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ABSTRACT: A follow-up nationwide survey on predictive genetic testing for late-onset neurological diseases in Japan was conducted. A questionnaire was sent to 89 institutional members of the Japan's National Liaison Council for Clinical Sections of Medical Genetics, and was returned by 60 (67.4%). A total of 301 clients with an interest in predictive testing were accumulated from April 2006 to March 2011. The greatest interest was shown for spinocerebellar degeneration (SCD, n=110), followed by myotonic dystrophy type 1 (DM1, n=69), Huntington's disease (HD, n=52) and familial amyloid polyneuropathy (FAP, n=35). The ratios of clients who actually underwent predictive testing were: SCD, 21.8%; DM1, 39.1%; HD, 26.9%; and FAP, 74.3%, indicating that predictive testing was conducted very cautiously for untreatable neurological diseases in Japan. Clinical geneticists were predominantly involved in genetic counseling, whereas the participation of non-medical doctor (non-MD) staff, including nurses, clinical psychologists and genetic counselors, was not common. Lack of non-MD counseling staff was one of the most serious issues in conducting predictive testing, which has not been improved since the previous survey performed in 2006. Institutional arrangements, such as revision of medical insurance system regarding genetic testing and counseling, might be necessary to resolve this issue.Journal of Human Genetics advance online publication, 2 May 2013; doi:10.1038/jhg.2013.34.
Journal of Human Genetics 05/2013; · 2.57 Impact Factor
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ABSTRACT: Objective
The precise penetrance of pheochromocytoma (PHEO) in multiple endocrine neoplasia type 2 (MEN2) has not been reported in a large cohort. In this study we aimed to clarify the codon specific penetrance of PHEO in MEN2.DesignWe established a study group designated the "MEN Consortium of Japan" in 2008, and asked physicians and surgeons to provide clinical and genetic information on patients they had treated up to 2011.Methods
Data were collected on patients identified as carriers of the RET mutation or diagnosed with medullary thyroid carcinoma (MTC) and/or PHEO with family history from 52 institutions all over Japan.ResultsOf 493 registered MEN2 patients, RET mutation data was available for 390. Of these, 144 developed PHEOs, while 246 did not. The penetrance of PHEO was 25% by age 30, 52% by age 50, and 88% by age 77 in RET mutation-carriers with a codon 634 mutation. All patients with a codon 918 mutation (MEN2B) developed PHEO by age 56. Less than 32% penetrance of PHEO was seen in patients with mutations at codons other than 634 and 918.Conclusions
Most patients with a codon 634 mutation develop PHEOs as well as MTC during their lifetime.
European Journal of Endocrinology 02/2013; · 3.42 Impact Factor
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Archives of surgery (Chicago, Ill.: 1960) 11/2012; 147(11):991-2. · 4.32 Impact Factor
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ABSTRACT: Multiple endocrine neoplasia type 1 (MEN1) is an autosomal dominantly inherited endocrine tumor syndrome characterized by tumor development in various endocrine organs such as the parathyroid, endocrine pancreas, anterior pituitary and adrenal cortex. The first extensive database for Asian patients with MEN1 was established by the MEN Consortium of Japan. Although the clinical features of Japanese patients with MEN1 are similar to those from Western countries, there are several characteristic differences between them. In particular, gastroenteropancreatic neuroendocrine tumor (GEPNET) is seen in approximately 60 % of patients with MEN1 in Japan. Although its development is the strongest prognostic factor in patients with MEN1, the characteristics of MEN1-associated GEPNET still remain unclear. This is especially true for the differences in clinical features of GEPNET with and without MEN1. Improved long-term survival is obtained by curative surgery for patients with MEN1-associated GEPNET. The current surgical indications are expanding even in patients with hepatic metastases because of the improved surgical outcome. This article reviews the clinical characteristics in these patients with a particular focus on surgery, diagnosis, surgical indications, surgical method, and surgical outcome.
Surgery Today 10/2012; · 1.22 Impact Factor
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ABSTRACT: Germline MEN1 mutation analysis is a powerful tool for an early diagnosis of multiple endocrine neoplasia type 1 (MEN1), an autosomal dominant familial cancer syndrome characterized by the parathyroid, pituitary and gastroenteropancreatic endocrine tumors. However, the clinical significance of MEN1 gene variants, especially missense and in-frame mutations as well as some splicing mutations, is not always obvious. We have previously shown that mutant menin proteins associated with MEN1 are rapidly degraded by the ubiquitin-proteasome pathway. We also demonstrated by a fluorescent immunocytochemical stability test that the stability of missense and in-frame deletion mutants varies widely but that unstable mutants were found only in MEN1 and related disorders and not in normal polymorphisms. In the present study, we evaluated by this stability test the pathogenicity of a novel MEN1 missense mutation, c.1118C>T, encoding a P373L mutant menin, identified in a suspected MEN1 patient. The results demonstrated that the mutant menin is highly unstable, indicating that this mutation is causative for MEN1. These findings encouraged us to proceed with presymptomatic genetic screening for this mutation among the family members, which resulted in the identification of asymptomatic mutation carriers. Thus, the information from the menin stability test was useful for genetic diagnosis and counseling of MEN1 in the case with a previously unreported MEN1 missense mutation.
Endocrine Journal 08/2012; · 2.03 Impact Factor
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Akihiro Sakurai,
Masanori Yamazaki,
Shinichi Suzuki,
Toshihiko Fukushima,
Tsuneo Imai,
Toyone Kikumori,
Takahiro Okamoto,
Kiyomi Horiuchi,
Shinya Uchino,
Shinji Kosugi,
Masanobu Yamada,
Izumi Komoto,
Kazuhiro Hanazaki,
Masatsune Itoh,
Tatsuya Kondo,
Masatomo Mihara,
Masayuki Imamura
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ABSTRACT: More than 50% of patients with multiple endocrine neoplasia type 1 (MEN1) develop gastroenteropancreatic neuroendocrine tumors (GEPNETs), and insulinoma is the second most common functioning GEPNET. Compared to other functioning and nonfunctioning GEPNETs in MEN1, insulinoma is considered to develop at a younger age. To clarify the clinical features of insulinoma developed in Japanese patients with MEN1, a recently constructed database of Japanese MEN1 patients was analyzed. Among 560 registered cases, insulinoma was seen in 69 patients and information on age at diagnosis was available for 54 patients. Tumors predominantly occurred in the body and tail of the pancreas. The mean age at diagnosis of insulinoma (34.8 ± 16.7 yrs) was significantly younger than that of gastrinoma (50.6 ± 14.3 yrs) and nonfunctioning tumor (44.7 ± 13.3 yrs) in patients with MEN1. Patients diagnosed as having insulinoma during middle-age (30 - 49 yrs) tended to have a long period from appearance of hypoglycemic symptoms to diagnosis of the tumor. Of note, 13 patients (24%) were diagnosed as having insulinoma before 20 yrs of age. Such young onset was not seen in other GEPNETs. Since the development of GEPNETs during adolescence is quite rare, insulinoma diagnosed before 20 yrs strongly suggests the presence of MEN1 and warrants further investigation, including MEN1 genetic testing. Also, clinicians should be aware that insulinoma can often be missed in middle-aged patients.
Endocrine Journal 06/2012; · 2.03 Impact Factor
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Akihiro Sakurai,
Tsuneo Imai,
Toyone Kikumori,
Kiyomi Horiuchi,
Takahiro Okamoto,
Shinya Uchino,
Shinji Kosugi,
Shinichi Suzuki,
Keiko Suyama,
Masanori Yamazaki,
Ai Sato
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ABSTRACT: OBJECTIVE: Thymic neuroendocrine tumor (Th-NET) occurs in 2-5% of patients with MEN1 and has high malignant potency accompanying recurrence and distant metastasis. While Th-NET is recognized to develop predominantly in males and heavy smokers, a number of female patients have been reported in the literature. The objective of this study is to clarify the clinical features of MEN1 patients with Th-NET using database analysis. DESIGN/PATIENTS: Clinical data of patients with Th-NET was extracted and analyzed from a recently constructed database of Japanese MEN1 patients. RESULTS: Among 560 registered cases, Th-NET was seen in 28 (5.0%) patients. Of note, 36% of patients (10/28) were female; only 1 patient among those was a smoker and another 6 patients were non-smokers. Age at diagnosis of Th-NET and MEN1, tumor size, prevalence of other MEN1-related tumors did not differ between male- and female patients. 10 year survival probability was 0.271 ± 0.106. CONCLUSIONS: Although the prevalence of Th-NET in females (3.2%) is significantly lower than that in males (7.6%), a considerable proportion of female patients develop Th-NET. Given that Th-NET is a major determinant of life expectancy of patients, our results alert clinicians who treat patients with MEN1 that surveillance of Th-NET is essential even for female patients without a smoking habit. © 2012 Blackwell Publishing Ltd.
Clinical Endocrinology 06/2012; · 3.17 Impact Factor
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Masanori Yamazaki,
Shin-Ichi Suzuki,
Shinji Kosugi,
Takahiro Okamoto,
Shinya Uchino,
Akihiro Miya,
Tsuneo Imai,
Hiroshi Kaji,
Izumi Komoto,
Daishu Miura,
Masanobu Yamada,
Takashi Uruno,
Kiyomi Horiuchi,
Ai Sato,
Akira Miyauchi,
Masayuki Imamura, Akihiro Sakurai
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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.
Endocrine Journal 06/2012; 59(9):797-807. · 2.03 Impact Factor
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Nippon rinsho. Japanese journal of clinical medicine 05/2012; 70 Suppl 3:801-5.
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ABSTRACT: Heterozygous germline mutation of the tumor suppressor gene MEN1 is responsible for multiple endocrine neoplasia type 1 (MEN1), a familial cancer syndrome characterized by pituitary, parathyroid and enteropancreatic tumors. Various mutations have been identified throughout the entire gene region in patients with MEN1 and its incomplete forms often manifested as familial isolated hyperparathyroidism and apparently sporadic parathyroid tumor. Mutation analysis of the MEN1 gene is a powerful tool for the early diagnosis of MEN1; however, the clinical significance of the identified mutations is not always obvious. In this study, a previously unreported missense MEN1 mutation, c.824G>T was identified in a patient with primary hyperparathyroidism and evaluated for its pathogenicity. This mutation was predicted to generate a putative missense menin protein, R275M. A stability test of the menin protein demonstrated that the stability of R275M mutant was reduced only slightly as compared with wild type menin, and therefore could not preclude the possibility that it was a rare benign polymorphism. However, further analysis of leukocyte mRNA and minigene experiments indicated that the mutant c.824G>T allele gives rise to abnormally spliced menin mRNA, and thereby confirmed that c.824G>T mutation is causative for MEN1. Thus, leukocyte mRNA analysis has been demonstrated useful to identify a splicing mutation of the MEN1 gene.
Endocrine Journal 03/2012; 59(6):523-30. · 2.03 Impact Factor
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Akihiro Sakurai,
Shinichi Suzuki,
Shinji Kosugi,
Takahiro Okamoto,
Shinya Uchino,
Akihiro Miya,
Tsuneo Imai,
Hiroshi Kaji,
Izumi Komoto,
Daishu Miura,
Masanobu Yamada,
Takashi Uruno,
Kiyomi Horiuchi,
Akira Miyauchi,
Masayuki Imamura
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ABSTRACT: Objective Multiple endocrine neoplasia type 1 (MEN1) is less well recognized in Asian countries, including Japan, than in the West. The clinical features and optimal management of MEN1 have yet to be clarified in Japan. The aim of this study was to clarify the clinical features of Japanese patients with MEN1.Design/Patients We established a MEN study group designated the ‘MEN Consortium of Japan’ in 2008, and asked physicians and surgeons to provide clinical and genetic information on patients they had treated. Of 680 registered patients, 560 were analysed.Measurements Clinical and genetic features of Japanese patients with MEN1 were examined.Results Primary hyperparathyroidism, gastroenteropancreatic neuroendocrine tumours (GEPNET), and pituitary tumours were seen in 94·4%, 58·6% and 49·6% of patients, respectively. The prevalence of insulinoma was higher in the Japanese than in the West (22%vs 10%). In addition, 37% of patients with thymic carcinoids were women, while most were men in western countries. The MEN1 mutation positive rate was 91·7% in familial cases and only 49·3% in sporadic cases. Eight novel mutations were identified. Despite the availability of genetic testing for MEN1, the application of genetic testing, especially presymptomatic diagnosis for at-risk family members appeared to be insufficient.Conclusions We established the first extensive database for Asian patients with MEN1. Although the clinical features of Japanese patients were similar to those in western countries, there were several characteristic differences between them.
Clinical Endocrinology 03/2012; 76(4):533 - 539. · 3.17 Impact Factor
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Akihiro Sakurai,
Shinichi Suzuki,
Shinji Kosugi,
Takahiro Okamoto,
Shinya Uchino,
Akihiro Miya,
Tsuneo Imai,
Hiroshi Kaji,
Izumi Komoto,
Daishu Miura, [......],
Kazuyo Kiribayashi,
Shigeki Koizumi,
Sanae Midorikawa,
Rika Miyabe,
Takuya Munekage,
Atsushi Ozawa,
Kazuo Shimizu,
Iwao Sugitani,
Hiroshi Takeyama,
Masanori Yamazaki
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ABSTRACT: Multiple endocrine neoplasia type 1 (MEN1) is less well recognized in Asian countries, including Japan, than in the West. The clinical features and optimal management of MEN1 have yet to be clarified in Japan. The aim of this study was to clarify the clinical features of Japanese patients with MEN1.
We established a MEN study group designated the 'MEN Consortium of Japan' in 2008, and asked physicians and surgeons to provide clinical and genetic information on patients they had treated. Of 680 registered patients, 560 were analysed.
Clinical and genetic features of Japanese patients with MEN1 were examined.
Primary hyperparathyroidism, gastroenteropancreatic neuroendocrine tumours (GEPNET), and pituitary tumours were seen in 94·4%, 58·6% and 49·6% of patients, respectively. The prevalence of insulinoma was higher in the Japanese than in the West (22%vs 10%). In addition, 37% of patients with thymic carcinoids were women, while most were men in western countries. The MEN1 mutation positive rate was 91·7% in familial cases and only 49·3% in sporadic cases. Eight novel mutations were identified. Despite the availability of genetic testing for MEN1, the application of genetic testing, especially presymptomatic diagnosis for at-risk family members appeared to be insufficient.
We established the first extensive database for Asian patients with MEN1. Although the clinical features of Japanese patients were similar to those in western countries, there were several characteristic differences between them.
Clinical Endocrinology 09/2011; 76(4):533-9. · 3.17 Impact Factor
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Akihiro Sakurai
Nippon rinsho. Japanese journal of clinical medicine 03/2011; 69 Suppl 2:669-73.
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Akihiro Sakurai
Nippon rinsho. Japanese journal of clinical medicine 03/2011; 69 Suppl 2:690-4.
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Akihiro Sakurai
Nippon rinsho. Japanese journal of clinical medicine 08/2010; 68 Suppl 8:58-64.
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Akihiro Sakurai
Nippon rinsho. Japanese journal of clinical medicine 08/2010; 68 Suppl 8:177-82.
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ABSTRACT: Neuroendocrine tumors develop in various organs in patients with multiple endocrine neoplasia type 1 (MEN1). Among those, tumors developed in upper gastrointestinal tract, thymus and bronchus have historically been called "carcinoid tumor". Occurrence of "carcinoid tumor" in other region is very rare and molecular pathogenesis of such tumors is unknown. We have experienced a patient with MEN1 who have developed an "ectopic" retroperitoneal neuroendocrine tumor. Genetic analysis of the MEN1 gene in tumor cells revealed a somatic mutation in exon 9 as well as a germline mutation in exon 10. Allele-specific amplification followed by sequence analysis revealed these two mutations exist on the different allele, indicating both alleles are functionally inactivated. Immunohistochemical staining with an anti-menin antibody revealed that wild-type menin is not expressed in tumor cells. Expression of p27(Kip1) protein is not observed in tumor cells, either. These results confirmed the inactivation of the MEN1 gene as a genetic cause of an ectopically developed neuroendocrine tumor in a patient with MEN1.
Endocrine Journal 07/2009; 56(7):887-95. · 2.03 Impact Factor
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Nihon Naika Gakkai Zasshi 01/2009; 97(12):3093-100.
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Nihon Naika Gakkai Zasshi 12/2008; 97(11):2832-7.
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Tsuyoshi Tanabe,
Masanori Yasuo,
Kenji Tsushima,
Kazuhisa Urushihata,
Hiroshi Yamamoto,
Masayuki Hanaoka,
Tomonobu Koizumi,
Keisaku Fujimoto,
Yoshitaka Yamazaki,
Yoshiki Hirose,
Hideaki Hamano, Akihiro Sakurai,
Keishi Kubo
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ABSTRACT: A patient with multiple endocrine neoplasia type 1 (MEN1) developed a mediastinal seminoma. The patient was a 46-year-old man who presented with respiratory symptoms. A diagnosis of mediastinal seminoma was pathologically confirmed and a complete remission was achieved by chemotherapy. During his hospital stay, hyperparathyroidism and multiple pancreatic tumors associated with hypergastrinemia were found. A diagnosis of MEN1 was made genetically. Although patients with MEN1 manifest a variety of neoplastic disorders, no cases of concurrent seminoma and MEN1 have previously been reported. In addition, no etiological relationship between seminoma and MEN1 has yet been reported.
Internal Medicine 02/2008; 47(18):1615-9. · 0.94 Impact Factor
