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Ren MJ, Zhang ZL, Tian C, Liu GQ, Zhang CS, Yu HB, Xin Q. Importance of early detection in multiple endocrine neoplasia type 1: Clinical insights and future directions. World J Gastrointest Oncol 2025; 17:100013. [DOI: 10.4251/wjgo.v17.i4.100013] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/05/2024] [Revised: 01/11/2025] [Accepted: 02/18/2025] [Indexed: 03/25/2025] Open
Abstract
Multiple endocrine neoplasia type 1 (MEN1) is an autosomal-inherited syndrome involving multiple endocrine tumors. It is characterized by multiple mutations in the tumor suppressor gene MEN1, which is located on chromosome 11q13. As main etiology of MEN1 is genetic mutations, clinical symptoms may vary. In this editorial, we comment on the article by Yuan et al. This article describes a case of (MEN1) characterized by low incidence and diagnostic complexity. MEN1 commonly presents as parathyroid, pancreatic, and pituitary tumors. Diagnosis requires a combination of serologic tests, magnetic resonance imaging, computed tomography, endoscopic ultrasonography, immunologic and pathology. The diagnosis is unique depending on the site of disease. Surgical resection is the treatment of choice for MEN1. The prognosis depends on the site of origin, but early detection and intervention is the most effective.
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Affiliation(s)
- Mei-Jing Ren
- Department of Pathology, Tianjin Third Center Hospital, Tianjin 300170, China
| | - Zi-Li Zhang
- Department of Gastrointestinal Surgery, Tianjin Third Center Hospital, Tianjin 300170, China
| | - Can Tian
- Department of Pathology, Tianjin Third Center Hospital, Tianjin 300170, China
| | - Gui-Qiu Liu
- Department of Pathology, Tianjin Third Center Hospital, Tianjin 300170, China
| | - Chuan-Shan Zhang
- Department of Pathology, Tianjin Third Center Hospital, Tianjin 300170, China
| | - Hai-Bo Yu
- Department of Laboratory, The Second Hospital of Tianjin Medical University, Tianjin 300211, China
| | - Qi Xin
- Department of Pathology, Tianjin Third Center Hospital, Tianjin 300170, China
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Eremkina AK, Pylina SV, Elfimova AR, Gorbacheva AM, Humbert L, López Picazo M, Hajrieva AV, Solodovnikova EN, Kovalevich LD, Vetchinkina EA, Bondarenko EV, Tarbaeva NV, Mokrysheva NG. Analysis of Bone Phenotype Differences in MEN1-Related and Sporadic Primary Hyperparathyroidism Using 3D-DXA. J Clin Med 2024; 13:6382. [PMID: 39518523 PMCID: PMC11546830 DOI: 10.3390/jcm13216382] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2024] [Revised: 10/04/2024] [Accepted: 10/17/2024] [Indexed: 11/16/2024] Open
Abstract
Background: The rarity and variability of MEN1-related primary hyperparathyroidism (mPHPT) has led to contradictory data regarding the bone phenotype in this patient population. Methods: A single-center retrospective study was conducted among young age- and sex-matched patients with mPHPT and sporadic hyperparathyroidism (sPHPT). The main parameters of calcium-phosphorus metabolism, bone remodeling markers, and bone mineral density (BMD) measurements were obtained during the active phase of hyperparathyroidism before parathyroidectomy (PTE) and 1 year after. Trabecular Bone Score (TBS) and 3D-DXA analysis of the proximal femur were used to evaluate the differences in bone architecture disruption between groups. Results: Patients with mPHPT had significant lower preoperative BMD compared to sPHPT at lumbar spine-LS (p = 0.002); femur neck-FN (p = 0.001); and total hip-TH (p = 0.002). 3D-DXA analysis showed the prevalence of cortical rather than trabecular bone damage in mPHPT compared to sPHPT: cortical thickness (p < 0.001); cortical surface BMD (p = 0.001); cortical volumetric BMD (p = 0.007); and trabecular volumetric BMD (p = 0.029). One year after, PTE DXA and 3D-DXA parameters were similar between groups, while 3D-visualisation showed more extensive regeneration in cortical sBMD and cortical thickness in mPHPT. Conclusions: mPHPT is associated with lower preoperative BMD values with predominant architecture disruption in the cortical bone. The absence of differences in DXA and 3D-DXA parameters 1 year after PTE between mPHPT/sPHPT combined with significantly lower BMD in mPHPT at the initial stage may indicate faster bone recovery after surgery in mPHPT than in sPHPT.
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Affiliation(s)
- Anna K. Eremkina
- Endocrinology Research Centre, 115478 Moscow, Russia; (S.V.P.); (A.R.E.); (A.M.G.); (A.V.H.); (E.N.S.); (L.D.K.); (E.A.V.); (E.V.B.); (N.V.T.); (N.G.M.)
| | - Svetlana V. Pylina
- Endocrinology Research Centre, 115478 Moscow, Russia; (S.V.P.); (A.R.E.); (A.M.G.); (A.V.H.); (E.N.S.); (L.D.K.); (E.A.V.); (E.V.B.); (N.V.T.); (N.G.M.)
| | - Alina R. Elfimova
- Endocrinology Research Centre, 115478 Moscow, Russia; (S.V.P.); (A.R.E.); (A.M.G.); (A.V.H.); (E.N.S.); (L.D.K.); (E.A.V.); (E.V.B.); (N.V.T.); (N.G.M.)
| | - Anna M. Gorbacheva
- Endocrinology Research Centre, 115478 Moscow, Russia; (S.V.P.); (A.R.E.); (A.M.G.); (A.V.H.); (E.N.S.); (L.D.K.); (E.A.V.); (E.V.B.); (N.V.T.); (N.G.M.)
| | | | | | - Angelina V. Hajrieva
- Endocrinology Research Centre, 115478 Moscow, Russia; (S.V.P.); (A.R.E.); (A.M.G.); (A.V.H.); (E.N.S.); (L.D.K.); (E.A.V.); (E.V.B.); (N.V.T.); (N.G.M.)
| | - Ekaterina N. Solodovnikova
- Endocrinology Research Centre, 115478 Moscow, Russia; (S.V.P.); (A.R.E.); (A.M.G.); (A.V.H.); (E.N.S.); (L.D.K.); (E.A.V.); (E.V.B.); (N.V.T.); (N.G.M.)
| | - Liliya D. Kovalevich
- Endocrinology Research Centre, 115478 Moscow, Russia; (S.V.P.); (A.R.E.); (A.M.G.); (A.V.H.); (E.N.S.); (L.D.K.); (E.A.V.); (E.V.B.); (N.V.T.); (N.G.M.)
| | - Ekaterina A. Vetchinkina
- Endocrinology Research Centre, 115478 Moscow, Russia; (S.V.P.); (A.R.E.); (A.M.G.); (A.V.H.); (E.N.S.); (L.D.K.); (E.A.V.); (E.V.B.); (N.V.T.); (N.G.M.)
| | - Ekaterina V. Bondarenko
- Endocrinology Research Centre, 115478 Moscow, Russia; (S.V.P.); (A.R.E.); (A.M.G.); (A.V.H.); (E.N.S.); (L.D.K.); (E.A.V.); (E.V.B.); (N.V.T.); (N.G.M.)
| | - Natalia V. Tarbaeva
- Endocrinology Research Centre, 115478 Moscow, Russia; (S.V.P.); (A.R.E.); (A.M.G.); (A.V.H.); (E.N.S.); (L.D.K.); (E.A.V.); (E.V.B.); (N.V.T.); (N.G.M.)
| | - Natalia G. Mokrysheva
- Endocrinology Research Centre, 115478 Moscow, Russia; (S.V.P.); (A.R.E.); (A.M.G.); (A.V.H.); (E.N.S.); (L.D.K.); (E.A.V.); (E.V.B.); (N.V.T.); (N.G.M.)
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Song A, Chen R, Guan W, Yu W, Yang Y, Wang J, Nie M, Jiang Y, Li M, Xia W, Xing X, Wang O. Trabecular Bone Score as a More Sensitive Tool to Evaluate Bone Involvement in MEN1-related Primary Hyperparathyroidism. J Clin Endocrinol Metab 2023; 109:135-142. [PMID: 37539859 DOI: 10.1210/clinem/dgad460] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/14/2023] [Revised: 07/07/2023] [Accepted: 08/02/2023] [Indexed: 08/05/2023]
Abstract
CONTEXT The skeletal involvement of multiple endocrine neoplasia type 1-related primary hyperparathyroidism (MHPT) is not exactly the same as that of sporadic primary hyperparathyroidism (SHPT). Trabecular bone score (TBS) as a texture parameter has been reported to reflect trabecular bone damage. OBJECTIVE This study aimed to compare the clinical characteristics, especially the skeletal involvement, between patients with MHPT and SHPT. METHODS The clinical characteristics were retrospectively collected in 120 patients with MHPT and compared with 360 patients with SHPT in the same period. Dual-energy X-ray absorptiometry were conducted in some patients with MHPT, in whom bone mineral density (BMD) and calculated TBS derived from lumbar spine dual-energy X-ray absorptiometry images were compared with those of patients with SHPT. RESULTS Although the duration of disease in the MHPT group was longer, the age at hospital visit was significantly lower than that in the SHPT group (43.5 [interquartile range, 31.5-52.0] vs 52.0 [interquartile range, 40.5-61.0], P < .001). The proportion of skeletal involvement in the MHPT group was significantly lower. However, in the subgroup of MHPT cases (n = 86) with data of BMD, there was no significant difference in skeletal involvement from SHPT cases matched for gender and age. Although the BMD and TBS in the lumbar spines of patients with MHPT were lower than those of patients with SHPT (BMD: 0.91 ± 0.18 g/cm2 vs 1.01 ± 0.17 g/cm2; TBS: 1.22 ± 0.14 vs 1.29 ± 0.11, P < .001). According to TBS, among 34 patients with MHPT with normal BMD, 15 patients had bone microstructure damage. CONCLUSION The cancellous bone microarchitecture was more severely damaged in patients with MHPT according to TBS, which suggested that TBS could be a sensitive supplemental index in addition to BMD to identify bone-involvement risk in patients with MHPT.
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Affiliation(s)
- An Song
- Key Laboratory of Endocrinology, Department of Endocrinology, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing 100730, China
| | - Rong Chen
- Key Laboratory of Endocrinology, Department of Endocrinology, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing 100730, China
| | - Wenmin Guan
- Department of Radiology, Beijing Friendship Hospital, Capital Medical University, Beijing 100050, China
| | - Wei Yu
- Department of Radiology, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing 100730, China
| | - Yi Yang
- Key Laboratory of Endocrinology, Department of Endocrinology, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing 100730, China
| | - Jiajia Wang
- Key Laboratory of Endocrinology, Department of Endocrinology, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing 100730, China
| | - Min Nie
- Key Laboratory of Endocrinology, Department of Endocrinology, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing 100730, China
| | - Yan Jiang
- Key Laboratory of Endocrinology, Department of Endocrinology, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing 100730, China
| | - Mei Li
- Key Laboratory of Endocrinology, Department of Endocrinology, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing 100730, China
| | - Weibo Xia
- Key Laboratory of Endocrinology, Department of Endocrinology, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing 100730, China
| | - Xiaoping Xing
- Key Laboratory of Endocrinology, Department of Endocrinology, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing 100730, China
| | - Ou Wang
- Key Laboratory of Endocrinology, Department of Endocrinology, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing 100730, China
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Мокрышева НГ, Еремкина АК, Милютина АП, Салимханов РХ, Абойшева ЕА, Бибик ЕЕ, Горбачева АМ, Елфимова АР, Ковалева ЕВ, Попов СВ, Мельниченко ГА. [Predicting the presence of MEN1 gene mutation based on the clinical phenotype of patients with primary hyperparathyroidism]. PROBLEMY ENDOKRINOLOGII 2023; 69:4-15. [PMID: 37968947 PMCID: PMC10680550 DOI: 10.14341/probl13322] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/28/2023] [Revised: 07/02/2023] [Accepted: 08/29/2023] [Indexed: 11/17/2023]
Abstract
BACKGROUND Timely referral of patients for genetic testing to rule out MEN1-associated primary PHPT is important factor in determining treatment strategy and prognosis. In the context of the limited availability of genetic testing, the search for clinical markers indicative of MEN1 gene mutations remains an extremely relevant task. AIM To determine the diagnostic value of clinical features of primary PHPT in young patients for predicting the presence of MEN1 gene mutations. MATERIALS AND METHODS A single-center, prospective study was conducted at the Endocrinology Research Centre, involving 273 patients with PHPT in the period 2015-2022. Based on the results of genetic and laboratory tests, patients were divided into three groups: those with MEN1 gene mutations (MEN+ group, n=71), those without MEN1 gene mutations - isolated sporadic PHPT (MEN- group, n=158), and patients with PHPT and associated endocrine gland disorders - MEN-1 syndrome phenocopies (PHEN group, n=32). Subgroups of patients younger than 40 years of age were also identified. Comparative analysis was performed among the independent groups and subgroups, and logistic regression analysis was used to develop a mathematical model for predicting the probability of the presence of MEN1 gene mutation. RESULTS Patients in the MEN+ and MEN- groups were comparable by gender and age at manifestation, as well as calcium-phosphorus metabolism parameters and PHPT complications. In the PHEN group, PHPT manifested at older age compared to the other groups (p<0.001 for all), with lower total calcium levels and a trend toward lower iPTH concentrations. The MEN+ group had a significantly higher frequency of multiglandular parathyroid (PG) involvement, PHPT recurrence, and positive family history compared to the MEN- and PHEN groups. Histologically, adenomas predominated in the PHEN and MEN- groups (92% and 94%, respectively), whereas hyperplasia of PGs were more common in the MEN+ group (49%). None of the PHEN patients had all three «classic» components of the MEN-1 syndrome, and the clinical course of PHPT was similar to that of the MEN- group. These differences were also observed in the subgroups of patients younger than 40 years, which formed the basis for the development of a mathematical model. The logistic regression equation for predicting the probability of the presence of the MEN1 gene mutation included eight predictors, with a diagnostic sensitivity of 96% and specificity of 98%. CONCLUSION Based on the analysis performed, eight hereditary predictors of PHPT within the MEN-1 syndrome were identified. A mathematical model was developed to predict the presence of the MEN1 gene mutation in patients, which demonstrated high classification performance on the training dataset. Further refinement of the model will help improve the quality of medical care for patients with PHPT.
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Affiliation(s)
- Н. Г. Мокрышева
- Национальный медицинский исследовательский центр эндокринологии
| | - А. К. Еремкина
- Национальный медицинский исследовательский центр эндокринологии
| | - А. П. Милютина
- Национальный медицинский исследовательский центр эндокринологии
| | | | - Е. А. Абойшева
- Национальный медицинский исследовательский центр эндокринологии
| | - Е. Е. Бибик
- Национальный медицинский исследовательский центр эндокринологии
| | - А. М. Горбачева
- Национальный медицинский исследовательский центр эндокринологии
| | - А. Р. Елфимова
- Национальный медицинский исследовательский центр эндокринологии
| | - Е. В. Ковалева
- Национальный медицинский исследовательский центр эндокринологии
| | - С. В. Попов
- Национальный медицинский исследовательский центр эндокринологии
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Miranda ISDM, Valadares LP, Barra GB, Mesquita PG, de Santana LB, de Castro LF, Rita THS, Naves LA. Clinical and molecular features of four Brazilian families with multiple endocrine neoplasia type 1. Front Endocrinol (Lausanne) 2023; 14:1117873. [PMID: 36967793 PMCID: PMC10036827 DOI: 10.3389/fendo.2023.1117873] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/07/2022] [Accepted: 02/20/2023] [Indexed: 03/12/2023] Open
Abstract
Objective Multiple endocrine neoplasia type 1 (MEN1) is an autosomal dominant syndrome characterized by its clinical variability and complexity in diagnosis and treatment. We performed both clinical and molecular descriptions of four families with MEN1 in a follow-up at a tertiary center in Brasília. Methods From a preliminary review of approximately 500 medical records of patients with pituitary neuroendocrine tumor (PitNET) from the database of the Neuroendocrinology Outpatient Clinic of the University Hospital of Brasília, a total of 135 patients met the criteria of at least two affected family members. From this cohort, we have identified 34 families: only four with a phenotype of MEN1 and the other 30 families with the phenotype of familial isolated pituitary adenoma (FIPA). Eleven patients with a clinical diagnosis of MEN1 from these four families were selected. Results Variants in MEN1 gene were identified in all families. One individual from each family underwent genetic testing using targeted high-throughput sequencing (HTS). All patients had primary hyperparathyroidism (PHPT), and the second most common manifestation was PitNET. One individual had well-differentiated liposarcoma, which has been previously reported in a single case of MEN1. Three variants previously described in the database and a novel variant in exon 2 have been found. Conclusions The study allowed the genotypic and phenotypic characterization of families with MEN1 in a follow-up at a tertiary center in Brasília.
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Pieterman CRC, Valk GD. Update on the clinical management of multiple endocrine neoplasia type 1. Clin Endocrinol (Oxf) 2022; 97:409-423. [PMID: 35319130 PMCID: PMC9540817 DOI: 10.1111/cen.14727] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/09/2021] [Revised: 02/22/2022] [Accepted: 02/28/2022] [Indexed: 11/30/2022]
Abstract
This review provides an overview of novel insights in the clinical management of patients with Multiple Endocrine Neoplasia Type 1, focusing on the last decade since the last update of the MEN1 guidelines. With regard to Diagnosis: Mutation-negative patients with 2/3 main manifestations have a different clinical course compared to mutation-positive patients. As for primary hyperparathyroidism: subtotal parathyroidectomy is the initial procedure of choice. Current debate centres around the timing of initial parathyroidectomy as well as the controversial topic of unilateral clearance in young patients. For duodenopancreatic neuroendocrine tumours (NETs), the main challenge is accurate and individualized risk stratification to enable personalized surveillance and treatment. Thymus NETs remain one of the most aggressive MEN1-related tumours. Lung NETs are more frequent than previously thought, generally indolent, but rare aggressive cases do occur. Pituitary adenomas are most often prolactinomas and nonfunctioning microadenomas with an excellent prognosis and good response to therapy. Breast cancer is recognized as part of the MEN1 syndrome in women and periodical screening is advised. Clinically relevant manifestations are already seen at the paediatric age and initiating screening in the second decade is advisable. MEN1 has a significant impact on quality of life and US data show a significant financial burden. In conclusion, patient outcomes have improved, but much is still to be achieved. For care tailored to the needs of the individual patient and improving outcomes on an individual basis, studies are now needed to define predictors of tumour behaviour and effects of more individualized interventions.
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Affiliation(s)
| | - Gerlof D. Valk
- Department of Endocrine OncologyUniversity Medical Center UtrechtUtrechtThe Netherlands
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Brescia MDG, Rodrigues KC, d’Alessandro AF, Alves Filho W, van der Plas WY, Kruijff S, Arap SS, Toledo SPDA, Montenegro FLDM, Lourenço DM. Impact of parathyroidectomy on quality of life in multiple endocrine neoplasia type 1. Endocr Connect 2022; 11:EC-22-0021. [PMID: 35583183 PMCID: PMC9254320 DOI: 10.1530/ec-22-0021] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/04/2022] [Accepted: 05/18/2022] [Indexed: 11/26/2022]
Abstract
BACKGROUND Potential influences of parathyroidectomy (PTx) on the quality of life (QoL) in multiple endocrine neoplasia type 1-related primary hyperparathyroidism (HPT/MEN1) are unknown. METHOD Short Form 36 Health Survey Questionnaire was prospectively applied to 30 HPT/MEN1 patients submitted to PTx (20, subtotal; 10, total with autograft) before, 6 and 12 months after surgery. Parameters that were analyzed included QoL, age, HPT-related symptoms, general pain, comorbidities, biochemical/hormonal response, PTx type and parathyroid volume. RESULTS Asymptomatic patients were younger (30 vs 38 years; P = 0.04) and presented higher QoL scores than symptomatic ones: Physical Component Summary score (PCS) 92.5 vs 61.2, P = 0.0051; Mental Component Summary score (MCS) 82.0 vs 56.0, P = 0.04. In both groups, QoL remained stable 1 year after PTx, independently of the number of comorbidities. Preoperative general pain was negatively correlated with PCS (r = -0.60, P = 0.0004) and MCS (r = -0.57, P = 0.0009). Also, moderate/intense pain was progressively (6/12 months) more frequent in cases developing hypoparathyroidism. The PTx type and hypoparathyroidism did not affect the QoL at 12 months although remnant parathyroid tissue volume did have a positive correlation (P = 0.0490; r = 0.3625) to PCS 12 months after surgery. Patients with one to two comorbidities had as pre-PTx PCS (P = 0.0015) as 12 months and post-PTx PCS (P = 0.0031) and MCS (P = 0.0365) better than patients with three to four comorbidities. CONCLUSION A variable QoL profile was underscored in HPT/MEN1 reflecting multiple factors associated with this complex disorder as comorbidities, advanced age at PTx and presence of preoperative symptoms or of general pain perception. Our data encourage the early indication of PTx in HPT/MEN1 by providing known metabolic benefits to target organs and avoiding potential negative impact on QoL.
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Affiliation(s)
- Marília D’Elboux Guimarães Brescia
- Endocrine Genetics Unit (LIM-25), Endocrinology Division, University of São Paulo School of Medicine (FMUSP), Faculdade de Medicina da Universidade de São Paulo (FMUSP), Hospital das Clinicas (HCFMUSP), São Paulo, São Paulo, Brazil
- Parathyroid Unit – LIM-28, Laboratório de Cirurgia de Cabeça e Pescoço, Division of Head and Neck Surgery, Department of Surgery, Hospital das Clinicas (HCFMUSP), University of São Paulo School of Medicine (FMUSP), Faculdade de Medicina, Universidade de São Paulo, São Paulo, São Paulo, Brazil
- Correspondence should be addressed to M D G Brescia:
| | - Karine Candido Rodrigues
- Endocrine Genetics Unit (LIM-25), Endocrinology Division, University of São Paulo School of Medicine (FMUSP), Faculdade de Medicina da Universidade de São Paulo (FMUSP), Hospital das Clinicas (HCFMUSP), São Paulo, São Paulo, Brazil
- Endocrine Oncology Division, Institute of Cancer of the State of São Paulo (ICESP), University of São Paulo School of Medicine (FMUSP), Faculdade de Medicina da Universidade de São Paulo (FMUSP), São Paulo, São Paulo, Brazil
| | - André Fernandes d’Alessandro
- Parathyroid Unit – LIM-28, Laboratório de Cirurgia de Cabeça e Pescoço, Division of Head and Neck Surgery, Department of Surgery, Hospital das Clinicas (HCFMUSP), University of São Paulo School of Medicine (FMUSP), Faculdade de Medicina, Universidade de São Paulo, São Paulo, São Paulo, Brazil
| | - Wellington Alves Filho
- Department of Surgery, Walter Cantidio University Hospital, Federal University of Ceara School of Medicine (FAMED-UFC), Fortaleza, Brazil
| | - Willemijn Y van der Plas
- Department of Surgery, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
| | - Schelto Kruijff
- Department of Surgery, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
| | - Sergio Samir Arap
- Parathyroid Unit – LIM-28, Laboratório de Cirurgia de Cabeça e Pescoço, Division of Head and Neck Surgery, Department of Surgery, Hospital das Clinicas (HCFMUSP), University of São Paulo School of Medicine (FMUSP), Faculdade de Medicina, Universidade de São Paulo, São Paulo, São Paulo, Brazil
| | - Sergio Pereira de Almeida Toledo
- Endocrine Genetics Unit (LIM-25), Endocrinology Division, University of São Paulo School of Medicine (FMUSP), Faculdade de Medicina da Universidade de São Paulo (FMUSP), Hospital das Clinicas (HCFMUSP), São Paulo, São Paulo, Brazil
| | - Fábio Luiz de Menezes Montenegro
- Parathyroid Unit – LIM-28, Laboratório de Cirurgia de Cabeça e Pescoço, Division of Head and Neck Surgery, Department of Surgery, Hospital das Clinicas (HCFMUSP), University of São Paulo School of Medicine (FMUSP), Faculdade de Medicina, Universidade de São Paulo, São Paulo, São Paulo, Brazil
| | - Delmar Muniz Lourenço
- Endocrine Genetics Unit (LIM-25), Endocrinology Division, University of São Paulo School of Medicine (FMUSP), Faculdade de Medicina da Universidade de São Paulo (FMUSP), Hospital das Clinicas (HCFMUSP), São Paulo, São Paulo, Brazil
- Endocrine Oncology Division, Institute of Cancer of the State of São Paulo (ICESP), University of São Paulo School of Medicine (FMUSP), Faculdade de Medicina da Universidade de São Paulo (FMUSP), São Paulo, São Paulo, Brazil
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Gorbacheva A, Eremkina A, Goliusova D, Krupinova J, Mokrysheva N. The role of menin in bone pathology. Endocr Connect 2022; 11:EC-21-0494.R2. [PMID: 35148273 PMCID: PMC8942318 DOI: 10.1530/ec-21-0494] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/17/2022] [Accepted: 02/11/2022] [Indexed: 12/02/2022]
Abstract
Multiple endocrine neoplasia type 1 (MEN1) is the most common cause of hereditary primary hyperparathyroidism (PHPT). Bone disorders are considered one of the key symptoms in PHPT present with the significant reduction in bone mineral density and low-energy fractures. Previously, these bone disorders were believed to be caused solely by the increase in the level of parathyroid hormone and its subsequent effect on bone resorption. The current paradigm, however, states that the mutations in the menin gene, which cause the development of MEN1, can also affect the metabolism of the cells of the osteoid lineage. This review analyzes both the proven and the potential intracellular mechanisms through which menin can affect bone metabolism.
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Affiliation(s)
- Anna Gorbacheva
- Endocrinology Research Center, Moscow, Russian Federation
- Correspondence should be addressed to A Gorbacheva:
| | - Anna Eremkina
- Endocrinology Research Center, Moscow, Russian Federation
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Еремкина АК, Сазонова ДВ, Бибик ЕЕ, Шейхова АЗ, Хайриева АВ, Буклемишев ЮВ, Мокрышева НГ. [Severe bone complications of primary hyperparathyroidism in a young patient with the rare verified mutation of MEN1]. PROBLEMY ENDOKRINOLOGII 2022; 68:81-93. [PMID: 35262299 PMCID: PMC9761876 DOI: 10.14341/probl12864] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 01/12/2022] [Revised: 02/13/2022] [Accepted: 02/18/2022] [Indexed: 06/14/2023]
Abstract
Multiple endocrine neoplasia type 1 syndrome (MEN1) is a rare inherited disorder that can include combinations of more than 20 endocrine and non-endocrine tumors. Unfortunately, none of the described MEN1 mutations has been associated with a peculiar clinical phenotype, even within members of the same family, thus a genotype-to-phenotype correlation does not exist. MEN1 syndrome is the most common cause of hereditary primary hyperparathyroidism (PHPT), the disease penetrance of which exceeds 50% by the age of 20 and reaches 95% by the age of 40. At the same time, PHPT with hyperplasia or adenomas of the parathyroid glands (PTG) is the most distinctive manifestation of the MEN1 syndrome. One of the main symptoms of PHPT, both in sporadic and hereditary forms of the disease, is bone damage. At the time of diagnosis in PHPT/MEN1, the bone mineral density is generally lower in comparison with the sporadic form of PHPT. This may be due to excessive secretion of parathyroid hormone during the period of peak bone mass, concomitant components of the syndrome, extended surgical treatment, and the direct effect of a mutation in the menin gene on bone remodeling. This clinical case describes a young patient with severe bone complications of PHPT and uncertain rare MEN1 mutation. PHPT was diagnosed five years later from the first onset of bone complications and repeated orthopedic operations. There was the «hungry bones» syndrome after successful surgery of PHPT, which was managed with vitamin D and calcium carbonate supplementation and there is a positive dynamic in increased bone mineral density in the main skeleton after 6 months.
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Affiliation(s)
- А. К. Еремкина
- Национальный медицинский исследовательский центр эндокринологии
| | - Д. В. Сазонова
- Национальный медицинский исследовательский центр эндокринологии
| | - Е. Е. Бибик
- Национальный медицинский исследовательский центр эндокринологии
| | - А. З. Шейхова
- Национальный медицинский исследовательский центр эндокринологии
| | - А. В. Хайриева
- Национальный медицинский исследовательский центр эндокринологии
| | - Ю. В. Буклемишев
- Национальный медицинский исследовательский центр травматологии и ортопедии им. Н.Н. Приорова
| | - Н. Г. Мокрышева
- Национальный медицинский исследовательский центр эндокринологии
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10
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Heterogeneity of the Clinical Presentation of the MEN1 LRG_509 c.781C>T (p.Leu261Phe) Variant Within a Three-Generation Family. Genes (Basel) 2021; 12:genes12040512. [PMID: 33807230 PMCID: PMC8067145 DOI: 10.3390/genes12040512] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2021] [Revised: 03/25/2021] [Accepted: 03/29/2021] [Indexed: 11/16/2022] Open
Abstract
Multiple neuroendocrine neoplasia type 1 (MEN1) is a rare genetic disorder with an autosomal dominant inheritance, predisposing carriers to benign and malignant tumors. The phenotype of MEN1 syndrome varies between patients in terms of tumor localization, age of onset, and clinical aggressiveness, even between affected members within the same family. We describe a heterogenic phenotype of the MEN1 variant c.781C>T (LRG_509t1), which was previously reported only once in a family with isolated hyperparathyroidism. A heterozygous missense variant in exon 4 of the gene was identified in the sequence of the MEN1 gene, i.e., c.781C>T, leading to the amino acid change p.Leu261Phe in a three-generation family. In the screened family, 5/6 affected members had already developed hyperparathyroidism. In the index patient and two other family members, an aggressive course of pancreatic neuroendocrine tumor (insulinoma and non-functioning neuroendocrine tumors) with dissemination was diagnosed. In the index patient, late diagnosis and slow progression of the disseminated neuroendocrine tumor have been observed (24 years of follow-up). The very rare variant of MEN1, LRG_509t1 c.781C>T /p.Leu261Phe (LRG_509p1), diagnosed within a three-generation family has a heterogenic clinical presentation. Further follow-up of the family members should be carried out to confirm the spectrum and exact time of clinical presentation.
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11
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Demirtaş CÖ, Ata P, Çetin A, Türkyılmaz A, Duman DG. A large Turkish pedigree with multiple endocrine neoplasia type 1 syndrome carrying a rare mutation: c.1680_1683 del TGAG. TURKISH JOURNAL OF GASTROENTEROLOGY 2020; 31:508-514. [PMID: 32897224 DOI: 10.5152/tjg.2020.19830] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
BACKGROUND AND AIMS Multiple endocrine neoplasia type 1 (MEN1) is an autosomal dominant syndrome characterized by tumors arising from endocrine glands with no specific genotype-phenotype correlation. Herein, we report the largest Turkish kindred with MEN1 inherited a scarce MEN1 mutation gene. MATERIALS AND METHODS Sixty-four year-old man, referred to our gastroenterology outpatient clinic for evaluation of pancreatic mass lesion, was diagnosed with MEN1-syndrome after endoscopic ultrasound guided sampling of the mass revealing pancreatic neuroendocrine tumor (pNET), and accompanying primary hyperparathyroidism (PHPT) and pituitary tumor. Genetic analysis by whole gene Sanger sequencing of MEN1 gene identified a frame-shift mutation in exon 10 (c.1680_1683delTGAG). All the relatives of the index case were proposed for clinical and genetic evaluation for MEN1-syndrome. RESULTS Of the 25 relatives of the index case, 17 were diagnosed MEN1-syndrome. Eighteen members among all relatives consented to genetic analysis and 11 had the same mutation as the index case. All the mutation positive members had MEN1, while none of mutation negative subjects had any sign of MEN1-syndrome. The frequencies of PHPT, pNET and pituitary tumors in this kindred were 94.1% (16/17), 29.4% (5/17) and 29.4% (5/17) respectively. CONCLUSION We report rare MEN1 gene mutation which was descibed in a single sporadic patient before. It inherited in at least three generations of a large family, which has proven strong dominant effect on MEN1 phenotype. Further researches may be conducted to clarify potential candidacy of this mutation, as a hotspot for MEN1 patients, especially in Turkish population.
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Affiliation(s)
- Coşkun Özer Demirtaş
- Department of Gastroenterology, Marmara University School of Medicine, Istanbul, Turkey
| | - Pınar Ata
- Department of Medical Genetics, Marmara University School of Medicine, Istanbul, Turkey
| | - Ali Çetin
- Department of Internal Medicine, Marmara University School of Medicine, Istanbul, Turkey
| | - Ayberk Türkyılmaz
- Department of Medical Genetics, Marmara University School of Medicine, Istanbul, Turkey
| | - Deniz Guney Duman
- Department of Gastroenterology, Marmara University School of Medicine, Istanbul, Turkey
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12
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Slouma M, Abbes M, Dhahri R, Litaiem N, Gueddiche N, Mansouri N, Msekni I, Gharsallah I, Metoui L, Louzir B. Multiple endocrine neoplasia type 1 revealed by a hip pathologic fracture. Clin Rheumatol 2020; 40:775-782. [PMID: 32666178 DOI: 10.1007/s10067-020-05281-3] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2020] [Revised: 06/23/2020] [Accepted: 07/06/2020] [Indexed: 01/26/2023]
Abstract
Multiple endocrine neoplasia type 1 is a rare autosomal inherited syndrome that affects a variety of endocrine tissues such as the parathyroid, endocrine pancreas, and anterior pituitary. Osseous complications are often misdiagnosed. We presented a case of a 46-year-old woman with pathological fractures of the lower limb. She had a history of type 1 diabetes and galactorrhea. Laboratory examinations showed hypercalcemia and an increased level of parathyroid hormone related to hyperparathyroidism. Serum chromogranin A level was increased at 9369 ng/mL (N < 102). A somatostatin receptor scintigraphy (octreoscan) revealed pathological uptake in the gastric wall, later cave adenopathy, and liver. The diagnosis of multiple endocrine neoplasia type 1 was made based on radiological and histological findings. The patient underwent a subtotal parathyroidectomy associated with somatostatin analog treatment leading to significant improvement. A literature review was conducted by searching PubMed using these following terms: multiple endocrine neoplasia type 1, hyperparathyroidism, fracture, menin, osteoporosis. We emphasized bone involvement related to multiple endocrine neoplasia type 1 syndrome. This diagnosis should be considered when pathological fractures occur in young patients with a history of endocrine disorder. We highlighted the importance of imaging features in making the diagnosis of multiple endocrine neoplasia type 1. Early management of this disease is necessary. Treatment including parathyroidectomy and somatostatin analogs leads to bone preservation and functional improvement.
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Affiliation(s)
- Maroua Slouma
- Department of Internal Medicine, Military Hospital, 1007, Tunis, Tunisia.
- Faculty of Medicine of Tunis, University of Tunis El Manar, Tunis, Tunisia.
| | - Maissa Abbes
- Department of Internal Medicine, Military Hospital, 1007, Tunis, Tunisia
- Faculty of Medicine of Tunis, University of Tunis El Manar, Tunis, Tunisia
| | - Rim Dhahri
- Department of Internal Medicine, Military Hospital, 1007, Tunis, Tunisia
- Faculty of Medicine of Tunis, University of Tunis El Manar, Tunis, Tunisia
| | - Noureddine Litaiem
- Faculty of Medicine of Tunis, University of Tunis El Manar, Tunis, Tunisia
- Department of Dermatology, Charles Nicolle Hospital, Tunis, Tunisia
| | - Nour Gueddiche
- Department of Internal Medicine, Military Hospital, 1007, Tunis, Tunisia
- Faculty of Medicine of Tunis, University of Tunis El Manar, Tunis, Tunisia
| | - Nada Mansouri
- Faculty of Medicine of Tunis, University of Tunis El Manar, Tunis, Tunisia
- Department of pathology, Military Hospital, Tunis, Tunisia
| | - Issam Msekni
- Faculty of Medicine of Tunis, University of Tunis El Manar, Tunis, Tunisia
- Department of pathology, Military Hospital, Tunis, Tunisia
| | - Imen Gharsallah
- Department of Internal Medicine, Military Hospital, 1007, Tunis, Tunisia
- Faculty of Medicine of Tunis, University of Tunis El Manar, Tunis, Tunisia
| | - Leila Metoui
- Department of Internal Medicine, Military Hospital, 1007, Tunis, Tunisia
- Faculty of Medicine of Tunis, University of Tunis El Manar, Tunis, Tunisia
| | - Bassem Louzir
- Department of Internal Medicine, Military Hospital, 1007, Tunis, Tunisia
- Faculty of Medicine of Tunis, University of Tunis El Manar, Tunis, Tunisia
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13
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Wang W, Nie M, Jiang Y, Li M, Meng X, Xing X, Wang O, Xia W. Impaired geometry, volumetric density, and microstructure of cortical and trabecular bone assessed by HR-pQCT in both sporadic and MEN1-related primary hyperparathyroidism. Osteoporos Int 2020; 31:165-173. [PMID: 31642976 DOI: 10.1007/s00198-019-05186-1] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/04/2019] [Accepted: 10/01/2019] [Indexed: 12/31/2022]
Abstract
UNLABELLED This study evaluated bone features of PHPT using HR-pQCT. The results showed both cortical and trabecular bones were significantly impaired in PHPT patients. Male and female PHPT patients suffered similar damages in bone. HR-pQCT indices were not observed to differ in MEN1 and sporadic PHPT patients. INTRODUCTION High-resolution peripheral quantitative CT is a novel imaging technique used to separately assess trabecular and cortical bone status of the radius and tibia in vivo. Using HR-pQCT, we aimed to evaluate bone features of primary hyperparathyroidism patients in a Chinese population and reveal similarities and differences in bone features in multiple endocrine neoplasia type 1-related PHPT and sporadic PHPT patients in the Chinese population. METHODS A case-control study was designed. In 58 PHPT patients and 58 sex- and age-matched healthy controls, the distal radius and tibia were scanned using HR-pQCT. Areal bone mineral density (aBMD) was also determined in PHPT patients using dual-energy X-ray absorptiometry (DXA). RESULTS In comparison with controls, PHPT patients were observed to exhibit reduced volumetric BMD at the cortical and trabecular compartments, thinner cortices, and more widely spaced trabeculae. Significant differences were still observed when comparing data of female and male patients with age-matched controls separately. MHPT patients (n = 11) were found to have lower aBMD Z-scores in the lumbar spine, trochanteric region, and total hip compared with sporadic PHPT patients (n = 47), while no differences were observed in HR-pQCT indices between the two groups. In multiple linear regression models, no significant correlations were identified between PTH and HR-pQCT indices. However, height was found to positively correlate with HR-pQCT-derived trabecular indices at both the radius and tibia. CONCLUSIONS PHPT affects geometry, volumetric density, and microstructure in both the cortical and trabecular bones in both male and female Chinese patients. MHPT patients were observed to have reduced aBMD as determined by DXA in the lumbar spine and hip in comparison with sporadic PHPT patients. However, HR-pQCT indices were not observed to differ.
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Affiliation(s)
- W Wang
- Key laboratory of Endocrinology, Ministry of Health, Department of Endocrinology, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Shuai Fuyuan 1#, Dongdan, Dongcheng district, Beijing, 100730, People's Republic of China
- Key Laboratory of Diabetes Mellitus Prevention and Research, Department of Endocrinology, Beijing Luhe Hospital, Capital Medical University, Beijing, People's Republic of China
| | - M Nie
- Key laboratory of Endocrinology, Ministry of Health, Department of Endocrinology, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Shuai Fuyuan 1#, Dongdan, Dongcheng district, Beijing, 100730, People's Republic of China
| | - Y Jiang
- Key laboratory of Endocrinology, Ministry of Health, Department of Endocrinology, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Shuai Fuyuan 1#, Dongdan, Dongcheng district, Beijing, 100730, People's Republic of China
| | - M Li
- Key laboratory of Endocrinology, Ministry of Health, Department of Endocrinology, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Shuai Fuyuan 1#, Dongdan, Dongcheng district, Beijing, 100730, People's Republic of China
| | - X Meng
- Key laboratory of Endocrinology, Ministry of Health, Department of Endocrinology, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Shuai Fuyuan 1#, Dongdan, Dongcheng district, Beijing, 100730, People's Republic of China
| | - X Xing
- Key laboratory of Endocrinology, Ministry of Health, Department of Endocrinology, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Shuai Fuyuan 1#, Dongdan, Dongcheng district, Beijing, 100730, People's Republic of China
| | - O Wang
- Key laboratory of Endocrinology, Ministry of Health, Department of Endocrinology, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Shuai Fuyuan 1#, Dongdan, Dongcheng district, Beijing, 100730, People's Republic of China.
| | - W Xia
- Key laboratory of Endocrinology, Ministry of Health, Department of Endocrinology, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Shuai Fuyuan 1#, Dongdan, Dongcheng district, Beijing, 100730, People's Republic of China.
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14
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Mele C, Mencarelli M, Caputo M, Mai S, Pagano L, Aimaretti G, Scacchi M, Falchetti A, Marzullo P. Phenotypes Associated With MEN1 Syndrome: A Focus on Genotype-Phenotype Correlations. Front Endocrinol (Lausanne) 2020; 11:591501. [PMID: 33312161 PMCID: PMC7708377 DOI: 10.3389/fendo.2020.591501] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/04/2020] [Accepted: 10/16/2020] [Indexed: 12/21/2022] Open
Abstract
Multiple endocrine neoplasia type 1 (MEN1) is a rare autosomal dominant inherited tumor syndrome, associated with parathyroid, pituitary, and gastro-entero-pancreatic (GEP) neuroendocrine tumors (NETs). MEN1 is usually consequent to different germline and somatic mutations of the MEN1 tumor suppressor gene, although phenocopies have also been reported. This review analyzed main biomedical databases searching for reports on MEN1 gene mutations and focused on aggressive and aberrant clinical manifestations to investigate the potential genotype-phenotype correlation. Despite efforts made by several groups, this link remains elusive to date and evidence that aggressive or aberrant clinical phenotypes may be related to specific mutations has been provided by case reports and small groups of MEN1 patients or families. In such context, a higher risk of aggressive tumor phenotypes has been described in relation to frameshift and non-sense mutations, and predominantly associated with aggressive GEP NETs, particularly pancreatic NETs. In our experience a novel heterozygous missense mutation at c.836C>A in exon 6 was noticed in a MEN1 patient operated for macro-prolactinoma, who progressively developed recurrent parathyroid adenomas, expanding gastrinomas and, long after the first MEN1 manifestation, a neuroendocrine uterine carcinoma. In conclusion, proof of genotype-phenotype correlation is limited but current evidence hints at the need for long-term interdisciplinary surveillance in patients with aggressive phenotypes and genetically confirmed MEN1.
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Affiliation(s)
- Chiara Mele
- Department of Translational Medicine, University of Piemonte Orientale, Novara, Italy
- Istituto Auxologico Italiano, IRCCS, Division of General Medicine, S. Giuseppe Hospital, Piancavallo, Italy
| | - Monica Mencarelli
- Istituto Auxologico Italiano, IRCCS, Laboratory of Molecular Biology, S. Giuseppe Hospital, Piancavallo, Italy
| | - Marina Caputo
- Department of Health Sciences, University of Piemonte Orientale, Novara, Italy
- Division of Endocrinology, University Hospital “Maggiore della Carità”, Novara, Italy
| | - Stefania Mai
- Istituto Auxologico Italiano, IRCCS, Laboratory of Metabolic Research, S. Giuseppe Hospital, Piancavallo, Italy
| | - Loredana Pagano
- Division of Endocrinology, Diabetology and Metabolism, Department of Medical Sciences, University of Turin, Turin, Italy
| | - Gianluca Aimaretti
- Department of Translational Medicine, University of Piemonte Orientale, Novara, Italy
- Division of Endocrinology, University Hospital “Maggiore della Carità”, Novara, Italy
| | - Massimo Scacchi
- Istituto Auxologico Italiano, IRCCS, Division of General Medicine, S. Giuseppe Hospital, Piancavallo, Italy
| | - Alberto Falchetti
- Istituto Auxologico Italiano, IRCCS, Rehabilitation Unit, S. Giuseppe Hospital, Unit for Bone Metabolism Diseases, Verbania, Italy
- Diabetes & Lab of Endocrine and Metabolic Research, Dept. of Clinical Sciences & Community Health, University of Milan, Milan, Italy
| | - Paolo Marzullo
- Department of Translational Medicine, University of Piemonte Orientale, Novara, Italy
- Istituto Auxologico Italiano, IRCCS, Division of General Medicine, S. Giuseppe Hospital, Piancavallo, Italy
- *Correspondence: Paolo Marzullo,
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15
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Lourenço DM, de Herder WW. Editorial: Early Genetic and Clinical Diagnosis in MEN1. Front Endocrinol (Lausanne) 2020; 11:218. [PMID: 32351454 PMCID: PMC7174644 DOI: 10.3389/fendo.2020.00218] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/17/2020] [Accepted: 03/26/2020] [Indexed: 11/13/2022] Open
Affiliation(s)
- Delmar M. Lourenço
- Endocrine Genetics Unit (LIM-25), Endocrinology Division, Hospital das Clínicas, University of São Paulo School of Medicine, São Paulo, Brazil
- Endocrine Oncology Division, Institute of Cancer of the State of São Paulo, São Paulo, Brazil
- *Correspondence: Delmar M. Lourenço Jr. ; ;
| | - Wouter W. de Herder
- Sector Endocrinology, Department of Internal Medicine, ENETS Centre of Excellence, Erasmus MC Cancer Institute, Erasmus MC - University Medical Center, Rotterdam, Netherlands
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16
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Wu Y, Gao L, Guo X, Wang Z, Lian W, Deng K, Lu L, Xing B, Zhu H. Pituitary adenomas in patients with multiple endocrine neoplasia type 1: a single-center experience in China. Pituitary 2019; 22:113-123. [PMID: 30637623 DOI: 10.1007/s11102-019-00939-x] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
PURPOSE To explore the clinical characteristics of pituitary adenomas in patients with MEN1 and to summarize treatment strategies for MEN1 in a Chinese population. METHODS We retrospectively analyzed 54 MEN1 patients with pituitary adenomas diagnosed at Peking Union Medical College Hospital from March 2003 to January 2017. Clinical data, laboratory testing results, treatments of involved glands and treatment responses were collected and analyzed. RESULTS The mean age at pituitary adenoma diagnosis was 53.9 ± 17.8. The patients initially consulted the Endocrinology, General Surgery and Neurosurgery departments, in descending frequency. The nonfunctioning adenoma, prolactinoma, GH-secreting adenoma, cosecreting adenoma, and ACTH-secreting adenoma subtypes accounted for 48.1%, 27.8%, 9.3%, 9.3% and 5.6% of the cases, respectively. The remission rate for prolactinomas was 46.2% (6/13) treated with bromocriptine. And the remission rates were 87.5% (7/8) and 100% (3/3) for GH-secreting adenomas and ACTH-secreting adenomas respectively achieved by transsphenoidal surgery. Nineteen (35.2%) patients with asymptomatic nonfunctioning pituitary adenomas showed no progression after a 35-month follow-up with close observation. Regarding treatment priority, patients with thymic carcinoid tumors received first-line surgery, 54% of the patients with enteropancreatic tumors had these tumors treated first, and 26% of all patients had their pituitary adenomas treated first. In acromegalic patients, pituitary lesions tended to be treated first (75%, p = 0.002). PHPT and adrenocortical adenomas can be managed with elective surgery. CONCLUSIONS The treatment of MEN1 requires cooperation between multidisciplinary teams. Individualized treatment according to the severity of glandular involvement is needed. GH-secreting and ACTH-secreting pituitary adenomas require active treatment, while nonfunctioning pituitary adenomas can be observed closely.
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Affiliation(s)
- Yanyan Wu
- Department of Neurosurgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100730, China
- China Pituitary Disease Registry Center, Chinese Pituitary Adenoma Specialist Council, Beijing, 100730, China
- Key Laboratory of Endocrinology of National Health and Family Planning Commission, Beijing, 100730, China
| | - Lu Gao
- Department of Neurosurgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100730, China
- China Pituitary Disease Registry Center, Chinese Pituitary Adenoma Specialist Council, Beijing, 100730, China
- Key Laboratory of Endocrinology of National Health and Family Planning Commission, Beijing, 100730, China
| | - Xiaopeng Guo
- Department of Neurosurgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100730, China
- China Pituitary Disease Registry Center, Chinese Pituitary Adenoma Specialist Council, Beijing, 100730, China
- Key Laboratory of Endocrinology of National Health and Family Planning Commission, Beijing, 100730, China
| | - Zihao Wang
- Department of Neurosurgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100730, China
- China Pituitary Disease Registry Center, Chinese Pituitary Adenoma Specialist Council, Beijing, 100730, China
- Key Laboratory of Endocrinology of National Health and Family Planning Commission, Beijing, 100730, China
| | - Wei Lian
- Department of Neurosurgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100730, China
- China Pituitary Disease Registry Center, Chinese Pituitary Adenoma Specialist Council, Beijing, 100730, China
- Key Laboratory of Endocrinology of National Health and Family Planning Commission, Beijing, 100730, China
| | - Kan Deng
- Department of Neurosurgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100730, China
- China Pituitary Disease Registry Center, Chinese Pituitary Adenoma Specialist Council, Beijing, 100730, China
- Key Laboratory of Endocrinology of National Health and Family Planning Commission, Beijing, 100730, China
| | - Lin Lu
- Department of Endocrinology, Peking Union Medical College Hospital, Beijing, 100730, China
| | - Bing Xing
- Department of Neurosurgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100730, China.
- China Pituitary Disease Registry Center, Chinese Pituitary Adenoma Specialist Council, Beijing, 100730, China.
- Key Laboratory of Endocrinology of National Health and Family Planning Commission, Beijing, 100730, China.
| | - Huijuan Zhu
- Department of Endocrinology, Peking Union Medical College Hospital, Beijing, 100730, China.
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Dantas NCB, Soares CEL, Martins MRA, Lourenço DM, Quidute ARP. Giant Prolactinoma Causing Hydrocephalus and Intracranial Hypertension as First Manifestations of Multiple Endocrine Neoplasia Type 1. Front Endocrinol (Lausanne) 2019; 10:582. [PMID: 31555208 PMCID: PMC6722186 DOI: 10.3389/fendo.2019.00582] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/07/2019] [Accepted: 08/09/2019] [Indexed: 11/13/2022] Open
Abstract
Context: Overall, giant prolactinomas are rare tumors (4%), especially those larger than 60 mm (1%). Despite the predominance of macroadenoma documented in multiple endocrine neoplasia type 1 (MEN1)-related prolactinoma, only three giant prolactinoma cases were described so far (size > 40 mm and prolactin > 1,000 ng/mL). None of them was larger than 60 mm or presented hydrocephalus or intracranial hypertension (ICH) as initial manifestation of MEN1. Case Description: A 21-years-old man presented with ICH as the first clinical manifestation of MEN1. He harbored a MEN1 germline mutation but refused periodic vigilance after normal hormonal screening at age 14 years. During investigation, magnetic resonance imaging (MRI) of the skull showed an expansive sellar/parasellar lesion (75 × 44 × 36 mm) with moderate to severe supratentorial obstructive hydrocephalus and an extremely high serum prolactin (PRL) of 10,800 ng/mL, without combined hypersecretion of other pituitary hormones. He was diagnosed with giant prolactinoma, and cabergoline was initiated. The patient evolved with early improvement of clinical complaints for hydrocephalus and ICH and PRL reached normal values (11 ng/mL) in association with significant tumoral shrinkage after 18 months on cabergoline. After 2 months of cabergoline, cerebrospinal fluid leakage was diagnosed and corrective surgery was provided. The mean dose of cabergoline was 3 mg/week throughout treatment. Conclusion: We reported the first case with hydrocephalus and ICH as the initial clinical manifestation of a giant prolactinoma in MEN1. From our knowledge, this is the largest MEN1-related prolactinoma reported so far. Notably, all four MEN1-related giant prolactinomas cases reported were younger than 21 years strengthening the importance to routine MEN1 genetic testing for prolactinoma in this age group. Also, they all had initial effective response with dopamine agonist ensuring this drug as first-line treatment for MEN1-related giant prolactinoma. However, the scarce number of treated patients and progression of cabergoline resistance in two of them suggest strict surveillance.
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Affiliation(s)
- Naiara C. B. Dantas
- Walter Cantídio University Hospital, Federal University of Ceará, Fortaleza, Brazil
| | - Carlos E. L. Soares
- Faculty of Medicine, Drug Research and Development Center (NPDM), Federal University of Ceará (UFC), Fortaleza, Brazil
| | - Manoel R. A. Martins
- Walter Cantídio University Hospital, Federal University of Ceará, Fortaleza, Brazil
| | - Delmar M. Lourenço
- Endocrine Genetics Unit (LIM-25), Endocrinology Division, Hospital das Clínicas, School of Medicine, University of São Paulo, São Paulo, Brazil
- Endocrine Oncology Division, Institute of Cancer of the State of São Paulo, São Paulo, Brazil
| | - Ana R. P. Quidute
- Walter Cantídio University Hospital, Federal University of Ceará, Fortaleza, Brazil
- Faculty of Medicine, Drug Research and Development Center (NPDM), Federal University of Ceará (UFC), Fortaleza, Brazil
- *Correspondence: Ana R. P. Quidute
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18
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Montenegro FLDM, Brescia MDG, Lourenço DM, Arap SS, d'Alessandro AF, de Britto e Silva Filho G, Toledo SPDA. Could the Less-Than Subtotal Parathyroidectomy Be an Option for Treating Young Patients With Multiple Endocrine Neoplasia Type 1-Related Hyperparathyroidism? Front Endocrinol (Lausanne) 2019; 10:123. [PMID: 30899245 PMCID: PMC6417394 DOI: 10.3389/fendo.2019.00123] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/15/2018] [Accepted: 02/11/2019] [Indexed: 12/13/2022] Open
Abstract
Background: The surgical treatment of primary hyperparathyroidism (HPT) in patients with multiple endocrine neoplasia type 1 (MEN1) has evolved due the concern of permanent hypoparathyroidism. As the diagnosis has increased, the extent of operation has decreased. Most MEN1 patients requiring parathyroidectomy are younger than 50 years and they pose a difficult balance to achieve between persistent HPT and life-long hypoparathyroidism. The aim of the present study is to review our experience with a large series of patients with MEN1-related HPT (HPT/MEN1) treated at a single institution in order to find clues to a better treatment decision in these younger cases. Method: Retrospective analysis of consecutive HPT/MEN1 cases treated at a single institution with different operations: total parathyroidectomy and immediate forearm autograft (TPTX-AG), subtotal (STPTX), unintentional less than subtotal (U-LSTPTX) and intentional less than subtotal parathyroidectomy (I-LSTPTX). Results: Considering 84 initial cases operated on since 2011 (TPTX-AG, 39; STPTX, 22, U-LSTPTX, 13, and I-LSTPTX, 10), the rates of hypoparathyroidism were 30.8% (U-LSTPTX), 28.2% (TPTX-AG), 13.6% (STPTX), and 0% (I-LSTPTX). Two-thirds of them (68%; 57/84) were young (<50 years) or asdolescents. MIBI scan was more sensitive to show parathyroid glands and bilateral disease. Considering the concordance of MIBI and ultrasound for the possibility of unilateral clearance, it would be suitable to 22.6% of the cases. Intra-operative parathormone showed a significant decay even after unilateral exploration, but longer follow up is necessary. Overall, there were seven (4%) adolescents in 161 cases treated from 1987 to 2018, three underwent TPTX-AG and four had U-LSTPTX. Five are euparathyroid, one had mild recurrence, and one required a reoperation after 8 years due to the residual gland. Conclusions: Young patients are the most frequent candidates to parathyroidectomy. Less extensive procedures may be planned only if carefully reviewed preoperative imaging studies suggest a localized disease. Patients and their relatives should be fully informed of the risks and benefits during consent process. Future research with larger cohorts and long-term results are necessary to clarify if less than I-LSPTX or unilateral clearance are really adequate in selected groups of patients with HPT/MEN1 presenting lower volume of disease detected by preoperative imaging studies.
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Affiliation(s)
- Fabio Luiz de Menezes Montenegro
- Parathyroid Unit- LIM-28, Laboratório de Cirurgia de Cabeça e Pescoço, Head and Neck Surgery, Department of Surgery, Hospital das Clinicas HCFMUSP, University of Sao Paulo School of Medicine, Faculdade de Medicina, Universidade de São Paulo, São Paulo, Brazil
- *Correspondence: Fabio Luiz de Menezes Montenegro
| | - Marilia D'Elboux Guimaraes Brescia
- Parathyroid Unit- LIM-28, Laboratório de Cirurgia de Cabeça e Pescoço, Head and Neck Surgery, Department of Surgery, Hospital das Clinicas HCFMUSP, University of Sao Paulo School of Medicine, Faculdade de Medicina, Universidade de São Paulo, São Paulo, Brazil
| | - Delmar Muniz Lourenço
- Endocrine Genetics Unit (LIM-25), Endocrinology Division, Hospital das Clinicas, University of Sao Paulo School of Medicine, Faculdade de Medicina, Universidade de São Paulo, São Paulo, Brazil
- Endocrine Oncology Division, Institute of Cancer of the State of Sao Paulo, University of Sao Paulo School of Medicine, Faculdade de Medicina, Universidade de São Paulo, São Paulo, Brazil
| | - Sergio Samir Arap
- Parathyroid Unit- LIM-28, Laboratório de Cirurgia de Cabeça e Pescoço, Head and Neck Surgery, Department of Surgery, Hospital das Clinicas HCFMUSP, University of Sao Paulo School of Medicine, Faculdade de Medicina, Universidade de São Paulo, São Paulo, Brazil
| | - Andre Fernandes d'Alessandro
- Parathyroid Unit- LIM-28, Laboratório de Cirurgia de Cabeça e Pescoço, Head and Neck Surgery, Department of Surgery, Hospital das Clinicas HCFMUSP, University of Sao Paulo School of Medicine, Faculdade de Medicina, Universidade de São Paulo, São Paulo, Brazil
| | - Gilberto de Britto e Silva Filho
- Parathyroid Unit- LIM-28, Laboratório de Cirurgia de Cabeça e Pescoço, Head and Neck Surgery, Department of Surgery, Hospital das Clinicas HCFMUSP, University of Sao Paulo School of Medicine, Faculdade de Medicina, Universidade de São Paulo, São Paulo, Brazil
| | - Sergio Pereira de Almeida Toledo
- Endocrine Genetics Unit (LIM-25), Endocrinology Division, Hospital das Clinicas, University of Sao Paulo School of Medicine, Faculdade de Medicina, Universidade de São Paulo, São Paulo, Brazil
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Kamilaris CDC, Stratakis CA. Multiple Endocrine Neoplasia Type 1 (MEN1): An Update and the Significance of Early Genetic and Clinical Diagnosis. Front Endocrinol (Lausanne) 2019; 10:339. [PMID: 31263451 PMCID: PMC6584804 DOI: 10.3389/fendo.2019.00339] [Citation(s) in RCA: 91] [Impact Index Per Article: 15.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/24/2018] [Accepted: 05/10/2019] [Indexed: 12/21/2022] Open
Abstract
Multiple endocrine neoplasia type 1 (MEN1) is a rare hereditary tumor syndrome inherited in an autosomal dominant manner and characterized by a predisposition to a multitude of endocrine neoplasms primarily of parathyroid, enteropancreatic, and anterior pituitary origin, as well as nonendocrine neoplasms. Other endocrine tumors in MEN1 include foregut carcinoid tumors, adrenocortical tumors, and rarely pheochromocytoma. Nonendocrine manifestations include meningiomas and ependymomas, lipomas, angiofibromas, collagenomas, and leiomyomas. MEN1 is caused by inactivating mutations of the tumor suppressor gene MEN1 which encodes the protein menin. This syndrome can affect all age groups, with 17% of patients developing MEN1-associated tumors before 21 years of age. Despite advances in the diagnosis and treatment of MEN1-associated tumors, patients with MEN1 continue to have decreased life expectancy primarily due to malignant neuroendocrine tumors. The most recent clinical practice guidelines for MEN1, published in 2012, highlight the need for early genetic and clinical diagnosis of MEN1 and recommend an intensive surveillance approach for both patients with this syndrome and asymptomatic carriers starting at the age of 5 years with the goal of timely detection and management of MEN1-associated neoplasms and ultimately decreased disease-specific morbidity and mortality. Unfortunately, there is no clear genotype-phenotype correlation and individual mutation-dependent surveillance is not possible currently.
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20
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Carvalho RA, Urtremari B, Jorge AAL, Santana LS, Quedas EPS, Sekiya T, Longuini VC, Montenegro FLM, Lerario AM, Toledo SPA, Marx SJ, Toledo RA, Lourenço DM. Germline mutation landscape of multiple endocrine neoplasia type 1 using full gene next-generation sequencing. Eur J Endocrinol 2018; 179:391-407. [PMID: 30324798 DOI: 10.1530/eje-18-0430] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/19/2018] [Accepted: 09/24/2018] [Indexed: 12/17/2022]
Abstract
Background Loss-of-function germline MEN1 gene mutations account for 75-95% of patients with multiple endocrine neoplasia type 1 (MEN1). It has been postulated that mutations in non-coding regions of MEN1 might occur in some of the remaining patients; however, this hypothesis has not yet been fully investigated. Objective To sequence for the entire MEN1 including promoter, exons and introns in a large MEN1 cohort and determine the mutation profile. Methods and patients A target next-generation sequencing (tNGS) assay comprising 7.2 kb of the full MEN1 was developed to investigate germline mutations in 76 unrelated MEN1 probands (49 familial, 27 sporadic). tNGS results were validated by Sanger sequencing (SS), and multiplex ligation-dependent probe amplification (MLPA) assay was applied when no mutations were identifiable by both tNGS and SS. Results Germline MEN1 variants were verified in coding region and splicing sites of 57/76 patients (74%) by both tNGS and SS (100% reproducibility). Thirty-eight different pathogenic or likely pathogenic variants were identified, including 13 new and six recurrent variants. Three large deletions were detected by MLPA only. No mutation was detected in 16 patients. In untranslated, regulatory or in deep intronic MEN1 regions of the 76 MEN1 cases, no point or short indel pathogenic variants were found in untranslated, although 33 benign/likely benign and three new VUS variants were detected. Conclusions Our study documents that point or short indel mutations in non-coding regions of MEN1 are very rare events. Also, tNGS proved to be a highly effective technology for routine genetic MEN1 testing.
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Affiliation(s)
- Rafael A Carvalho
- Unidade de Endocrinologia Genetica UEG, Laboratorio de Endocrinologia Celular e Molecular LIM-25, Disciplina de Endocrinologia
| | - Betsaida Urtremari
- Unidade de Endocrinologia Genetica UEG, Laboratorio de Endocrinologia Celular e Molecular LIM-25, Disciplina de Endocrinologia
| | - Alexander A L Jorge
- Unidade de Endocrinologia Genetica UEG, Laboratorio de Endocrinologia Celular e Molecular LIM-25, Disciplina de Endocrinologia
| | - Lucas S Santana
- Unidade de Endocrinologia Genetica UEG, Laboratorio de Endocrinologia Celular e Molecular LIM-25, Disciplina de Endocrinologia
| | - Elisangela P S Quedas
- Unidade de Endocrinologia Genetica UEG, Laboratorio de Endocrinologia Celular e Molecular LIM-25, Disciplina de Endocrinologia
| | - Tomoko Sekiya
- Unidade de Endocrinologia Genetica UEG, Laboratorio de Endocrinologia Celular e Molecular LIM-25, Disciplina de Endocrinologia
| | - Viviane C Longuini
- Unidade de Endocrinologia Genetica UEG, Laboratorio de Endocrinologia Celular e Molecular LIM-25, Disciplina de Endocrinologia
| | - Fabio L M Montenegro
- Unidade de Paratireoide, Laboratorio de Cirurgia Vascular e da Cabeça e Pescoço LIM-28, Disciplina de Cirurgia de Cabeça e Pescoço, Hospital das Clinicas HCFMUSP, Faculdade de Medicina, Universidade de Sao Paulo, Sao Paulo, Sao Paulo, Brazil
| | - Antonio M Lerario
- Division of Metabolism, Department of Internal Medicine, Endocrinology and Diabetes, University of Michigan, Ann Arbor, Michigan, USA
| | - Sergio P A Toledo
- Unidade de Endocrinologia Genetica UEG, Laboratorio de Endocrinologia Celular e Molecular LIM-25, Disciplina de Endocrinologia
- Endocrinology Division, Federal University of Sao Paulo (UNIFESP), São Paulo, Brazil
| | - Stephen J Marx
- Unidade de Endocrinologia Genetica UEG, Laboratorio de Endocrinologia Celular e Molecular LIM-25, Disciplina de Endocrinologia
- Endocrinology, Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), Bethesda, Maryland, USA
| | | | - Delmar M Lourenço
- Unidade de Endocrinologia Genetica UEG, Laboratorio de Endocrinologia Celular e Molecular LIM-25, Disciplina de Endocrinologia
- Disciplina de Endocrinologia, Instituto do Cancer do Estado de Sao Paulo ICESP, Faculdade de Medicina, Universidade de Sao Paulo, Sao Paulo, Sao Paulo, Brazil
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21
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de Laat JM, van Leeuwaarde RS, Valk GD. The Importance of an Early and Accurate MEN1 Diagnosis. Front Endocrinol (Lausanne) 2018; 9:533. [PMID: 30254610 PMCID: PMC6141626 DOI: 10.3389/fendo.2018.00533] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/18/2018] [Accepted: 08/22/2018] [Indexed: 12/16/2022] Open
Abstract
Multiple Endocrine Neoplasia type 1 (MEN1) is a rare autosomal dominant inherited condition, causing significant morbidity, and a reduction of life expectancy. A timely and accurate diagnosis of MEN1 is paramount to improve disease outcomes. This enables early identification of tumor manifestations allowing timely treatment for reducing morbidity and improving survival. Current management of MEN1 poses two challenges regarding the MEN1 diagnosis: diagnostic delay and the issue of phenocopies. A delay in diagnosis can be caused by a delay in identifying the index case, and by a delay in identifying affected family members of an index case. At present, lag time between diagnosis of MEN1 in index cases and genetic testing of family members was estimated to be 3.5 years. A subsequent delay in diagnosing affected family members was demonstrated to cause potential harm. Non-index cases have been found to develop clinically relevant tumor manifestations during the lag times. Centralized care, monitoring of patients outcomes on a national level and thereby improving awareness of physicians treating MEN1 patients, will contribute to improved care. The second challenge relates to "phenocopies." Phenocopies refers to the 5-25% of clinically diagnosed patients with MEN1in whom no mutation can be found. Up to now, the clinical diagnosis of MEN1 is defined as the simultaneous presence of at least two of the three characteristic tumors (pituitary, parathyroids, or pancreatic islets). These clinically diagnosed patients undergo intensive follow up. Recent insights, however, challenge the validity of this clinical criterion. The most common mutation-negative MEN1 phenotype is the combination of primary hyperparathyroidism and a pituitary adenoma. This phenotype might also be caused by mutations in the CDKN1B gene, causing the recently described MEN4 syndrome. Moreover, primary hyperparathyroidism and pituitary adenoma are relatively common in the general population. Limiting follow-up in patients with a sporadic co-occurrence of pHPT and PIT could reduce exposure to radiation from imaging, healthcare costs and anxiety.
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22
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Agarwal SK. The future: genetics advances in MEN1 therapeutic approaches and management strategies. Endocr Relat Cancer 2017; 24:T119-T134. [PMID: 28899949 PMCID: PMC5679100 DOI: 10.1530/erc-17-0199] [Citation(s) in RCA: 52] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/21/2017] [Accepted: 08/08/2017] [Indexed: 02/01/2023]
Abstract
The identification of the multiple endocrine neoplasia type 1 (MEN1) gene in 1997 has shown that germline heterozygous mutations in the MEN1 gene located on chromosome 11q13 predisposes to the development of tumors in the MEN1 syndrome. Tumor development occurs upon loss of the remaining normal copy of the MEN1 gene in MEN1-target tissues. Therefore, MEN1 is a classic tumor suppressor gene in the context of MEN1. This tumor suppressor role of the protein encoded by the MEN1 gene, menin, holds true in mouse models with germline heterozygous Men1 loss, wherein MEN1-associated tumors develop in adult mice after spontaneous loss of the remaining non-targeted copy of the Men1 gene. The availability of genetic testing for mutations in the MEN1 gene has become an essential part of the diagnosis and management of MEN1. Genetic testing is also helping to exclude mutation-negative cases in MEN1 families from the burden of lifelong clinical screening. In the past 20 years, efforts of various groups world-wide have been directed at mutation analysis, molecular genetic studies, mouse models, gene expression studies, epigenetic regulation analysis, biochemical studies and anti-tumor effects of candidate therapies in mouse models. This review will focus on the findings and advances from these studies to identify MEN1 germline and somatic mutations, the genetics of MEN1-related states, several protein partners of menin, the three-dimensional structure of menin and menin-dependent target genes. The ongoing impact of all these studies on disease prediction, management and outcomes will continue in the years to come.
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Affiliation(s)
- Sunita K Agarwal
- Metabolic Diseases BranchNational Institute of Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, Maryland, USA
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23
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Kong J, Wang O, Nie M, Shi J, Hu Y, Jiang Y, Li M, Xia W, Meng X, Xing X. Clinical and Genetic Analysis of Multiple Endocrine Neoplasia Type 1-Related Primary Hyperparathyroidism in Chinese. PLoS One 2016; 11:e0166634. [PMID: 27846313 PMCID: PMC5112846 DOI: 10.1371/journal.pone.0166634] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2016] [Accepted: 11/01/2016] [Indexed: 12/14/2022] Open
Abstract
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.
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Affiliation(s)
- Jing Kong
- Department of Endocrinology, Key Laboratory of Endocrinology, National Health and Family Planning Commission, Peking Union Medical College Hospital, Chinese Academy of Medical Science & Peking Union Medical College, Beijing, People’s Republic of China
| | - Ou Wang
- Department of Endocrinology, Key Laboratory of Endocrinology, National Health and Family Planning Commission, Peking Union Medical College Hospital, Chinese Academy of Medical Science & Peking Union Medical College, Beijing, People’s Republic of China
- * E-mail: (OW); (XX)
| | - Min Nie
- Department of Endocrinology, Key Laboratory of Endocrinology, National Health and Family Planning Commission, Peking Union Medical College Hospital, Chinese Academy of Medical Science & Peking Union Medical College, Beijing, People’s Republic of China
| | - Jie Shi
- Department of Pathology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, People’s Republic of China
| | - Yingying Hu
- Department of Laboratory Medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Science & Peking Union Medical College, Beijing, People’s Republic of China
| | - Yan Jiang
- Department of Endocrinology, Key Laboratory of Endocrinology, National Health and Family Planning Commission, Peking Union Medical College Hospital, Chinese Academy of Medical Science & Peking Union Medical College, Beijing, People’s Republic of China
| | - Mei Li
- Department of Endocrinology, Key Laboratory of Endocrinology, National Health and Family Planning Commission, Peking Union Medical College Hospital, Chinese Academy of Medical Science & Peking Union Medical College, Beijing, People’s Republic of China
| | - Weibo Xia
- Department of Endocrinology, Key Laboratory of Endocrinology, National Health and Family Planning Commission, Peking Union Medical College Hospital, Chinese Academy of Medical Science & Peking Union Medical College, Beijing, People’s Republic of China
| | - Xunwu Meng
- Department of Endocrinology, Key Laboratory of Endocrinology, National Health and Family Planning Commission, Peking Union Medical College Hospital, Chinese Academy of Medical Science & Peking Union Medical College, Beijing, People’s Republic of China
| | - Xiaoping Xing
- Department of Endocrinology, Key Laboratory of Endocrinology, National Health and Family Planning Commission, Peking Union Medical College Hospital, Chinese Academy of Medical Science & Peking Union Medical College, Beijing, People’s Republic of China
- * E-mail: (OW); (XX)
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24
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Silva AM, Vodopivec D, Christakis I, Lyons G, Wei Q, Waguespack SG, Petak SM, Grubbs E, Lee JE, Perrier N. Operative intervention for primary hyperparathyroidism offers greater bone recovery in patients with sporadic disease than in those with multiple endocrine neoplasia type 1-related hyperparathyroidism. Surgery 2016; 161:107-115. [PMID: 27842919 DOI: 10.1016/j.surg.2016.06.065] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2016] [Revised: 04/29/2016] [Accepted: 06/11/2016] [Indexed: 01/05/2023]
Abstract
BACKGROUND We investigated whether the outcome of bone disease of primary hyperparathyroidism differs in multiple endocrine neoplasia type 1-associated disease and sporadic hyperparathyroidism at 1-year postoperatively. METHODS Multiple endocrine neoplasia type 1/hyperparathyroidism and sporadic hyperparathyroidism patients who underwent parathyroidectomy from 1990 to 2013 and dual-energy x-ray absorptiometry at baseline and 1-year postoperatively were included. Preoperative and postoperative dual-energy x-ray absorptiometry measurements (bone mineral density and Z-score at the lumbar spine, total hip, and femoral neck) were analyzed. RESULTS We evaluated 14 multiple endocrine neoplasia type 1/hyperparathyroidism and 104 sporadic hyperparathyroidism patients. The preoperative Z-scores at the lumbar spine, total hip, and femoral neck were lower in the multiple endocrine neoplasia type 1/hyperparathyroidism group (P = .05, P = .04, and P = .0081, respectively). Comparison of preoperative and postoperative dual-energy x-ray absorptiometry measurements demonstrated that the multiple endocrine neoplasia type 1/hyperparathyroidism group had a significantly higher Z-score at the lumbar spine (P = .02) at 1 year after operation, whereas the sporadic hyperparathyroidism group had a significantly higher Z-score at the lumbar spine, total hip, and femoral neck (P < .0001, P = .0004, and P = .0001) and higher bone mineral density at the lumbar spine (P = .0001). CONCLUSION Long-term monitoring of these patients using dual-energy x-ray absorptiometry is required to assess outcomes and facilitate decisions on the timing of operative intervention.
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Affiliation(s)
- Angelica M Silva
- Department of Surgical Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, TX
| | - Danica Vodopivec
- Department of Surgical Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, TX
| | - Ioannis Christakis
- Department of Surgical Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, TX
| | - Genevieve Lyons
- Department of Biostatistics, The University of Texas M. D. Anderson Cancer Center, Houston, TX
| | - Qiu Wei
- Department of Surgical Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, TX
| | - Steven G Waguespack
- Department of Endocrine Neoplasia and Hormonal Disorders, The University of Texas M. D. Anderson Cancer Center, Houston, TX
| | - Steven M Petak
- Department of Endocrine Neoplasia and Hormonal Disorders, The University of Texas M. D. Anderson Cancer Center, Houston, TX
| | - Elizabeth Grubbs
- Department of Surgical Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, TX
| | - Jeffrey E Lee
- Department of Surgical Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, TX
| | - Nancy Perrier
- Department of Surgical Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, TX.
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Matrozova J, Vandeva S, Zacharieva S. Case Report: A case report of acromegaly associated with primary aldosteronism. F1000Res 2014; 3:58. [PMID: 25210615 PMCID: PMC4156025 DOI: 10.12688/f1000research.3-58.v2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 05/27/2014] [Indexed: 11/20/2022] Open
Abstract
We describe a patient with a rare combination of acromegaly and primary aldosteronism. A 37 year-old female patient was diagnosed with acromegaly on the basis of typical clinical, hormonal and image characteristics. She presented also with one of the most common co-morbidities – arterial hypertension. The patient has been regularly followed-up and after three surgical interventions, irradiation and adjuvant treatment with a dopamine agonist, acromegaly was finally controlled in 2008 (20 years after diagnosis). Arterial hypertension however, remained a therapeutic problem even after prescription of four antihypertensive drugs. She had normal biochemical parameters, except for low potassium levels 3.2 (3.5-5.6) mmol/l. This raised the suspicion of primary hyperaldosteronism, confirmed by a high aldosterone to plasma rennin activity ratio, high aldosterone level after a Captopril challenge test and visualization of a 35 mm left adrenal nodule on a CT scan. After an operation, the patient recovered from hypokalemia and antihypertensive therapy was reduced to a small dose of a Ca blocker. Co-morbid arterial hypertension is common in acromegaly, though it is rare for this to be caused by Conn’s adenoma. The association of Conn’s adenoma with acromegaly has been interpreted in two lines: as a component of multiple endocrine neoplasia type (MEN1) syndrome or as a direct mitogenic effect of hyperactivated GH-IGF1 axis.
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Affiliation(s)
- Joanna Matrozova
- Clinical Center of Endocrinology and Gerontology, Medical University - Sofia, 1431, Sofia, Bulgaria
| | - Silvia Vandeva
- Clinical Center of Endocrinology and Gerontology, Medical University - Sofia, 1431, Sofia, Bulgaria
| | - Sabina Zacharieva
- Clinical Center of Endocrinology and Gerontology, Medical University - Sofia, 1431, Sofia, Bulgaria
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26
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Longuini VC, Lourenço DM, Sekiya T, Meirelles O, Goncalves TD, Coutinho FL, Francisco G, Osaki LH, Chammas R, Alves VAF, Siqueira SAC, Schlesinger D, Naslavsky MS, Zatz M, Duarte YAO, Lebrão ML, Gama P, Lee M, Molatore S, Pereira MAA, Jallad RS, Bronstein MD, Cunha-Neto MB, Liberman B, Fragoso MCBV, Toledo SPA, Pellegata NS, Toledo RA. Association between the p27 rs2066827 variant and tumor multiplicity in patients harboring MEN1 germline mutations. Eur J Endocrinol 2014; 171:335-42. [PMID: 24920291 DOI: 10.1530/eje-14-0130] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
OBJECTIVE 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. DESIGN 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. METHODS 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. RESULTS 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. CONCLUSIONS 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.
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Affiliation(s)
- Viviane C Longuini
- Endocrine Genetics Unit (Laboratorio de Investigacao Medica/LIM-25)Neuroendocrinology UnitNeuroendocrinology-Neurosurgery UnitAdrenal Unit (LIM-42)General Endocrinology UnitExperimental Oncology Laboratory (LIM-24)Department of PathologyNursing SchoolSchool of Public Health of Hospital das ClínicasUniversity of Sao Paulo School of Medicine, Sao Paulo, BrazilBrigadeiro HospitalSao Paulo, BrazilHuman Genome Research CenterUniversity of Sao Paulo, Sao Paulo, BrazilInstituto do CérebroInstituto Israelita de Ensino e Pesquisa Albert Einstein, Sao Paulo, BrazilNational Institute of AgingNational Institutes of Health (NIH), Bethesda, Maryland, USAInstitute of PathologyHelmholtz Zentrum München, Neuherberg, GermanyInstitute of Biomedical SciencesUniversity of Sao Paulo, Sao Paulo, BrazilDivision of EndocrinologyFederal University of Sao Paulo (UNIFESP), Sao Paulo, Brazil
| | - Delmar M Lourenço
- Endocrine Genetics Unit (Laboratorio de Investigacao Medica/LIM-25)Neuroendocrinology UnitNeuroendocrinology-Neurosurgery UnitAdrenal Unit (LIM-42)General Endocrinology UnitExperimental Oncology Laboratory (LIM-24)Department of PathologyNursing SchoolSchool of Public Health of Hospital das ClínicasUniversity of Sao Paulo School of Medicine, Sao Paulo, BrazilBrigadeiro HospitalSao Paulo, BrazilHuman Genome Research CenterUniversity of Sao Paulo, Sao Paulo, BrazilInstituto do CérebroInstituto Israelita de Ensino e Pesquisa Albert Einstein, Sao Paulo, BrazilNational Institute of AgingNational Institutes of Health (NIH), Bethesda, Maryland, USAInstitute of PathologyHelmholtz Zentrum München, Neuherberg, GermanyInstitute of Biomedical SciencesUniversity of Sao Paulo, Sao Paulo, BrazilDivision of EndocrinologyFederal University of Sao Paulo (UNIFESP), Sao Paulo, Brazil
| | - Tomoko Sekiya
- Endocrine Genetics Unit (Laboratorio de Investigacao Medica/LIM-25)Neuroendocrinology UnitNeuroendocrinology-Neurosurgery UnitAdrenal Unit (LIM-42)General Endocrinology UnitExperimental Oncology Laboratory (LIM-24)Department of PathologyNursing SchoolSchool of Public Health of Hospital das ClínicasUniversity of Sao Paulo School of Medicine, Sao Paulo, BrazilBrigadeiro HospitalSao Paulo, BrazilHuman Genome Research CenterUniversity of Sao Paulo, Sao Paulo, BrazilInstituto do CérebroInstituto Israelita de Ensino e Pesquisa Albert Einstein, Sao Paulo, BrazilNational Institute of AgingNational Institutes of Health (NIH), Bethesda, Maryland, USAInstitute of PathologyHelmholtz Zentrum München, Neuherberg, GermanyInstitute of Biomedical SciencesUniversity of Sao Paulo, Sao Paulo, BrazilDivision of EndocrinologyFederal University of Sao Paulo (UNIFESP), Sao Paulo, Brazil
| | - Osorio Meirelles
- Endocrine Genetics Unit (Laboratorio de Investigacao Medica/LIM-25)Neuroendocrinology UnitNeuroendocrinology-Neurosurgery UnitAdrenal Unit (LIM-42)General Endocrinology UnitExperimental Oncology Laboratory (LIM-24)Department of PathologyNursing SchoolSchool of Public Health of Hospital das ClínicasUniversity of Sao Paulo School of Medicine, Sao Paulo, BrazilBrigadeiro HospitalSao Paulo, BrazilHuman Genome Research CenterUniversity of Sao Paulo, Sao Paulo, BrazilInstituto do CérebroInstituto Israelita de Ensino e Pesquisa Albert Einstein, Sao Paulo, BrazilNational Institute of AgingNational Institutes of Health (NIH), Bethesda, Maryland, USAInstitute of PathologyHelmholtz Zentrum München, Neuherberg, GermanyInstitute of Biomedical SciencesUniversity of Sao Paulo, Sao Paulo, BrazilDivision of EndocrinologyFederal University of Sao Paulo (UNIFESP), Sao Paulo, Brazil
| | - Tatiana D Goncalves
- Endocrine Genetics Unit (Laboratorio de Investigacao Medica/LIM-25)Neuroendocrinology UnitNeuroendocrinology-Neurosurgery UnitAdrenal Unit (LIM-42)General Endocrinology UnitExperimental Oncology Laboratory (LIM-24)Department of PathologyNursing SchoolSchool of Public Health of Hospital das ClínicasUniversity of Sao Paulo School of Medicine, Sao Paulo, BrazilBrigadeiro HospitalSao Paulo, BrazilHuman Genome Research CenterUniversity of Sao Paulo, Sao Paulo, BrazilInstituto do CérebroInstituto Israelita de Ensino e Pesquisa Albert Einstein, Sao Paulo, BrazilNational Institute of AgingNational Institutes of Health (NIH), Bethesda, Maryland, USAInstitute of PathologyHelmholtz Zentrum München, Neuherberg, GermanyInstitute of Biomedical SciencesUniversity of Sao Paulo, Sao Paulo, BrazilDivision of EndocrinologyFederal University of Sao Paulo (UNIFESP), Sao Paulo, Brazil
| | - Flavia L Coutinho
- Endocrine Genetics Unit (Laboratorio de Investigacao Medica/LIM-25)Neuroendocrinology UnitNeuroendocrinology-Neurosurgery UnitAdrenal Unit (LIM-42)General Endocrinology UnitExperimental Oncology Laboratory (LIM-24)Department of PathologyNursing SchoolSchool of Public Health of Hospital das ClínicasUniversity of Sao Paulo School of Medicine, Sao Paulo, BrazilBrigadeiro HospitalSao Paulo, BrazilHuman Genome Research CenterUniversity of Sao Paulo, Sao Paulo, BrazilInstituto do CérebroInstituto Israelita de Ensino e Pesquisa Albert Einstein, Sao Paulo, BrazilNational Institute of AgingNational Institutes of Health (NIH), Bethesda, Maryland, USAInstitute of PathologyHelmholtz Zentrum München, Neuherberg, GermanyInstitute of Biomedical SciencesUniversity of Sao Paulo, Sao Paulo, BrazilDivision of EndocrinologyFederal University of Sao Paulo (UNIFESP), Sao Paulo, Brazil
| | - Guilherme Francisco
- Endocrine Genetics Unit (Laboratorio de Investigacao Medica/LIM-25)Neuroendocrinology UnitNeuroendocrinology-Neurosurgery UnitAdrenal Unit (LIM-42)General Endocrinology UnitExperimental Oncology Laboratory (LIM-24)Department of PathologyNursing SchoolSchool of Public Health of Hospital das ClínicasUniversity of Sao Paulo School of Medicine, Sao Paulo, BrazilBrigadeiro HospitalSao Paulo, BrazilHuman Genome Research CenterUniversity of Sao Paulo, Sao Paulo, BrazilInstituto do CérebroInstituto Israelita de Ensino e Pesquisa Albert Einstein, Sao Paulo, BrazilNational Institute of AgingNational Institutes of Health (NIH), Bethesda, Maryland, USAInstitute of PathologyHelmholtz Zentrum München, Neuherberg, GermanyInstitute of Biomedical SciencesUniversity of Sao Paulo, Sao Paulo, BrazilDivision of EndocrinologyFederal University of Sao Paulo (UNIFESP), Sao Paulo, Brazil
| | - Luciana H Osaki
- Endocrine Genetics Unit (Laboratorio de Investigacao Medica/LIM-25)Neuroendocrinology UnitNeuroendocrinology-Neurosurgery UnitAdrenal Unit (LIM-42)General Endocrinology UnitExperimental Oncology Laboratory (LIM-24)Department of PathologyNursing SchoolSchool of Public Health of Hospital das ClínicasUniversity of Sao Paulo School of Medicine, Sao Paulo, BrazilBrigadeiro HospitalSao Paulo, BrazilHuman Genome Research CenterUniversity of Sao Paulo, Sao Paulo, BrazilInstituto do CérebroInstituto Israelita de Ensino e Pesquisa Albert Einstein, Sao Paulo, BrazilNational Institute of AgingNational Institutes of Health (NIH), Bethesda, Maryland, USAInstitute of PathologyHelmholtz Zentrum München, Neuherberg, GermanyInstitute of Biomedical SciencesUniversity of Sao Paulo, Sao Paulo, BrazilDivision of EndocrinologyFederal University of Sao Paulo (UNIFESP), Sao Paulo, Brazil
| | - Roger Chammas
- Endocrine Genetics Unit (Laboratorio de Investigacao Medica/LIM-25)Neuroendocrinology UnitNeuroendocrinology-Neurosurgery UnitAdrenal Unit (LIM-42)General Endocrinology UnitExperimental Oncology Laboratory (LIM-24)Department of PathologyNursing SchoolSchool of Public Health of Hospital das ClínicasUniversity of Sao Paulo School of Medicine, Sao Paulo, BrazilBrigadeiro HospitalSao Paulo, BrazilHuman Genome Research CenterUniversity of Sao Paulo, Sao Paulo, BrazilInstituto do CérebroInstituto Israelita de Ensino e Pesquisa Albert Einstein, Sao Paulo, BrazilNational Institute of AgingNational Institutes of Health (NIH), Bethesda, Maryland, USAInstitute of PathologyHelmholtz Zentrum München, Neuherberg, GermanyInstitute of Biomedical SciencesUniversity of Sao Paulo, Sao Paulo, BrazilDivision of EndocrinologyFederal University of Sao Paulo (UNIFESP), Sao Paulo, Brazil
| | - Venancio A F Alves
- Endocrine Genetics Unit (Laboratorio de Investigacao Medica/LIM-25)Neuroendocrinology UnitNeuroendocrinology-Neurosurgery UnitAdrenal Unit (LIM-42)General Endocrinology UnitExperimental Oncology Laboratory (LIM-24)Department of PathologyNursing SchoolSchool of Public Health of Hospital das ClínicasUniversity of Sao Paulo School of Medicine, Sao Paulo, BrazilBrigadeiro HospitalSao Paulo, BrazilHuman Genome Research CenterUniversity of Sao Paulo, Sao Paulo, BrazilInstituto do CérebroInstituto Israelita de Ensino e Pesquisa Albert Einstein, Sao Paulo, BrazilNational Institute of AgingNational Institutes of Health (NIH), Bethesda, Maryland, USAInstitute of PathologyHelmholtz Zentrum München, Neuherberg, GermanyInstitute of Biomedical SciencesUniversity of Sao Paulo, Sao Paulo, BrazilDivision of EndocrinologyFederal University of Sao Paulo (UNIFESP), Sao Paulo, Brazil
| | - Sheila A C Siqueira
- Endocrine Genetics Unit (Laboratorio de Investigacao Medica/LIM-25)Neuroendocrinology UnitNeuroendocrinology-Neurosurgery UnitAdrenal Unit (LIM-42)General Endocrinology UnitExperimental Oncology Laboratory (LIM-24)Department of PathologyNursing SchoolSchool of Public Health of Hospital das ClínicasUniversity of Sao Paulo School of Medicine, Sao Paulo, BrazilBrigadeiro HospitalSao Paulo, BrazilHuman Genome Research CenterUniversity of Sao Paulo, Sao Paulo, BrazilInstituto do CérebroInstituto Israelita de Ensino e Pesquisa Albert Einstein, Sao Paulo, BrazilNational Institute of AgingNational Institutes of Health (NIH), Bethesda, Maryland, USAInstitute of PathologyHelmholtz Zentrum München, Neuherberg, GermanyInstitute of Biomedical SciencesUniversity of Sao Paulo, Sao Paulo, BrazilDivision of EndocrinologyFederal University of Sao Paulo (UNIFESP), Sao Paulo, Brazil
| | - David Schlesinger
- Endocrine Genetics Unit (Laboratorio de Investigacao Medica/LIM-25)Neuroendocrinology UnitNeuroendocrinology-Neurosurgery UnitAdrenal Unit (LIM-42)General Endocrinology UnitExperimental Oncology Laboratory (LIM-24)Department of PathologyNursing SchoolSchool of Public Health of Hospital das ClínicasUniversity of Sao Paulo School of Medicine, Sao Paulo, BrazilBrigadeiro HospitalSao Paulo, BrazilHuman Genome Research CenterUniversity of Sao Paulo, Sao Paulo, BrazilInstituto do CérebroInstituto Israelita de Ensino e Pesquisa Albert Einstein, Sao Paulo, BrazilNational Institute of AgingNational Institutes of Health (NIH), Bethesda, Maryland, USAInstitute of PathologyHelmholtz Zentrum München, Neuherberg, GermanyInstitute of Biomedical SciencesUniversity of Sao Paulo, Sao Paulo, BrazilDivision of EndocrinologyFederal University of Sao Paulo (UNIFESP), Sao Paulo, BrazilEndocrine Genetics Unit (Laboratorio de Investigacao Medica/LIM-25)Neuroendocrinology UnitNeuroendocrinology-Neurosurgery UnitAdrenal Unit (LIM-42)General Endocrinology UnitExperimental Oncology Laboratory (LIM-24)Department of PathologyNursing SchoolSchool of Public Health of Hospital das ClínicasUniversity of Sao Paulo School of Medicine, Sao Paulo, BrazilBrigadeiro HospitalSao Paulo, BrazilHuman Genome Research CenterUniversity of Sao Paulo, Sao Paulo, BrazilInstituto do CérebroInstituto Israelita de Ensino e Pesquisa Albert Einstein, Sao Paulo, BrazilNational Institute of AgingNational Institutes of Health (NIH), Bethesda, Maryland, USAInstitute of PathologyHelmholtz Zentrum München, Neuherberg, GermanyInstitute of Biomedical SciencesUniversity of Sao Paulo, Sao Paulo, BrazilDivision of EndocrinologyFederal University of Sao Paulo (UNIFESP), Sao Paulo, Brazil
| | - Michel S Naslavsky
- Endocrine Genetics Unit (Laboratorio de Investigacao Medica/LIM-25)Neuroendocrinology UnitNeuroendocrinology-Neurosurgery UnitAdrenal Unit (LIM-42)General Endocrinology UnitExperimental Oncology Laboratory (LIM-24)Department of PathologyNursing SchoolSchool of Public Health of Hospital das ClínicasUniversity of Sao Paulo School of Medicine, Sao Paulo, BrazilBrigadeiro HospitalSao Paulo, BrazilHuman Genome Research CenterUniversity of Sao Paulo, Sao Paulo, BrazilInstituto do CérebroInstituto Israelita de Ensino e Pesquisa Albert Einstein, Sao Paulo, BrazilNational Institute of AgingNational Institutes of Health (NIH), Bethesda, Maryland, USAInstitute of PathologyHelmholtz Zentrum München, Neuherberg, GermanyInstitute of Biomedical SciencesUniversity of Sao Paulo, Sao Paulo, BrazilDivision of EndocrinologyFederal University of Sao Paulo (UNIFESP), Sao Paulo, Brazil
| | - Mayana Zatz
- Endocrine Genetics Unit (Laboratorio de Investigacao Medica/LIM-25)Neuroendocrinology UnitNeuroendocrinology-Neurosurgery UnitAdrenal Unit (LIM-42)General Endocrinology UnitExperimental Oncology Laboratory (LIM-24)Department of PathologyNursing SchoolSchool of Public Health of Hospital das ClínicasUniversity of Sao Paulo School of Medicine, Sao Paulo, BrazilBrigadeiro HospitalSao Paulo, BrazilHuman Genome Research CenterUniversity of Sao Paulo, Sao Paulo, BrazilInstituto do CérebroInstituto Israelita de Ensino e Pesquisa Albert Einstein, Sao Paulo, BrazilNational Institute of AgingNational Institutes of Health (NIH), Bethesda, Maryland, USAInstitute of PathologyHelmholtz Zentrum München, Neuherberg, GermanyInstitute of Biomedical SciencesUniversity of Sao Paulo, Sao Paulo, BrazilDivision of EndocrinologyFederal University of Sao Paulo (UNIFESP), Sao Paulo, Brazil
| | - Yeda A O Duarte
- Endocrine Genetics Unit (Laboratorio de Investigacao Medica/LIM-25)Neuroendocrinology UnitNeuroendocrinology-Neurosurgery UnitAdrenal Unit (LIM-42)General Endocrinology UnitExperimental Oncology Laboratory (LIM-24)Department of PathologyNursing SchoolSchool of Public Health of Hospital das ClínicasUniversity of Sao Paulo School of Medicine, Sao Paulo, BrazilBrigadeiro HospitalSao Paulo, BrazilHuman Genome Research CenterUniversity of Sao Paulo, Sao Paulo, BrazilInstituto do CérebroInstituto Israelita de Ensino e Pesquisa Albert Einstein, Sao Paulo, BrazilNational Institute of AgingNational Institutes of Health (NIH), Bethesda, Maryland, USAInstitute of PathologyHelmholtz Zentrum München, Neuherberg, GermanyInstitute of Biomedical SciencesUniversity of Sao Paulo, Sao Paulo, BrazilDivision of EndocrinologyFederal University of Sao Paulo (UNIFESP), Sao Paulo, Brazil
| | - Maria Lucia Lebrão
- Endocrine Genetics Unit (Laboratorio de Investigacao Medica/LIM-25)Neuroendocrinology UnitNeuroendocrinology-Neurosurgery UnitAdrenal Unit (LIM-42)General Endocrinology UnitExperimental Oncology Laboratory (LIM-24)Department of PathologyNursing SchoolSchool of Public Health of Hospital das ClínicasUniversity of Sao Paulo School of Medicine, Sao Paulo, BrazilBrigadeiro HospitalSao Paulo, BrazilHuman Genome Research CenterUniversity of Sao Paulo, Sao Paulo, BrazilInstituto do CérebroInstituto Israelita de Ensino e Pesquisa Albert Einstein, Sao Paulo, BrazilNational Institute of AgingNational Institutes of Health (NIH), Bethesda, Maryland, USAInstitute of PathologyHelmholtz Zentrum München, Neuherberg, GermanyInstitute of Biomedical SciencesUniversity of Sao Paulo, Sao Paulo, BrazilDivision of EndocrinologyFederal University of Sao Paulo (UNIFESP), Sao Paulo, Brazil
| | - Patricia Gama
- Endocrine Genetics Unit (Laboratorio de Investigacao Medica/LIM-25)Neuroendocrinology UnitNeuroendocrinology-Neurosurgery UnitAdrenal Unit (LIM-42)General Endocrinology UnitExperimental Oncology Laboratory (LIM-24)Department of PathologyNursing SchoolSchool of Public Health of Hospital das ClínicasUniversity of Sao Paulo School of Medicine, Sao Paulo, BrazilBrigadeiro HospitalSao Paulo, BrazilHuman Genome Research CenterUniversity of Sao Paulo, Sao Paulo, BrazilInstituto do CérebroInstituto Israelita de Ensino e Pesquisa Albert Einstein, Sao Paulo, BrazilNational Institute of AgingNational Institutes of Health (NIH), Bethesda, Maryland, USAInstitute of PathologyHelmholtz Zentrum München, Neuherberg, GermanyInstitute of Biomedical SciencesUniversity of Sao Paulo, Sao Paulo, BrazilDivision of EndocrinologyFederal University of Sao Paulo (UNIFESP), Sao Paulo, Brazil
| | - Misu Lee
- Endocrine Genetics Unit (Laboratorio de Investigacao Medica/LIM-25)Neuroendocrinology UnitNeuroendocrinology-Neurosurgery UnitAdrenal Unit (LIM-42)General Endocrinology UnitExperimental Oncology Laboratory (LIM-24)Department of PathologyNursing SchoolSchool of Public Health of Hospital das ClínicasUniversity of Sao Paulo School of Medicine, Sao Paulo, BrazilBrigadeiro HospitalSao Paulo, BrazilHuman Genome Research CenterUniversity of Sao Paulo, Sao Paulo, BrazilInstituto do CérebroInstituto Israelita de Ensino e Pesquisa Albert Einstein, Sao Paulo, BrazilNational Institute of AgingNational Institutes of Health (NIH), Bethesda, Maryland, USAInstitute of PathologyHelmholtz Zentrum München, Neuherberg, GermanyInstitute of Biomedical SciencesUniversity of Sao Paulo, Sao Paulo, BrazilDivision of EndocrinologyFederal University of Sao Paulo (UNIFESP), Sao Paulo, Brazil
| | - Sara Molatore
- Endocrine Genetics Unit (Laboratorio de Investigacao Medica/LIM-25)Neuroendocrinology UnitNeuroendocrinology-Neurosurgery UnitAdrenal Unit (LIM-42)General Endocrinology UnitExperimental Oncology Laboratory (LIM-24)Department of PathologyNursing SchoolSchool of Public Health of Hospital das ClínicasUniversity of Sao Paulo School of Medicine, Sao Paulo, BrazilBrigadeiro HospitalSao Paulo, BrazilHuman Genome Research CenterUniversity of Sao Paulo, Sao Paulo, BrazilInstituto do CérebroInstituto Israelita de Ensino e Pesquisa Albert Einstein, Sao Paulo, BrazilNational Institute of AgingNational Institutes of Health (NIH), Bethesda, Maryland, USAInstitute of PathologyHelmholtz Zentrum München, Neuherberg, GermanyInstitute of Biomedical SciencesUniversity of Sao Paulo, Sao Paulo, BrazilDivision of EndocrinologyFederal University of Sao Paulo (UNIFESP), Sao Paulo, Brazil
| | - Maria Adelaide A Pereira
- Endocrine Genetics Unit (Laboratorio de Investigacao Medica/LIM-25)Neuroendocrinology UnitNeuroendocrinology-Neurosurgery UnitAdrenal Unit (LIM-42)General Endocrinology UnitExperimental Oncology Laboratory (LIM-24)Department of PathologyNursing SchoolSchool of Public Health of Hospital das ClínicasUniversity of Sao Paulo School of Medicine, Sao Paulo, BrazilBrigadeiro HospitalSao Paulo, BrazilHuman Genome Research CenterUniversity of Sao Paulo, Sao Paulo, BrazilInstituto do CérebroInstituto Israelita de Ensino e Pesquisa Albert Einstein, Sao Paulo, BrazilNational Institute of AgingNational Institutes of Health (NIH), Bethesda, Maryland, USAInstitute of PathologyHelmholtz Zentrum München, Neuherberg, GermanyInstitute of Biomedical SciencesUniversity of Sao Paulo, Sao Paulo, BrazilDivision of EndocrinologyFederal University of Sao Paulo (UNIFESP), Sao Paulo, Brazil
| | - Raquel S Jallad
- Endocrine Genetics Unit (Laboratorio de Investigacao Medica/LIM-25)Neuroendocrinology UnitNeuroendocrinology-Neurosurgery UnitAdrenal Unit (LIM-42)General Endocrinology UnitExperimental Oncology Laboratory (LIM-24)Department of PathologyNursing SchoolSchool of Public Health of Hospital das ClínicasUniversity of Sao Paulo School of Medicine, Sao Paulo, BrazilBrigadeiro HospitalSao Paulo, BrazilHuman Genome Research CenterUniversity of Sao Paulo, Sao Paulo, BrazilInstituto do CérebroInstituto Israelita de Ensino e Pesquisa Albert Einstein, Sao Paulo, BrazilNational Institute of AgingNational Institutes of Health (NIH), Bethesda, Maryland, USAInstitute of PathologyHelmholtz Zentrum München, Neuherberg, GermanyInstitute of Biomedical SciencesUniversity of Sao Paulo, Sao Paulo, BrazilDivision of EndocrinologyFederal University of Sao Paulo (UNIFESP), Sao Paulo, Brazil
| | - Marcello D Bronstein
- Endocrine Genetics Unit (Laboratorio de Investigacao Medica/LIM-25)Neuroendocrinology UnitNeuroendocrinology-Neurosurgery UnitAdrenal Unit (LIM-42)General Endocrinology UnitExperimental Oncology Laboratory (LIM-24)Department of PathologyNursing SchoolSchool of Public Health of Hospital das ClínicasUniversity of Sao Paulo School of Medicine, Sao Paulo, BrazilBrigadeiro HospitalSao Paulo, BrazilHuman Genome Research CenterUniversity of Sao Paulo, Sao Paulo, BrazilInstituto do CérebroInstituto Israelita de Ensino e Pesquisa Albert Einstein, Sao Paulo, BrazilNational Institute of AgingNational Institutes of Health (NIH), Bethesda, Maryland, USAInstitute of PathologyHelmholtz Zentrum München, Neuherberg, GermanyInstitute of Biomedical SciencesUniversity of Sao Paulo, Sao Paulo, BrazilDivision of EndocrinologyFederal University of Sao Paulo (UNIFESP), Sao Paulo, Brazil
| | - Malebranche B Cunha-Neto
- Endocrine Genetics Unit (Laboratorio de Investigacao Medica/LIM-25)Neuroendocrinology UnitNeuroendocrinology-Neurosurgery UnitAdrenal Unit (LIM-42)General Endocrinology UnitExperimental Oncology Laboratory (LIM-24)Department of PathologyNursing SchoolSchool of Public Health of Hospital das ClínicasUniversity of Sao Paulo School of Medicine, Sao Paulo, BrazilBrigadeiro HospitalSao Paulo, BrazilHuman Genome Research CenterUniversity of Sao Paulo, Sao Paulo, BrazilInstituto do CérebroInstituto Israelita de Ensino e Pesquisa Albert Einstein, Sao Paulo, BrazilNational Institute of AgingNational Institutes of Health (NIH), Bethesda, Maryland, USAInstitute of PathologyHelmholtz Zentrum München, Neuherberg, GermanyInstitute of Biomedical SciencesUniversity of Sao Paulo, Sao Paulo, BrazilDivision of EndocrinologyFederal University of Sao Paulo (UNIFESP), Sao Paulo, Brazil
| | - Bernardo Liberman
- Endocrine Genetics Unit (Laboratorio de Investigacao Medica/LIM-25)Neuroendocrinology UnitNeuroendocrinology-Neurosurgery UnitAdrenal Unit (LIM-42)General Endocrinology UnitExperimental Oncology Laboratory (LIM-24)Department of PathologyNursing SchoolSchool of Public Health of Hospital das ClínicasUniversity of Sao Paulo School of Medicine, Sao Paulo, BrazilBrigadeiro HospitalSao Paulo, BrazilHuman Genome Research CenterUniversity of Sao Paulo, Sao Paulo, BrazilInstituto do CérebroInstituto Israelita de Ensino e Pesquisa Albert Einstein, Sao Paulo, BrazilNational Institute of AgingNational Institutes of Health (NIH), Bethesda, Maryland, USAInstitute of PathologyHelmholtz Zentrum München, Neuherberg, GermanyInstitute of Biomedical SciencesUniversity of Sao Paulo, Sao Paulo, BrazilDivision of EndocrinologyFederal University of Sao Paulo (UNIFESP), Sao Paulo, Brazil
| | - Maria Candida B V Fragoso
- Endocrine Genetics Unit (Laboratorio de Investigacao Medica/LIM-25)Neuroendocrinology UnitNeuroendocrinology-Neurosurgery UnitAdrenal Unit (LIM-42)General Endocrinology UnitExperimental Oncology Laboratory (LIM-24)Department of PathologyNursing SchoolSchool of Public Health of Hospital das ClínicasUniversity of Sao Paulo School of Medicine, Sao Paulo, BrazilBrigadeiro HospitalSao Paulo, BrazilHuman Genome Research CenterUniversity of Sao Paulo, Sao Paulo, BrazilInstituto do CérebroInstituto Israelita de Ensino e Pesquisa Albert Einstein, Sao Paulo, BrazilNational Institute of AgingNational Institutes of Health (NIH), Bethesda, Maryland, USAInstitute of PathologyHelmholtz Zentrum München, Neuherberg, GermanyInstitute of Biomedical SciencesUniversity of Sao Paulo, Sao Paulo, BrazilDivision of EndocrinologyFederal University of Sao Paulo (UNIFESP), Sao Paulo, Brazil
| | - Sergio P A Toledo
- Endocrine Genetics Unit (Laboratorio de Investigacao Medica/LIM-25)Neuroendocrinology UnitNeuroendocrinology-Neurosurgery UnitAdrenal Unit (LIM-42)General Endocrinology UnitExperimental Oncology Laboratory (LIM-24)Department of PathologyNursing SchoolSchool of Public Health of Hospital das ClínicasUniversity of Sao Paulo School of Medicine, Sao Paulo, BrazilBrigadeiro HospitalSao Paulo, BrazilHuman Genome Research CenterUniversity of Sao Paulo, Sao Paulo, BrazilInstituto do CérebroInstituto Israelita de Ensino e Pesquisa Albert Einstein, Sao Paulo, BrazilNational Institute of AgingNational Institutes of Health (NIH), Bethesda, Maryland, USAInstitute of PathologyHelmholtz Zentrum München, Neuherberg, GermanyInstitute of Biomedical SciencesUniversity of Sao Paulo, Sao Paulo, BrazilDivision of EndocrinologyFederal University of Sao Paulo (UNIFESP), Sao Paulo, BrazilEndocrine Genetics Unit (Laboratorio de Investigacao Medica/LIM-25)Neuroendocrinology UnitNeuroendocrinology-Neurosurgery UnitAdrenal Unit (LIM-42)General Endocrinology UnitExperimental Oncology Laboratory (LIM-24)Department of PathologyNursing SchoolSchool of Public Health of Hospital das ClínicasUniversity of Sao Paulo School of Medicine, Sao Paulo, BrazilBrigadeiro HospitalSao Paulo, BrazilHuman Genome Research CenterUniversity of Sao Paulo, Sao Paulo, BrazilInstituto do CérebroInstituto Israelita de Ensino e Pesquisa Albert Einstein, Sao Paulo, BrazilNational Institute of AgingNational Institutes of Health (NIH), Bethesda, Maryland, USAInstitute of PathologyHelmholtz Zentrum München, Neuherberg, GermanyInstitute of Biomedical SciencesUniversity of Sao Paulo, Sao Paulo, BrazilDivision of EndocrinologyFederal University of Sao Paulo (UNIFESP), Sao Paulo, Brazil
| | - Natalia S Pellegata
- Endocrine Genetics Unit (Laboratorio de Investigacao Medica/LIM-25)Neuroendocrinology UnitNeuroendocrinology-Neurosurgery UnitAdrenal Unit (LIM-42)General Endocrinology UnitExperimental Oncology Laboratory (LIM-24)Department of PathologyNursing SchoolSchool of Public Health of Hospital das ClínicasUniversity of Sao Paulo School of Medicine, Sao Paulo, BrazilBrigadeiro HospitalSao Paulo, BrazilHuman Genome Research CenterUniversity of Sao Paulo, Sao Paulo, BrazilInstituto do CérebroInstituto Israelita de Ensino e Pesquisa Albert Einstein, Sao Paulo, BrazilNational Institute of AgingNational Institutes of Health (NIH), Bethesda, Maryland, USAInstitute of PathologyHelmholtz Zentrum München, Neuherberg, GermanyInstitute of Biomedical SciencesUniversity of Sao Paulo, Sao Paulo, BrazilDivision of EndocrinologyFederal University of Sao Paulo (UNIFESP), Sao Paulo, Brazil
| | - Rodrigo A Toledo
- Endocrine Genetics Unit (Laboratorio de Investigacao Medica/LIM-25)Neuroendocrinology UnitNeuroendocrinology-Neurosurgery UnitAdrenal Unit (LIM-42)General Endocrinology UnitExperimental Oncology Laboratory (LIM-24)Department of PathologyNursing SchoolSchool of Public Health of Hospital das ClínicasUniversity of Sao Paulo School of Medicine, Sao Paulo, BrazilBrigadeiro HospitalSao Paulo, BrazilHuman Genome Research CenterUniversity of Sao Paulo, Sao Paulo, BrazilInstituto do CérebroInstituto Israelita de Ensino e Pesquisa Albert Einstein, Sao Paulo, BrazilNational Institute of AgingNational Institutes of Health (NIH), Bethesda, Maryland, USAInstitute of PathologyHelmholtz Zentrum München, Neuherberg, GermanyInstitute of Biomedical SciencesUniversity of Sao Paulo, Sao Paulo, BrazilDivision of EndocrinologyFederal University of Sao Paulo (UNIFESP), Sao Paulo, Brazil
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Nunes VS, Souza GL, Perone D, Conde SJ, Nogueira CR. Frequency of multiple endocrine neoplasia type 1 in a group of patients with pituitary adenoma: genetic study and familial screening. Pituitary 2014; 17:30-7. [PMID: 23334809 DOI: 10.1007/s11102-013-0462-8] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 10/27/2022]
Abstract
The purpose of this study it was to evaluate the frequency of Multiple Endocrine Neoplasia type 1 (MEN1) in patients with pituitary adenoma and to perform genetic analysis and familial screening of those individuals afflicted with MEN1. 144 patients with pituitary adenoma at Botucatu Medical School, UNESP-Univ Estadual Paulista, were assessed retrospectively for MEN1 during the years of 2005-2011. The patients were evaluated for the presence of primary hyperparathyroidism (PHP) and enteropancreatic tumors. Genetic analysis was performed for the individuals with clinically diagnosed MEN1. Thirteen patients met the diagnostic criteria for MEN1, but three individuals belong to the same family and they were considered as a single MEN1 event, revealing 7.7 % frequency of MEN1 in this patient group. Genetic analysis showed MEN1 mutations in four index cases: IVS4+1 G>A, IVS3-6 C>T, c.1547insC and a new D180A mutation. One patient did not agree to participate in the genetic study and another one was referred for follow up in other hospital. Only polymorphisms were found in the other individuals, one of which was novel. We identified a high frequency of MEN1 in pituitary adenoma patients. Since PHP is one of the most common MEN1 tumor and patients are mostly asymptomatic, we suggest that all pituitary adenoma patients have their calcium profile analyzed.
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Affiliation(s)
- V S Nunes
- Laboratory of Molecular Biology, Department of Internal Medicine, Botucatu Medical School, UNESP, Univ Estadual Paulista, Botucatu, Brazil,
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Toledo SPA, Lourenço DM, Toledo RA. A differential diagnosis of inherited endocrine tumors and their tumor counterparts. Clinics (Sao Paulo) 2013; 68:1039-56. [PMID: 23917672 PMCID: PMC3715026 DOI: 10.6061/clinics/2013(07)24] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/04/2013] [Accepted: 03/26/2013] [Indexed: 12/15/2022] Open
Abstract
Inherited endocrine tumors have been increasingly recognized in clinical practice, although some difficulties still exist in differentiating these conditions from their sporadic endocrine tumor counterparts. Here, we list the 12 main topics that could add helpful information and clues for performing an early differential diagnosis to distinguish between these conditions. The early diagnosis of patients with inherited endocrine tumors may be performed either clinically or by mutation analysis in at-risk individuals. Early detection usually has a large impact in tumor management, allowing preventive clinical or surgical therapy in most cases. Advice for the clinical and surgical management of inherited endocrine tumors is also discussed. In addition, recent clinical and genetic advances for 17 different forms of inherited endocrine tumors are briefly reviewed.
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Affiliation(s)
- Sergio P A Toledo
- Division of Endocrinology, Endocrine Genetics Unit (LIM-25), Faculdade de Medicina da Universidade de São Paulo, São Paulo/SP, Brazil.
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Genetic and clinical features of multiple endocrine neoplasia types 1 and 2. JOURNAL OF ONCOLOGY 2012; 2012:705036. [PMID: 23209466 PMCID: PMC3503399 DOI: 10.1155/2012/705036] [Citation(s) in RCA: 62] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/30/2012] [Accepted: 09/16/2012] [Indexed: 12/12/2022]
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.
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Kann PH, Bartsch D, Langer P, Waldmann J, Hadji P, Pfützner A, Klüsener J. Peripheral bone mineral density in correlation to disease-related predisposing conditions in patients with multiple endocrine neoplasia type 1. J Endocrinol Invest 2012; 35:573-9. [PMID: 21791969 DOI: 10.3275/7880] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
Abstract
BACKGROUND AND AIM Patients with multiple endocrine neoplasia type 1 (MEN1) often have low bone mineral density (BMD) attributed to primary hyperparathyroidism (pHPT). However, in MEN1 patients, other endocrine dysfunctions and conditions such as hypercortisolism, hypogonadism, and GH deficiency due to pituitary manifestation, and surgery on the upper gastrointestinal tract may affect BMD. SUBJECTS AND METHODS In 23 patients with MEN1 (10 females, 13 males; 46±12 yr), BMD was determined by quantitative computed tomography at the forearm (pqCT), compared to a reference population and related to different conditions suspected to affect bone metabolism in MEN1. RESULTS In this cohort, Z-score for trabecular BMD was -0.85±1.18 and for total BMD -1.16±1.04. There was a similar trend towards lower BMD in uncontrolled hyperparathyroidism, hypercortisolism, hypogonadism/GH deficiency and the state after surgery at the upper gastrointestinal tract. CONCLUSIONS These data while confirming previous observations on reduced BMD in patients with MEN1, however, challenge its only or even predominant association with pHPT. Other conditions such as hypercortisolism, somatotrophic/ gonadotrophic pituitary insufficiency, and previous upper gastrointestinal surgery seem to be factors contributing to the risk of developing osteoporosis.
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Affiliation(s)
- P H Kann
- Division of Endocrinology and Diabetology, Faculty of Medicine and University Hospital, Philipp's University, Marburg, Germany.
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Lips CJ, Dreijerink KM, Links TP, Höppener JW. Recent results of basic and clinical research in MEN1: opportunities to improve early detection and treatment. Expert Rev Endocrinol Metab 2012; 7:331-344. [PMID: 30780845 DOI: 10.1586/eem.12.22] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
Due to the variable expression of multiple endocrine neoplasia type 1 (MEN1), it is difficult to predict the course of the disease. However, knowledge about the normal function of the MEN1 gene product, together with the effects of cellular derangement by subsequent genetic events, has increased considerably. At first, the possible existence of a genotype-phenotype correlation is discussed. Thus, mild- and late-onset phenotypes may be distinguished from more malignant phenotypes depending on the character of the primary MEN1 disease gene mutation. Subsequently, tumor-promoting factors such as gender, additional genetic mutations and ecogenetic factors may contribute to the course of the disease. New developments in management are based on the knowledge and experience of the multidisciplinary teams involved. Finally, the metabolic effects of MEN1 mutations in aged patients are discussed. Early identification of predisposition to the disease, together with knowledge about the natural history of specific mutations, risks of additional mutations and periodic clinical monitoring, allow early treatment and may improve life expectancy and quality of life.
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Affiliation(s)
- Cornelis Jm Lips
- a Department of Internal Medicine and Endocrinology, University Medical Center, Utrecht & The Hague, The Netherlands
- d Department of Internal Medicine and Endocrinology, University Medical Center, Utrecht & The Hague, The Netherlands.
| | - Koen Ma Dreijerink
- a Department of Internal Medicine and Endocrinology, University Medical Center, Utrecht & The Hague, The Netherlands
| | - Thera P Links
- b Department of Endocrinology, University Medical Center Groningen, The Netherlands
| | - Jo Wm Höppener
- c Department of Metabolic Diseases, University Medical Center, Utrecht, The Netherlands
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Abstract
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.
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Affiliation(s)
- Brigitte Delemer
- Service d'endocrinologie-diabète-nutrition, CHU de Reims, France.
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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 multiple endocrine neoplasia type 1 related tumors are crucial for determining the best surgical strategies in each individual case with pancreatic endocrine tumors.
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Toledo RA, Sekiya T, Longuini VC, Coutinho FL, Lourenço DM, Toledo SPA. Narrowing the gap of personalized medicine in emerging countries: the case of multiple endocrine neoplasias in Brazil. Clinics (Sao Paulo) 2012; 67 Suppl 1:3-6. [PMID: 22584698 PMCID: PMC3328830 DOI: 10.6061/clinics/2012(sup01)02] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/06/2022] Open
Abstract
The finished version of the human genome sequence was completed in 2003, and this event initiated a revolution in medical practice, which is usually referred to as the age of genomic or personalized medicine. Genomic medicine aims to be predictive, personalized, preventive, and also participative (4Ps). It offers a new approach to several pathological conditions, although its impact so far has been more evident in mendelian diseases. This article briefly reviews the potential advantages of this approach, and also some issues that may arise in the attempt to apply the accumulated knowledge from genomic medicine to clinical practice in emerging countries. The advantages of applying genomic medicine into clinical practice are obvious, enabling prediction, prevention, and early diagnosis and treatment of several genetic disorders. However, there are also some issues, such as those related to: (a) the need for approval of a law equivalent to the Genetic Information Nondiscrimination Act, which was approved in 2008 in the USA; (b) the need for private and public funding for genetics and genomics; (c) the need for development of innovative healthcare systems that may substantially cut costs (e.g. costs of periodic medical followup); (d) the need for new graduate and postgraduate curricula in which genomic medicine is emphasized; and (e) the need to adequately inform the population and possible consumers of genetic testing, with reference to the basic aspects of genomic medicine.
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Affiliation(s)
- Rodrigo A Toledo
- Endocrine Genetics Unit, Endocrinology Division, Hospital das Clínicas, Faculdade de Medicina, Universidade de São Paulo, São Paulo, SP, Brazil.
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Lips CJ, Dreijerink KM, Höppener JW. Variable clinical expression in patients with a germline MEN1 disease gene mutation: clues to a genotype-phenotype correlation. Clinics (Sao Paulo) 2012; 67 Suppl 1:49-56. [PMID: 22584706 PMCID: PMC3328827 DOI: 10.6061/clinics/2012(sup01)10] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
Multiple endocrine neoplasia type 1 is an inherited endocrine tumor syndrome, predominantly characterized by tumors of the parathyroid glands, gastroenteropancreatic tumors, pituitary adenomas, adrenal adenomas, and neuroendocrine tumors of the thymus, lungs or stomach. Multiple endocrine neoplasia type 1 is caused by germline mutations of the multiple endocrine neoplasia type 1 tumor suppressor gene. The initial germline mutation, loss of the wild-type allele, and modifying genetic and possibly epigenetic and environmental events eventually result in multiple endocrine neoplasia type 1 tumors. Our understanding of the function of the multiple endocrine neoplasia type 1 gene product, menin, has increased significantly over the years. However, to date, no clear genotype-phenotype correlation has been established. In this review we discuss reports on exceptional clinical presentations of multiple endocrine neoplasia type 1, which may provide more insight into the pathogenesis of this disorder and offer clues for a possible genotype-phenotype correlation.
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Affiliation(s)
- Cornelis J Lips
- Department of Internal Medicine & Endocrinology, University Medical Center Utrecht, Utrecht, The Netherlands.
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Syro LV, Scheithauer BW, Kovacs K, Toledo RA, Londoño FJ, Ortiz LD, Rotondo F, Horvath E, Uribe H. Pituitary tumors in patients with MEN1 syndrome. Clinics (Sao Paulo) 2012; 67 Suppl 1:43-8. [PMID: 22584705 PMCID: PMC3328811 DOI: 10.6061/clinics/2012(sup01)09] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/26/2023] Open
Abstract
We briefly review the characteristics of pituitary tumors associated with multiple endocrine neoplasia type 1. Multiple endocrine neoplasia type 1 is an autosomal-dominant disorder most commonly characterized by tumors of the pituitary, parathyroid, endocrine-gastrointestinal tract, and pancreas. A MEDLINE search for all available publications regarding multiple endocrine neoplasia type 1 and pituitary adenomas was undertaken. The prevalence of pituitary tumors in multiple endocrine neoplasia type 1 may vary from 10% to 60% depending on the studied series, and such tumors may occur as the first clinical manifestation of multiple endocrine neoplasia type 1 in 25% of sporadic and 10% of familial cases. Patients were younger and the time between initial and subsequent multiple endocrine neoplasia type 1 endocrine lesions was significantly longer when pituitary disease was the initial manifestation of multiple endocrine neoplasia type 1. Tumors were larger and more invasive and clinical manifestations related to the size of the pituitary adenoma were significantly more frequent in patients with multiple endocrine neoplasia type 1 than in subjects with non-multiple endocrine neoplasia type 1. Normalization of pituitary hypersecretion was much less frequent in patients with multiple endocrine neoplasia type 1 than in subjects with non-multiple endocrine neoplasia type 1. Pituitary tumors in patients with multiple endocrine neoplasia type 1 syndrome tend to be larger, invasive and more symptomatic, and they tend to occur in younger patients when they are the initial presentation of multiple endocrine neoplasia type 1.
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Affiliation(s)
- Luis V Syro
- Department of Neurosurgery, Clinica Medellin, Hospital Pablo Tobon Uribe, Medellin, Colombia.
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Coutinho FL, Lourenco DM, Toledo RA, Montenegro FLM, Toledo SPA. Post-surgical follow-up of primary hyperparathyroidism associated with multiple endocrine neoplasia type 1. Clinics (Sao Paulo) 2012; 67 Suppl 1:169-72. [PMID: 22584724 PMCID: PMC3328812 DOI: 10.6061/clinics/2012(sup01)28] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/19/2022] Open
Abstract
The bone mineral density increments in patients with sporadic primary hyperparathyroidism after parathyroidectomy have been studied by several investigators, but few have investigated this topic in primary hyperparathyroidism associated with multiple endocrine neoplasia type 1. Further, as far as we know, only two studies have consistently evaluated bone mineral density values after parathyroidectomy in cases of primary hyperparathyroidism associated with multiple endocrine neoplasia type 1. Here we revised the impact of parathyroidectomy (particularly total parathyroidectomy followed by autologous parathyroid implant into the forearm) on bone mineral density values in patients with primary hyperparathyroidism associated with multiple endocrine neoplasia type 1. Significant increases in bone mineral density in the lumbar spine and femoral neck values were found, although no short-term (15 months) improvement in bone mineral density at the proximal third of the distal radius was observed. Additionally, short-term and medium-term calcium and parathyroid hormone values after parathyroidectomy in patients with primary hyperparathyroidism associated with multiple endocrine neoplasia type 1 are discussed. In most cases, this surgical approach was able to restore normal calcium/parathyroid hormone levels and ultimately lead to discontinuation of calcium and calcitriol supplementation.
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Affiliation(s)
- Flavia L Coutinho
- Endocrine Genetics Unit (LIM-25), Endocrinology Division, Hospital das Clínicas, Faculdade de Medicina, Universidade de São Paulo, São Paulo, Brazil.
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Lourenço DM, Coutinho FL, Toledo RA, Gonçalves TD, Montenegro FLM, Toledo SPA. Biochemical, bone and renal patterns in hyperparathyroidism associated with multiple endocrine neoplasia type 1. Clinics (Sao Paulo) 2012; 67 Suppl 1:99-108. [PMID: 22584713 PMCID: PMC3329618 DOI: 10.6061/clinics/2012(sup01)17] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/17/2023] Open
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 1 related 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.
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Affiliation(s)
- Delmar M Lourenço
- Endocrine Genetics Unit, Division of Endocrinology, Hospital das Clínicas, Faculdade de Medicina, Universidade de São Paulo, São Paulo, SP, Brazil.
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Giusti F, Tonelli F, Brandi ML. Primary hyperparathyroidism in multiple endocrine neoplasia type 1: when to perform surgery? Clinics (Sao Paulo) 2012; 67 Suppl 1:141-4. [PMID: 22584719 PMCID: PMC3328829 DOI: 10.6061/clinics/2012(sup01)23] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/18/2022] Open
Abstract
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.
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Affiliation(s)
- Francesca Giusti
- Bone and Mineral Metabolism Unit, Department of Internal Medicine, University Hospital of Careggi, Florence, Italy
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40
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Yamazaki M, Suzuki SI, Kosugi S, Okamoto T, Uchino S, Miya A, Imai T, Kaji H, Komoto I, Miura D, Yamada M, Uruno T, Horiuchi K, Sato A, Miyauchi A, Imamura M, Sakurai A. Delay in the diagnosis of multiple endocrine neoplasia type 1: typical symptoms are frequently overlooked. Endocr J 2012; 59:797-807. [PMID: 22673601 DOI: 10.1507/endocrj.ej12-0071] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/23/2022] Open
Abstract
The morbidity and mortality of individuals with multiple endocrine neoplasia type 1 (MEN1) can be reduced by early diagnosis of MEN1 and related endocrine tumors. To find factors contributing to early diagnosis, we collected clinical information on MEN1 patients through a MEN study group, "MEN Consortium of Japan" and analyzed the time of initial symptom-dependent detection of parathyroid tumors, gastro-entero-pancreatic neuroendocrine tumors (GEPNETs) and pituitary tumors, and that of tumor detection-dependent MEN1 diagnosis in 560 patients. Main tumors were identified up to 7.0 years after symptoms appeared and there was no difference in age at the diagnosis of GEPNETs alone between probands and family members. In patients with typical symptoms (peptic ulcers, urolithiasis, fasting hypoglycemia, bone fracture/loss and amenorrhea), the mean interval between symptom manifestation and tumor detection was extended up to 9.6 years. In particular, 21.7% (5/23) of patients with amenorrhea were diagnosed with pituitary tumors in under one year. In patients with peptic ulcers (from parathyroid tumors or GEPNETs) and urolithiasis (from parathyroid tumors), the interval was positively correlated with age at tumor detection. The interval between tumor detection and MEN1 diagnosis was also prolonged to approximately four years in patients with fasting hypoglycemia (from GEPNETs) and amenorrhea. A substantial delay in the diagnosis of symptom-related tumors and subsequent MEN1 and inadequate screening of GEPNETs in family members were indicated. A greater understanding of MEN1 may assist medical practitioners to make earlier diagnoses, to share patients' medical information and to give family members sufficient disease information.
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Affiliation(s)
- Masanori Yamazaki
- Division of Diabetes, Endocrinology and Metabolism, Department of Internal Medicine, Shinshu University School of Medicine, Matsumoto 390-8621, Japan
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Montenegro FLDM, Lourenço DM, Tavares MR, Arap SS, Nascimento CP, Massoni Neto LM, D'Alessandro A, Toledo RA, Coutinho FL, Brandão LG, de Britto e Silva Filho G, Cordeiro AC, Toledo SPA. Total parathyroidectomy in a large cohort of cases with hyperparathyroidism associated with multiple endocrine neoplasia type 1: experience from a single academic center. Clinics (Sao Paulo) 2012; 67 Suppl 1:131-9. [PMID: 22584718 PMCID: PMC3328834 DOI: 10.6061/clinics/2012(sup01)22] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/13/2023] Open
Abstract
Most cases of sporadic primary hyperparathyroidism present disturbances in a single parathyroid gland and the surgery of choice is adenomectomy. Conversely, hyperparathyroidism associated with multiple endocrine neoplasia type 1 (hyperparathyroidism/multiple endocrine neoplasia type 1) is an asynchronic, asymmetrical multiglandular disease and it is surgically approached by either subtotal parathyroidectomy or total parathyroidectomy followed by parathyroid auto-implant to the forearm. In skilful hands, the efficacy of both approaches is similar and both should be complemented by prophylactic thymectomy. In a single academic center, 83 cases of hyperparathyroidism/ multiple endocrine neoplasia type 1 were operated on from 1987 to 2010 and our first surgical choice was total parathyroidectomy followed by parathyroid auto-implant to the non-dominant forearm and, since 1997, associated transcervical thymectomy to prevent thymic carcinoid. Overall, 40% of patients were given calcium replacement (mean intake 1.6 g/day) during the first months after surgery, and this fell to 28% in patients with longer follow-up. These findings indicate that several months may be needed in order to achieve a proper secretion by the parathyroid auto-implant. Hyperparathyroidism recurrence was observed in up to 15% of cases several years after the initial surgery. Thus, long-term follow-up is recommended for such cases. We conclude that, despite a tendency to subtotal parathyroidectomy worldwide, total parathyroidectomy followed by parathyroid auto-implant is a valid surgical option to treat hyperparathyroidism/multiple endocrine neoplasia type 1. Larger comparative systematic studies are needed to define the best surgical approach to hyperparathyroidism/multiple endocrine neoplasia type 1.
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Affiliation(s)
- Fabio Luiz de Menezes Montenegro
- Department of Surgery, Head and Neck Surgery Section, Hospital das Clínicas, Faculdade de Medicina, Universidade de São Paulo, São Paulo, SP, Brazil.
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Fabbri HC, Mello MPD, Soardi FC, Esquiaveto-Aun AM, Oliveira DMD, Denardi FC, Moura-Neto A, Garmes HM, Baptista MTM, Matos PSD, Lemos-Marini SHVD, D'Souza-Li LFR, Guerra-Júnior G. Long-term follow-up of an 8-year-old boy with insulinoma as the first manifestation of a familial form of multiple endocrine neoplasia type 1. ACTA ACUST UNITED AC 2011; 54:754-60. [PMID: 21340165 DOI: 10.1590/s0004-27302010000800016] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2010] [Accepted: 11/18/2010] [Indexed: 11/22/2022]
Abstract
Multiple endocrine neoplasia type 1 (MEN1) is an autosomal dominant hereditary cancer syndrome characterized mostly by parathyroid, enteropancreatic, and anterior pituitary tumors. We present a case of an 8-year-old boy referred because of hypoglycemic attacks. His diagnosis was pancreatic insulinoma. Paternal grandmother died due to repeated gastroduodenal ulcerations and a paternal aunt presented similar manifestations. At a first evaluation, the father presented only gastric ulceration but subsequently developed hyperparathyroidism and lung carcinoid tumor. During almost 15 years of follow-up, three brothers and the index case presented hyperparathyroidism and hyperprolactinemia. Molecular study showed a G to A substitution in intron 4, at nine nucleotides upstream of the splicing acceptor site, causing a splicing mutation. All affected members of the family have the same mutation. Paternal grandmother and aunt were not studied and the mother does not carry any mutation. MEN1 is a rare condition that requires permanent medical assistance. Early clinical and genetic identification of affected individuals is essential for their own surveillance and also for genetic counseling.
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Affiliation(s)
- Helena Campos Fabbri
- Center for Molecular Biology and Genetic Engineering, Universidade Estadual de Campinas, SP, Brazil
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Lourenço DM, Coutinho FL, Toledo RA, Montenegro FLM, Correia-Deur JEM, Toledo SPA. Early-onset, progressive, frequent, extensive, and severe bone mineral and renal complications in multiple endocrine neoplasia type 1-associated primary hyperparathyroidism. J Bone Miner Res 2010; 25:2382-91. [PMID: 20499354 DOI: 10.1002/jbmr.125] [Citation(s) in RCA: 60] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/07/2022]
Abstract
Differences in bone mineral density (BMD) patterns have been recently reported between multiple endocrine neoplasia type 1-related primary hyperparathyroidism (HPT/MEN1) and sporadic primary HPT. However, studies on the early and later outcomes of bone/renal complications in HPT/MEN1 are lacking. In this cross-sectional study, performed in a tertiary academic hospital, 36 patients cases with uncontrolled HPT from 8 unrelated MEN1 families underwent dual-energy X-ray absorptiometry (DXA) scanning of the proximal one-third of the distal radius (1/3DR), femoral neck, total hip, and lumbar spine (LS). The mean age of the patients was 38.9 ± 14.5 years. Parathyroid hormone (PTH)/calcium values were mildly elevated despite an overall high percentage of bone demineralization (77.8%). In the younger group (<50 years of age), demineralization in the 1/3DR was more frequent, more severe, and occurred earlier (40%; Z-score -1.81 ± 0.26). The older group (>50 years of age) had a higher frequency of bone demineralization at all sites (p < .005) and a larger number of affected bone sites (p < .0001), and BMD was more severely compromised in the 1/3DR (p = .007) and LS (p = .002). BMD values were lower in symptomatic (88.9%) than in asymptomatic HPT patients (p < .006). Patients with long-standing HPT (>10 years) and gastrinoma/HPT presented significantly lower 1/3DR BMD values. Urolithiasis occurred earlier (<30 years) and more frequently (75%) and was associated with related renal comorbidities (50%) and renal insufficiency in the older group (33%). Bone mineral- and urolithiasis-related renal complications in HPT/MEN1 are early-onset, frequent, extensive, severe, and progressive. These data should be considered in the individualized clinical/surgical management of patients with MEN1-associated HPT.
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Affiliation(s)
- Delmar M Lourenço
- Endocrine Genetics Unit (LIM-25), Division of Endocrinology, University of São Paulo School of Medicine, São Paulo, Brazil
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Affiliation(s)
- Maria Luisa Brandi
- Department of Internal Medicine, University of Florence, Viale Pieraccini 6, 50139 Florence, Italy.
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Toledo RA, Mendonca BB, Fragoso MCBV, Soares IC, Almeida MQ, Moraes MB, Lourenço DM, Alves VAF, Bronstein MD, Toledo SPA. Isolated familial somatotropinoma: 11q13-loh and gene/protein expression analysis suggests a possible involvement of aip also in non-pituitary tumorigenesis. Clinics (Sao Paulo) 2010; 65:407-15. [PMID: 20454499 PMCID: PMC2862671 DOI: 10.1590/s1807-59322010000400010] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/22/2010] [Revised: 03/25/2010] [Accepted: 03/25/2010] [Indexed: 11/30/2022] Open
Abstract
OBJECTIVE Non-pituitary tumors have been reported in a subset of patients harboring germline mutations in the aryl hydrocarbon receptor-interacting protein (AIP) gene. However, no detailed investigations of non-pituitary tumors of AIP-mutated patients have been reported so far. PATIENTS We examined a MEN1- and p53-negative mother-daughter pair with acromegaly due to somatotropinoma. Subsequently, the mother developed a large virilizing adrenocortical carcinoma and a grade II B-cell non-Hodgkin's lymphoma. DESIGN Mutational analysis was performed by automated sequencing. Loss-of-heterozygosity (LOH) analysis was carried out by sequencing and microsatellite analysis. AIP expression was assessed through quantitative PCR (qPCR) and immunohistochemistry. RESULTS The functional inactivating mutation c.241C>T (R81X), which blocks the AIP protein from interacting with phosphodiesterase 4A (PDE4A), was identified in the heterozygous state in the leukocyte DNA of both patients. Analyzing the tumoral DNA revealed that the AIP wild-type allele was lost in the daughter's somatotropinoma and the mother's adrenocortical carcinoma. Both tumors displayed low AIP protein expression levels. Low AIP gene expression was confirmed by qPCR in the adrenocortical carcinoma. No evidence of LOH was observed in the DNA sample from the mother's B-cell lymphoma, and this tumor displayed normal AIP immunostaining. CONCLUSIONS Our study presents the first molecular analysis of non-pituitary tumors in AIP-mutated patients. The finding of AIP inactivation in the adrenocortical tumor suggests that further investigation of the potential role of this recently identified tumor suppressor gene in non-pituitary tumors, mainly in those tumors in which the cAMP and the 11q13 locus are implicated, is likely to be worthwhile.
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Affiliation(s)
- Rodrigo A Toledo
- Unidade de Endocrinologia Genética, LIM/25, Hospital das Clínicas, Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil.
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Coutinho FL, Lourenço DM, Toledo RA, Montenegro FLM, Correia-Deur JEM, Toledo SPA. Bone mineral density analysis in patients with primary hyperparathyroidism associated with multiple endocrine neoplasia type 1 after total parathyroidectomy. Clin Endocrinol (Oxf) 2010; 72:462-8. [PMID: 19650788 DOI: 10.1111/j.1365-2265.2009.03672.x] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
Abstract
OBJECTIVE Limited data have been reported on the effect of parathyroidectomy (PTx) on bone mineral density (BMD) in the setting of patients with hyperparathyroidism (HPT) associated with multiple endocrine neoplasia type 1 (MEN1). This study investigates the impact of total PTx on BMD in patients with HPT/MEN1. DESIGN AND PATIENTS A case series study was performed in a tertiary academic hospital. A total of 16 HPT/MEN1 patients from six families harbouring MEN1 germline mutations were subjected to total PTx followed by parathyroid auto-implant in the forearm. MEASUREMENTS Bone mineral density values were assessed using dual-energy X-ray absorptiometry. RESULTS Before PTx, reduced BMD (Z-score <-2.0) was highly prevalent in the proximal one-third of the distal radius (1/3 DR) (50%), lumbar spine (LS) (43.7%), ultradistal radius (UDR) (43.7%), femoral neck (FN) (25%) and total femur (TF) (18.7%) in the patients. Fifteen months after PTx, we observed a BMD improvement in the LS (from 0.843 to 0.909 g/cm(2); +8.4%, P = 0.001), FN (from 0.745 to 0.798 g/cm(2); +7.7%, P = 0.0001) and TF (from 0.818 to 0.874 g/cm(2); +6.9%, P < 0.0001). No significant change was noticed in the 1/3 DR and UDR after PTx. CONCLUSIONS This data confirmed BMD recovery in the LS and FN after PTx in HPT/MEN1 patients. We also documented a significant BMD increase in the TF and no change in both the 1/3 DR and UDR BMD after PTx. Our data suggest that LS and proximal femur are the most informative sites to evaluate the short-term BMD outcome after PTx in HPT/MEN1 subjects.
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Affiliation(s)
- Flavia L Coutinho
- Endocrine Genetics Unit (LIM-25), Division of Endocrinology, Hospital das Clínicas, University of São Paulo School of Medicine, Sao Paulo, Brazil
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Toledo RA, Wagner SM, Coutinho FL, Lourenço DM, Azevedo JA, Longuini VC, Reis MTA, Siqueira SAC, Lucon AM, Tavares MR, Fragoso MCBV, Pereira AA, Dahia PLM, Mulligan LM, Toledo SPA. High penetrance of pheochromocytoma associated with the novel C634Y/Y791F double germline mutation in the RET protooncogene. J Clin Endocrinol Metab 2010; 95:1318-27. [PMID: 20080836 DOI: 10.1210/jc.2009-1355] [Citation(s) in RCA: 40] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
Abstract
CONTEXT Previous studies have shown that double RET mutations may be associated with unusual multiple endocrine neoplasia type 2 (MEN 2) phenotypes. OBJECTIVE Our objective was to report the clinical features of patients harboring a previously unreported double mutation of the RET gene and to characterize this mutation in vitro. PATIENTS Sixteen patients from four unrelated families and harboring the C634Y/Y791F double RET germline mutation were included in the study. RESULTS Large pheochromocytomas measuring 6.0-14 cm and weighing up to 640 g were identified in the four index cases. Three of the four tumors were bilateral. High penetrance of pheochromocytoma was also seen in the C634Y/Y791F-mutation-positive relatives (seven of nine, 77.7%). Of these, two cases had bilateral tumors, one presented with multifocal tumors, two cases had large tumors (>5 cm), and one case, which was diagnosed with a large (5.5 x 4.5 x 4.0 cm) pheochromocytoma, reported early onset of symptoms of the disease (14 yr old). The overall penetrance of pheochromocytoma was 84.6% (11 of 13). Development of medullary thyroid carcinoma in our patients seemed similar to that observed in patients with codon 634 mutations. Haplotype analysis demonstrated that the mutation did not arise from a common ancestor. In vitro studies showed the double C634Y/Y791F RET receptor was significantly more phosphorylated than either activated wild-type receptor or single C634Y and Y791F RET mutants. CONCLUSIONS Our data suggest that the natural history of the novel C634Y/Y791F double mutation carries a codon 634-like pattern of medullary thyroid carcinoma development, is associated with increased susceptibility to unusually large bilateral pheochromocytomas, and is likely more biologically active than each individual mutation.
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Affiliation(s)
- Rodrigo A Toledo
- Faculdade de Medicina da Universidade de São Paulo, Avenida Dr. Arnaldo, 455, 5 degrees andar, Cerqueira César, 012406-903, São Paulo, Brazil.
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Current World Literature. Curr Opin Oncol 2010; 22:70-5. [DOI: 10.1097/cco.0b013e328334b4d9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
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Abstract
Multiple endocrine neoplasia type 1 (MEN 1) is an autosomal-dominant inherited tumor syndrome characterized by hyperplasia and/or tumors in the parathyroid glands, the pancreatic islets, the anterior pituitary and adrenal glands, as well as neuroendocrine tumors in the thymus, lungs and stomach, and tumors in nonendocrine tissues. In 1997, the responsible MEN1 gene was identified as a tumor-suppressor gene and its product was named menin. In this review, guidelines for early diagnosis, including MEN1 gene mutation analysis, and treatment, including periodic clinical monitoring, have been formulated, enabling improvement of life expectancy and quality of life. Identification of menin-interacting proteins has provided new insights into the function of menin, notably involving regulation of gene transcription related to proliferation and apoptosis, genome stability and DNA repair, and endocrine/metabolic homeostasis. In the near future, target-directed intervention may prevent or delay the onset of MEN 1-related tumors.
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Affiliation(s)
- Cornelis Jm Lips
- a University Medical Center Utrecht, Department of Internal Medicine, Wassenaarseweg 109, 2596 CN The Hague, The Netherlands.
| | - Koen Dreijerink
- b University Medical Center Utrecht, Department of Internal Medicine, F02.126, PO Box 85500, 3508 GA, Utrecht, The Netherlands.
| | - Thera P Links
- c University Medical Center Groningen, Department of Internal Medicine, PO Box 30001, 9700 RB Groningen, The Netherlands.
| | - Jo Wm Höppener
- d Department of Metabolic and Endocrine Diseases, PO Box 85090, 3508 AB Utrecht.
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