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Pancreatitis as the first manifestation of multiple endocrine neoplasia type 2A
Dora, José Miguel;Siqueira, Débora Rodrigues;Meyer, Erika L. Souza;Pu?ales, Márcia Khaled;Maia, Ana Luiza;
Arquivos Brasileiros de Endocrinologia & Metabologia , 2008, DOI: 10.1590/S0004-27302008000800021
Abstract: multiple endocrine neoplasia type 2a (men2a) is an autosomal dominant inherited condition that predisposes to the triad of medullary thyroid cancer (mtc), pheochromocytoma (pheo), and primary hyperparathyroidism (pht). nearly 100% of men2a are associated with germ line mutation of the ret proto-oncogene (ret), and dna-based ret genotype analysis is now considered essential for earlier diagnosis. the first manifestation of men2a is most often due to mtc, and less frequently to pheo. rarely, men2a is recognized during the search for pht associated conditions. most patients with primary hyperparathyroidism are asymptomatic, and the focus of the presentation may be the side effects of chronic hypercalcemia, osteoporosis, renal lithiasis, peptic ulcer disease, and hypertension. hypercalcemic pancreatitis is rare, being an uncommon first manifestation of pht. here, we report on a patient who presented recurrent pancreatitis as the first manifestation of men2a. in the present case, prompt sequential dosage of calcium, diagnosis of pht, and genetic analysis would have resulted in pancreatitis prevention and early men2a management.
RET Germline Mutations Identified by Exome Sequencing in a Chinese Multiple Endocrine Neoplasia Type 2A/Familial Medullary Thyroid Carcinoma Family  [PDF]
Xiao-Ping Qi, Ju-Ming Ma, Zhen-Fang Du, Rong-Biao Ying, Jun Fei, Hang-Yang Jin, Jian-Shan Han, Jin-Quan Wang, Xiao-Ling Chen, Chun-Yue Chen, Wen-Ting Liu, Jia-Jun Lu, Jian-Guo Zhang, Xian-Ning Zhang
PLOS ONE , 2011, DOI: 10.1371/journal.pone.0020353
Abstract: Background Whole exome sequencing provides a labor-saving and direct means of genetic diagnosis of hereditary disorders in which the pathogenic gene harbors a large cohort of exons. We set out to demonstrate a suitable example of genetic diagnosis of MEN 2A/FMTC (multiple endocrine neoplasia type 2/familial medullary thyroid carcinoma) using this approach. Methodology/Principal Findings We sequenced the whole exome of six individuals from a large Chinese MEN2A/FMTC pedigree to identify the variants of the RET (REarranged during Transfection) protooncogene and followed this by validation. Then prophylactic or surgical thyroidectomy with modified or level VI lymph node dissection and adrenalectomy were performed for the carriers. The cases were closely followed up. Massively parallel sequencing revealed four missense mutations of RET. We unexpectedly discovered that the proband's daughter with MEN 2A-related MTC presented a novel p.C634Y/V292M/R67H/R982C compound mutation, due to the involvement of p.C634Y in the proband with MEN 2A and p.V292M/R67H/R982C in the proband's husband with FMTC. In the maternal origin, p.C634Y caused bilateral MTC in all 5 cases and bilateral pheochromocytoma in 2 of the 5; the earliest onset age was 28 years. In the paternal origin, one of the six p.V292M/R67H/R982C carriers presented bilateral MTC (70 years old), one only had bilateral C-cell hyperplasia (44 years), two had bilateral multi-nodules (46 and 48 years) and two showed no abnormality (22 and 19 years). Conclusions/Significance The results confirmed the successful clinical utility of whole exome sequencing, and our data suggested that the p.C634Y/V292M/R67H/R982C mutation of RET exhibited a more aggressive clinical phenotype than p.C634Y or p.V292M/R67H/R982C, while p.V292M/R67H/R982C presented a relatively milder pathogenicity of MTC and likely predisposed to FMTC.
Biochemical, bone and renal patterns in hyperparathyroidism associated with multiple endocrine neoplasia type 1
Louren?o Jr., Delmar M.;Coutinho, Flavia L.;Toledo, Rodrigo A.;Gon?alves, Tatiana Denck;Montenegro, Fabio L. M.;Toledo, Sergio P. A.;
Clinics , 2012, DOI: 10.6061/clinics/2012(Sup01)17
Abstract: primary hyperparathyroidism associated with multiple endocrine neoplasia type i (hyperparathyroidism/multiple endocrine neoplasia type 1) differs in many aspects from sporadic hyperparathyroidism, which is the most frequently occurring form of hyperparathyroidism. bone mineral density has frequently been studied in sporadic hyperparathyroidism but it has very rarely been examined in cases of hyperparathyroidism/multiple endocrine neoplasia type 1. cortical bone mineral density in hyperparathyroidism/multiple endocrine neoplasia type 1 cases has only recently been examined, and early, severe and frequent bone mineral losses have been documented at this site. early bone mineral losses are highly prevalent in the trabecular bone of patients with hyperparathyroidism/multiple endocrine neoplasia type 1. in summary, bone mineral disease in multiple endocrine neoplasia type 1related hyperparathyroidism is an early, frequent and severe disturbance, occurring in both the cortical and trabecular bones. in addition, renal complications secondary to sporadic hyperparathyroidism are often studied, but very little work has been done on this issue in hyperparathyroidism/multiple endocrine neoplasia type 1. it has been recently verified that early, frequent, and severe renal lesions occur in patients with hyperparathyroidism/multiple endocrine neoplasia type 1, which may lead to increased morbidity and mortality. in this article we review the few available studies on bone mineral and renal disturbances in the setting of hyperparathyroidism/multiple endocrine neoplasia type 1. we performed a meta-analysis of the available data on bone mineral and renal disease in cases of multiple endocrine neoplasia type 1-related hyperparathyroidism.
Genotype-phenotype correlation in multiple endocrine neoplasia type 2
Raue, Friedhelm;Frank-Raue, Karin;
Clinics , 2012, DOI: 10.6061/clinics/2012(Sup01)13
Abstract: multiple endocrine neoplasia type 2 is an autosomal-dominant hereditary cancer syndrome caused by missense gain-of-function mutations of the rearranged during transfection proto-oncogene, which encodes the receptor tyrosine kinase, on chromosome 10. it has a strong penetrance of medullary thyroid carcinomas and can be associated with bilateral pheochromocytoma and primary hyperparathyroidism. multiple endocrine neoplasia type 2 is divided into three varieties depending on its clinical features: multiple endocrine neoplasia type 2a, multiple endocrine neoplasia type 2b, and familial medullary thyroid carcinoma. the specific rearranged during transfection mutation may suggest a predilection toward a particular phenotype and clinical course of medullary thyroid carcinoma, with strong genotype-phenotype correlations. offering rearranged during transfection testing is the best practice for the clinical management of patients at risk of developing multiple endocrine neoplasia type 2, and multiple endocrine neoplasia type 2 has become a classic model for the integration of molecular medicine into patient care. recommendations on the timing of prophylactic thyroidectomy and extent of surgery are based on the classification of rearranged during transfection mutations into risk levels according to genotype-phenotype correlations. earlier identification of patients with hereditary medullary thyroid carcinoma can change the presentation from clinical tumor to preclinical disease, resulting in a high cure rate of affected patients and a much better prognoses.
Non-Invasive Prenatal Diagnosis of Multiple Endocrine Neoplasia Type 2A Using COLD-PCR Combined with HRM Genotyping Analysis from Maternal Serum  [PDF]
Hada C. Macher, Maria A. Martinez-Broca, Amalia Rubio-Calvo, Cristina Leon-Garcia, Manuel Conde-Sanchez, Alzenira Costa, Elena Navarro, Juan M. Guerrero
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0051024
Abstract: The multiple endocrine neoplasia type 2A (MEN2A) is a monogenic disorder characterized by an autosomal dominant pattern of inheritance which is characterized by high risk of medullary thyroid carcinoma in all mutation carriers. Although this disorder is classified as a rare disease, the patients affected have a low life quality and a very expensive and continuous treatment. At present, MEN2A is diagnosed by gene sequencing after birth, thus trying to start an early treatment and by reduction of morbidity and mortality. We first evaluated the presence of MEN2A mutation (C634Y) in serum of 25 patients, previously diagnosed by sequencing in peripheral blood leucocytes, using HRM genotyping analysis. In a second step, we used a COLD-PCR approach followed by HRM genotyping analysis for non-invasive prenatal diagnosis of a pregnant woman carrying a fetus with a C634Y mutation. HRM analysis revealed differences in melting curve shapes that correlated with patients diagnosed for MEN2A by gene sequencing analysis with 100% accuracy. Moreover, the pregnant woman carrying the fetus with the C634Y mutation revealed a melting curve shape in agreement with the positive controls in the COLD-PCR study. The mutation was confirmed by sequencing of the COLD-PCR amplification product. In conclusion, we have established a HRM analysis in serum samples as a new primary diagnosis method suitable for the detection of C634Y mutations in MEN2A patients. Simultaneously, we have applied the increase of sensitivity of COLD-PCR assay approach combined with HRM analysis for the non-invasive prenatal diagnosis of C634Y fetal mutations using pregnant women serum.
Estudio del protooncogen Ret en neoplasia endocrina multiple 2A y en carcinoma medular en tiroides familiar: Hallazgos clínico-patológicos en portadores asintomáticos Analysis of the RET protooncogene in multiple endocrine neoplasia 2A and in familial medullary thyroid carcinoma: Clinical-pathological findings in asymptomatic carriers  [cached]
S. Belli,M. E. Storani,R. J. Dourisboure,E. J. Podesta
Medicina (Buenos Aires) , 2003,
Abstract: El 25% de los carcinomas medulares de tiroides son hereditarios. Se presentan en forma de familiar (CMTF 5%) o como neoplasia endocrina múltiple (MEN) tipo 2A (17%) o 2B (3%), y comparten la herencia, autosómica dominante, de una mutación germinal en el protooncogen RET en uno de 12 codones conocidos. Estudiamos 7 familias (5 CMTF y 2 MEN 2A) con el objeto de detectar la mutación familiar e identificar a los portadores asintomáticos. Seis de las siete mutaciones (4 CMTF y 2 MEN 2A) fueron en el codón más frecuente, el 634, y una familia con CMTF presentó una mutación germinal novel: una transición T>C en el codón 630, resultando el cambio C630A. De los 57 individuos estudiados, 25 (43.85 %) fueron portadores de la mutación, 7 de éstos (28%) eran portadores asintomáticos de los cuales 5 eran ni os, con una edad X-=11±3.2 a os y fueron tiroidectomizados. Presentaron hiperplasia de células C y focos de microcarcinoma en ambos lóbulos tiroideos aun cuando la calcitonina basal o estimulada con pentagastrina fueron normales. En conclusión, describimos una mutación germinal novel en el protooncogen RET: C630A y el hallazgo de enfermedad de la célula C en los portadores asintomáticos, que enfatiza la importancia de la tiroidectomía profiláctica tan pronto como se confirma el diagnóstico molecular. Twenty five percent of the medullary thyroid carcinoma (MTC) is hereditary and 5% is familiar (FMTC), or considered as multiple endocrine neoplasia (MEN) type 2A (17%) or 2B (3%). These diseases are the result of the autosomic dominant inheritance of a mutation in the RET protooncogene, in one out of 12 different known codons. We analyzed 7 families (2 MEN 2A and 5 FMTC). Six mutations were detected in the most frequent codon, 634 (2 MEN 2A y 4 FMTC) and one family with FMTC presented a novel mutation: a transition T>C at codon 630, resulting a C630A change. Among 57 individuals studied, 25 (43.85%) presented the mutation. Seven (28%) were asymptomatic carriers, including 5 children aged 11±3.2 years. The children underwent total thyroidectomy. The histopathologic examination showed C cells hyperplasia and microcarcinoma focus in both lobes, even in the presence of normal, basal or pentagastrine stimulated, calcitonine levels. In conclusion, we describe a germline novel mutation in the RET protooncogene: C630A; and the corresponding findings of C-cell disease in gene mutated carriers that emphasize the importance of prophylactic thyroidectomy as soon as the molecular diagnosis is confirmed.
Genetic and Clinical Features of Multiple Endocrine Neoplasia Types 1 and 2  [PDF]
C. Romei,E. Pardi,F. Cetani,R. Elisei
Journal of Oncology , 2012, DOI: 10.1155/2012/705036
Abstract: Multiple endocrine neoplasia (MEN) are clinical inherited syndromes affecting different endocrine glands. Three different patterns of MEN syndromes can occur (MEN 1, MEN 2A, and MEN 2B). MEN syndromes are very rare, affect all ages and both sexes are equally affected. MEN 1 is characterized by the neoplastic transformation of the parathyroid glands, pancreatic islets, anterior pituitary, and gastrointestinal tract. Heterozygous MEN 1 germline mutations have been detected in about 70–80% of patients with MEN 1. The mutations are scattered throughout the entire genomic sequence of the gene. MEN 1 patients are characterized by variable clinical features, thus suggesting the lack of a genotype-phenotype correlation. Therapeutical approaches are different according to the different endocrinopathies. The prognosis is generally good if adequate treatment is provided. In MEN 2 syndromes, the medullary thyroid cancer (MTC) is almost invariably present and can be associated with pheochromocytoma (PHEO) and/or multiple adenomatosis of parathyroid glands with hyperparathyroidism (PHPT). The different combination of the endocrine neoplasia gives origin to 3 syndromes: MEN 2A, MEN 2B, and FMTC. The clinical course of MTC varies considerably in the three syndromes. It is very aggressive in MEN 2B, almost indolent in the majority of patients with FMTC and with variable degrees of aggressiveness in patients with MEN 2A. Activating germline point mutations of the RET protooncogene are present in 98% of MEN 2 families. A strong genotype-phenotype correlation has been observed and a specific RET mutation may be responsible for a more or less aggressive clinical course. The treatment of choice for primary MTC is total thyroidectomy with central neck lymph nodes dissection. Nevertheless, 30% of MTC patients, especially in MEN 2B and 2A, are not cured by surgery. Recently, developed molecular therapeutics that target the RET pathway have shown very promising activity in clinical trials of patients with advanced MTC. MEN 2 prognosis is strictly dependent on the MTC aggressiveness and thus on the success of the initial treatment. 1. Introduction The term multiple endocrine neoplasia (MEN) defines clinical inherited syndromes affecting different endocrine glands, each with its own characteristic pattern [1, 2]. In some cases, the tumors are malignant, in others, benign. Benign or malignant tumors of nonendocrine tissues occur as components of some of these tumor syndromes. Three different patterns of MEN syndromes can occur (MEN 1, MEN 2A, and MEN 2B) with some new variants such
Studies on a pedigree of multiple endocrine neoplasia type 2A caused by RET proto-oncogene C634R mutation with G691S, R982C polymorphisms with review of literature
Ping CHEN,Guo-qing YANG,Wei-jun GU,Nan JIN
Medical Journal of Chinese People's Liberation Army , 2013,
Abstract: Objective  To analyze the clinical characteristics and mutation of RET proto-oncogene in a pedigree with multiple endocrine neoplasia type 2A (MEN2A). Methods  The clinical data of a proband and other 10 family members were collected, the genomic DNA of their peripheral blood were extracted, the overall exons of RET proto-oncogene were amplified by PCR , and the PCR products were then purified and direct DNA sequence analysis was performed. Results  Different clinical features were found in three of the family members. Three missense mutations, C634R and G691S in exon 11 and R982C in exon 18, were detected in RET proto-oncogene. The three of family members had shown MEN2A related signs, and no such mutations were detected in the other family members. Conclusions  Genetic screening set the diagnosis of MEN2A at the gene level, and help analyze the family members at risk. Patients in this case may show typical clinical manifestations of MEN2A, which indicates that C634R mutation combined with G691S and R982C polymorphisms lead to the increase of downstream signal activation of the RET protein as the single C634R mutation along does.
Surgical treatment of pancreatic endocrine tumors in multiple endocrine neoplasia type 1
Machado, Marcel Cerqueira Cesar;
Clinics , 2012, DOI: 10.6061/clinics/2012(Sup01)24
Abstract: surgical approaches to pancreatic endocrine tumors associated with multiple endocrine neoplasia type 1 may differ greatly from those applied to sporadic pancreatic endocrine tumors. presurgical diagnosis of multiple endocrine neoplasia type 1 is therefore crucial to plan a proper intervention. of note, hyperparathyroidism/multiple endocrine neoplasia type 1 should be surgically treated before pancreatic endocrine tumors/multiple endocrine neoplasia type 1 resection, apart from insulinoma. non-functioning pancreatic endocrine tumors/multiple endocrine neoplasia type 1 >1 cm have a high risk of malignancy and should be treated by a pancreatic resection associated with lymphadenectomy. the vast majority of patients with gastrinoma/multiple endocrine neoplasia type 1 present with tumor lesions at the duodenum, so the surgery of choice is subtotal or total pancreatoduodenectomy followed by regional lymphadenectomy. the usual surgical treatment for insulinoma/multiple endocrine neoplasia type 1 is distal pancreatectomy up to the mesenteric vein with or without spleen preservation, associated with enucleation of tumor lesions in the pancreatic head. surgical procedures for glucagonomas, somatostatinomas, and vipomas/ multiple endocrine neoplasia type 1 are similar to those applied to sporadic pancreatic endocrine tumors. some of these surgical strategies for pancreatic endocrine tumors/multiple endocrine neoplasia type 1 still remain controversial as to their proper extension and timing. furthermore, surgical resection of single hepatic metastasis secondary to pancreatic endocrine tumors/multiple endocrine neoplasia type 1 may be curative and even in multiple liver metastases surgical resection is possible. hepatic trans-arterial chemo-embolization is usually associated with surgical resection. liver transplantation may be needed for select cases. finally, pre-surgical clinical and genetic diagnosis of multiple endocrine neoplasia type 1 syndrome and localization of multip
Mechanical Complication with Broviac Repair Kit in a 4-Year-Old Boy with MEN 2a  [PDF]
Sergio B. Sesia,Frank-Martin Haecker,Johannes Mayr
International Journal of Pediatrics , 2009, DOI: 10.1155/2009/693583
Abstract: Background. Mechanical complications in the use of indwelling central venous catheters (CVCs) such as the Broviac catheter (BC) include kinking, occlusion, dislocation or leaking. We report on a mechanical complication after using a repair kit for the BC. Method. A 4-year old boy, suffering from multiple endocrine neoplasia type 2a (MEN 2a), intestinal aganglionosis (Hirschsprung's disease), and short bowel syndrome, required a BC for home parenteral nutrition. Result. Due to recurrent leakage of the BC, 5 subsequent repairs were necessary within seven months. During one repair a metallic tube belonging to the repair kit was found to have migrated proximally to the skin entrance level within the BC and requiring surgical removal. Conclusion. To our knowledge, this is the first report focusing on such a serious complication using a BC and its repair kit. The proximal migration of this metallic tube constitutes a distinct theoretical risk of endothoracic foreign body embolization.
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