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PloS One 2016Multiple endocrine neoplasia type 1-related primary hyperparathyroidism (MHPT) differs in many aspects from sporadic PHPT (SHPT). The aims of this study were to...
OBJECTIVE
Multiple endocrine neoplasia type 1-related primary hyperparathyroidism (MHPT) differs in many aspects from sporadic PHPT (SHPT). The aims of this study were to summarize the clinical features and genetic background of Chinese MHPT patients and compare the severity of the disease with those of SHPT.
DESIGN AND METHODS
A total of 40 MHPT (27 sporadic, 7 families) and 169 SHPT cases of Chinese descent were retrospectively analyzed. X-rays and ultrasound were used to assess the bone and urinary system. Dual energy x-ray absorptiometry (DXA) were performed to measure bone mineral density (BMD). Besides direct sequencing of the MEN1 and CDKN1B genes, multiplex ligation-dependent probe amplification (MLPA) was used to screen gross deletion for the MEN1 gene.
RESULTS
Compared with SHPT patients, MHPT patients showed lower prevalence of typical X-ray changes related to PHPT (26.3% vs. 55.7%, P = 0.001) but higher prevalence of urolithiasis/renal calcification (40.2% vs. 60.0%, P = 0.024). MHPT patients showed higher phosphate level (0.84 vs. 0.73mmol/L, P<0.05) but lower ALP (103.0 vs. 174.0U/L, P<0.001) and PTH (4.0 vs. 9.8×upper limit, P<0.001) levels than SHPT patients. There were no significant differences in BMD Z-scores at the lumbar spine and femoral neck between the two groups. Mutations in the MEN1 gene were detected in 27 MHPT cases. Among the nine novel mutations were novel, one of them involved the deletion of exon 5 and 6.
CONCLUSIONS
MHPT patients experienced more common kidney complications but less skeletal issues, and a milder biochemical manifestation compared with SHPT patients. MEN1 mutation detection rate was 79.4% and 9 of the identified mutations were novel.
Topics: Absorptiometry, Photon; Adult; Aged; Asian People; Bone Density; Cyclin-Dependent Kinase Inhibitor p27; Female; Genetic Testing; Humans; Hyperparathyroidism, Primary; Kidney; Lumbar Vertebrae; Male; Middle Aged; Multiple Endocrine Neoplasia Type 1; Muscle, Skeletal; Mutation; Proto-Oncogene Proteins
PubMed: 27846313
DOI: 10.1371/journal.pone.0166634 -
Medicine Dec 2021Multiple Endocrine Neoplasia type 1 (MEN1) is a familial syndrome that results from the disruption of a tumor suppressor protein called MENIN. Its management is...
RATIONALE
Multiple Endocrine Neoplasia type 1 (MEN1) is a familial syndrome that results from the disruption of a tumor suppressor protein called MENIN. Its management is challenging, as MEN1 affects different endocrine tissues and predisposes to both benign and malignant tumors. MENIN-deficient cells have recently been recognized to play a role in triggering autoimmunity. Herein, we present a case of MEN1 with multiple endocrine and autoimmune disorders.
PATIENT CONCERNS
A 50 years old female with a 25 years history of complicated nephrolithiasis presented with primary hyperparathyroidism.
DIAGNOSES
Over several decades, she was diagnosed with recurrent primary hyperparathyroidism, autoimmune thyroiditis, multinodular goiter, pernicious anemia, metastatic gastric type 1 neuroendocrine tumor, macroprolactinemia, gonadotropin deficiency, mucosa-associated lymphoid tissue lymphoma of the thyroid gland, positive anti-calcium sensor receptor antibodies, and BRCA 1/2-negative invasive breast cancer. The autoimmune regulator gene was sequenced, but no pathogenic variants were found. Next-generation sequencing revealed both a pathogenic MEN1 mutation and a benign CDC73 gene variant. Familial genetic screening revealed a large kindred with multiple carriers of one or both genetic variants (MEN1 = 19; CDC73 = 7).
INTERVENTIONS
The patient underwent surgical excision of three parathyroid glands, total thyroidectomy and breast tumorectomy plus tamoxifen, and monthly injections of octreotide. The patient and family members with the MEN1 mutation are under a life-long surveillance program for MEN1 prototypic tumors.
OUTCOMES
The patient was stable and alive during a 24-years follow-up period.
LESSONS
With the present case, the authors highlight a new interplay between MENIN and the immune system, which may have implications for future targeted life-long surveillance and treatment of MEN1 patients.
Topics: Autoimmune Diseases; Autoimmunity; Female; Humans; Hyperparathyroidism, Primary; Intestinal Neoplasms; Middle Aged; Multiple Endocrine Neoplasia Type 1; Neuroendocrine Tumors; Pancreatic Neoplasms; Proto-Oncogene Proteins; Stomach Neoplasms; Thyroidectomy
PubMed: 34889280
DOI: 10.1097/MD.0000000000028145 -
Journal of Internal Medicine Jun 1998Somatostatin receptors are expressed on the majority of neuroendocrine tumours. The presence of these receptors is clinically useful. First, long-term treatment with... (Review)
Review
Somatostatin receptors are expressed on the majority of neuroendocrine tumours. The presence of these receptors is clinically useful. First, long-term treatment with somatostatin analogues controls hormonal hypersecretion, which controls flushing attacks, watery diarrhoea, hypoglycaemia and electrolyte disorders in patients with carcinoids and islet cell tumours. Secondly, somatostatin receptor imaging is used to localize primary neuroendocrine tumours and to visualize the spread of the disease. Thirdly internalization of somatostatin receptors by primary neuroendocrine tumours opens the possibility of carrying out radio- and chemotherapy with somatostatin analogues coupled to beta-emitting radionuclides and chemotherapeutic drugs. The presence and role of somatostatin receptors on the tumours which occur in multiple endocrine neoplasia and von Hippel-Lindau disease are discussed.
Topics: Gene Expression Regulation, Neoplastic; Humans; Multiple Endocrine Neoplasia; Receptors, Somatostatin; von Hippel-Lindau Disease
PubMed: 9681860
DOI: 10.1046/j.1365-2796.1998.00340.x -
Clinics (Sao Paulo, Brazil) 2012Multiple endocrine neoplasias are autosomal dominant disorders characterized by the occurrence of tumors in at least two endocrine glands. Two MEN syndromes have long... (Review)
Review
Multiple endocrine neoplasias are autosomal dominant disorders characterized by the occurrence of tumors in at least two endocrine glands. Two MEN syndromes have long been known and are well characterized: the MEN type 1 (MEN1) and type 2 (MEN2). These syndromes are caused by germline mutations in the MEN1 and RET genes, respectively, and have a different tumor spectrum. Recently, a variant of the MEN syndromes arose spontaneously in a rat colony and was named MENX. Affected animals consistently develop multiple endocrine tumors, with a spectrum that shares features with both MEN1 and MEN2 human syndromes. Genetic studies identified a germline mutation in the Cdkn1b gene, encoding the p27 cell cycle inhibitor, as the causative mutation for MENX. Capitalizing on these findings, heterozygous germline mutations in the human homologue, CDKN1B, were searched for and identified in patients with multiple endocrine tumors. As a consequence of this discovery, a novel human MEN syndrome, named MEN4, was recognized, which is caused by mutations in p27. Altogether, these studies identified Cdkn1b/CDKN1B as a novel tumor susceptibility gene for multiple endocrine tumors in both rats and humans. Here we review the characteristics of the MENX and MEN4 syndromes and we briefly address the main function of p27 and how they are affected by MENX/4-associated mutations.
Topics: Adrenal Gland Neoplasms; Adrenal Glands; Animals; Cyclin-Dependent Kinase Inhibitor p27; Germ-Line Mutation; Humans; Hyperplasia; Multiple Endocrine Neoplasia; Mutation; Rats
PubMed: 22584700
DOI: 10.6061/clinics/2012(sup01)04 -
The Journal of Clinical Endocrinology... Sep 2019The clinical phenotype of multiple endocrine neoplasia type 4 (MEN4) is undefined due to a limited number of published cases. Knowledge on disease manifestation in MEN4... (Review)
Review
CONTEXT
The clinical phenotype of multiple endocrine neoplasia type 4 (MEN4) is undefined due to a limited number of published cases. Knowledge on disease manifestation in MEN4 is essential for developing prevention programs and treatment.
OBJECTIVE
To expand current knowledge of the MEN4 phenotype including assessment of penetrance.
DESIGN
This is a case report and a brief review of previously published MEN4 cases.
PATIENTS
We report a large Danish family with multiple cases of endocrine tumors that segregated with a pathogenic variant in the CDKN1B gene.
MAIN OUTCOME/RESULT
The medical history of the proband included primary hyperparathyroidism and Cushing disease. Genetic analysis identified a pathogenic variant in CDKN1B (c.121_122delTT, p.Leu41Asnfs*83). Among the family members, another 12 individuals were identified as carriers of the same variant, which segregated with development of endocrine tumors. Hypercalcemia due to primary hyperparathyroidism occurred in all 13 of the available carriers of the genetic variant, and 4 patients also had functioning or nonfunctioning pituitary adenomas, whereas 1 patient had a metastatic neuroendocrine tumor (carcinoid). Loss-of-heterozygosity was detected in two of five parathyroid adenomas, supporting that CDKN1B acts as a tumor suppressor gene. Thirty cases representing 16 different CDKN1B variants have previously been reported, and these cases presented primarily with primary hyperparathyroidism and functioning and nonfunctioning pituitary tumors.
CONCLUSION
Hypercalcemia due to primary hyperparathyroidism and pituitary tumors are common in MEN4. Gastrointestinal neuroendocrine tumors appear to be less prevalent in MEN4 than in MEN1.
Topics: Biomarkers; Cyclin-Dependent Kinase Inhibitor p27; Female; Humans; Hypercalcemia; Hyperparathyroidism, Primary; Loss of Heterozygosity; Male; Middle Aged; Multiple Endocrine Neoplasia; Mutation; Neuroendocrine Tumors; Pedigree; Pituitary Neoplasms; Prognosis
PubMed: 30990521
DOI: 10.1210/jc.2019-00082 -
Surgical Oncology Clinics of North... Apr 2023Multiple endocrine neoplasia type 1 syndrome (MEN1) is a disease caused by mutations in the MEN1 tumor suppressor gene leading to hyperparathyroidism, pituitary... (Review)
Review
Multiple endocrine neoplasia type 1 syndrome (MEN1) is a disease caused by mutations in the MEN1 tumor suppressor gene leading to hyperparathyroidism, pituitary adenomas, and entero-pancreatic neuroendocrine tumors. Pancreatic neuroendocrine tumors (PNETs) are a major cause of mortality in patients with MEN1. Identification of consistent genotype-phenotype correlations has remained elusive, but MEN1 mutations in exons 2, 9, and 10 may be associated with metastatic PNETs; patients with these mutations may benefit from more intensive surveillance and aggressive treatment. In addition, epigenetic differences between MEN1-associated PNETs and sporadic PNETs are beginning to emerge, but further investigation is required to establish clear phenotypic associations.
Topics: Humans; Genotype; Multiple Endocrine Neoplasia Type 1; Neuroectodermal Tumors, Primitive; Neuroendocrine Tumors; Pancreatic Neoplasms; Phenotype
PubMed: 36925188
DOI: 10.1016/j.soc.2022.10.008 -
Italian Journal of Pediatrics Mar 2012Multiple Endocrine Neoplasia type 2B (MEN 2B) is an autosomal dominant complex oncologic neurocristopathy including medullary thyroid carcinoma, pheochromocytoma,... (Review)
Review
Multiple Endocrine Neoplasia type 2B (MEN 2B) is an autosomal dominant complex oncologic neurocristopathy including medullary thyroid carcinoma, pheochromocytoma, gastrointestinal disorders, marphanoid face, and mucosal multiple ganglioneuromas. Medullary thyroid carcinoma is the major cause of mortality in MEN 2B syndrome, and it often appears during the first years of life. RET proto-oncogene germline activating mutations are causative for MEN 2B. The 95% of MEN 2B patients are associated with a point mutation in exon 16 (M918/T). A second point mutation at codon 883 has been found in 2%-3% of MEN 2B cases. RET proto-oncogene is also involved in different neoplastic and not neoplastic neurocristopathies. Other RET mutations cause MEN 2A syndrome, familial medullary thyroid carcinoma, or Hirschsprung's disease. RET gene expression is also involved in Neuroblastoma. The main diagnosis standards are the acetylcholinesterase study of rectal mucosa and the molecular analysis of RET. In our protocol the rectal biopsy is, therefore, the first approach. RET mutation detection offers the possibility to diagnose MEN 2B predisposition at a pre-clinical stage in familial cases, and to perform an early total prophylactic thyroidectomy. The surgical treatment of MEN 2B is total thyroidectomy with cervical limphadenectomy of the central compartment of the neck. When possible, this intervention should be performed with prophylactic aim before 1 year of age in patients with molecular genetic diagnosis. Recent advances into the mechanisms of RET proto-oncogene signaling and pathways of RET signal transduction in the development of MEN 2 and MTC will allow new treatment possibilities.
Topics: Biopsy; Child; Child, Preschool; Codon; Gene Expression; Genetic Predisposition to Disease; Humans; Infant; Lymph Node Excision; Multiple Endocrine Neoplasia Type 2b; Point Mutation; Prognosis; Proto-Oncogene Mas; Proto-Oncogene Proteins c-ret; Signal Transduction; Thyroid Neoplasms; Thyroidectomy
PubMed: 22429913
DOI: 10.1186/1824-7288-38-9 -
Clinics (Sao Paulo, Brazil) 2012Primary hyperparathyroidism is a common endocrinological disorder. In rare circumstances, it is associated with familial syndromes, such as multiple endocrine neoplasia... (Review)
Review
Primary hyperparathyroidism is a common endocrinological disorder. In rare circumstances, it is associated with familial syndromes, such as multiple endocrine neoplasia type 1. This syndrome is caused by a germline mutation in the multiple endocrine neoplasia type 1 gene encoding the tumor-suppressor protein menin. Usually, primary hyperparathyroidism is the initial clinical expression in carriers of multiple endocrine neoplasia type 1 mutations, occurring in more than 90% of patients and appearing at a young age (20-25 years). Multiple endocrine neoplasia type 1/primary hyperparathyroidism is generally accompanied by multiglandular disease, clinically manifesting with hypercalcemia, although it can remain asymptomatic for a long time and consequently not always be recognized early. Surgery is the recommended treatment. The goal of this short review is to discuss the timing of surgery in patients when primary hyperparathyroidism is associated with multiple endocrine neoplasia type 1.
Topics: Germ-Line Mutation; Humans; Hyperparathyroidism, Primary; Multiple Endocrine Neoplasia Type 1; Parathyroid Neoplasms; Parathyroidectomy; Pedigree; Thymectomy
PubMed: 22584719
DOI: 10.6061/clinics/2012(sup01)23 -
International Journal of Molecular... Oct 2020Multiple endocrine neoplasia type 1 (MEN1) is a rare inherited tumor syndrome, characterized by the development of multiple neuroendocrine tumors (NETs) in a single... (Review)
Review
Multiple endocrine neoplasia type 1 (MEN1) is a rare inherited tumor syndrome, characterized by the development of multiple neuroendocrine tumors (NETs) in a single patient. Major manifestations include primary hyperparathyroidism, gastro-entero-pancreatic neuroendocrine tumors, and pituitary adenomas. In addition to these main NETs, various combinations of more than 20 endocrine and non-endocrine tumors have been described in MEN1 patients. Despite advances in diagnostic techniques and treatment options, which are generally similar to those of sporadic tumors, patients with MEN1 have a poor life expectancy, and the need for targeted therapies is strongly felt. MEN1 is caused by germline heterozygous inactivating mutations of the gene, which encodes menin, a tumor suppressor protein. The lack of a direct genotype-phenotype correlation does not permit the determination of the exact clinical course of the syndrome. One of the possible causes of this lack of association could be ascribed to epigenetic factors, including microRNAs (miRNAs), single-stranded non-coding small RNAs that negatively regulate post-transcriptional gene expression. Some miRNAs, and their deregulation, have been associated with MEN1 tumorigenesis. Recently, an extracellular class of miRNAs has also been identified (c-miRNAs); variations in their levels showed association with various human diseases, including tumors. The aim of this review is to provide a general overview on the involvement of miRNAs in MEN1 tumor development, to be used as possible targets for novel molecular therapies. The potential role of c-miRNAs as future non-invasive diagnostic and prognostic biomarkers of MEN1 will be discussed as well.
Topics: Animals; Biomarkers, Tumor; Circulating MicroRNA; Humans; Multiple Endocrine Neoplasia Type 1; Proto-Oncogene Proteins
PubMed: 33066578
DOI: 10.3390/ijms21207592 -
Endocrine-related Cancer Oct 2017Multiple endocrine neoplasia (MEN) refers to a group of autosomal dominant disorders with generally high penetrance that lead to the development of a wide spectrum of... (Review)
Review
Multiple endocrine neoplasia (MEN) refers to a group of autosomal dominant disorders with generally high penetrance that lead to the development of a wide spectrum of endocrine and non-endocrine manifestations. The most frequent among these conditions is MEN type 1 (MEN1), which is caused by germline heterozygous loss-of-function mutations in the tumor suppressor gene MEN1 is characterized by primary hyperparathyroidism (PHPT) and functional or nonfunctional pancreatic neuroendocrine tumors and pituitary adenomas. Approximately 10% of patients with familial or sporadic MEN1-like phenotype do not have mutations or deletions. A novel MEN syndrome was discovered, initially in rats (MENX), and later in humans (MEN4), which is caused by germline mutations in the putative tumor suppressor The most common phenotype of the 19 established cases of MEN4 that have been described to date is PHPT followed by pituitary adenomas. Recently, somatic or germline mutations in were also identified in patients with sporadic PHPT, small intestinal neuroendocrine tumors, lymphoma and breast cancer, demonstrating a novel role for as a tumor susceptibility gene for other neoplasms. In this review, we report on the genetic characterization and clinical features of MEN4.
Topics: Cyclin-Dependent Kinase Inhibitor p27; Female; Humans; Male; Multiple Endocrine Neoplasia; Mutation; Neuroendocrine Tumors
PubMed: 28824003
DOI: 10.1530/ERC-17-0243