

Recurrent thymic carcinoid tumor in familial isolated primary hyperparathyroidism

Familial isolated primary hyperparathyroidism(FIPH) is associated with multiple endocrine neoplasia type 1(MEN1) syn-drome, primary hyperparathyroidism accompanied by jaw-tumor syndrome, and familial hypocalciuric hypercalcemia. FIPH may be an early stage of MEN1 or an allelic variant of MEN1. Thymic carcinoid tumor is a rare tumor in MEN1 syndrome. Here, the authors report the case of a 40-year-old man diagnosed with recurrent thymic carcinoid tumor and FIPH. Both the patient and his elder sister had been previously diagnosed to have FIPH with a novel frameshift mutation in the MEN1 gene. Initially, the patient underwent thymectomy because of an incidental finding of a mediastinal mass in his chest X-ray, and had remained asymptomatic over the following 4 years. Pancreas computed tomography conducted to evaluate MEN1 syndrome revealed anterior and middle mediastinal masses, and resultantly, massive mass excision was performed. Histological findings disclosed atypical carcinoids with infiltrative margins. In view of the thymic carcinoid tumor relapse that occurred in this patient, the authors recommend that regular pancreas and pituitary imaging studies be conducted for FIPH associated with a MEN1 gene mutation.