2021/10/25 更新

写真a

ナガサキ ケイスケ
長崎 啓祐
NAGASAKI Keisuke
所属
医歯学総合病院 小児科 講師
職名
講師
外部リンク

学位

  • 博士(医学) ( 2004年4月   新潟大学 )

研究キーワード

  • 先天性甲状腺機能低下症

  • 先天性内分泌疾患

  • 21水酸化酵素欠損症

  • 副甲状腺機能低下症

  • 小児がん生存者

  • バセドウ病

  • 新生児マススクリ−ニング

研究分野

  • ライフサイエンス / 遺伝学

  • ライフサイエンス / 代謝、内分泌学

  • ライフサイエンス / 胎児医学、小児成育学

  • ライフサイエンス / 衛生学、公衆衛生学分野:実験系を含む

経歴(researchmap)

  • 新潟大学   医歯学総合病院 小児科   病院准教授

    2019年6月 - 現在

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  • 新潟大学   医歯学総合病院   講師

    2013年1月 - 2019年5月

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  • 国立研究開発法人国立成育医療研究センター   分子内分泌研究部   共同研究員

    2011年7月 - 2013年3月

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  • 新潟大学   大学院医歯学総合研究科内部環境医学講座小児科   助教

    2008年1月 - 2013年12月

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経歴

  • 新潟大学   医歯学総合病院 小児科   講師

    2015年1月 - 現在

  • 新潟大学   医学部 医学科   助教

    2010年1月 - 2014年12月

  • 新潟大学   医歯学総合研究科 生体機能調節医学専攻 内部環境医学   助教

    2010年1月 - 2014年12月

  • 新潟大学   医歯学総合病院 小児科   特任助教

    2007年4月 - 2009年12月

所属学協会

  • アジア太平洋小児内分泌学会

    2012年1月 - 現在

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  • 欧州小児内分泌学会

    2010年1月 - 現在

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  • 日本人類遺伝学会

    2006年7月 - 現在

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  • 日本甲状腺学会

    2006年4月 - 現在

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  • 日本糖尿病学会

    2005年4月 - 現在

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  • 日本マススクリーニング学会

    2003年4月 - 現在

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  • 日本内分泌学会

    2000年4月 - 現在

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  • 日本小児内分泌学会

    1999年10月 - 現在

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  • 日本小児科学会

    1995年6月 - 現在

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委員歴

  • 日本小児科学会   倫理委員会委員  

    2020年4月 - 現在   

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    団体区分:学協会

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  • 日本マススクリーニング学会   将来計画委員会  

    2019年9月 - 現在   

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    団体区分:学協会

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  • 日本小児内分泌学会   女性支援・ワークライフバランス委員会委員  

    2017年9月 - 現在   

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    団体区分:学協会

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  • 日本内分泌学会   専門医制度改革対応委員会委員  

    2017年9月   

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    団体区分:学協会

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  • 日本小児内分泌学会   甲状腺委員会 副委員長  

    2017年9月   

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    団体区分:学協会

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  • 日本甲状腺学会   小児甲状腺疾患診療委員会  

    2015年10月 - 現在   

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    団体区分:学協会

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  • 日本内分泌学会   専門医認定部会小児科試験委員 委員長  

    2015年10月 - 現在   

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    団体区分:学協会

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  • 日本甲状腺学会   学会雑誌編集委員会  

    2015年10月 - 現在   

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    団体区分:学協会

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  • 日本甲状腺学会   甲状腺専門医委員会  

    2015年9月 - 現在   

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    団体区分:学協会

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  • 日本小児内分泌学会   CCS委員会  

    2013年9月 - 現在   

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    団体区分:学協会

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  • 日本小児内分泌学会   内分泌代謝専門医委員会 委員長  

    2013年9月 - 現在   

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    団体区分:学協会

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  • 日本小児内分泌学会   ガイドライン委員会  

    2013年9月 - 2015年9月   

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    団体区分:学協会

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  • 日本小児内分泌学会   マススクリーニング委員会 委員  

    2009年9月 - 現在   

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    団体区分:学協会

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論文

  • Congenital Hypothyroidism Due to Truncating PAX8 Mutations: A Case Series and Molecular Function Studies. 査読 国際誌

    Megumi Iwahashi-Odano, Keisuke Nagasaki, Maki Fukami, Junko Nishioka, Shuichi Yatsuga, Yumi Asakura, Masanori Adachi, Koji Muroya, Tomonobu Hasegawa, Satoshi Narumi

    The Journal of clinical endocrinology and metabolism   105 ( 11 )   2020年11月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    CONTEXT: PAX8 is a transcription factor required for thyroid development, and its mutation causes congenital hypothyroidism (CH). More than 20 experimentally verified loss-of-function PAX8 mutations have been described, and all but one were located in the DNA-binding paired domain. OBJECTIVE: We report the identification and functional characterization of 3 novel truncating PAX8 mutations located outside the paired domain. METHODS: Three CH probands, diagnosed in the frame of newborn screening, had thyroid hypoplasia and were treated with levothyroxine. Next-generation sequencing-based mutation screening was performed. Functionality of the identified mutations were verified with Western blotting, intracellular localization assays, and transactivation assays with use of HeLa cells. Luciferase complementation assays were used to evaluate the effect of mutations on the interaction between PAX8 and its partner, NKX2-1. RESULTS: Each proband had novel truncating PAX8 mutations that were I160Sfs*52, Q213Efs*27, and F342Rfs*85. Western blotting showed destabilization of the I160fs-PAX8 protein. Q213fs-PAX8 and F342fs-PAX8 showed normal protein expression levels and normal nuclear localization, but showed loss of transactivation of the luciferase reporter. By luciferase complementation assays, we showed that PAX8-NKX2-1 interaction was defective in Q213fs-PAX8. We also characterized the recombinant PAX8 proteins, and found that the protein sequence corresponding to exon 10 (363-400 aa residues) was essential for the PAX8-NKX2-1 interaction. CONCLUSIONS: Clinical and molecular findings of 3 novel truncating PAX8 mutations located outside the paired domain were reported. Experiments using cultured cells and recombinant proteins showed that the C-terminal portion (ie, 363-400 aa) of PAX8 is required for the PAX8-NKX2-1 interaction.

    DOI: 10.1210/clinem/dgaa584

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  • A Japanese Family with DICER1 Syndrome Found in Childhood-Onset Multinodular Goitre. 査読 国際誌

    Keisuke Nagasaki, Nao Shibata, Hiromi Nyuzuki, Sunao Sasaki, Yohei Ogawa, Satoshi Soda, Takahiko Kogai, Akira Hishinuma

    Hormone research in paediatrics   1 - 6   2020年10月

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    記述言語:英語  

    INTRODUCTION: Germline DICER1 mutations have recently been identified in familial multinodular goitre (MNG). The natural history of thyroid nodules in DICER1 carriers in children is unclear. The purpose of this study was to describe the clinical and genetic findings of childhood-onset MNG with DICER1 carrier in a patient who underwent total thyroidectomy. CASE PRESENTATION: The 6-year-old proband had a thyroid nodule, and the number and size of nodules increased over 3 years. A total thyroidectomy was chosen because of the rapid rise in thyroglobulin levels, discomfort when swallowing, and the mother's history of poorly differentiated thyroid cancer (PDTC). Histopathology revealed adenomatous goitre without malignant cells. Her mother, maternal aunt, and maternal grandmother also had thyroid nodules removed during adolescence. Also, her mother had PDTC with lung metastases, and her maternal aunt had an ovarian germ cell tumour. DICER1 mutation analysis identified a heterozygous novel nonsense mutation (c.4509C>G, p.Y1503X) for the patient, her mother, her maternal grandmother, and her asymptomatic elder brother. Y1503X was identified in all resected thyroid tissues, while heterozygous D1709G, D1810V, and E1813K mutations were identified in individual nodules. DISCUSSION/CONCLUSION: A thyroid nodule was detected in chemotherapy- or radiotherapy-naïve patient with DICER1 carrier aged 6 years, and MNG developed over 3 years. This pedigree highlights the natural history of nodular disease in DICER1 carriers and identifies a possible association between DICER1 and more aggressive malignancies.

    DOI: 10.1159/000511140

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  • Foetal virilisation caused by overproduction of non-aromatisable 11-oxygenated C19 steroids in maternal adrenal tumour. 査読 国際誌

    Keisuke Nagasaki, Kaoru Takase, Chikahiko Numakura, Keiko Homma, Tomonobu Hasegawa, Maki Fukami

    Human reproduction (Oxford, England)   2020年8月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    It is widely believed that adrenal tumours and ovarian luteomas in pregnant women cause virilisation of female foetuses through overproduction of testosterone and/or androstenedione. However, this notion raises a fundamental question as to how these classic androgens pass through the placenta without being converted by aromatase into oestrogens. Here, we report a case of maternal adrenal tumour, in which overproduction of 11-oxygenated C19 steroids (11ox C19s), newly characterised non-aromatisable androgens in humans, caused foetal virilisation. The female proband presented with severely virilised external genitalia at birth. The mother exhibited hirsutism, hyperglycaemia and hypertension and was diagnosed as having adrenal tumour. The mother was subjected to comprehensive steroid measurement. Serum levels of 11ox C19s were markedly elevated. In contrast, testosterone and androstenedione levels remained within the normal range, and levels of most other steroids in the conventional and backdoor androgenic pathways were normal or only mildly elevated. After tumour removal, levels of 11ox C19s were markedly reduced. These results provide the first evidence that 11ox C19s can be synthesised in adrenal adenomas and, due to their non-aromatisable nature, can pass through the placental barrier to cause foetal virilisation. These findings highlight a unique pathogenic property of these newly specified androgens in humans.

    DOI: 10.1093/humrep/deaa221

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  • Retrospective study of the renal function using estimated glomerular filtration rate and congenital anomalies of the kidney-urinary tract in pediatric Turner syndrome. 査読 国際誌

    Yukie Izumita, Satsuki Nishigaki, Mari Satoh, Noriyuki Takubo, Chikahiko Numakura, Ikuko Takahashi, Shun Soneda, Yoshifusa Abe, Hotaka Kamasaki, Yoshiaki Ohtsu, Junko Igaki, Yukihiro Hasegawa, Keisuke Nagasaki

    Congenital anomalies   2020年7月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Although Turner syndrome (TS) is frequently associated with congenital anomalies of the kidney-urinary tract (CAKUT), which is a major cause of pediatric chronic kidney disease, renal function in TS is usually considered normal. The present study aimed to analyze the frequency of renal dysfunction and CAKUT in pediatric patients with TS. Our study included 122 patients with TS between the ages of 2 and 18 years from 30 hospitals across Japan. Clinical data related to renal function and CAKUT were retrospectively collected. The estimated glomerular filtration rate (eGFR) was calculated using the serum creatinine-based formula recommended by the Japanese Society for Pediatric Nephrology. An eGFR <90 mL/min/1.73 m2 for two consecutive years was defined as renal dysfunction. Fifteen (13.5%) of 122 patients had CAKUT, and four patients had renal dysfunction (3.2%, 95% confidence interval: 0%-6.7%). Three of the four did not have CAKUT. Of the CAKUT manifestations, horseshoe kidney, renal hypodysplasia, and multicystic dysplastic kidney were seen in nine, two, and one patient, respectively. Eight of the nine patients with horseshoe kidney had a normal renal function; however, the remaining patient with renal hypodysplasia had renal dysfunction. A small percentage of patients with pediatric TS may had an eGFR below 90 mL/min/1.73 m2 which was not necessarily associated with CAKUT.

    DOI: 10.1111/cga.12384

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  • Rare variant of the epigenetic regulator SMCHD1 in a patient with pituitary hormone deficiency. 査読 国際誌

    Kenichi Kinjo, Keisuke Nagasaki, Koji Muroya, Erina Suzuki, Keisuke Ishiwata, Kazuhiko Nakabayashi, Atsushi Hattori, Koji Nagao, Ryu-Suke Nozawa, Chikashi Obuse, Kenji Miyado, Tsutomu Ogata, Maki Fukami, Mami Miyado

    Scientific reports   10 ( 1 )   10985 - 10985   2020年7月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Isolated hypogonadotropic hypogonadism (IHH), combined pituitary hormone deficiency (CPHD), and septo-optic dysplasia (SOD) constitute a disease spectrum whose etiology remains largely unknown. This study aimed to clarify whether mutations in SMCHD1, an epigenetic regulator gene, might underlie this disease spectrum. SMCHD1 is a causative gene for Bosma arhinia microphthalmia syndrome characterized by arhinia, microphthalmia and IHH. We performed mutation screening of SMCHD1 in patients with etiology-unknown IHH (n = 31) or CPHD (n = 43, 19 of whom also satisfied the SOD diagnostic criteria). Rare variants were subjected to in silico analyses and classified according to the American College of Medical Genetics and Genomics guidelines. Consequently, a rare likely pathogenic variant, p.Asp398Asn, was identified in one patient. The patient with p.Asp398Asn exhibited CPHD, optic nerve hypoplasia, and a thin retinal nerve fiber layer, and therefore satisfied the criteria of SOD. This patient showed a relatively low DNA methylation level of the 52 SMCHD1-target CpG sites at the D4Z4 locus. Exome sequencing for the patient excluded additional variants in other IHH/CPHD-causative genes. In vitro assays suggested functional impairment of the p.Asp398Asn variant. These results provide the first indication that SMCHD1 mutations represent a rare genetic cause of the HH-related disease spectrum.

    DOI: 10.1038/s41598-020-67715-x

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  • Timing of hyponatremia development in patients with salt-wasting-type 21-hydroxylase deficiency. 査読

    Rohi Shima, Kentaro Sawano, Nao Shibata, Hiromi Nyuzuki, Sunao Sasaki, Hidetoshi Sato, Yohei Ogawa, Yuki Abe, Keisuke Nagasaki, Akihiko Saitoh

    Clinical pediatric endocrinology : case reports and clinical investigations : official journal of the Japanese Society for Pediatric Endocrinology   29 ( 3 )   105 - 110   2020年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Newborn screening (NBS) can detect 21-hydroxylase deficiency (21-OHD), allowing for early treatment initiation. However, many patients present with adrenal crises or hyponatremia at their first visit. Age (in days) of hyponatremia development in infants with salt-wasting (SW)-type 21-OHD remains unclear. Therefore, we determined the earliest age of hyponatremia diagnosis in this retrospective observational study using medical records of 40 patients with classic 21-OHD in Niigata Prefecture, Japan, from April 1989 to March 2019. We determined the earliest diagnosis of hyponatremia (serum sodium levels < 130 mEq/L) and created a sodium decrease rate model to estimate hyponatremia development age. Of 23 patients with SW-type 21-OHD, 10 (43.5%) were identified during NBS; the earliest case to present with hyponatremia was at day 7. Serum sodium levels were significantly and negatively correlated with age in days, and hyponatremia was estimated to develop at 6.6 d after birth. Genotype or serum 17-hydroxyprogesterone levels were not associated with sodium decrease rate. Thus, hyponatremia development age is earlier (within 7 d) than the previously described time-point (10-14 d) in infants with SW-type 21-OHD. Efforts to reduce the time lag from obtaining results to consultation may be required in patients with high 17-hydroxyprogesterone levels on NBS.

    DOI: 10.1297/cpe.29.105

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  • Present status of prophylactic thyroidectomy in pediatric multiple endocrine neoplasia 2: a nationwide survey in Japan 1997-2017. 査読 国際誌

    Rie Matsushita, Keisuke Nagasaki, Tadayuki Ayabe, Yoko Miyoshi, Saori Kinjo, Hidenori Haruna, Kenji Ihara, Tomonobu Hasegawa, Shinobu Ida, Keiichi Ozono, Kanshi Minamitani

    Journal of pediatric endocrinology & metabolism : JPEM   32 ( 6 )   585 - 595   2019年6月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Background In Japan, prophylactic thyroidectomy involves out-of-pocket expense. The American Thyroid Association (ATA) recommends prophylactic thyroidectomy for medullary thyroid carcinoma (MTC) during early childhood in patients with multiple endocrine neoplasia type 2 (MEN2). The ATA reports a high frequency of postoperative complications in childhood, which also influenced the delay of prophylactic thyroidectomy in Japan. Methods This retrospective study of multiple medical centers in Japan included individuals aged <20 years diagnosed with germline RET mutations between 1997 and 2017. The onset and onset possibility were defined based on confirmed lesions or calcitonin levels. The definition of risk and prophylactic thyroidectomy were based on the ATA 2015 revised guideline. Results Twenty-one patients with MEN2 were enrolled (highest risk, n = 5; high risk, n = 5; and moderate risk, n = 11). The cumulative incidence of the onset/onset possibility reached 50% at 5 and 8 years and 100% at 9 years and 17 years in high- and moderate-risk patients, respectively. Of 7 patients with MEN2A, 71% underwent prophylactic thyroidectomy. Only one 5-year-old patient (C634Y) had increased serum calcitonin level after prophylactic thyroidectomy in the MEN2A group. The only permanent complication, which did not occur in patients who underwent total thyroidectomy alone, was hypoparathyroidism (33% of patients). This permanent complication occurred with clinically developed MTC. No permanent postoperative complications occurred in patients aged 5-6 years. Conclusions Prophylactic thyroidectomy reduces recurrence and postoperative complications in pediatric patients with MEN2. Early thyroidectomy based on only calcitonin level could possibly reduce thyroidectomy delay.

    DOI: 10.1515/jpem-2018-0444

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  • Levothyroxine Dosage as Predictor of Permanent and Transient Congenital Hypothyroidism: A Multicenter Retrospective Study in Japan. 査読 国際誌

    Tomoyo Itonaga, Shinji Higuchi, Kazuhiro Shimura, Keisuke Nagasaki, Mari Satoh, Noriyuki Takubo, Ikuko Takahashi, Hirotake Sawada, Yukihiro Hasegawa

    Hormone research in paediatrics   92 ( 1 )   45 - 51   2019年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    BACKGROUND: Congenital hypothyroidism (CH) can be divided into 2 types, transient CH (T-CH) and permanent CH (P-CH), depending on the requirement of levothyroxine (LT4) for life-long treatment. Several studies have recently reported that the LT4 dosage is useful for predicting the LT4 requirement, but none of the studies followed their patients to puberty. OBJECTIVE: To determine the cutoff value for the LT4 dosage as a predictor of the LT4 requirement after puberty in patients with CH. METHODS: The LT4 dosage and clinical data on 99 patients with CH who were followed at the participating hospitals from the neonatal period to 15 years of age or older were retrospectively analyzed. Based on their LT4 requirement at their last hospital visit, the participants were divided into the P-CH group (n = 75), who were treated with LT4, and the T-CH group (n = 24), who were not. RESULTS: At age 1 year, a higher LT4 dosage was required for the P-CH group (median 3.75 vs. 2.88 µg/kg/day; p < 0.001). When the LT4 dosage cutoff value at age 1 year was set at 4.79 and 1.74 µg/kg/day, the specificity of P-CH and T-CH (for denying T-CH and P-CH, respectively) was 100 and 97%, respectively. CONCLUSIONS: An LT4 dosage above 4.7 µg/kg/day and below 1.8 µg/kg/day at age 1 year may help predict P-CH and T-CH, respectively.

    DOI: 10.1159/000502418

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  • 新生児マススクリーニングTSH高値を呈したDown症候群の頻度と臨床的特徴

    柴田 奈央, 入月 浩美, 佐藤 英利, 内山 絢乃, 野村 道代, 帆苅 恵子, 浅見 直, 長崎 啓祐

    日本マス・スクリーニング学会誌   28 ( 3 )   315 - 320   2018年12月

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    記述言語:日本語   出版者・発行元:日本マススクリーニング学会  

    新生児マススクリーニング(以下NBS)のTSH高値として、しばしばDown症候群を経験するが、その頻度や臨床像についての報告は限られている。過去14年の新潟県NBSでTSH精査者となった児のうち、Down症候群(21トリソミー)と確定診断された患者についての臨床情報を収集した。【対象と方法】2002年4月〜2016年3月の14年間に新潟県内でNBSを受けた306,214人のうちTSH高値で精査対象になった305人。このうち精査機関で、身体的特徴等からDown症候群が疑われ、末梢血G-bandにより21トリソミーが確定している患者12人を調べた。新潟大学医歯学総合病院に受診歴のある10人については、臨床情報の詳細に関して診療録を用いて後方視的に検討した。【結果】精査者305人のうち、Down症候群(21トリソミー)と診断されているのは12人(3.9%、男児6人)であった。12人のうち、NBS初回精査(TSH 30μIU/ml以上)4人、再採血で精査(TSH 8μIU/ml以上)8人であった。経過詳細を得られた10人(年齢中央値9.0歳:2.7〜12.2歳)の臨床像は以下の通りである。1)甲状腺形態:正所性10人(低形成5人、正常大5人)。2)精査時甲状腺機能検査所見:サブクリニカルCH(TSH高値/FT4正常)5人、顕性CH(TSH高値/FT4低下)4人、正常1人。3)レボチロキシンNa内服:生後3ヵ月以内に10人内服開始。再評価を行なった7人のうち内服中止4人(中止時年齢:6.9歳、5.9歳、5.0歳、2ヵ月)【結語】NBSでTSH高値となったDown症候群患者(21トリソミー)は甲状腺サイズが小さいものが多く、一過性甲状腺機能低下症が半数以上を占めた。(著者抄録)

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  • Nonsense mutations in FZD2 cause autosomal-dominant omodysplasia: Robinow syndrome-like phenotypes. 査読 国際誌

    Nagasaki K, Nishimura G, Kikuchi T, Nyuzuki H, Sasaki S, Ogawa Y, Saitoh A

    American journal of medical genetics. Part A   176 ( 3 )   739 - 742   2018年3月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Omodysplasia-2 (OMOD2; OMIM%16475) is a rare autosomal dominant (AD) skeletal dysplasia characterized by shortened humeri, short first metacarpal, craniofacial dysmorphism (frontal bossing, depressed nasal bridge, bifid nasal tip, and long philtrum), and variable degrees of genitourinary anomalies. This clinical phenotype overlaps with that of AD type Robinow syndrome. Recently, a mutation in FZD2 encoding a Frizzled Class Receptor 2 has been identified in a family with AD omodysplasia (an affected girl and her affected mother). Here, we present the second report on a heterozygous novel nonsense FZD2 mutation in OMOD2 or Robinow syndrome-like phenotype. The proband was a 16-year-old boy, who has been followed from infancy to adolescence. He presented with rhizomelic short stature with elbow restriction, mild facial dysmorphism (depressed broad bridge, short nose, anteverted nostrils, long philtrum, and low-set ears), and genital hypoplasia. Radiological examination in infancy showed short, broad humeri with relatively narrow distal ends, mildly broad femora, thick proximal ulnae with hypoplastic, dislocated proximal radii, and short first metacarpals. The abnormal skeletal pattern was persistent in adolescence; however, the humeri and femora became less undermodeled, while the humeri and radii became mildly bowed. Molecular analysis identified a de novo, heterozygous, nonsense mutation (c.1640C>A, p.S547*) in FZD2. The affected codon was next to the previously reported mutation (p.Trp548*). The results indicate that OMOD2 or Robinow syndome-like phenotype can be caused by a heterozygous nonsense FZD2 mutation impairing Wnt signaling. Further molecular studies will permit better clarification of the phenotypic spectrum in patients with OMOD2.

    DOI: 10.1002/ajmg.a.38623

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  • Association between monoallelic TSHR mutations and congenital hypothyroidism: a statistical approach. 査読 国際誌

    Abe K, Narumi S, Suwanai AS, Adachi M, Muroya K, Asakura Y, Nagasaki K, Abe T, Hasegawa T

    European journal of endocrinology   178 ( 2 )   137 - 144   2018年2月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    OBJECTIVE: Biallelic TSHR mutations cause congenital hypothyroidism (CH). Serum TSH levels of monoallelic mutation carriers range from normal to mildly elevated, and thus the size of its effect remains unclear. The objectives were to examine the association between monoallelic TSHR mutations and positivity at newborn screening (NBS) for CH, and to test whether the association was modified by another genetic factor. SUBJECTS AND METHODS: We enrolled 395 patients that had a positive result in NBS and sequenced TSHR. Monoallelic TSHR mutation carriers were further sequenced for DUOX2. Molecular functions of the mutations were verified in vitro. The frequency of the mutations in the study subjects was compared with a theoretical value in the Japanese general population. Odds ratio (OR) for NBS positivity associated with the mutation was calculated. Using Bayes' theorem, we estimated a posterior probability of NBS positivity given the mutation. RESULTS: Twenty-six monoallelic TSHR mutation carriers were found. Four out of the 26 also had a monoallelic DUOX2 mutation (double heterozygotes). The frequencies of monoallelic TSHR mutation carriers (6.6%) and double heterozygotes (1.0%) were significantly higher than those in the general population (0.58% and 0.0087%, respectively). OR for NBS positivity of having a monoallelic TSHR mutation or being a double heterozygote was 12.0 or 117.9, respectively. Posterior probability of NBS positivity was 0.38% in monoallelic TSHR mutation carriers and 3.8% in double heterozygotes. CONCLUSIONS: Monoallelic TSHR mutations are significantly associated with NBS positivity, and the association is further strengthened by the coexistence of monoallelic DUOX2 mutations.

    DOI: 10.1530/eje-16-1049

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  • Temple syndrome: comprehensive molecular and clinical findings in 32 Japanese patients. 査読 国際誌

    Kagami M, Nagasaki K, Kosaki R, Horikawa R, Naiki Y, Saitoh S, Tajima T, Yorifuji T, Numakura C, Mizuno S, Nakamura A, Matsubara K, Fukami M, Ogata T

    Genetics in medicine : official journal of the American College of Medical Genetics   19 ( 12 )   1356 - 1366   2017年12月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    PurposeTemple syndrome (TS14) is a rare imprinting disorder caused by aberrations at the 14q32.2 imprinted region. Here, we report comprehensive molecular and clinical findings in 32 Japanese patients with TS14.MethodsWe performed molecular studies for TS14 in 356 patients with variable phenotypes, and clinical studies in all TS14 patients, including 13 previously reported.ResultsWe identified 19 new patients with TS14, and the total of 32 patients was made up of 23 patients with maternal uniparental disomy (UPD(14)mat), six patients with epimutations, and three patients with microdeletions. Clinical studies revealed both Prader-Willi syndrome (PWS)-like marked hypotonia and Silver-Russell syndrome (SRS)-like phenotype in 50% of patients, PWS-like hypotonia alone in 20% of patients, SRS-like phenotype alone in 20% of patients, and nonsyndromic growth failure in the remaining 10% of patients in infancy, and gonadotropin-dependent precocious puberty in 76% of patients who were pubescent or older.ConclusionThese results suggest that TS14 is not only a genetically diagnosed entity but also a clinically recognizable disorder. Genetic testing for TS14 should be considered in patients with growth failure plus both PWS-like hypotonia and SRS-like phenotypes in infancy, and/or precocious puberty, as well as a familial history of Kagami-Ogata syndrome due to maternal microdeletion at 14q32.2.

    DOI: 10.1038/gim.2017.53

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  • PTEN mutation in a Japanese boy with autonomously functioning thyroid nodule. 査読 国際誌

    Nyuzuki H, Kogai T, Hishinuma A, Ogawa Y, Saitoh A, Nagasaki K

    Pediatrics international : official journal of the Japan Pediatric Society   59 ( 11 )   1223 - 1224   2017年11月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    DOI: 10.1111/ped.13427

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  • 先天性中枢性甲状腺機能低下症の診療状況の全国調査

    長崎 啓祐, 窪田 拓生, 小林 弘典, 澤田 浩武, 沼倉 周彦, 原田 正平, 高澤 啓, 南谷 幹史, 石井 智弘, 岡田 賢, 鎌崎 穂高, 杉原 茂孝, 安達 昌功, 田島 敏広, 日本小児内分泌学会マス・スクリーニング委員会

    日本マス・スクリーニング学会誌   27 ( 1 )   9 - 15   2017年5月

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    記述言語:日本語   出版者・発行元:日本マススクリーニング学会  

    先天性中枢性甲状腺機能低下症(以下CCH)の診療現状を明らかにすることを目的に全国的な調査を行った。【対象と方法】日本小児内分泌学会評議員に対して、CCH症例の調査をE-mailで依頼し、詳細な臨床情報を収集した。【結果】一次調査の回答率は47%であった。過去10年間のCCH例は155名で、原発性CHのおよそ8%に相当した。二次調査で78名(男性55名、女性23名)の詳細な臨床情報がえられた。78名中TSH単独欠損例は19名(男15名、女4名)で、7名がFT4スクリーニングで発見された。他の下垂体前葉機能低下を伴う例は59名で、7名はFT4スクリーニングで、約1/2は乳児期以降に発見されていた。【結語】CCHの発症頻度は1/50,000人以上で、男児に多くTSH単独欠損症は1/4を占めた。TSH単独欠損症は、FT4スクリーニングを行っていない地域では、見逃されている可能性がある。下垂体機能低下症の半数は、FT4スクリーニングにより早期発見が期待される。(著者抄録)

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  • Long term survival of a patient with Perlman syndrome due to novel compound heterozygous missense mutations in RNB domain of DIS3L2. 査読 国際誌

    Soma N, Higashimoto K, Imamura M, Saitoh A, Soejima H, Nagasaki K

    American journal of medical genetics. Part A   173 ( 4 )   1077 - 1081   2017年4月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Perlman syndrome is a rare overgrowth syndrome characterized by polyhydramnios, macrosomia, distinctive facial appearance, renal dysplasia, and a predisposition to Wilms' tumor. The syndrome is often associated with a high neonatal mortality rate and there are few reports of long-term survivors. We studied a 6-year-old Japanese female patient, who was diagnosed with Perlman syndrome, with novel compound heterozygous mutations in DIS3L2 (c.[367-2A > G];[1328T > A]), who has survived long term. Most reported DIS3L2 mutations have been the homozygous deletion of exon 6 or exon 9, and these mutations would certainly have caused the loss of both RNA binding and degradation activity. We have identified new compound heterozygous mutations in the DIS3L2 of this long-term survivor of Perlman syndrome. The reason our patient has survived long-term would be a missense mutation (c.1328 T > A, p.Met443Lys) having retained RNA binding in both the cold-shock domains and the S1 domain, and through partial RNA degradation. If partial exonuclease functions remain in at least one allele, long-term survival may be possible. Further studies of Perlman syndrome patients with proven DIS3L2 mutations are needed to clarify genotype-phenotype correlation.

    DOI: 10.1002/ajmg.a.38111

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  • Clinical characteristics of septo-optic dysplasia accompanied by congenital central hypothyroidism in Japan. 査読

    Nagasaki K, Kubota T, Kobayashi H, Sawada H, Numakura C, Harada S, Takasawa K, Minamitani K, Ishii T, Okada S, Kamasaki H, Sugihara S, Adachi M, Tajima T

    Clinical pediatric endocrinology : case reports and clinical investigations : official journal of the Japanese Society for Pediatric Endocrinology   26 ( 4 )   207 - 213   2017年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Septo-optic dysplasia (SOD) is a congenital anomaly in which agenesis of the septum pellucidum and optic nerve hypoplasia are accompanied by hypopituitarism. Typically, the symptoms develop in 3 organs, the brain, eyes, and pituitary, and approximately one third of the patients present with all of the three cardinal features. The diagnostic criteria for SOD were established in Japan in 2015. The purpose of this study is to review clinical features regarding SOD patients with hypopituitarism in Japan. In this study, 21 patients with SOD were identified by a questionnaire survey for congenital central hypothyroidism. All 3 symptoms of SOD, agenesis of the septum pellucidum, optic nerve hypoplasia, and endocrine abnormalities, were noted in 8 of the 21 patients. Various combinations of pituitary hormone deficiencies were observed in patients with SOD, although SOD is a rare, heterogeneous, and phenotypically variable disorder, some patients develop hypoglycemia and convulsions after birth, and early intervention with hormone replacement is necessary in severe cases. In addition, 14 cases were complicated by both developmental delay and epilepsy, and 16 cases involved eye abnormalities. Therefore, in addition to an early endocrinological diagnosis and hormone replacement, consultation with both pediatric neurologists and pediatric ophthalmologists is necessary.

    DOI: 10.1297/cpe.26.207

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  • A novel mutation in the human mineralocorticoid receptor gene in a Japanese family with autosomal-dominant pseudohypoaldosteronism type 1. 査読

    Nishizaki Y, Hiura M, Sato H, Ogawa Y, Saitoh A, Nagasaki K

    Clinical pediatric endocrinology : case reports and clinical investigations : official journal of the Japanese Society for Pediatric Endocrinology   25 ( 4 )   135 - 138   2016年10月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    DOI: 10.1297/cpe.25.135

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  • Beckwith-Wiedemann syndrome and pseudohypoparathyroidism type Ib in a patient with multilocus imprinting disturbance: a female-dominant phenomenon? 査読 国際誌

    Sano S, Matsubara K, Nagasaki K, Kikuchi T, Nakabayashi K, Hata K, Fukami M, Kagami M, Ogata T

    Journal of human genetics   61 ( 8 )   765 - 9   2016年8月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Although recent studies have often revealed the presence of multilocus imprinting disturbance (MLID) at differentially methylated regions (DMRs) in patients with imprinting disorders (IDs), most patients exhibit clinical features of the original ID only. Here we report a Japanese female patient with Beckwith-Wiedemann syndrome and pseudohypoparathyroidism type Ib. Molecular studies revealed marked methylation defects (MDs) at the Kv-DMR and the GNAS-DMRs and variable MDs at four additional DMRs, in the absence of a mutation in ZFP57, NLRP2, NLRP7, KHDC3L and NLRP5. It is likely that the MDs at the Kv-DMR and the GNAS-DMRs were sufficient to cause clinically recognizable IDs, whereas the remaining MDs were insufficient to result in clinical consequences or took place at DMRs with no disease-causing imprinted gene(s). The development of MLID and the two IDs of this patient may be due to a mutation in a hitherto unknown gene for MLID, or to a reduced amount of DNA methyltransferase-1 (DNMT1) available for the methylation maintenance of DMRs because of the consumption of DNMT1 by the maintenance of X-inactivation. In support of the latter possibility, such co-existence of two IDs has primarily been identified in female patients, and MLID has predominantly been identified as loss of methylations.

    DOI: 10.1038/jhg.2016.45

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  • Natural course of congenital hypothyroidism by dual oxidase 2 mutations from the neonatal period through puberty. 査読 国際誌

    Maruo Y, Nagasaki K, Matsui K, Mimura Y, Mori A, Fukami M, Takeuchi Y

    European journal of endocrinology   174 ( 4 )   453 - 63   2016年4月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    AIM: We previously reported that biallelic mutations in dual oxidase 2 (DUOX2) cause transient hypothyroidism. Since then, many cases with DUOX2 mutations have been reported. However, the clinical features and prognosis of individuals with DUOX2 defects have not been clarified. OBJECTIVE: We investigated the prognosis of patients with congenital hypothyroidism (CH) due to DUOX2 mutations. PATIENTS: Twenty-five patients were identified by a neonatal screening program and included seven familial cases. Their serum TSH values ranged from 18.9 to 734.6  mU/l. Twenty-two of the patients had low serum free thyroxine (fT4) levels (0.17-1.1  ng/dl). Twenty-four of the patients were treated with L-thyroxine. METHODS: We analyzed the DUOX2, thyroid peroxidase, Na(+)/I(-) symporter, and dual oxidase maturation factor 2 genes of these 25 patients by PCR-amplified direct sequencing. An additional 11 genes were analyzed in 11 of the 25 patients using next-generation sequencing. RESULTS: All patients had biallelic DUOX2 mutations, and seven novel alleles were detected. Fourteen of the patients were able to discontinue replacement therapy, and seven were receiving reduced L-thyroxine doses. Normalization of thyroglobulin lagged several years behind the completion of treatment. Two patients showed permanent hypothyroidism. Except for one case of a learning disability, growth and psychomotor development were normal. CONCLUSION: The prognosis of Japanese patients with DUOX2 defects was usually transient CH. Delayed improvement of thyroglobulin indicates that these patients have subclinical hypothyroidism. Hypothyroidism did not recur in patients during the study period (up to 18 years old).

    DOI: 10.1530/eje-15-0959

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  • Criteria for radiologic diagnosis of hypochondroplasia in neonates. 査読 国際誌

    Saito T, Nagasaki K, Nishimura G, Wada M, Nyuzuki H, Takagi M, Hasegawa T, Amano N, Murotsuki J, Sawai H, Yamada T, Sato S, Saitoh A

    Pediatric radiology   46 ( 4 )   513 - 8   2016年4月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    BACKGROUND: A radiologic diagnosis of hypochondroplasia is hampered by the absence of age-dependent radiologic criteria, particularly in the neonatal period. OBJECTIVE: To establish radiologic criteria and scoring system for identifying neonates with fibroblast growth factor receptor 3 (FGFR3)-associated hypochondroplasia. MATERIALS AND METHODS: This retrospective study included 7 hypochondroplastic neonates and 30 controls. All subjects underwent radiologic examination within 28 days after birth. We evaluated parameters reflecting the presence of (1) short ilia, (2) squared ilia, (3) short greater sciatic notch, (4) horizontal acetabula, (5) short femora, (6) broad femora, (7) metaphyseal flaring, (8) lumbosacral interpedicular distance narrowing and (9) ovoid radiolucency of the proximal femora. RESULTS: Only parameters 1, 3, 4, 5 and 6 were statistically different between the two groups. Parameters 3, 5 and 6 did not overlap between the groups, while parameters 1 and 4 did. Based on these results, we propose a scoring system for hypochondroplasia. Two major criteria (parameters 3 and 6) were assigned scores of 2, whereas 4 minor criteria (parameters 1, 4, 5 and 9) were assigned scores of 1. All neonates with hypochondroplasia in our material scored ≥6. CONCLUSION: Our set of diagnostic radiologic criteria might be useful for early identification of hypochondroplastic neonates.

    DOI: 10.1007/s00247-015-3518-2

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  • Guidelines for Mass Screening of Congenital Hypothyroidism (2014 revision). 査読

    Mass Screening Committee, Japanese Society for Pediatric Endocrinology, Japanese Society for Mass Screening, Nagasaki K, Minamitani K, Anzo M, Tajima T

    Clinical pediatric endocrinology : case reports and clinical investigations : official journal of the Japanese Society for Pediatric Endocrinology   24 ( 3 )   107 - 33   2015年7月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Purpose of developing the guidelines: Mass screening for congenital hypothyroidism started in 1979 in Japan, and the prognosis for intelligence has been improved by early diagnosis and treatment. The incidence was about 1/4000 of the birth population, but it has increased due to diagnosis of subclinical congenital hypothyroidism. The disease requires continuous treatment, and specialized medical facilities should make a differential diagnosis and treat subjects who are positive in mass screening to avoid unnecessary treatment. The Guidelines for Mass Screening of Congenital Hypothyroidism (1998 version) were developed by the Mass Screening Committee of the Japanese Society for Pediatric Endocrinology in 1998. Subsequently, new findings on prognosis and problems in the adult phase have emerged. Based on these new findings, the 1998 guidelines were revised in the current document (hereinafter referred to as the Guidelines). Target disease/conditions: Primary congenital hypothyroidism. Users of the Guidelines: Physician specialists in pediatric endocrinology, pediatric specialists, physicians referring patients to pediatric practitioners, general physicians, laboratory technicians in charge of mass screening, and patients.

    DOI: 10.1297/cpe.24.107

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  • Guidelines for diagnosis and treatment of 21-hydroxylase deficiency (2014 revision). 査読

    Mass Screening Committee, Japanese Society for, Pediatric Endocrinology, Japanese Society for, Mass Screening, Ishii T, Anzo M, Adachi M, Onigata K, Kusuda S, Nagasaki K, Harada S, Horikawa R, Minagawa M, Minamitani K, Mizuno H, Yamakami Y, Fukushi M, Tajima T

    Clinical pediatric endocrinology : case reports and clinical investigations : official journal of the Japanese Society for Pediatric Endocrinology   24 ( 3 )   77 - 105   2015年7月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Purpose of developing the guidelines: The first guidelines for diagnosis and treatment of 21-hydroxylase deficiency (21-OHD) were published as a diagnostic handbook in Japan in 1989, with a focus on patients with severe disease. The "Guidelines for Treatment of Congenital Adrenal Hyperplasia (21-Hydroxylase Deficiency) Found in Neonatal Mass Screening (1999 revision)" published in 1999 were revised to include 21-OHD patients with very mild or no clinical symptoms. Accumulation of cases and experience has subsequently improved diagnosis and treatment of the disease. Based on these findings, the Mass Screening Committee of the Japanese Society for Pediatric Endocrinology further revised the guidelines for diagnosis and treatment. Target disease/conditions: 21-hydroxylase deficiency. Users of the guidelines: Physician specialists in pediatric endocrinology, pediatric specialists, referring pediatric practitioners, general physicians; and patients.

    DOI: 10.1297/cpe.24.77

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  • Clinical, biochemical, and genetic features of non-classical 21-hydroxylase deficiency in Japanese children. 査読

    Kashimada K, Ishii T, Nagasaki K, Ono M, Tajima T, Yokota I, Hasegawa Y

    Endocrine journal   62 ( 3 )   277 - 82   2015年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Non-classical 21-hydroxylase deficiency (NC21-OHD) is a mild form of 21-hydroxylase deficiency lacking apparent symptoms of androgen excess at birth. Most NC21-OHD cases are diagnosed after the onset of puberty, while a substantial number of patients are not diagnosed during childhood. Previous studies have reported ethnic differences in the prevalence of NC21-OHD. To date, the clinical features of NC21-OHD in Japanese children have not been systemically reported. Thus, we performed 3 independent analyses: retrospective analyses of newborn screening in 2 major Japanese cities (Sapporo and Niigata) and a national surveillance collecting clinical information from pediatric endocrinologists throughout the country. During the last 10 years, one case of NC21-OHD was diagnosed by newborn screening in each city, resulting in incidences of 2.0 (95% confidence interval = 0.0-5.9) and 2.1 (0.0-6.2) per 1,000,000 in Sapporo and Niigata, respectively. We collected information from 85% of the 135 Councilors of Japanese Society of Pediatric Endocrinology. Fifteen NC21-OHD patients were diagnosed during childhood, resulting in the estimated prevalence of 0.58 (0.28-1.1) per 1,000,000. Eleven patients were discovered by newborn screening, 7 patients developed hyperandrogenism symptoms (2-8 years of age, median 7), and 9 patients were treated with hydrocortisone at the time of the survey. Ten out of 13 patients showed compound heterozygosity for the P30L mutation of CYP21A2. Our study suggests that the prevalence/incidence of NC21-OHD is lower than that in Western countries, and that the age for initial onset of androgen excess symptoms varies during the prepubertal period.

    DOI: 10.1507/endocrj.ej14-0377

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  • Long-term follow-up study for a patient with Floating-Harbor syndrome due to a hotspot SRCAP mutation. 査読 国際誌

    Nagasaki K, Asami T, Sato H, Ogawa Y, Kikuchi T, Saitoh A, Ogata T, Fukami M

    American journal of medical genetics. Part A   164A ( 3 )   731 - 5   2014年3月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Floating-Harbor syndrome (FHS) is a rare autosomal dominant disorder characterized by short stature, skeletal malformations, speech delay, and dysmorphic facial appearance. Recently, mutations in SRCAP encoding a coactivator for cAMP-response element binding protein (CREB)-binding protein have been identified in small number of patients with FHS. Here, we report on long-term follow-up data of a male patient with a SRCAP mutation. The patient presented with mild hypothyroidism and renal hypouricemia, in addition to several FHS-compatible features including growth impairment, cognitive disability, facial dysmorphisms, and hypertension. He showed delayed bone age from infancy to 9 years of age and markedly accelerated bone age with the formation of cone-shaped epiphyses and early epiphysial fusions after the onset of puberty. His pubertal sexual development was almost age appropriate. Two-year treatment with growth hormone (GH) did not significantly improve the growth velocity. Molecular analysis identified a de novo heterozygous nonsense mutation (p.R2444X) in the last exon of SRCAP, which has been most common mutation detected in patients from other ethnic groups. These results indicate that perturbed skeletal maturation from infancy through adolescence is a characteristic feature in patients with SRCAP mutations. Furthermore, our data imply that GH therapy exerted only a marginal effect on the growth of this patient, and that renal hypouricemia may be a novel complication of FHS.

    DOI: 10.1002/ajmg.a.36314

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  • Association between compound heterozygous mutations of SLC34A3 and hypercalciuria. 査読 国際誌

    Abe Y, Nagasaki K, Watanabe T, Abe T, Fukami M

    Hormone research in paediatrics   82 ( 1 )   65 - 71   2014年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    BACKGROUND: Mutations in SLC34A3 have been shown to cause hereditary hypophosphatemic rickets with hypercalciuria (HHRH). Patients with compound heterozygous or homozygous mutations develop skeletal lesions in addition to hypercalciuria, hypophosphatemia and/or elevated 1,25-dihydroxy vitamin D [1,25-(OH)2D] levels. Here, we report a case of hypercalciuria without skeletal lesions in a patient with compound heterozygous mutations of SLC34A3. CASE PRESENTATION: A 3-year-old girl presented with microscopic hematuria. Laboratory data revealed elevated 1,25-(OH)2D levels and serum calcium, reduced serum inorganic phosphorus and hypercalciuria. In addition, the ratio of maximal rate of renal tubular reabsorption of phosphate to glomerular filtration rate was reduced. Abdominal ultrasound revealed bilateral nephrocalcinosis. These data were consistent with HHRH, but the patient had no clinical features of rickets or any family history of skeletal disease. Genetic analysis revealed compound heterozygous mutations of c.175+1 G>A and c.1234 C>T in SLC34A3. CONCLUSIONS: This is the report of a patient with compound heterozygous mutations of SLC34A3 and normal skeletal features. Biallelic mutations in SLC34A3 can thus be associated with hypercalciuria not accompanied by rickets. Orally administered inorganic phosphate is predicted to improve symptoms in these patients, hence screening for SLC34A3 mutations should be considered in patients with hypercalciuria of unknown etiology.

    DOI: 10.1159/000360291

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  • A study of the etiology of transient congenital hypothyroidism in Niigata Prefecture, Japan. 査読

    Nagasaki K, Narumi S, Abe K, Asami T, Sato H, Ogawa Y, Kikuchi T, Hasegawa T, Saitoh A

    International journal of pediatric endocrinology   2013年

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    掲載種別:研究論文(学術雑誌)  

    DOI: 10.1186/1687-9856-2013-s1-o55

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  • Neuromuscular symptoms in a patient with familial pseudohypoparathyroidism type Ib diagnosed by methylation-specific multiplex ligation-dependent probe amplification. 査読

    Nagasaki K, Tsuchiya S, Saitoh A, Ogata T, Fukami M

    Endocrine journal   60 ( 2 )   231 - 6   2013年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Pseudohypoparathyroidism type Ib (PHP-Ib) is a rare genetic disorder characterized by hypocalcemia and hyperphosphatemia due to imprinting defects in the maternally derived GNAS allele. Patients with PHP-Ib are usually identified by tetany, convulsions, and/or muscle cramps, whereas a substantial fraction of patients remain asymptomatic and are identified by familial studies. Although previous studies on patients with primary hypoparathyroidism have indicated that hypocalcemia can be associated with various neuromuscular abnormalities, such clinical features have been rarely described in patients with PHP-Ib. Here, we report a 12-year-old male patient with familial PHP-Ib and unique neuromuscular symptoms. The patient presented with general fatigue, steppage gait, and myalgia. Physical examinations revealed muscular weakness and atrophies in the lower legs, a shortening of the bilateral Achilles' tendons and absence of deep tendon reflexes. Laboratory tests showed hypocalcemia, hyperphosphatemia, elevated serum intact PTH level, and impaired responses of urinary phosphate and cyclic AMP in an Ellsworth-Howard test, in addition to an elevated serum creatine kinase level. Clinical features of the patient were significantly improved after 1 month of treatment with alfacalcidol and calcium. Methylation-specific multiplex ligation-dependent probe amplification (MS-MLPA) and subsequent PCR analyses identified a methylation defect at exon A/B of GNAS and a microdeletion involving exons 4-6 of the GNAS neighboring gene STX16 in the patient and in his asymptomatic brother. The results suggest that various neuromuscular features probably associated with hypocalcemia can be the first symptoms of PHP-Ib, and that MS-MLPA serves as a powerful tool for screening of GNAS abnormalities in patients with atypical manifestations.

    DOI: 10.1507/endocrj.ej12-0257

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  • PRKAR1A mutation affecting cAMP-mediated G protein-coupled receptor signaling in a patient with acrodysostosis and hormone resistance. 査読

    Nagasaki K, Iida T, Sato H, Ogawa Y, Kikuchi T, Saitoh A, Ogata T, Fukami M

    The Journal of clinical endocrinology and metabolism   2012年9月

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    掲載種別:研究論文(学術雑誌)  

    DOI: 10.1210/jc.2012-1369

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  • Radiological clues to the early diagnosis of hypochondroplasia in the neonatal period: report of two patients. 査読 国際誌

    Saito T, Nagasaki K, Nishimura G, Takagi M, Hasegawa T, Uchiyama M

    American journal of medical genetics. Part A   158A ( 3 )   630 - 4   2012年3月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Hypochondroplasia (HCH) is the mildest phenotype among fibroblast growth factor receptor 3 (FGFR3)-associated skeletal dysplasias. Affected individuals usually presents with mild short stature in preschool age. It was uncommon that a diagnosis of HCH is made in young affected children. Recently, however, prenatal ultrasound (US) has increased likelihood of detecting in utero mild short limbs. There have been a few reports on the early diagnosis of HCH in the neonatal period preceded by a suspicion of skeletal dysplasia on fetal US. However, the proper diagnosis of HCH is hampered by absence of the radiological criteria relevant to age, particularly those in the neonatal period. We report on the clinical and radiological findings in two HCH children with a FGFR3 mutation. In both children, fetal US showed short femora and relatively increased biparietal diameter (BPD). However, postnatal assessment failed to make a specific diagnosis in the neonatal period. The correct diagnosis of HCH was accomplished by reassessment after exacerbation of postnatal short stature. In retrospective radiological review, the radiological findings relevant to HCH were discernible more easily in the neonatal period than at age of 3 years.

    DOI: 10.1002/ajmg.a.34424

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  • A family of pseudohypoparathyroidism type Ia with an 850-kb submicroscopic deletion encompassing the whole GNAS locus. 査読

    Mitsui T, Nagasaki K, Takagi M, Narumi S, Ishii T, Hasegawa T

    American journal of medical genetics. Part A   2012年1月

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    掲載種別:研究論文(学術雑誌)  

    DOI: 10.1002/ajmg.a.34393

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  • Nonclassic TSH resistance: TSHR mutation carriers with discrepantly high thyroidal iodine uptake. 査読

    Narumi S, Nagasaki K, Ishii T, Muroya K, Asakura Y, Adachi M, Hasegawa T

    The Journal of clinical endocrinology and metabolism   2011年8月

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    掲載種別:研究論文(学術雑誌)  

    DOI: 10.1210/jc.2011-0070

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  • A study of the etiology of congenital hypothyroidism in the Niigata prefecture of Japan in patients born between 1989 and 2005 and evaluated at ages 5-19. 査読 国際誌

    Nagasaki K, Asami T, Ogawa Y, Kikuchi T, Uchiyama M

    Thyroid   21 ( 4 )   361 - 5   2011年4月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    BACKGROUND: The prevalence of congenital hypothyroidism (CH) increased during the period 1994-2002 in Japan. The reasons for these recently described increases in the prevalence of CH remain unclear. Moreover, the proportion of patients with different etiologies CH in the more recently diagnosed patients has not been established. In this study, we determined the etiologies of CH that were detected by neonatal screening in Niigata refecture, Japan. METHODS: A total of 100 patients having a diagnosis of CH (41 men and 59 women, aged 5-19 years old) were evaluated. To determine the etiology of CH, the patients underwent a ¹²³I thyroidal radioiodine uptake test, a scintigram, a saliva to plasma radioiodine ratio analysis, a perchlorate discharge test, thyroid ultrasonography, measurements of thyroidal function and thyroglobulin, and a thyrotropin (TSH)-releasing hormone tolerance test. RESULTS: Patients with overt CH (n=34, elevated TSH levels with low free thyroxine levels) made up 34% of the total group, 56% of the patients had subclinical CH (n=56, elevated TSH levels with normal free thyroxinelevels), and 10% had normal thyroid function. These were patients who were considered to have transient hypothyroidism or hyperthyrotropinemia. Thyroid dysgenesis was the diagnosis in 73% of patients with overt CH, and the most of these had ectopic thyroid tissue. In contrast, thyroid dysgenesis was the diagnosis in only 36% of the patients with subclinical CH. CONCLUSIONS: Only 50% of our patients with CH detected by neonatal screening had thyroid dysgenesis. With an increase in the percentage of patients with subclinical hypothyroidism, the prevalence of thyroid dyshormogenesis has increased. Studies of the frequency and etiology of CH should consider overt and subclinical CH separately.

    DOI: 10.1089/thy.2010.0005

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  • Two cases of 22q11.2 deletion syndrome with anorectal anomalies and growth retardation. 査読 国際誌

    Nagasaki K, Itoh M, Naoki O, Kubota M, Kikuchi T, Uchiyama M

    Journal of pediatric endocrinology & metabolism : JPEM   24 ( 7-8 )   585 - 6   2011年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Clinical features associated with the deletion of 22q11.2 are highly variable. Most are diagnosed by cardinal congenital heart disease or hypoparathyroidism. In cases without major features, an early accurate diagnosis of 22q11.2 deletion syndrome is difficult. Congenital anorectal malformations (ARM), which can be detected soon after birth, have been rarely reported in 22q11.2 deletion syndrome. We report two cases of 22q11.2 deletion syndrome with ARM who showed growth retardation. ARM was detected in both patients without congenital heart disease or hypoparathyroidism at early infancy and they were followed by pediatric surgeons. Later, failure to thrive or short stature became evident, and they consulted with pediatric endocrinologists who subsequently confirmed the diagnosis of 22q11.2 deletion by fluorescent in situ hybridization analysis. The combination of ARM and growth retardation may lead to an early diagnosis of 22q11.2 deletion syndrome.

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  • Evaluation of parathyroid gland function using sodium bicarbonate infusion test for 22q11.2 deletion syndrome. 査読 国際誌

    Nagasaki K, Iwasaki Y, Ogawa Y, Kikuchi T, Uchiyama M

    Hormone research in paediatrics   75 ( 1 )   14 - 8   2011年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    BACKGROUND/AIMS: 22q11.2 Deletion syndrome is a congenital malformation syndrome with hypoparathyroidism. The spectrum of parathyroid gland dysfunction ranges from severe neonatal hypocalcemia to subclinical hypoparathyroidism. The parathyroid hormone (PTH) secretory reserve is reduced in a significant number of 22q11.2 deletion syndrome patients with normocalcemia. The aim of this study was to investigate hypoparathyroid function using the bicarbonate infusion test for 22q11.2 deletion syndrome with normocalcemia. METHODS: sodium bicarbonate solution [7% (w/v); 40 ml/m(2) body surface area] was infused for 2 min, and blood samples for the determination of plasma ionized calcium and plasma intact PTH were serially obtained. The test was conducted on five 22q11.2 deletion syndrome patients with normocalcemia. RESULTS: two patients presented increments of intact PTH levels (peak value - basal value) of 70 pg/ml or higher during the test, whereas the remaining 3 showed PTH level increments of <30 pg/ml. The former 2 patients were diagnosed as having normal parathyroid gland function, and the latter 3 patients as having subclinical hypoparathyroidism. CONCLUSION: the bicarbonate infusion test may be a valuable method for the evaluation of residual parathyroid gland function in patients with 22q11.2 deletion syndrome. Screening of subclinical hypoparathyroidism should be considered in the regular follow-up of patients with 22q11.2 deletion syndrome, even in cases with normocalcemia.

    DOI: 10.1159/000315904

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  • The occurrence of neonatal acute respiratory disorders in 21-hydroxylase deficiency. 査読

    Nagasaki K, Asami T, Abe Y, Usuda T, Kikuchi T, Uchiyama M

    Endocrine journal   58 ( 7 )   603 - 6   2011年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Patients with 21-hydroxyase deficiency (21-OHD) usually do not present clinical symptoms other than female ambiguous genitalia and skin pigmentation at birth. However, we have found a case of neonatal transient tachypnea with spontaneous pneumomediastinum in a neonate with 21-OHD at birth. The purpose of this study was to investigate the occurrence of neonatal respiratory disorders in 21-OHD patients. From April 1989 to March 2009, 478,337 Japanese newborns were screened for congenital adrenal hyperplasia in Niigata prefecture. Among these newborns, 26 patients were diagnosed as having 21-OHD. We investigated the presence of neonatal respiratory disorders based on the retrospective medical records of 24 full-term patients with 21-OHD. Three of the 24 patients (12.5%) had neonatal acute respiratory disorders. Neonatal transient tachypnea developed in all patients with only oxygenation for two or three days after birth. Chest X-rays showed spontaneous pneumothorax or pneumomediastinum in two patients. In conclusion, 21-OHD patients may present with acute respiratory disorders, especially transient tachypnea with spontaneous pneumothorax, at birth. In cases of delivering mothers having other children with 21-OHD, newborns require attention regarding neonatal respiratory disorders if a prenatal diagnosis has not been performed.

    DOI: 10.1507/endocrj.k11e-036

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  • Metabolic effects of growth hormone replacement in two pediatric patients with growth without growth hormone. 査読

    Nagasaki K, Tsumanuma I, Yoneoka Y, Jinguji S, Ogawa Y, Kikuchi T, Uchiyama M

    Endocrine journal   57 ( 9 )   771 - 5   2010年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Growth without growth hormone (GH) has occasionally been described in patients who have had tumors removed in the hypothalamic-pituitary area. Most of these patients have metabolic abnormalities such as obesity, dyslipidemia and fatty liver. This report describes the metabolic beneficial effects of GH replacement in pediatric patients with growth without GH. Two children in whom the growth without GH phenomenon occurred after therapy for brain tumors participated in this study. Case 1 is a 15-yr-old Japanese girl, diagnosed as having Langerhans cell histiocytosis with multiple intracranial lesions at the age of two. She showed a slight body fat increase, dyslipidemia and fatty liver. Case 2 is a 10-yr-old Indonesian boy, diagnosed with craniopharyngioma at the age of three. He was obese and had low bone mineral density (BMD). In both cases, GH replacement therapy was started at 0.042 mg/kg/week for 12 months. Body composition, BMD, and visceral abdominal area were measured every 3 months. Serum fasting blood glucose, insulin, ALT, lipid profile, leptin, and adiponectin levels were also measured every 3 months. Case 1 showed improvement of transaminase (ALT from 64 to 16 IU/L) and triglyceride (from 239 to 129 mg/dL) over 12 months, but did not show a decrease in visceral fat area or of body fat percentage. Case 2 showed a decrease in body fat percentage and visceral fat area, accompanied by elevated serum adiponectin and decreased leptin levels. In conclusion, twelve months GH replacement therapy improves metabolic abnormalities in pediatric patients with growth without GH.

    DOI: 10.1507/endocrj.k10e-180

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  • Novel C617Y mutation in the 7th transmembrane segment of luteinizing hormone/choriogonadotropin receptor in a Japanese boy with peripheral precocious puberty. 査読

    Nagasaki K, Katsumata N, Ogawa Y, Kikuchi T, Uchiyama M

    Endocrine journal   57 ( 12 )   1055 - 60   2010年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Testotoxicosis, also known as familial male-limited precocious puberty, is an autosomal dominant form of gonadotropin-independent precocious puberty caused by heterozygous constitutively activating mutations of the LHCGR gene encoding the luteinizing hormone/choriogonadotropin receptor (LH/CGR). The patient is an 8-year-old boy who started to develop pubic hair and penile enlargement at 6 years of age. The patient had elevated serum testosterone levels, but initially exhibited a prepubertal response of gonadotropins to GnRH, which was followed by central activation of the hypothalamo-pituitary-gonadal axis. The father reported having experienced precocious puberty, and is 158 cm tall. There is no history of short stature and precocious puberty in the family except for the father. The LHCGR gene was analyzed by direct DNA sequencing of amplified PCR products from the patient and his parents. The wild-type and mutant LH/CGRs were transiently expressed in COS-1 cells and cAMP levels in the cells were determined with or without hCG stimulation. Genetic analysis revealed a novel C617Y mutation of the LHCGR gene in the patient and his mother, while his father had no mutations. Functional expression study demonstrated around 15% increase in the basal intracellular cAMP level in cells expressing the mutant LH/CGR compared with that in cells expressing the wild-type receptor. We have reported the first missense C617Y mutation located in the 7th transmembrane segment of LH/CGR causing testotoxicosis. The modest phenotype of our patient may be explained, at least in part, by the modest increase in the intracellular cAMP level caused by the C617Y mutation.

    DOI: 10.1507/endocrj.k10e-227

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  • H62L Mutation of CYP21A2 Identified in the Non-classical Form of 21-Hydroxylase Deficiency. 査読

    Nagasaki K, Usui T, Asami T, Ogawa Y, Kikuchi T, Uchiyama M

    Clinical Pediatric Endocrinology   18 ( 4 )   111 - 3   2009年10月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    DOI: 10.1297/cpe.18.111

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  • Spontaneous regression of isolated neurohypophyseal langerhans cell histiocytosis with diabetes insipidus. 査読

    Nagasaki K, Tsumanuma I, Yoneoka Y, Ogawa Y, Kikuchi T, Uchiyama M

    Endocrine journal   56 ( 5 )   721 - 5   2009年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    In pediatric and adolescent patients, the most common causes for a thickened pituitary stalk with central diabetes insipidus are germ cell tumors, lymphocytic infundibuloneurohypophysitis (LIN), and Langerhans cell histiocytosis (LCH). We describe here a 13-year-old girl who had an abrupt onset of polyuria and polydipsia. Magnetic resonance imaging of the brain revealed thickening of the pituitary stalk, and loss of the physiological hyperintense signal of the posterior pituitary gland. Based on a histopathology, she was diagnosed as having LCH. Another LCH lesion was not detected. The prognoses for LCH patients with single-system and single-site are generally good so we decided on only simple observation. The lesion spontaneously regressed 3 months later, resembling a typical self-limiting course of LIN. In conclusion, the present case suggests that 1) radiological differential diagnosis between LIN and LCH is so difficult that histological confirmation is crucial for correct diagnosis, 2) some past cases of histologically-unconfirmed LIN can include LCH, 3) solitary neurohypophyseal LCH can shrink spontaneously up to near remission level.

    DOI: 10.1507/endocrj.k09e-045

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  • Mutation of a gene for thyroid transcription factor-1 (TITF1) in a patient with clinical features of resistance to thyrotropin. 査読

    Nagasaki K, Narumi S, Asami T, Kikuchi T, Hasegawa T, Uchiyama M

    Endocrine journal   55 ( 5 )   875 - 8   2008年10月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Resistance to TSH (RTSH [MIM 275200]) is a heterogeneous condition defined by variable degree of insensitivity to biologically active TSH. While this condition is classically caused by loss-of-function mutations of the TSH receptor gene (TSHR), several patients have exhibited RTSH-like phenotype in the apparent absence of TSHR mutations, and some of them have mutations of PAX8 or GNAS1. We identified a Japanese boy with congenital hypothyroidism who suffered from recurrent lower respiratory infection during infancy and choreoathetosis at a later age. At 14 years of age, he was diagnosed as having RTSH, on the basis of compensated hypothyroidism (TSH, 30.2 mU/L; FT4, 1.2 ng/dl), disproportionate increments of thyroid hormones and TSH during a TRH test (DeltaFT3, 0.4 pg/ml; DeltaT3, 13 ng/dl; and DeltaTSH, 88.3 mU/L), and normal ultrasound thyroid image and radioactive iodine uptakes. Molecular analysis for TITF1 revealed a novel de novo heterozygous deletion/insertion mutation (c.470_479delinsGCG,) that is predicted to lose the entire homeodomain and the NK2-specific domain. We suggest that a heterozygous loss-of-function TITF1 mutation can also cause RTSH-compatible phenotype.

    DOI: 10.1507/endocrj.k08e-124

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  • Longitudinal growth of the short bones of the hand in a girl with pseudohypoparathyroidism type ia. 査読

    Nagasaki K, Asami T, Kikuchi T, Uchiyama M

    Clinical pediatric endocrinology : case reports and clinical investigations : official journal of the Japanese Society for Pediatric Endocrinology   16 ( 1 )   23 - 9   2007年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Brachydactyly is a common feature of pseudohypoparathyroidism (PHP) type Ia. We studied the longitudinal growth of the short bones in the hand of a 15-yr-old girl with PHP type Ia who had been followed for congenital hypothyroidism. Radiographs of the hand of the patient, who had been X-rayed every year since 2 yr of age, were studied. She showed cone-shaped epiphyses of the hand at 2 yr of age before showing brachydactyly. At 4 yr of age, she showed brachydactyly and an advanced bone age, and some short bones were prematurely fused at 6 yr of age. The short bones without cone-shaped epiphyses were also short as a result of a disturbance of the longitudinal bone elongation. In conclusion, the brachydactyly of PHP type Ia is thus considered to be caused by both early epiphyseal fusion with cone-shaped epiphyses and a disturbance of the longitudinal bone elongation.

    DOI: 10.1297/cpe.16.23

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  • Two cases of pseudohypoparathyroidism type ia in duozygotic twins with different phenotypes. 査読

    Nagasaki K, Shimomura Y, Suyama T, Magara S, Ogawa Y, Hiura M, Kikuchi T, Uchiyama M

    Clinical pediatric endocrinology : case reports and clinical investigations : official journal of the Japanese Society for Pediatric Endocrinology   14 ( 2 )   39 - 44   2005年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Pseudohypoparathyroidism (PHP) type Ia is characterized by hypocalcemia due to PTH resistance and by features of Albright's hereditary osteodystrophy, including short stature, obesity, subcutaneous calcification and brachydactyly. A wide variety of clinical and biochemical manifestations have been reported. We report two cases of PHP type Ia in duozygotic twins with different phenotypes. The proband was a 10-yr-old girl. She showed subcutaneous ossification, shortening of the metacarpal bone, short stature, obesity and round face. She had normocalcemia (8.9 mg/dl), high-normal phosphate (5.0 mg/dl) and increased levels of serum intact PTH (152 pg/ml) and TSH (9.17 μIU/ml) levels. Her twin younger brother had atypical Albright's hereditary osteodystrophy with only mild obesity and subcutaneous calcifications, but he showed a low level of serum calcium (7.0 mg/dl) and high levels of serum phosphate (7.6 mg/dl), intact PTH (377 pg/ml) and TSH (6.9 μIU/ml). We diagnosed them as having PHP type Ia on the basis of clinical and biochemical findings, Ellsworth-Howard test and family history. There is considerable variability in clinical and biochemical features of PHP type Ia even among affected duozygotic twins. The differences of intrauterine environment and growth history cannot account for the variable phenotypes of PHP type Ia. Even if a patient shows no AHO features, examination of all family members should be undertaken.

    DOI: 10.1297/cpe.14.39

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  • Obese Japanese children have low bone mineral density after puberty. 査読

    Nagasaki K, Kikuchi T, Hiura M, Uchiyama M

    Journal of bone and mineral metabolism   22 ( 4 )   376 - 81   2004年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    The purpose of this study was to determine the relationship between BMD and childhood obesity. We examined 1070 obese children (722 boys and 348 girls) aged 7 to 15 years. Their mean relative weight, as a percentage of the standard weight for age, height, and sex, was 152.9 +/- 14%. BMD was assessed, by a digital image processing method, in the second metacarpal bone of the left hand. We compared our results with those of healthy nonobese Japanese children based on both chronological and bone age. Mean BMD values for bone age in the obese children were significantly higher than those in control groups in boys aged 11 years and under and girls 9 years and under. On the other hand, in boys over 12 years old, BMD values for bone age were lower than those in the control groups. In girls over 11 years old, BMD values tended to be lower than those in the control groups. In conclusion, we studied the BMD of obese children from the point of view of advanced bone age. Our results showed that BMD was higher than in prepubertal obese children, but a low BMD value was found after puberty, due to poor gain of BMD during puberty. It is important to prevent obesity in childhood in order to prevent the low BMD after puberty.

    DOI: 10.1007/s00774-004-0498-y

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  • A Japanese family with a heterozygous novel mutation in the Indian hedgehog gene exhibiting a broad spectrum of clinical features and radiological findings. 国際誌

    Takanori Onuki, Nao Shibata, Shota Hiroshima, Kentaro Sawano, Keisuke Nagasaki

    Congenital anomalies   2021年9月

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    担当区分:責任著者   記述言語:英語   掲載種別:研究論文(学術雑誌)  

    DOI: 10.1111/cga.12445

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  • A case of adolescent trichorhinophalangeal syndrome undergoing pelvic osteotomy for bilateral acetabular dysplasia.

    Kentaro Sawano, Hiromi Nyuzuki, Keisuke Nagasaki, Hayato Suzuki, Ken Suda, Dai Miyasaka, Norio Imai, Akihiko Saitoh

    Journal of orthopaedic science : official journal of the Japanese Orthopaedic Association   2021年9月

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  • Two cases of cytochrome P450 oxidoreductase deficiency with severe scoliosis and surgery requirement. 国際誌

    Takanori Onuki, Yoshiaki Ohtsu, Shota Hiroshima, Kentaro Sawano, Keisuke Nagasaki

    Congenital anomalies   61 ( 5 )   202 - 203   2021年9月

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    担当区分:責任著者   記述言語:英語   掲載種別:研究論文(学術雑誌)  

    DOI: 10.1111/cga.12434

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  • Peripheral precocious puberty in a girl with an intracranial hCG-producing tumor: case report and literature review.

    Nao Shibata, Hiromi Nyuzuki, Sunao Sasaki, Yohei Ogawa, Masayasu Okada, Keisuke Nagasaki

    Endocrine journal   2021年7月

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    担当区分:責任著者   記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Human chorionic gonadotropin (hCG)-producing tumors cause peripheral precocious puberty (PP) in boys, but generally not in girls. Homology between LH and hCG activates the LH receptor in testicular Leydig cells, increases testosterone production, and causes virilization. However, since FSH action is required for follicle development, hCG action alone does not increase estradiol (E2) production and does not cause feminization. Only a few cases of peripheral PP with hCG tumors in girls have been reported. We describe the case of a 7-year-old Japanese girl with peripheral PP associated with an hCG-producing tumor. She had prolonged vomiting, loss of appetite, and Tanner stage III breast development. Although no apparent increase in growth rate, bone age was advanced at 9.8 years. Serum E2 was slightly elevated and LH and FSH were below the measurement sensitivity, and abdominal ultrasonography and computed tomography images showed no abnormal findings in the uterus or ovaries. Subsequently, she developed visual field disturbance and loss of consciousness, and brain magnetic resonance imaging revealed an intracranial tumor. Based on pathological findings and abnormally high serum hCG-β level (48,800 IU/L), intracranial choriocarcinoma was diagnosed. 2.5 months after the start of chemotherapy, the hCG-β level became almost negative and the breast development disappeared synchronously. Tissue immunostaining of the tumor showed strong positivity for aromatase and hCG, indicating that the choriocarcinoma cells themselves may have produced estrogen via aromatase. This unique case highlights the possibility that hCG-producing tumors can cause peripheral PP in girls as well as boys.

    DOI: 10.1507/endocrj.EJ21-0117

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  • Re-Evaluation of the Prevalence of Permanent Congenital Hypothyroidism in Niigata, Japan: A Retrospective Study. 国際誌

    Keisuke Nagasaki, Hidetoshi Sato, Sunao Sasaki, Hiromi Nyuzuki, Nao Shibata, Kentaro Sawano, Shota Hiroshima, Tadashi Asami

    International journal of neonatal screening   7 ( 2 )   2021年5月

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    担当区分:筆頭著者, 責任著者   記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Although newborn screening (NBS) for congenital hypothyroidism (CH) in Japan started more than 40 years ago, the prevalence of CH remains unclear. Prevalence estimations among NBS-positive CH individuals include those with transient hypothyroidism and transient hyperthyrotropinemia, and re-evaluation with increasing age is necessary to clarify the actual incidence. Thus, we re-evaluated the incidence of permanent CH. Of the 106,114 patients who underwent NBS in the Niigata Prefecture, Japan, between April 2002 and March 2006, 116 were examined further due to high thyroid-stimulating hormone levels (>8 mIU/L) and were included in the study. We retrospectively evaluated their levothyroxine sodium (LT4) replacement therapy status from the first visit to 15 years of age. Of the 116 NBS-positive patients, 105 (91%) were initially examined in our department. Of these, 72 (69%) started LT4 replacement therapy on the first visit. Subsequently, 27 patients continued LT4 replacement until 15 years of age after multiple re-evaluations. The prevalence of permanent CH in the Niigata Prefecture during this period was 1 in 2500-3500 children. Ultimately, 62.5% of patients on LT4 replacement discontinued treatment by 15 years of age. This is the first study to clarify the true prevalence of permanent CH in Japan.

    DOI: 10.3390/ijns7020027

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  • Long-term Effect of Aromatase Inhibition in Aromatase Excess Syndrome. 国際誌

    Gerhard Binder, Akie Nakamura, Roland Schweizer, Tsutomu Ogata, Maki Fukami, Keisuke Nagasaki

    The Journal of clinical endocrinology and metabolism   106 ( 5 )   1491 - 1500   2021年4月

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    担当区分:最終著者   記述言語:英語   掲載種別:研究論文(学術雑誌)  

    CONTEXT: Aromatase excess syndrome (AEXS) is a very rare disorder characterized by prepubertal gynecomastia, bone age acceleration, and early growth arrest. Heterozygote submicroscopic rearrangements within the promotor of CYP19A1 result in overexpression of aromatase and enhanced aromatization of androgens. OBJECTIVE: The objective was to study long-term treatment effects of an aromatase inhibitor. METHODS: Data from 7 boys with AEXS were retrospectively collected. Genetic analysis revealed upstream of CYP19A1 a 165 901 bp deletion in 4 German cousins, a 198 662 bp deletion in 2 Japanese brothers, and a 387 622 bp tandem duplication in a Japanese boy. RESULTS: All boys developed prepubertal gynecomastia, at median 9.0 years of age (range: 7.0-11.0). Height was +1.20 standard deviation score (SDS) (-0.24 to +1.98); predicted adult height was -1.29 SDS (-3.29 to +1.09). Four boys were treated with 1.0 mg of anastrozole daily, while 3 reached adult height untreated. Treatment with anastrozole was stopped after 5.6 years (4.0-6.8). Three treated boys exceeded their prognosis by 2.4, 6.9, and 8.1 cm, while 1 untreated boy fell below the prognosis by 8.6 cm. One treated with a low dose and 2 untreated reached their prognosis. Adult heights were -0.91 SDS with anastrozole (-2.86 to -0.29) and -0.15 SDS without (-2.31 to -0.03). Distance to target height was -0.22 SDS with anastrozole (-1.72 to +0.52) and +0.54 SDS without (+0.23 to +1.30). CONCLUSION: Spontaneous growth in AEXS varied, even in the same family. Our data suggest that early started, long-term inhibition by anastrozole promotes adult height in boys with AEXS.

    DOI: 10.1210/clinem/dgab054

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  • Regulation of Serum Sodium Levels during Chemotherapy Using Selective Arginine Vasopressin V2-Receptor Antagonist Tolvaptan in a Four-Year-Old Girl with a Suprasellar Germ Cell Tumor. 国際誌

    Shota Hiroshima, Hiromi Nyuzuki, Sunao Sasaki, Yohei Ogawa, Keisuke Nagasaki

    Children (Basel, Switzerland)   8 ( 4 )   2021年4月

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    担当区分:責任著者   記述言語:英語  

    There are limited reports on the use of tolvaptan for syndrome of inappropriate antidiuretic hormone secretion (SIADH) in children. Managing serum sodium levels in SIADH patients during chemotherapy is often difficult because of the need for massive fluid infusions. We report the course of the use of tolvaptan for the treatment of hyponatremia during chemotherapy in a four-year-old girl with a suprasellar germ cell tumor. The patient was a Japanese girl who presented with left ptosis with a mass in the pituitary gland and cavernous sinus. She was diagnosed with an intermediate-grade germ cell tumor and was treated with carboplatin and etoposide combination chemotherapy. She developed hyponatremia due to SIADH caused by intravenous infusion therapy before chemotherapy. Subsequently, tolvaptan (3.25 mg; 0.20 mg/kg/dose) was administered orally to control serum sodium levels. After 4 h of administration, a marked increase in urine volume of up to 15 mL/kg/h was observed, and serum sodium level increased from 126 to 138 mEq/L after 10 h of tolvaptan administration, followed by a decrease in urine volume. The use of tolvaptan in pediatric patients with SIADH who require intravenous hydration during chemotherapy can be useful for the management of serum sodium balance.

    DOI: 10.3390/children8040293

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  • 若年者バセドウ病のチアマゾール単独治療、チアマゾール+無機ヨウ素併用治療の有効性と安全性に関する多施設共同観察研究 後ろ向きコホート研究

    大江 秀美, 南谷 幹史, 荒田 尚子, 長谷川 奉延, 伊藤 順庸, 猪俣 弘明, 内野 眞也, 鬼形 和道, 佐藤 浩一, 杉原 茂孝, 長崎 啓祐, 鳴海 覚志, 長谷川 行洋, 原田 正平, 深田 修司, 久門 真子, 御前 隆, 横谷 進, 吉村 弘, 金城 さおり, 春名 英典, 松下 理恵, 宮田 市郎, 三善 陽子, 虫本 雄一, 堀川 玲子, 室谷 浩二, 日本甲状腺学会小児甲状腺疾患診療委員会

    日本内分泌学会雑誌   96 ( 4 )   927 - 927   2021年4月

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    記述言語:日本語   出版者・発行元:(一社)日本内分泌学会  

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  • 本邦における胎児甲状腺腫性甲状腺機能低下症の実態調査

    宮田 市郎, 木村 妙, 綾部 匡之, 伊藤 順庸, 金城 さおり, 春名 英典, 松下 理恵, 三善 陽子, 虫本 雄一, 長崎 啓祐, 長谷川 奉延, 南谷 幹史, 日本小児内分泌学会甲状腺委員会

    日本内分泌学会雑誌   97 ( 1 )   268 - 268   2021年4月

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    記述言語:日本語   出版者・発行元:(一社)日本内分泌学会  

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  • Investigation of TSH receptor blocking antibodies in childhood-onset atrophic autoimmune thyroiditis.

    Keisuke Nagasaki, Akie Nakamura, Takeru Yamauchi, Hotaka Kamasaki, Yosuke Hara, Junko Kanno, Satomi Koyama, Yoshiaki Ohtsu, Ikuko Takahashi, Shigeru Suzuki, Kenichi Kashimada, Toshihiro Tajima

    Clinical pediatric endocrinology : case reports and clinical investigations : official journal of the Japanese Society for Pediatric Endocrinology   30 ( 2 )   79 - 84   2021年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Atrophic autoimmune thyroiditis (AAT) is a type of autoimmune hypothyroidism without goiter. TSH receptor-blocking antibodies (TSBAb) are involved in its etiology in adults. Reportedly, this disease is extremely rare in children. In this study, we aimed to investigate the prevalence of TSBAb during AAT onset in children using a commercially available cell-based bioassay TSAb kit. We conducted a multicenter retrospective observational study. We collected data of patients with AAT who were < 15 yr old, enrolled in a collaborative research group, and diagnosed since July 2003. AAT was defined as acquired autoimmune hypothyroidism without thyroid enlargement. Eighteen patients (including 15 females) whose TSH receptor antibody (TRAb) or TSBAb levels were measured within a year from the initial visit were included. The median age at diagnosis was 9.3 years, and the estimated time between onset and diagnosis was 2.6 yr. The positive rate for either TSBAb or TRAb was 38.8% (95% confidence interval: 18.3-59.5%). There were no significant differences in age, the estimated time between onset and diagnosis, and FT4 levels at diagnosis between the TSBAb-positive and -negative groups. Unlike previous reports, we showed that the prevalence of TSBAb-positivity in childhood-onset AATs is not rare, as in adults.

    DOI: 10.1297/cpe.30.79

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  • Degeneration of dopaminergic neurons and impaired intracellular trafficking in Atp13a2 deficient zebrafish. 査読 国際誌

    Hiromi Nyuzuki, Shinji Ito, Keisuke Nagasaki, Yohei Nitta, Noriko Matsui, Akihiko Saitoh, Hideaki Matsui

    IBRO reports   9   1 - 8   2020年12月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    ATP13A2 is the autosomal recessive causative gene for juvenile-onset Parkinson's disease (PARK9, Parkinson's disease 9), also known as Kufor-Rakeb syndrome. The disease is characterized by levodopa-responsive Parkinsonism, supranuclear gaze palsy, spasticity, and dementia. Previously, we have reported that Atp13a2 deficient medaka fish showed dopaminergic neurodegeneration and lysosomal dysfunction, indicating that lysosome-autophagy impairment might be one of the key pathogeneses of Parkinson's disease. Here, we established Atp13a2 deficient zebrafish using CRISPR/Cas9 gene editing. We found that the number of TH + neurons in the posterior tuberculum and the locus coeruleus significantly reduced (dopaminergic neurons, 64 % at 4 months and 37 % at 12 months, p < 0.001 and p < 0.05, respectively; norepinephrine neurons, 52 % at 4 months and 40 % at 12 months, p < 0.001 and p < 0.05, respectively) in Atp13a2 deficient zebrafish, proving the degeneration of dopaminergic neurons. In addition, we found the reduction (60 %, p < 0.05) of cathepsin D protein expression in Atp13a2 deficient zebrafish using immunoblot. Transmission electron microscopy analysis using middle diencephalon samples from Atp13a2 deficient zebrafish showed lysosome-like bodies with vesicle accumulation and fingerprint-like structures, suggesting lysosomal dysfunction. Furthermore, a significant reduction (p < 0.001) in protein expression annotated with vesicle fusion with Golgi apparatus in Atp13a2 deficient zebrafish by liquid-chromatography tandem mass spectrometry suggested intracellular trafficking impairment. Therefore, we concluded that Atp13a2 deficient zebrafish exhibited degeneration of dopaminergic neurons, lysosomal dysfunction and the possibility of intracellular trafficking impairment, which would be the key pathogenic mechanism underlying Parkinson's disease.

    DOI: 10.1016/j.ibror.2020.05.002

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  • 多発性内分泌腫瘍2型小児患者の甲状腺髄様癌と医療状況について 日本小児内分泌学会全国調査からみえた本邦における小児期予防的甲状腺全摘術/極早期摘出の現状

    松下 理恵, 長崎 啓祐, 綾部 匡之, 三善 陽子, 金城 さおり, 春名 英典, 井原 健二, 長谷川 奉延, 位田 忍, 大薗 恵一, 南谷 幹史, 日本小児内分泌学会甲状腺委員会

    遺伝性腫瘍   20 ( 3 )   117 - 123   2020年12月

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    記述言語:日本語   出版者・発行元:(一社)日本遺伝性腫瘍学会  

    多発性内分泌腫瘍症(multiple endocrine neoplasia;MEN)2型はRET遺伝子の病的バリアントを原因とする遺伝性腫瘍症である。MEN2型の遺伝性甲状腺髄様癌はほぼ完全浸透率を示す悪性腫瘍で乳幼児期からも発生し、再発が多いため早期発見と治療が重要である。遺伝性甲状腺髄様癌は、海外では予防的甲状腺全摘が推奨されている。一般的に幼少期の甲状腺手術の合併症リスクは高いが、幼少時の甲状腺全摘のみの予防的甲状腺全摘/極早期摘出は、高年齢の進行段階で中央区域以上のリンパ節郭清を伴うよりは手術合併症が少ないことが複数の調査で示されている。日本では予防的甲状腺全摘が保険で認められていない。費用や医療環境も鑑みると、本邦で再発も手術合併症も減らし生涯の質を向上させるためには、現時点ではRET遺伝子の病的バリアント保有者はカルシトニン値上昇後に極早期甲状腺全摘出を行うことが現実的な選択肢であろう。(著者抄録)

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    その他リンク: https://search.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2020&ichushi_jid=J07424&link_issn=&doc_id=20210119320001&doc_link_id=10.18976%2Fjsht.20.3_117&url=https%3A%2F%2Fdoi.org%2F10.18976%2Fjsht.20.3_117&type=J-STAGE&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00007_3.gif

  • Clinical characteristics of cytochrome P450 oxidoreductase deficiency: a nationwide survey in Japan. 査読

    Shuichi Yatsuga, Naoko Amano, Akari Nakamura-Utsunomiya, Hironori Kobayashi, Kei Takasawa, Keisuke Nagasaki, Akie Nakamura, Satsuki Nishigaki, Chikahiko Numakura, Ikuma Fujiwara, Kanshi Minamitani, Tomonobu Hasegawa, Toshihiro Tajima

    Endocrine journal   67 ( 8 )   853 - 857   2020年8月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Cytochrome P450 oxidoreductase deficiency (PORD) is a disorder of steroidogenesis that causes various symptoms such as skeletal malformations, disorders of sex development, and adrenal insufficiency. The aim of this study was to elucidate the clinical characteristics, especially age at diagnosis and treatment, of PORD from the perinatal period to adulthood in Japan. The first questionnaire was sent to 183 council members of the Japanese Society for Pediatric Endocrinology on 1 September 2018. The response rate was 65%, and a total of 39 patients with PORD were examined at 20 hospitals. The second questionnaire was sent in November 2018 to the council members examining these 39 patients with PORD. The response rate was 77%, and we received clinical information on 30 of the 39 patients. The two novel clinical findings were the age at diagnosis and the treatment of Japanese patients with PORD. In many cases, PORD can be diagnosed at <3 months of age. Hydrocortisone as the primary treatment during infancy can be used daily or in stressful situations; however, because patients with PORD generally have mild to moderate adrenal insufficiency, some might be able to avoid hydrocortisone treatment. Patients with PORD should be carefully followed up, and treatment should be optimized as for patients with other types of adrenal insufficiency. Other characteristics in the present study were similar to those described in previous reports.

    DOI: 10.1507/endocrj.EJ20-0011

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  • チトクロームP450オキソドレダクターゼ欠損症 日本の全国調査

    八ツ賀 秀一, 天野 直子, 宇都宮 朱里, 小林 弘典, 高澤 啓, 長崎 啓祐, 中村 明枝, 西垣 五月, 沼倉 周彦, 藤原 幾磨, 南谷 幹史, 長谷川 奉延, 田島 敏広

    日本内分泌学会雑誌   96 ( 1 )   320 - 320   2020年8月

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    記述言語:日本語   出版者・発行元:(一社)日本内分泌学会  

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  • 小児・AYA世代がん患者の内分泌診療における成人診療科への移行の現状と問題点

    三善 陽子, 依藤 亨, 清水 千佳子, 長崎 啓祐, 川井 正信, 石黒 寛之, 岡田 賢, 菅野 潤子, 田久保 憲行, 室谷 浩二, 伊藤 純子, 堀川 玲子, 横谷 進, 大薗 恵一

    日本内分泌学会雑誌   96 ( 1 )   243 - 243   2020年8月

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    記述言語:日本語   出版者・発行元:(一社)日本内分泌学会  

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  • 小児・AYA世代がん患者の内分泌診療における移行期医療 全国調査結果

    三善 陽子, 依藤 亨, 長崎 啓祐, 川井 正信, 石黒 寛之, 岡田 賢, 菅野 潤子, 田久保 憲行, 室谷 浩二, 伊藤 純子, 堀川 玲子, 横谷 進, 大薗 恵一, 日本小児内分泌学会CCS委員会

    日本小児科学会雑誌   124 ( 2 )   314 - 314   2020年2月

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    記述言語:日本語   出版者・発行元:(公社)日本小児科学会  

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  • 小児・AYA世代がん患者の内分泌診療における移行期医療の現状(日本小児内分泌学会全国調査)

    三善 陽子, 依藤 亨, 横谷 進, 長崎 啓祐, 川井 正信, 石黒 寛之, 岡田 賢, 菅野 潤子, 田久保 憲行, 室谷 浩二, 伊藤 純子, 堀川 玲子, 清水 千佳子, 大薗 恵一

    日本がん・生殖医療学会誌   3 ( 1 )   128 - 128   2020年1月

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    記述言語:日本語   出版者・発行元:(NPO)日本がん・生殖医療学会  

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  • A nationwide questionnaire survey targeting Japanese pediatric endocrinologists regarding transitional care in childhood, adolescent, and young adult cancer survivors. 査読

    Yoko Miyoshi, Tohru Yorifuji, Chikako Shimizu, Keisuke Nagasaki, Masanobu Kawai, Hiroyuki Ishiguro, Satoshi Okada, Junko Kanno, Noriyuki Takubo, Koji Muroya, Junko Ito, Reiko Horikawa, Susumu Yokoya, Keiichi Ozono

    Clinical pediatric endocrinology : case reports and clinical investigations : official journal of the Japanese Society for Pediatric Endocrinology   29 ( 2 )   55 - 62   2020年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Existing guidelines recommend long-term follow-up of childhood cancer survivors (CCS). However, in Japan, transitional care for CCS has not been established. To ascertain the current status in Japan, and to cultivate a better understanding, a questionnaire survey was conducted on transitional care in CCS, and adolescent and young adult (AYA) cancer survivors. Questionnaires were distributed to 183 councilors (137 institutions) of the Japanese Society for Pediatric Endocrinology. A total of 131 responses, representative of 174 councilors, were obtained. The response rate was 95%. Among the respondents, 91% had experience in medical care for cancer patients, while 63% had experience in transitional care; however, the number of patients referred to adult clinics was small. Further, 89% acknowledged the availability of adult endocrinologists who were willing to accept these patients; although their numbers were insufficient. Pediatric endocrinologists highlighted difficulties in medical examinations concerning infertility, obesity, pregnancy/delivery, and gonadal dysfunction, in that order. Staff and time shortages were listed as some of the challenges faced by medical staff, while multisystem morbidity was listed for patients. This nationwide questionnaire survey revealed that Japanese pediatric endocrinologists require cooperation between related departments and collaborative infrastructure to develop transitional care for cancer survivors.

    DOI: 10.1297/cpe.29.55

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  • Letter to the Editor: Testosterone priming increased growth hormone peak levels in the stimulation test and suppressed gonadotropin secretion in three Japanese adolescent boys. 査読

    Kentaro Sawano, Keisuke Nagasaki

    Clinical pediatric endocrinology : case reports and clinical investigations : official journal of the Japanese Society for Pediatric Endocrinology   29 ( 4 )   201 - 201   2020年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    DOI: 10.1297/cpe.29.201

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  • Schaaf-Yang syndrome shows a Prader-Willi syndrome-like phenotype during infancy. 査読 国際誌

    Yutaka Negishi, Daisuke Ieda, Ikumi Hori, Yasuyuki Nozaki, Takanori Yamagata, Hirofumi Komaki, Jun Tohyama, Keisuke Nagasaki, Hiroko Tada, Shinji Saitoh

    Orphanet journal of rare diseases   14 ( 1 )   277 - 277   2019年12月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    BACKGROUND: Schaaf-Yang syndrome (SYS) is a newly recognized imprinting related syndrome, which is caused by a truncating variant in maternally imprinted MAGEL2 located in 15q11-q13. Yet, precise pathomechanism remains to be solved. We sequenced MAGEL2 in patients suspected Prader-Willi syndrome (PWS) to delineate clinical presentation of SYS. We examined 105 patients with clinically suspected PWS but without a specific PWS genetic alteration. Sanger sequencing of the entire MAGEL2 gene and methylation-specific restriction enzyme treatment to detect the parent of origin were performed. Clinical presentation was retrospectively assessed in detail. RESULTS: Truncating variants in MAGEL2 were detected in six patients (5.7%), including a pair of siblings. All truncating variants in affected patients were on the paternally derived chromosome, while the healthy father of the affected siblings inherited the variant from his mother. Patients with MAGEL2 variants shared several features with PWS, such as neonatal hypotonia, poor suck, and obesity; however, there were also unique features, including arthrogryposis and a failure to acquire meaningful words. Additionally, an episode of neurological deterioration following febrile illness was confirmed in four of the six patients, which caused severe neurological sequalae. CONCLUSIONS: SYS can be present in infants suspected with PWS but some unique features, such as arthrogryposis, can help discriminate between the two syndromes. An episode of neurological deterioration following febrile illness should be recognized as an important complication.

    DOI: 10.1186/s13023-019-1249-4

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  • Genetic abnormalities in a large cohort of Coffin-Siris syndrome patients. 査読 国際誌

    Futoshi Sekiguchi, Yoshinori Tsurusaki, Nobuhiko Okamoto, Keng Wee Teik, Seiji Mizuno, Hiroshi Suzumura, Bertrand Isidor, Winnie Peitee Ong, Muzhirah Haniffa, Susan M White, Mari Matsuo, Kayoko Saito, Shubha Phadke, Tomoki Kosho, Patrick Yap, Manisha Goyal, Lorne A Clarke, Rani Sachdev, George McGillivray, Richard J Leventer, Chirag Patel, Takanori Yamagata, Hitoshi Osaka, Yoshiya Hisaeda, Hirofumi Ohashi, Kenji Shimizu, Keisuke Nagasaki, Junpei Hamada, Sumito Dateki, Takashi Sato, Yasutsugu Chinen, Tomonari Awaya, Takeo Kato, Kougoro Iwanaga, Masahiko Kawai, Takashi Matsuoka, Yoshikazu Shimoji, Tiong Yang Tan, Seema Kapoor, Nerine Gregersen, Massimiliano Rossi, Mathieu Marie-Laure, Lesley McGregor, Kimihiko Oishi, Lakshmi Mehta, Greta Gillies, Paul J Lockhart, Kate Pope, Anju Shukla, Katta Mohan Girisha, Ghada M H Abdel-Salam, David Mowat, David Coman, Ok Hwa Kim, Marie-Pierre Cordier, Kate Gibson, Jeff Milunsky, Jan Liebelt, Helen Cox, Salima El Chehadeh, Annick Toutain, Ken Saida, Hiromi Aoi, Gaku Minase, Naomi Tsuchida, Kazuhiro Iwama, Yuri Uchiyama, Toshifumi Suzuki, Kohei Hamanaka, Yoshiteru Azuma, Atsushi Fujita, Eri Imagawa, Eriko Koshimizu, Atsushi Takata, Satomi Mitsuhashi, Satoko Miyatake, Takeshi Mizuguchi, Noriko Miyake, Naomichi Matsumoto

    Journal of human genetics   64 ( 12 )   1173 - 1186   2019年12月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Coffin-Siris syndrome (CSS, MIM#135900) is a congenital disorder characterized by coarse facial features, intellectual disability, and hypoplasia of the fifth digit and nails. Pathogenic variants for CSS have been found in genes encoding proteins in the BAF (BRG1-associated factor) chromatin-remodeling complex. To date, more than 150 CSS patients with pathogenic variants in nine BAF-related genes have been reported. We previously reported 71 patients of whom 39 had pathogenic variants. Since then, we have recruited an additional 182 CSS-suspected patients. We performed comprehensive genetic analysis on these 182 patients and on the previously unresolved 32 patients, targeting pathogenic single nucleotide variants, short insertions/deletions and copy number variations (CNVs). We confirmed 78 pathogenic variations in 78 patients. Pathogenic variations in ARID1B, SMARCB1, SMARCA4, ARID1A, SOX11, SMARCE1, and PHF6 were identified in 48, 8, 7, 6, 4, 1, and 1 patients, respectively. In addition, we found three CNVs including SMARCA2. Of particular note, we found a partial deletion of SMARCB1 in one CSS patient and we thoroughly investigated the resulting abnormal transcripts.

    DOI: 10.1038/s10038-019-0667-4

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  • Germline-Derived Gain-of-Function Variants of Gsα-Coding GNAS Gene Identified in Nephrogenic Syndrome of Inappropriate Antidiuresis. 査読 国際誌

    Mami Miyado, Maki Fukami, Shuji Takada, Miho Terao, Kazuhiko Nakabayashi, Kenichiro Hata, Yoichi Matsubara, Yoko Tanaka, Goro Sasaki, Keisuke Nagasaki, Masaaki Shiina, Kazuhiro Ogata, Youhei Masunaga, Hirotomo Saitsu, Tsutomu Ogata

    Journal of the American Society of Nephrology : JASN   30 ( 5 )   877 - 889   2019年5月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    BACKGROUND: The stimulatory G-protein α-subunit encoded by GNAS exons 1-13 (GNAS-Gsα) mediates signal transduction of multiple G protein-coupled receptors, including arginine vasopressin receptor 2 (AVPR2). Various germline-derived loss-of-function GNAS-Gsα variants of maternal and paternal origin have been found in pseudohypoparathyroidism type Ia and pseudopseudohypoparathyroidism, respectively. Specific somatic gain-of-function GNAS-Gsα variants have been detected in McCune-Albright syndrome and may result in phosphate wasting. However, no germline-derived gain-of-function variant has been identified, implying that such a variant causes embryonic lethality. METHODS: We performed whole-exome sequencing in two families with dominantly inherited nephrogenic syndrome of inappropriate antidiuresis (NSIAD) as a salient phenotype after excluding a gain-of-function variant of AVPR2 and functional studies for identified variants. RESULTS: Whole-exome sequencing revealed two GNAS-Gsα candidate variants for NSIAD: GNAS-Gsα p.(F68_G70del) in one family and GNAS-Gsα p.(M255V) in one family. Both variants were absent from public and in-house databases. Of genes with rare variants, GNAS-Gsα alone was involved in AVPR2 signaling and shared by the families. Protein structural analyses revealed a gain-of-function-compatible conformational property for p.M255V-Gsα, although such assessment was not possible for p.F68_G70del-Gsα. Both variants had gain-of-function effects that were significantly milder than those of McCune-Albright syndrome-specific somatic Gsα variants. Model mice for p.F68_G70del-Gsα showed normal survivability and NSIAD-compatible phenotype, whereas those for p.M255V-Gsα exhibited severe failure to thrive. CONCLUSIONS: This study shows that germline-derived gain-of-function rare variants of GNAS-Gsα exist and cause NSIAD as a novel Gsα-mediated genetic disease. It is likely that AVPR2 signaling is most sensitive to GNAS-Gsα's gain-of-function effects.

    DOI: 10.1681/ASN.2018121268

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  • Delineation of LZTR1 mutation-positive patients with Noonan syndrome and identification of LZTR1 binding to RAF1-PPP1CB complexes. 査読 国際誌

    Ikumi Umeki, Tetsuya Niihori, Taiki Abe, Shin-Ichiro Kanno, Nobuhiko Okamoto, Seiji Mizuno, Kenji Kurosawa, Keisuke Nagasaki, Makoto Yoshida, Hirofumi Ohashi, Shin-Ichi Inoue, Yoichi Matsubara, Ikuma Fujiwara, Shigeo Kure, Yoko Aoki

    Human genetics   138 ( 1 )   21 - 35   2019年1月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    RASopathies are a group of developmental disorders caused by mutations in genes that regulate the RAS/MAPK pathway and include Noonan syndrome (NS), Costello syndrome, cardiofaciocutaneous syndrome and other related disorders. Whole exome sequencing studies recently identified LZTR1, PPP1CB and MRAS as new causative genes in RASopathies. However, information on the phenotypes of LZTR1 mutation-positive patients and functional properties of the mutations are limited. To identify variants of LZTR1, PPP1CB, and MRAS, we performed a targeted next-generation sequencing and reexamined previously analyzed exome data in 166 patients with suspected RASopathies. We identified eight LZTR1 variants, including a de novo variant, in seven probands who were suspicious for NS and one known de novo PPP1CB variant in a patient with NS. One of the seven probands had two compound heterozygous LZTR1 variants, suggesting autosomal recessive inheritance. All probands with LZTR1 variants had cardiac defects, including hypertrophic cardiomyopathy and atrial septal defect. Five of the seven probands had short stature or intellectual disabilities. Immunoprecipitation of endogenous LZTR1 followed by western blotting showed that LZTR1 bound to the RAF1-PPP1CB complex. Cells transfected with a small interfering RNA against LZTR1 exhibited decreased levels of RAF1 phosphorylated at Ser259. These are the first results to demonstrate LZTR1 in association with the RAF1-PPP1CB complex as a component of the RAS/MAPK pathway.

    DOI: 10.1007/s00439-018-1951-7

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  • Polysomnography as an indicator for cervicomedullary decompression to treat foramen magnum stenosis in achondroplasia. 査読 国際誌

    Masakazu Sano, Nao Takahashi, Keisuke Nagasaki, Makoto Oishi, Junichi Yoshimura, Yukihiko Fujii

    Child's nervous system : ChNS : official journal of the International Society for Pediatric Neurosurgery   34 ( 11 )   2275 - 2281   2018年11月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    OBJECTIVE: Management of cervicomedullary compression due to foramen magnum stenosis in achondroplasia remains controversial, especially for patients with no symptoms or mild symptoms. We examined the effectiveness of polysomnography (PSG) as an indicator for cervicomedullary decompression treatment. METHODS: We retrospectively reviewed nine achondroplasia cases (mean age 1 year and 9 months) treated from 2008 to 2015. All patients were examined by PSG, magnetic resonance imaging (MRI), and otolaryngeal fibroscopy. We analyzed demographic data, clinical presentation, degree and type of respiratory impairment, severity of foramen magnum stenosis and concomitant cervicomedullary compression, treatment (conservative or surgical), and clinical outcome. RESULTS: Eight of nine patients presented with no severe symptoms in the daytime. However, MRI revealed four severe, four moderate, and one mild case of cervicomedullary compression, and PSG demonstrated severe sleep apnea in four cases and moderate sleep apnea in five cases. All sleep apnea cases were obstructive or obstructive-dominant. Fibroscopy revealed no upper airway stenosis in six cases and mild stenosis in three cases. Four patients who had severe sleep-related respiratory disturbance on PSG and severe or moderate cervicomedullary compression were treated by cervicomedullary decompression. Three of these patients demonstrated improved sleep respiration soon after surgery, while one required temporary tracheostomy due to bilateral vocal cord paralysis caused by compression during intratracheal intubation. CONCLUSION: Polysomnography can be a useful indicator for cervicomedullary decompression surgery, especially in cases of seemingly asymptomatic achondroplasia with severe foramen magnum stenosis.

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  • Successful treatment of psoriatic arthritis associated with adrenal hypoplasia congenita using infliximab. 査読 国際誌

    Kiyoto Kimura, Atsushi Fujimoto, Tokiko Deguchi, Osamu Ansai, Yuko Tsuchida, Natsumi Hama, Naoki Kondo, Keisuke Nagasaki, Waka Ishida, Riichiro Abe

    European journal of dermatology : EJD   28 ( 5 )   707 - 708   2018年10月

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    記述言語:英語  

    DOI: 10.1684/ejd.2018.3382

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  • Clinical characteristics of adolescent cases with type A insulin resistance syndrome caused by heterozygous mutations in the β-subunit of INSR. 査読 国際誌

    Takasawa K, Tsuji-Hosokawa A, Takishima S, Wada Y, Nagasaki K, Dateki S, Numakura C, Hijikata A, Shirai T, Kashimada K, Morio T

    Journal of diabetes   11 ( 1 )   46 - 54   2018年6月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    BACKGROUND: Type A insulin resistance (IR) is a rare form of severe congenital IR that is frequently caused by heterozygous mutations in the insulin receptor (INSR) gene. Although Type A IR requires appropriate intervention from the early stages of diabetes, proper diagnosis of this disease is challenging, and accumulation of cases with detailed clinical profiles and genotypes is required. METHODS: Herein we report on six peripubertal patients with clinically diagnosed Type A IR, including four patients with an identified INSR mutation. To clarify the clinical features of Type A IR due to INSR mutation, we validated the clinical characteristics of Type A IR patients with identified INSR mutations by comparing them with mutation-negative patients. RESULTS: Four heterozygous missense mutations within the β-subunit of INSR were detected: Gly1146Arg, Arg1158Trp, Arg1201Trp, and one novel Arg1201Pro mutation. There were no obvious differences in clinical phenotypes, except for normal lipid metabolism and autosomal dominant inheritance, between Type A IR due to INSR mutations and Type A IR due to other factors. However, our analysis revealed that the extent of growth retardation during the fetal period is correlated with the severity of insulin signaling impairment. CONCLUSIONS: The present study details the clinical features of four patients with genetically proven Type A IR. Further accumulation of genetically proven cases and long-term treatment prognoses following early diagnosis are required to further elucidate the dynamics of this disease.

    DOI: 10.1111/1753-0407.12797

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  • Incidence rate and characteristics of symptomatic vitamin D deficiency in children: a nationwide survey in Japan. 査読

    Kubota T, Nakayama H, Kitaoka T, Nakamura Y, Fukumoto S, Fujiwara I, Hasegawa Y, Ihara K, Kitanaka S, Koyama S, Kusuda S, Mizuno H, Nagasaki K, Ozono K

    Endocrine journal   65 ( 6 )   593 - 599   2018年3月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    There is concern that vitamin D deficiency is prevalent among children in Japan as well as worldwide. We conducted a nationwide epidemiologic survey of symptomatic vitamin D deficiency to observe its incidence rate among Japanese children. A questionnaire inquiring the number of new patients with vitamin D deficiency rickets and/or hypocalcemia for 3 years was sent to 855 randomly selected hospitals with a pediatrics department in Japan. In this survey, we found that 250 children were diagnosed with symptomatic vitamin D deficiency. The estimated number of patients with symptomatic vitamin D deficiency per year was 183 (95% confidence interval (CI): 145-222). The overall annual incidence rate among children under 15 years of age was 1.1 per 100,000 population (95% CI: 0.9-1.4). The second survey has provided detailed information on 89 patients with symptomatic vitamin D deficiency under 5 years of age in hospitals in the current research group. The nationwide and second surveys estimated the overall annual incidence rate of symptomatic vitamin D deficiency in children under 5 years of age to be 3.5 (2.7-4.2) per 100,000 population. The second survey revealed 83% had bowed legs, 88% had exclusive breastfeeding, 49% had a restricted and/or unbalanced diet and 31% had insufficient sun exposure among the 89 patients. This is the first nationwide survey on definitive clinical vitamin D deficiency in children in Japan. Elucidating the frequency and characteristics of symptomatic vitamin D deficiency among children is useful to develop preventative public health strategies.

    DOI: 10.1507/endocrj.ej18-0008

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  • (Epi)genotype-Phenotype Analysis in 69 Japanese Patients With Pseudohypoparathyroidism Type I. 査読 国際誌

    Sano S, Nakamura A, Matsubara K, Nagasaki K, Fukami M, Kagami M, Ogata T

    Journal of the Endocrine Society   2 ( 1 )   9 - 23   2018年1月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Context: Pseudohypoparathyroidism type I (PHP-I) is divided into PHP-Ia with Albright hereditary osteodystrophy and PHP-Ib, which usually shows no Albright hereditary osteodystrophy features. Although PHP-Ia and PHP-Ib are typically caused by genetic defects involving α subunit of the stimulatory G protein (Gsα)-coding GNAS exons and methylation defects of the GNAS differentially methylated regions (DMRs) on the maternal allele, respectively, detailed phenotypic characteristics still remains to be examined. Objective: To clarify phenotypic characteristics according to underlying (epi)genetic causes. Patients and Methods: We performed (epi)genotype-phenotype analysis in 69 Japanese patients with PHP-I; that is, 28 patients with genetic defects involving Gsα-coding GNAS exons (group 1) consisting of 12 patients with missense variants (subgroup A) and 16 patients with null variants (subgroup B), as well as 41 patients with methylation defects (group 2) consisting of 21 patients with broad methylation defects of the GNAS-DMRs (subgroup C) and 20 patients with an isolated A/B-DMR methylation defect accompanied by the common STX16 microdeletion (subgroup D). Results: Although (epi)genotype-phenotype findings were grossly similar to those reported previously, several important findings were identified, including younger age at hypocalcemic symptoms and higher frequencies of hyperphosphatemia in subgroup C than in subgroup D, development of brachydactyly in four patients of subgroup C, predominant manifestation of subcutaneous ossification in subgroup B, higher frequency of thyrotropin resistance in group 1 than in group 2, and relatively low thyrotropin values in four patients with low T4 values and relatively low luteinizing hormone/follicle-stimulating hormone values in five adult females with ovarian dysfunction. Conclusion: The results imply the presence of clinical findings characteristic of each underlying cause and provide useful information on the imprinting status of Gsα.

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  • Incidence and Characteristics of Adrenal Crisis in Children Younger than 7 Years with 21-Hydroxylase Deficiency: A Nationwide Survey in Japan. 査読 国際誌

    Ishii T, Adachi M, Takasawa K, Okada S, Kamasaki H, Kubota T, Kobayashi H, Sawada H, Nagasaki K, Numakura C, Harada S, Minamitani K, Sugihara S, Tajima T

    Hormone research in paediatrics   89 ( 3 )   166 - 171   2018年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    BACKGROUND/AIMS: We aimed to evaluate the incidence and characteristics of adrenal crisis in Japanese children with 21-hydroxylase deficiency (21-OHD). METHODS: We conducted a retrospective nationwide survey for the councilors of the Japanese Society for Pediatric Endocrinology (JSPE) regarding adrenal crisis in children under 7 years with 21-OHD, admitted to hospitals from 2011 through 2016. We defined adrenal crisis as the acute impairment of general health due to glucocorticoid deficiency with at least two of symptoms, signs, or biochemical abnormalities. RESULTS: The councilors of the JSPE in 83 institutions responded to this survey (response rate, 60.1%). Data analyses of 378 patients with 1,101.4 person-years (PYs) revealed that 67 patients (17.7%) experienced at least 1 episode of hospital admission for adrenal crisis at the median age of 2 years. The incidence of adrenal crisis was calculated as 10.9 per 100 PYs (95% confidence interval [CI] 9.6-12.2). Infections were the most common precipitating factors, while no factor was observed in 12.5%. Hypoglycemia occurred concomitantly in 27.4%. One patient died from severe hypoglycemia, resulting in a mortality rate of 0.09 per 100 PYs (95% CI 0.0-0.2). CONCLUSION: Adrenal crisis is not rare and can be accompanied by disastrous hypoglycemia in children with 21-OHD.

    DOI: 10.1159/000486393

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  • Next generation sequencing-based mutation screening of 86 patients with idiopathic short stature. 査読

    Hattori A, Katoh-Fukui Y, Nakamura A, Matsubara K, Kamimaki T, Tanaka H, Dateki S, Adachi M, Muroya K, Yoshida S, Ida S, Mitani M, Nagasaki K, Fukami M

    Endocrine journal   64 ( 10 )   947 - 954   2017年10月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Although mutations in ACAN, FGFR3, NPR2, and SHOX typically lead to skeletal dysplasia, and mutations in GHRHR, GH1, GHR, STAT5B, IGF1, IGFALS, and IGF1R usually underlie hormonal defects of the growth hormone (GH)-insulin-like growth factor 1 (IGF1) axis, such mutations have also been identified in patients with idiopathic short stature (ISS). Of these, SHOX abnormalities are known to account for a certain percentage of ISS cases, whereas the frequency of mutations in the other 10 genes in ISS cohorts remains unknown. Here, we performed next-generation sequencing-based mutation screening of the 10 genes in 86 unrelated Japanese ISS patients without SHOX abnormalities. We searched for rare protein-altering variants. The functional significance of the identified variants was assessed by in silico analyses. Consequently, we identified 18 heterozygous rare variants in 19 patients, including four probable damaging variants in ACAN, six pathogenicity-unknown variants in FGFR3, GHRHR, GHR, and IGFALS, and eight possible benign variants. Pathogenic variants in NPR2, GH1, and IGF1 were absent from our cohort. Unlike previously reported patients with ACAN mutations, our four patients with ACAN variants manifested non-specific short stature with age-appropriate or mildly delayed bone ages, and had parents of normal stature. These results indicate that ACAN mutations can underlie ISS without characteristic skeletal features, and that such mutations are possibly associated with de novo occurrence or low penetrance. In addition, our data imply that mutations in FGFR3, NPR2, and GH-IGF1 axis genes play only limited roles in the etiology of ISS.

    DOI: 10.1507/endocrj.ej17-0150

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  • Continuous hypomethylation of the KCNQ1OT1:TSS-DMR in monochorionic twins discordant for Beckwith-Wiedemann syndrome. 査読 国際誌

    Inoue T, Nakamura A, Matsubara K, Nyuzuki H, Nagasaki K, Oka A, Fukami M, Kagami M

    American journal of medical genetics. Part A   173 ( 10 )   2847 - 2850   2017年10月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    DOI: 10.1002/ajmg.a.38419

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  • Safety and efficacy of treatment with asfotase alfa in patients with hypophosphatasia: Results from a Japanese clinical trial. 査読 国際誌

    Kitaoka T, Tajima T, Nagasaki K, Kikuchi T, Yamamoto K, Michigami T, Okada S, Fujiwara I, Kokaji M, Mochizuki H, Ogata T, Tatebayashi K, Watanabe A, Ozono K

    Clinical endocrinology   87 ( 1 )   10 - 19   2017年7月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    OBJECTIVE: Hypophosphatasia (HPP) is a rare skeletal disease characterized by hypomineralization and low alkaline phosphatase activity. Asfotase alfa (AA) has been recently developed to treat HPP complications. This study evaluated its safety and efficacy in Japan. DESIGN: Open-label, multicentre, prospective trial. Patients were enrolled in 11 hospitals from June 2014 to July 2015. PATIENTS: Thirteen patients (9 females, 4 males) ages 0 days to 34 years at baseline were enrolled and treated with AA (2 mg/kg three times weekly subcutaneously in all but one patient). All had ALPL gene mutations. HPP forms were perinatal (n=6), infantile (n=5), childhood (n=1) and adult (n=1). MEASUREMENTS: Safety determined from adverse events (AEs) and laboratory data was the primary outcome measure. Efficacy was assessed as a secondary outcome measure from overall survival, respiratory status, rickets severity and gross motor development. RESULTS: Injection site reactions were the most frequent AEs. Serious AEs possibly related to treatment were convulsion and hypocalcaemia observed in a patient with the perinatal form. In addition, hypercalcaemia and/or hyperphosphatemia was observed in three patients with the infantile form and a low-calcium and/or low-phosphate formula was given to these patients. With respect to efficacy, all patients survived and the radiographic findings, developmental milestones and respiratory function improved. CONCLUSION: Asfotase alfa therapy improved skeletal, respiratory and physical symptoms with a few serious AEs in patients with HPP. Our results add support to the safety and efficacy of AA therapy for HPP patients.

    DOI: 10.1111/cen.13343

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  • Occipitocervical Fusion for Severe Atlantoaxial Dislocation in an Underdeveloped Child with Chondrodysplasia Punctata: A Case Report. 査読

    Tanaka Y, Watanabe K, Katsumi K, Ohashi M, Nagasaki K, Hirano T

    JBJS case connector   2017年

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    掲載種別:研究論文(学術雑誌)  

    DOI: 10.2106/jbjs.cc.16.00121

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  • Childbirth and fertility preservation in childhood and adolescent cancer patients: a second national survey of Japanese pediatric endocrinologists. 査読

    Miyoshi Y, Yorifuji T, Horikawa R, Takahashi I, Nagasaki K, Ishiguro H, Fujiwara I, Ito J, Oba M, Fujisaki H, Kato M, Shimizu C, Kato T, Matsumoto K, Ozono K

    Clinical pediatric endocrinology : case reports and clinical investigations : official journal of the Japanese Society for Pediatric Endocrinology   26 ( 2 )   81 - 88   2017年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Although existing guidelines recommend long-term follow-up of childhood cancer survivors (CCSs), their fertility has not been fully investigated in Japan. To address this issue, we organized a working panel consisting of medical specialists in foundation hospitals. We conducted questionnaire surveys targeting pediatric endocrinologists regarding reproduction in pediatric and adolescent cancer patients in collaboration with the CCS committee of the Japanese Society for Pediatric Endocrinology (JSPE). The first questionnaire was sent to 178 directors or councilors of the JSPE, and the second was sent to those who had provided answers on their experience with childbirth or fertility preservation. A total of 151 responses (84.8%) were obtained in the first survey. In the second survey, the response rate was 100% (39 respondents). There were 27 answers describing experiences with childbirth (16 from partners of male CCSs, 22 from female CCSs). A few cases of premature birth and low birth weight were reported. There were 25 answers describing experiences with fertility preservation; 21 were from male and 17 from female CCSs. It was mainly physicians who recommended fertility preservation. This nationwide questionnaire survey revealed that a limited number of Japanese pediatric endocrinologists had experience with childbirth and fertility preservation in CCSs. A further long-term follow-up study of their fertility is needed.

    DOI: 10.1297/cpe.26.81

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  • Systematic molecular analyses of SHOX in Japanese patients with idiopathic short stature and Leri-Weill dyschondrosteosis. 査読 国際誌

    Shima H, Tanaka T, Kamimaki T, Dateki S, Muroya K, Horikawa R, Kanno J, Adachi M, Naiki Y, Tanaka H, Mabe H, Yagasaki H, Kure S, Matsubara Y, Japanese SHOX study group

    Journal of human genetics   61 ( 7 )   585 - 91   2016年7月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    The etiology of idiopathic short stature (ISS) and Leri-Weill dyschondrosteosis (LWD) in European patients is known to include SHOX mutations and copy-number variations (CNVs) involving SHOX and/or the highly evolutionarily conserved non-coding DNA elements (CNEs) flanking the gene. However, the frequency and types of SHOX abnormalities in non-European patients and the clinical importance of mutations in the CNEs remains to be clarified. Here, we performed systematic molecular analyses of SHOX for 328 Japanese patients with ISS or LWD. SHOX abnormalities accounted for 3.8% of ISS and 50% of LWD cases. CNVs around SHOX were identified in 16 cases, although the ~47 kb deletion frequently reported in European patients was absent in our cases. Probably damaging mutations and benign/silent substitutions were detected in four cases, respectively. Although CNE-linked substitutions were detected in 15 cases, most of them affected poorly conserved nucleotides and were shared by unaffected individuals. These results suggest that the frequency and mutation spectrum of SHOX abnormalities are comparable between Asian and European patients, with the exception of a European-specific downstream deletion. Furthermore, this study highlights the clinical importance and genetic heterogeneity of the SHOX-flanking CNVs, and indicates a limited clinical significance of point mutations in the CNEs.

    DOI: 10.1038/jhg.2016.18

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  • Complex Genomic Rearrangement Within the GNAS Region Associated With Familial Pseudohypoparathyroidism Type 1b. 査読 国際誌

    Nakamura A, Hamaguchi E, Horikawa R, Nishimura Y, Matsubara K, Sano S, Nagasaki K, Matsubara Y, Umezawa A, Tajima T, Ogata T, Kagami M, Okamura K, Fukami M

    The Journal of clinical endocrinology and metabolism   101 ( 7 )   2623 - 7   2016年7月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    CONTEXT: Pseudohypoparathyroidism type 1b (PHP-1b) results from methylation defects at the G protein stimulatory α subunit (GNAS) exon A/B-differentially methylated region (DMR). Although microduplications in the GNAS region were recently identified in two PHP-1b patients, genetic information on these patients remained fragmentary. CASE DESCRIPTION: A 20-year-old Japanese male and his mother presented with hypocalcemia and elevated blood levels of intact PTH. The proband had a maternal uncle who was previously diagnosed with PHP-1b. Methylation-specific multiplex ligation-dependent probe amplification, array-based comparative genomic hybridization, pyrosequencing, fluorescence in situ hybridization, and whole-genome sequencing were performed for this family. The proband, mother, and uncle carried maternally derived approximately 133-kb duplication-triplication-duplication rearrangements at 20q13.32 involving NESP55, NESPAS, XLαs, and exon A/B-DMR but not STX16 or the Gsα coding region. These individuals exhibited partial methylation defects of NESP55-, NESPAS-, and XLαs-DMRs, which were ascribable to the increased copy numbers of these regions retaining the maternally derived methylation pattern and loss of methylation of exon A/B-DMR, which was inexplicable by the copy-number alterations. Fusion junctions of the rearrangement resided within non-repeat sequences and were accompanied by short-templated insertions. CONCLUSIONS: Our results indicate that maternally derived copy-number gains in the GNAS region mediated by nonhomologous end-joining and/or by break-induced replication can underlie autosomal dominant PHP-1b. These rearrangements likely affect methylation of exon A/B-DMR by disconnecting or disrupting its cis-acting regulator(s). This study provides a novel example of human disorders resulting from functional disturbance in the cis-regulatory machinery of DNA methylation.

    DOI: 10.1210/jc.2016-1725

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  • Gonadal function, fertility, and reproductive medicine in childhood and adolescent cancer patients: a national survey of Japanese pediatric endocrinologists. 査読

    Miyoshi Y, Yorifuji T, Horikawa R, Takahashi I, Nagasaki K, Ishiguro H, Fujiwara I, Ito J, Oba M, Kawamoto H, Fujisaki H, Kato M, Shimizu C, Kato T, Ozono K

    Clinical pediatric endocrinology : case reports and clinical investigations : official journal of the Japanese Society for Pediatric Endocrinology   25 ( 2 )   45 - 57   2016年4月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    An increasing number of pediatric cancer patients survive, and treatment-related infertility represents one of the most important issues for these patients. While official guidelines in Japan recommend long-term follow-up of childhood cancer survivors (CCSs), their gonadal function and fertility have not been clarified. To address this issue, we organized a working panel to compile evidence from long-term survivors who received treatments for cancer during childhood or adolescence. In collaboration with members of the CCS Committee of the Japanese Society for Pediatric Endocrinology (JSPE), we conducted a questionnaire survey regarding reproductive function in pediatric cancer patients. A cross-sectional survey was sent to 178 JSPE-certified councilors who were asked to self-evaluate the medical examinations they had performed. A total of 151 responses were obtained, revealing that 143 endocrinologists were involved in the care of CCSs. A quarter of the respondents reported having experienced issues during gonadal or reproductive examinations. Several survivors did not remember or fully understand the explanation regarding gonadal damage, and faced physical and psychological distress when discussing the risk of becoming infertile. Pediatric endocrinologists had anxieties regarding their patients' infertility and the risk of miscarriage, premature birth, and delivery problems. Only a limited number of endocrinologists had experience with managing childbirth and fertility preservation. Many councilors mentioned the necessity for inter-disciplinary communication among healthcare providers. Both endocrinologists and oncologists should set and follow a uniform clinical guideline that includes management of fertility of CCSs.

    DOI: 10.1297/cpe.25.45

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  • Formulation for Effective Screening and Management of Nonalcoholic Steatohepatitis: Noninvasive NAFLD Management Strategy. 査読 国際誌

    Hirose K, Kanefuji T, Suda T, Sugitani S, Nagasaki K, Kubota T, Igarashi M, Terai S

    Gastroenterology research and practice   2016   6343656 - 6343656   2016年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    To establish a versatile means for screening and management of nonalcoholic steatohepatitis (NASH), shear wave velocity was measured in 20 normal controls and 138 consecutive nonalcoholic fatty liver disease (NAFLD) cases. Referencing biochemical properties in 679 healthy volunteers, a formula to distinguish NASH suspects was established and validated in another cohort of 138 histologically proven NAFLD cases. NASH and simple steatosis (SS) suspects were selected based on a plot of shear wave velocity against age. A formula consisting of five factors (γ-glutamyl transpeptidase, alkaline phosphatase, platelet counts, body mass index, and presence/absence of type 2 diabetes mellitus) distinguished NASH suspects from SS suspects with area under the receiver operating characteristic curve values of 86% and 84% in the development and validation cohorts. Among 25 NAFLD cases in which shear wave velocity was repeatedly measured, 8 and 9 cases revealed an increase or decrease, respectively, of shear wave velocity in the entire liver, and the corresponding change in shear wave velocity was primarily observed in the right lobe or the left lateral segment, respectively. These results suggest that the new formula and sequential shear wave velocity measurements at each segment enable high throughput screening of NASH suspects and noninvasive assessment of pathophysiological alleviation/aggravation in cases of NASH.

    DOI: 10.1155/2016/6343656

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  • Successful Combined Treatment for Atrophic Thyroiditis With Growth Hormone Deficiency. 査読 国際誌

    Otsuka T, Tajima N, Nagasaki K, Okazaki M

    Global pediatric health   3   2333794X16670082   2016年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    DOI: 10.1177/2333794x16670082

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  • Testicular dysgenesis/regression without campomelic dysplasia in patients carrying missense mutations and upstream deletion of SOX9. 査読 国際誌

    Katoh-Fukui Y, Igarashi M, Nagasaki K, Horikawa R, Nagai T, Tsuchiya T, Suzuki E, Miyado M, Hata K, Nakabayashi K, Hayashi K, Matsubara Y, Baba T, Fukami M

    Molecular genetics & genomic medicine   3 ( 6 )   550 - 7   2015年11月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    SOX9 haploinsufficiency underlies campomelic dysplasia (CD) with or without testicular dysgenesis. Current understanding of the phenotypic variability and mutation spectrum of SOX9 abnormalities remains fragmentary. Here, we report three patients with hitherto unreported SOX9 abnormalities. These patients were identified through molecular analysis of 33 patients with 46,XY disorders of sex development (DSD). Patients 1-3 manifested testicular dysgenesis or regression without CD. Patients 1 and 2 carried probable damaging mutations p.Arg394Gly and p.Arg437Cys, respectively, in the SOX9 C-terminal domain but not in other known 46,XY DSD causative genes. These substitutions were absent from ~120,000 alleles in the exome database. These mutations retained normal transactivating activity for the Col2a1 enhancer, but showed impaired activity for the Amh promoter. Patient 3 harbored a maternally inherited ~491 kb SOX9 upstream deletion that encompassed the known 32.5 kb XY sex reversal region. Breakpoints of the deletion resided within nonrepeat sequences and were accompanied by a short-nucleotide insertion. The results imply that testicular dysgenesis and regression without skeletal dysplasia may be rare manifestations of SOX9 abnormalities. Furthermore, our data broaden pathogenic SOX9 abnormalities to include C-terminal missense substitutions which lead to target-gene-specific protein dysfunction, and enhancer-containing upstream microdeletions mediated by nonhomologous end-joining.

    DOI: 10.1002/mgg3.165

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  • Impact of a novel homozygous mutation in nicotinamide nucleotide transhydrogenase on mitochondrial DNA integrity in a case of familial glucocorticoid deficiency. 査読 国際誌

    Fujisawa Y, Napoli E, Wong S, Song G, Yamaguchi R, Matsui T, Nagasaki K, Ogata T, Giulivi C

    BBA clinical   3   70 - 78   2015年6月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    BACKGROUND: Familial Glucocorticoid Deficiency (FGD) is a rare autosomal recessive disorder that is characterized by isolated glucocorticoid deficiency. Recently, mutations in the gene encoding for the mitochondrial nicotinamide nucleotide transhydrogenase (NNT) have been identified as a causative gene for FGD; however, no NNT activities have been reported in FGD patients carrying NNT mutations. METHODS: Clinical, biochemical and molecular analyses of lymphocytes from FDG homozygous and heterozygous carriers for the F215S NNT mutation. RESULTS: In this study, we described an FGD-affected Japanese patient carrying a novel NNT homozygous mutation (c.644T>C; F215S) with a significant loss-of-function (NNT activity = 31% of healthy controls) in peripheral blood cells' mitochondria. The NNT activities of the parents, heterozygous for the mutation, were 61% of controls. CONCLUSIONS: Our results indicated that (i) mitochondrial biogenesis (citrate synthase activity) and/or mtDNA replication (mtDNA copy number) were affected at ≤60% NNT activity because these parameters were affected in individuals carrying either one or both mutated alleles; and (ii) other outcomes (mtDNA deletions, protein tyrosine nitration, OXPHOS capacity) were affected at ≤30% NNT activity as also observed in murine cerebellar mitochondria from C57BL/6J (NNT-/-) vs. C57BL/6JN (NNT+/+) substrains. GENERAL SIGNIFICANCE: By studying a family affected with a novel point mutation in the NNT gene, a gene-dose response was found for various mitochondrial outcomes providing for novel insights into the role of NNT in the maintenance of mtDNA integrity beyond that described for preventing oxidative stress.

    DOI: 10.1016/j.bbacli.2014.12.003

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  • Molecular basis of non-syndromic hypospadias: systematic mutation screening and genome-wide copy-number analysis of 62 patients. 査読

    Kon M, Suzuki E, Dung VC, Hasegawa Y, Mitsui T, Muroya K, Ueoka K, Igarashi N, Nagasaki K, Oto Y, Hamajima T, Yoshino K, Igarashi M, Kato-Fukui Y, Fukami M

    Human reproduction (Oxford, England)   2015年3月

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    掲載種別:研究論文(学術雑誌)  

    DOI: 10.1093/humrep/deu364

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  • Silver-Russell syndrome without body asymmetry in three patients with duplications of maternally derived chromosome 11p15 involving CDKN1C. 査読 国際誌

    Nakashima S, Kato F, Kosho T, Nagasaki K, Kikuchi T, Kagami M, Fukami M, Ogata T

    Journal of human genetics   60 ( 2 )   91 - 5   2015年2月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    We report duplications of maternally derived chromosome 11p15 involving CDKN1C encoding a negative regulator for cell proliferation in three Japanese patients (cases 1 and 2 from family A and case 3 from family B) with Silver-Russell syndrome (SRS) phenotype lacking hemihypotrophy. Chromosome analysis showed 46,XX,der(16)t(11;16)(p15.3;q24.3)mat in case 1, 46,XY,der(16)t(11;16)(p15.3;q24.3)mat in case 2 and a de novo 46,XX,der(17)t(11;17)(p15.4;q25.3) in case 3. Genomewide oligonucleotide-based array comparative genomic hybridization, microsatellite analysis, pyrosequencing-based methylation analysis and direct sequence analysis revealed the presence of maternally derived extra copies of the distal chromosome 11p involving the wild-type CDKN1C (a ~7.98 Mb region in cases 1 and 2 and a ~4.43 Mb region in case 3). The results, in conjunction with the previous findings in patients with similar duplications encompassing CDKN1C and in those with intragenic mutations of CDKN1C, imply that duplications of CDKN1C, as well as relatively mild gain-of-function mutations of CDKN1C lead to SRS subtype that usually lack hemihypotrophy.

    DOI: 10.1038/jhg.2014.100

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  • Heterozygous defects in PAX6 gene and congenital hypopituitarism. 査読 国際誌

    Takagi M, Nagasaki K, Fujiwara I, Ishii T, Amano N, Asakura Y, Muroya K, Hasegawa Y, Adachi M, Hasegawa T

    European journal of endocrinology   172 ( 1 )   37 - 45   2015年1月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    BACKGROUND: The prevalence of congenital hypopituitarism (CH) attributable to known transcription factor mutations appears to be rare and other causative genes for CH remain to be identified. Due to the sporadic occurrence of CH, de novo chromosomal rearrangements could be one of the molecular mechanisms participating in its etiology, especially in syndromic cases. OBJECTIVE: To identify the role of copy number variations (CNVs) in the etiology of CH and to identify novel genes implicated in CH. SUBJECTS AND METHODS: We enrolled 88 (syndromic: 30; non-syndromic: 58) Japanese CH patients. We performed an array comparative genomic hybridization screening in the 30 syndromic CH patients. For all the 88 patients, we analyzed PAX6 by PCR-based sequencing. RESULTS: We identified one heterozygous 310-kb deletion of the PAX6 enhancer region in one patient showing isolated GH deficiency (IGHD), cleft palate, and optic disc cupping. We also identified one heterozygous 6.5-Mb deletion encompassing OTX2 in a patient with bilateral anophthalmia and multiple pituitary hormone deficiency. We identified a novel PAX6 mutation, namely p.N116S in one non-syndromic CH patient showing IGHD. The p.N116S PAX6 was associated with an impairment of the transactivation capacities of the PAX6-binding elements. CONCLUSIONS: This study showed that heterozygous PAX6 mutations are associated with CH patients. PAX6 mutations may be associated with diverse clinical features ranging from severely impaired ocular and pituitary development to apparently normal phenotype. Overall, this study identified causative CNVs with a possible role in the etiology of CH in <10% of syndromic CH patients.

    DOI: 10.1530/eje-14-0255

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  • Endocrinopathies in a boy with cryptic copy-number variations on 4q, 7q and Xp. 査読 国際誌

    Okuno M, Ogata T, Nakabayashi K, Urakami T, Fukami M, Nagasaki K

    Human genome variation   2   15020 - 15020   2015年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    We report a male patient with three copy-number variations (CNVs) and unique phenotype. He carried ~11.2 Mb terminal duplication on 4q, ~13.4 Mb terminal deletion on 7q and ~1.7 Mb interstitial duplication on Xp22.31, which were identified by array-based comparative genomic hybridization. He manifested mental retardation, mild brain anomalies and skeletal deformities ascribable to these CNVs, together with central precocious puberty and mild adrenocorticotropic hormone overproduction of unknown etiologies.

    DOI: 10.1038/hgv.2015.20

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  • Criteria of radiological diagnosis for neonates with hypochondroplasia. 査読

    Nagasaki K, Saito T, Takagi M, Hasegawa T, Nishimura G

    International journal of pediatric endocrinology   2015年

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    掲載種別:研究論文(学術雑誌)  

    DOI: 10.1186/1687-9856-2015-s1-o24

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  • Comprehensive next-generation sequencing analyses of hypoparathyroidism: identification of novel GCM2 mutations. 査読 国際誌

    Mitsui T, Narumi S, Inokuchi M, Nagasaki K, Nakazawa M, Sasaki G, Hasegawa T

    The Journal of clinical endocrinology and metabolism   99 ( 11 )   E2421-8   2014年11月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    CONTEXT: In most patients with hypoparathyroidism (HP), the etiology is not defined clinically. Eight genes (AIRE, CASR, CLDN16, GATA3, GCM2, PTH, TBCE, and TRPM6) are known to be responsible genes associated with HP; however, no previous study has screened the eight responsible genes comprehensively in HP patients. OBJECTIVES: This study was conducted to determine the genetic defect in HP patients. We also described clinical and molecular findings of two HP patients with novel GCM2 mutations. SUBJECTS AND METHODS: We enrolled 20 nonconsanguineous Japanese patients with child-onset permanent HP without 22q11 deletion. Mutations and genomic rearrangements involving the eight genes were screened by targeted next-generation sequencing (NGS). We also screened genetic rearrangements by array comparative genomic hybridization (aCGH) in the mutation-negative patients. A putative deletion, which was suspected by NGS, was additionally analyzed by droplet digital PCR (ddPCR) and junction PCR. Identified novel nucleotide-level GCM2 mutants were characterized in vitro. RESULTS: We identified seven patients with a single gene disorder, including a CASR mutation, GATA3 mutations, and novel GCM2 mutations (R367Tfs*15, T370M, and the deletion encompassing exon 1). This submicroscopic deletion, which had been suspected by NGS, could not be detected by aCGH and was confirmed by ddPCR and junction PCR. Functional studies of R367Tfs*- and T370M-GCM2 demonstrated a reduction of target gene transactivation in both. CONCLUSIONS: Using comprehensive NGS analyses, we identified the genetic defect in 35% of HP patients in our cohort and discovered novel GCM2 mutations including submicroscopic deletion that was undetectable by aCGH.

    DOI: 10.1210/jc.2014-2174

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  • Aromatase excess syndrome in a family with upstream deletion of CYP19A1. 査読

    Shihara D, Miyado M, Nakabayashi K, Shozu M, Ogata T, Nagasaki K, Fukami M

    Clinical endocrinology   2014年8月

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    掲載種別:研究論文(学術雑誌)  

    DOI: 10.1111/cen.12329

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  • Aromatase excess syndrome: a rare autosomal dominant disorder leading to pre- or peri-pubertal onset gynecomastia. 査読

    Fukami M, Miyado M, Nagasaki K, Shozu M, Ogata T

    Pediatric endocrinology reviews : PER   2014年3月

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    掲載種別:研究論文(学術雑誌)  

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  • A pineal region germ cell tumor with rapid enlargement after a long-term follow-up: case report. 査読 国際誌

    Shinya Jinguji, Masafumi Fukuda, Keisuke Nagasaki, Yukihiko Fujii

    Neurosurgery   72 ( 4 )   E687-93; discussion E693   2013年4月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    BACKGROUND AND IMPORTANCE: The natural history of pineal region germ cell tumors (GCTs) is not well known. We report a rare case of a pineal region GCT showing rapid enlargement within 2 months, after 7 years with no growth. CLINICAL PRESENTATION: A boy presented with gonadotropin-independent precocious puberty at 6 years 10 months of age. Although a slight elevation of β-human chorionic gonadotropin suggested that a small pineal cystic lesion observed on magnetic resonance imaging might be an β-human chorionic gonadotropin--producing tumor, it was not clear whether the mass was truly a GCT. Accordingly, we followed up the pineal lesion and serum pituitary gonadotropin levels for approximately 7 years. After this period without essential tumor growth, the pineal tumor suddenly showed rapid enlargement, which prompted treatment. A histopathological investigation revealed a mixed GCT with a germinoma and an immature teratoma. Serum pituitary gonadotropin levels at 5 years after the first examination had increased to normal pubertal ranges. Although the pituitary gonadotropin levels had remained low during the period with no tumor growth, the gonadotropin levels were elevated and had continued to increase at least 2 years before the rapid enlargement of the tumor. CONCLUSION: These phenomena suggest that levels of neuroendocrinological parameters such as pituitary gonadotropin at puberty might affect the enlargement of pineal region GCTs, which might account for the natural history of GCTs, ie, their frequent detection at puberty.

    DOI: 10.1227/NEU.0b013e318284708a

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  • Factors affecting functional outcomes in long-term survivors of intracranial germinomas: a 20-year experience in a single institution. 査読 国際誌

    Jinguji S, Yoshimura J, Nishiyama K, Aoki H, Nagasaki K, Natsumeda M, Yoneoka Y, Fukuda M, Fujii Y

    Journal of neurosurgery. Pediatrics   11 ( 4 )   454 - 63   2013年4月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    OBJECT: Radiation monotherapy-prophylactic craniospinal or whole-brain irradiation paired with a radiation boost to the primary tumor-is the standard treatment for intracranial germinomas at the authors' institution. The authors assessed long-term outcomes of patients with germinoma who underwent therapy and identified factors affecting them. METHODS: The authors retrospectively analyzed data obtained in 46 patients (35 males and 11 females, age 5-43 years at diagnosis) who had been treated for intracranial germinomas between 1990 and 2009 at the authors' institution. Thirty patients had germinomas in localized regions and 16 in multiple regions. Thirty-eight patients (83%) underwent radiotherapy alone (craniospinal irradiation in 32 and whole-brain irradiation in 6). Seven patients underwent radiochemotherapy and 1 underwent chemotherapy alone. The mean radiation doses for the whole brain, spine, and primary tumor site were 26.9, 26.6, and 49.8 Gy, respectively. The median follow-up period was 125 months. RESULTS: The 10-year overall and recurrence-free survival rates were 93.3% and 89.3%, respectively. None of the 38 patients who received radiation monotherapy developed a recurrent lesion, whereas 1 of 7 who underwent radiochemotherapy and the 1 patient who underwent chemotherapy had a recurrent lesion. Of the entire population, 26 patients required hormone replacement therapy, 2 had short stature, and 1 developed a radiation-induced meningioma. Seventeen of the 25 childhood- or adolescent-onset patients were 19 years or older at the latest follow-up visit, 15 of whom graduated from senior high school, and only 2 of whom graduated from college. Of 34 patients who were 19 years or older at the latest visit, 4 were students, 18 worked independently, 4 worked in sheltered workplaces, and 8 were unemployed. Of the 34 patients, 4 got married after the initial treatment, 3 of whom had children. There were 8 patients (17%) with low postoperative Karnofsky Performance Scale (KPS) scores that were significantly associated with impaired neurocognitive functions, severe surgical complications, and neurological impairments. In 10 of the 46 patients, KPS scores at the latest visit were lower than their postoperative KPS scores. These decreases in KPS scores were significantly correlated with a delayed decline in neurocognitive functions in childhood-onset patients and a postoperative impairment of neurocognitive functions in patients with adolescent- or adult-onset germinoma. CONCLUSIONS: No tumor recurrence occurred in germinoma patients treated with the authors' radiation monotherapy, which appears to be effective enough to cure the tumor. Brain damage caused by tumors themselves and surgical complications were found to adversely affect functional outcomes in patients regardless of their age. Although radiotherapy rarely caused late adverse effects in patients with adolescent- or adult-onset, in some childhood-onset lesions, the radiation seems to carry the risk of neurocognitive dysfunctions, which are attributable to late adverse effects. Accordingly, treatments for germinoma patients should be selected according to a patient's age and the extent of the tumor and with particular care to avoid surgical complications.

    DOI: 10.3171/2012.12.peds12336

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  • A novel homozygous mutation of the nicotinamide nucleotide transhydrogenase gene in a Japanese patient with familial glucocorticoid deficiency. 査読

    Yamaguchi R, Kato F, Hasegawa T, Katsumata N, Fukami M, Matsui T, Nagasaki K, Ogata T

    Endocrine journal   2013年

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    掲載種別:研究論文(学術雑誌)  

    DOI: 10.1507/endocrj.ej13-0024

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  • Thyroid-stimulating hormone (thyrotropin)-secretion pituitary adenoma in an 8-year-old boy: case report. 査読 国際誌

    Nakayama Y, Jinguji S, Kumakura S, Nagasaki K, Natsumeda M, Yoneoka Y, Saito T, Fujii Y

    Pituitary   15 ( 1 )   110 - 5   2012年3月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    In this report, an extremely rare case of pediatric thyrotropin-secreting pituitary macroadenoma (TSHoma) is described. An 8-year-old boy, complaining of unsteady gait, was suspected of endocrinopathy because of emaciation and muscle weakness of the legs. Endocrinological work-up established a diagnosis of hyperthyroidism due to syndrome of inappropriate secretion of TSH. Magnetic resonance imaging showed a pituitary macroadenoma with suprasellar and sphenoidal extension without cavernous sinus invasion. He underwent an endoscopic endonasal transsphenoidal adenomectory due to the diagnosis of TSHoma. The adenoma was soft and it was totally removed. Histopathological staining confirmed diagnosis of TSHoma. Postoperative evaluation revealed a subnormal level of TSH (from 13-21 to 0.03 micro U/ml), normalization of alpha-subunit (from 10.0 to 0.09 ng/ml), and as a result, hypothyroidism. The boy left the hospital with oral levothyroxine that continued until 12 months of discharge. The present 8-year-old case is the youngest case to the best of our knowledge based on a bibliographical search. Reasons for endocrinological remission following adenomectomy are (1) correct diagnosis without delay: lack of cavernous sinus invasion, (2) soft and non-fibrous adenoma tissue, and (3) endoscopic technique with wide vision and illumination: safe even for a 8-year-old child. Early recognition/detection and pituitary-conserving adenomectomy can cure TSHoma and avoid long-term medical therapy and/or irradiation, which contribute to the best interests of patients with TSHoma.

    DOI: 10.1007/s11102-010-0275-y

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  • West syndrome associated with mosaic duplication of FOXG1 in a patient with maternal uniparental disomy of chromosome 14. 査読 国際誌

    Tohyama J, Yamamoto T, Hosoki K, Nagasaki K, Akasaka N, Ohashi T, Kobayashi Y, Saitoh S

    American journal of medical genetics. Part A   155A ( 10 )   2584 - 8   2011年10月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    FOXG1 on chromosome 14 has recently been suggested as a dosage-sensitive gene. Duplication of this gene could cause severe epilepsy and developmental delay, including infantile spasms. Here, we report on a female patient diagnosed with maternal uniparental disomy of chromosome 14 and West syndrome who carried a small supernumerary marker chromosome. A chromosomal analysis revealed mosaicism of 47,XX, + mar[8]/46,XX[18]. Spectral karyotyping multicolor fluorescence in situ hybridization analysis confirmed that the marker chromosome was derived from chromosome 14. A DNA methylation test at MEG3 in 14q32.2 and microsatellite analysis using polymorphic markers on chromosome 14 confirmed that the patient had maternal uniparental disomy 14 as well as a mosaic small marker chromosome of paternal origin containing the proximal long arm of chromosome 14. Microarray-based comparative genomic hybridization analysis conclusively defined the region of the gain of genomic copy numbers at 14q11.2-q12, encompassing FOXG1. The results of the analyses of our patient provide further evidence that not only duplication but also a small increase in the dosage of FOXG1 could cause infantile spasms.

    DOI: 10.1002/ajmg.a.34224

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  • Autonomously functioning thyroid nodule in a four-year-old boy with Sotos syndrome. 査読

    Nyuzuki H, Nagasaki K, Matsuyama H, Tomita M, Imai C, Ogawa Y, Kikuchi T, Uchiyama M

    Pediatrics international : official journal of the Japan Pediatric Society   2011年2月

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    掲載種別:研究論文(学術雑誌)  

    DOI: 10.1111/j.1442-200x.2010.03306.x

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  • The Relationship between Preheparin Lipoprotein Lipase and Metabolic Derangements in Obese Japanese Children. 査読

    Abe Y, Kikuchi T, Nagasaki K, Hiura M, Tanaka Y, Ogawa Y, Uchiyama M

    Clinical Pediatric Endocrinology   20 ( 1 )   13 - 20   2011年1月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    The aim of this study was to clarify the relationship between preheparin lipoprotein lipase (LPL) and derangements of metabolic status in obese Japanese children. We examined 102 obese children (55 boys and 47 girls; mean age 10.9 yr). Anthropometry, blood pressure and levels of liver transaminases, serum lipids and lipoproteins, uric acid, fasting blood glucose (FBG), serum insulin, LPL, leptin and adiponectin were measured. The subjects were divided into the metabolic syndrome (MS) and non-MS groups. The levels of LPL were compared between these groups. Statistical analysis showed that the LPL levels were significantly lower in the MS group compared with the non-MS group, with the levels decreasing progressively as the number of MS components increased. We conclude that LPL levels decrease also in obese Japanese children with a deteriorated metabolic status in the same way as in adults.

    DOI: 10.1297/cpe.20.13

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  • Molecular analysis of the GATA3 gene in five Japanese patients with HDR syndrome. 査読

    Nakamura A, Fujiwara F, Hasegawa Y, Ishizu K, Mabe A, Nakagawa H, Nagasaki K, Jo W, Tajima T

    Endocrine journal   2011年

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    掲載種別:研究論文(学術雑誌)  

    DOI: 10.1507/endocrj.k10e-246

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  • Shear wave velocity is a useful marker for managing nonalcoholic steatohepatitis. 査読 国際誌

    Osaki A, Kubota T, Suda T, Igarashi M, Nagasaki K, Tsuchiya A, Yano M, Tamura Y, Takamura M, Kawai H, Yamagiwa S, Kikuchi T, Nomoto M, Aoyagi Y

    World journal of gastroenterology   16 ( 23 )   2918 - 25   2010年6月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    AIM: To investigate whether a noninvasive measurement of tissue strain has a potential usefulness for management of nonalcoholic steatohepatitis (NASH). METHODS: In total 26 patients, 23 NASHs and 3 normal controls were enrolled in this study. NASH was staged based on Brunt criterion. At a region of interest (ROI), a shear wave was evoked by implementing an acoustic radiation force impulse (ARFI), and the propagation velocity was quantified. RESULTS: Shear wave velocity (SWV) could be reproducibly quantified at all ROIs in all subjects except for 4 NASH cases, in which a reliable SWV value was not calculated at several ROIs. An average SWV of 1.34 +/- 0.26 m/s in fibrous stage 0-1 was significantly slower than 2.20 +/- 0.74 m/s and 2.90 +/- 1.01 m/s in stages 3 and 4, respectively, but was not significantly different from 1.79 +/- 0.78 m/s in stage 2. When a cutoff value was set at 1.47 m/s, receiver operating characteristic analysis showed significance to dissociate stages 3 and 4 from stage 0-1 (P = 0.0092) with sensitivity, specificity and area under curve of 100%, 75% and 94.2%, respectively. In addition, the correlation between SWV and hyaluronic acid was significant (P < 0.0001), while a tendency toward negative correlation was observed with serum albumin (P = 0.053). CONCLUSION: The clinical implementation of ARFI provides noninvasive repeated evaluations of liver stiffness at an arbitrary position, which has the potential to shed new light on NASH management.

    DOI: 10.3748/wjg.v16.i23.2918

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  • Usefulness of GPT for diagnosis of metabolic syndrome in obese Japanese children. 査読

    Abe Y, Kikuchi T, Nagasaki K, Hiura M, Tanaka Y, Ogawa Y, Uchiyama M

    Journal of atherosclerosis and thrombosis   16 ( 6 )   902 - 9   2009年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    AIM: The aim of this study was to evaluate the usefulness of glutamate pyruvate transaminase (GPT) levels in the diagnosis of metabolic syndrome (MS) in obese Japanese children. METHODS: We examined 193 obese boys (mean age: 12.1 yrs; mean percent overweight [POW]: 53.9%) and 37 obese girls (mean age: 11.4 yrs; mean POW: 57.2%). Anthropometric measurements, blood pressure and levels of liver transaminases, serum lipids and lipoproteins, fasting blood glucose (FBG), serum insulin and adiponectin were measured. The subjects were divided into either an MS or a non-MS group according to the MS definition criteria for Japanese children. RESULTS: The level of GPT was significantly higher in the MS group in both genders. Correlation analysis revealed positive correlations between GPT and waist circumference, blood pressure, maximum preperitoneal fat thickness, serum insulin and homeostasis model assessment-insulin resistance (HOMA-R), but no correlation between GPT and FBG. ANOVA showed a significant difference in GPT levels between MS and non-MS subgroups, whereas there was no difference in FBG between the two groups. Receiver operating characteristic curves demonstrated that GPT was clearly superior to FBG as a diagnostic marker of MS. CONCLUSION: We conclude that an elevation in GPT in obese children most likely reflects insulin resistance and that GPT is superior to FBG as a marker of MS.

    DOI: 10.5551/jat.1933

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  • Low adiponectin state is associated with metabolic abnormalities in obese children, particularly depending on apolipoprotein E phenotype. 査読 国際誌

    Wardaningsih E, Miida T, Seino U, Fueki Y, Ito M, Nagasaki K, Kikuchi T, Uchiyama M, Hirayama S, Hanyu O, Miyake K, Okada M

    Annals of clinical biochemistry   45 ( Pt 5 )   496 - 503   2008年9月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    BACKGROUND: Adiponectin links obesity with insulin resistance, which causes various metabolic abnormalities including dyslipidaemia. Apolipoprotein E (apoE) phenotypes also affect lipoprotein profiles. We aimed to determine whether low adiponectin concentrations are associated with insulin resistance and downstream metabolic abnormalities in obese children. METHODS: We measured fasting concentrations of lipids, apoE, glucose, insulin and adiponectin, as well as anthropometric parameters, in 191 obese children aged 6-15 years. ApoE phenotypes were determined by isoelectric focusing. Boys (n = 79) and girls (n = 39) with apoE3/3 were classified into tertiles according to their adiponectin concentrations. Metabolic parameters, were compared among these three groups in boys and girls separately. RESULTS: The low adiponectin groups had higher median homeostasis model assessment of insulin resistance (HOMA-IR) than the middle and high adiponectin groups in both boys [5.3 (low) versus 3.1 (middle; P < 0.05) and 3.5 (high; P < 0.05)] and girls [5.0 (low) versus 4.4 (middle) and 3.0 (high; P < 0.05)]. However, only boys who were in the low adiponectin group exhibited significantly higher concentrations of blood pressure, triglycerides, LDL-cholesterol, and remnant-like particle-cholesterol, and lower concentrations of HDL-cholesterol compared with the middle or high adiponectin groups. CONCLUSION: Low adiponectin concentration is associated with insulin resistance in obese children. Furthermore, decreased adiponectin with E3/3 exhibited more prominent downstream metabolic abnormalities in obese boys than in obese girls.

    DOI: 10.1258/acb.2008.007237

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  • Lower birth weight associated with current overweight status is related with the metabolic syndrome in obese Japanese children. 査読 国際誌

    Abe Y, Kikuchi T, Nagasaki K, Hiura M, Tanaka Y, Ogawa Y, Uchiyama M

    Hypertension research : official journal of the Japanese Society of Hypertension   30 ( 7 )   627 - 34   2007年7月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    The purpose of this study was to clarify the relationship between lower birth weight and current overweight status and to examine the involvement of these factors in the development of the metabolic syndrome (MS) in obese Japanese children. We examined 97 obese boys (mean age 11.3 years; mean percentage overweight [POW] 52.4%) and 29 obese girls (mean age 11.1 years; mean POW 58.3%). The anthropometric measurements, blood pressure, fasting serum insulin and blood glucose, liver enzymes, lipids and lipoproteins were measured. Birth weight and gestational weeks were also recorded. The subjects were divided into either an MS group or a Non-MS group using criteria proposed for Japanese children. We compared the weight parameters (birth weight, current weight and current weight-to-birth weight ratio [WBWR]) between the two groups and analyzed the relationships between the weight parameters and metabolic derangements. There were no significant differences in age or anthropometric measurements between the two groups. However, birth weight in the MS group was lower than that in the Non-MS group, while WBWR of the MS group was higher than that in the Non-MS group. Blood pressure and serum insulin correlated positively with WBWR. These findings suggested that lower birth weight with current overweight status was associated with the MS in obese Japanese children. We were unable to clarify whether subjects with lower birth weight who achieved proper weight gains had the same risk as subjects with appropriate birth weight. However, they should be assisted to grow adequately to prevent future metabolic derangements.

    DOI: 10.1291/hypres.30.627

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  • Different skeletal phenotypes in a mother and two daughters with short stature homeobox-containing haploinsufficiency. 査読

    Nagasaki K, Kikuchi T, Uchiyama M

    Clinical pediatric endocrinology : case reports and clinical investigations : official journal of the Japanese Society for Pediatric Endocrinology   16 ( 3 )   69 - 74   2007年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Haploinsufficiency of the short stature homeobox-containing (SHOX) gene causes Turner skeletal features such as short metacarpals, cubitus valgus, and Madelung deformity. We report the clinical findings of a Japanese family consisting of two daughters with SHOX haploinsufficiency (46, X, del(X) (p.22.3)) and their mother with 45,X [9]/ 46, X, del(X) (p22.3) [11] karyotype. Physical and auxological examinations revealed a mesomelic appearance, cubitus valgus, a short neck and short stature in the daughters, but on the other hand, only a short neck and short stature in the mother. Radiological studies indicated markedly curved radii in the daughters, but only mild curvature of the radii in the mother. Regular menstruation had taken place since the age of 12 yr in the elder daughter, but the mother had irregular menstruation and she had received fertility treatment for pregnancy. The different skeletal phenotypes of the mother and her daughters with SHOX haploinsufficiency might be due to the mild gonadal estrogen deficiency found in the mother, which was caused by mosaic Turner syndrome, and the phenotypic variability of SHOX haploinsufficiency.

    DOI: 10.1297/cpe.16.69

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  • Lower birth weight and visceral fat accumulation are related to hyperinsulinemia and insulin resistance in obese Japanese children. 査読 国際誌

    Tanaka Y, Kikuchi T, Nagasaki K, Hiura M, Ogawa Y, Uchiyama M

    Hypertension research : official journal of the Japanese Society of Hypertension   28 ( 6 )   529 - 36   2005年6月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    This study aimed to reveal the relation of birth weight (or the birth weight standard deviation score [BWSDS]) and visceral fat accumulation to hyperinsulinemia and insulin resistance. We examined obese Japanese children (650 boys and 317 girls) with a mean age of 10.3 years (range, 6-15 years). The mean percentage of overweight to the standard body weight of Japanese children was 52.1% in boys and 51.4% in girls. Abdominal fat thickness (maximum preperitoneal fat thickness; Pmax) was measured using ultrasonography. The fasting serum insulin and plasma glucose levels were measured, and the homeostasis model assessment-insulin resistance (HOMA-R) and quantitative insulin sensitivity check index (QUICKI) were calculated. We divided the subjects into four groups according to their birth weight or BWSDS, and compared anthropometric measurements, Pmax, blood pressure, serum insulin levels, HOMA-R and QUICKI among the quartiles. The relationships of both birth weight (or BWSDS) and Pmax to serum insulin levels (or HOMA-R, QUICKI) were examined with multiple regression analyses. The fasting serum insulin level and HOMA-R were highest in the quartile with the lowest birth weight or BWSDS. The birth weight and BWSDS were inversely related to the serum insulin levels and HOMA-R, positively related to QUICKI, and independent of Pmax. Our findings suggest that both lower birth weight and visceral fat accumulation may be independently related to hyperinsulinemia and insulin resistance in obese Japanese children.

    DOI: 10.1291/hypres.28.529

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  • Usefulness of serum adiponectin level as a diagnostic marker of metabolic syndrome in obese Japanese children. 査読 国際誌

    Ogawa Y, Kikuchi T, Nagasaki K, Hiura M, Tanaka Y, Uchiyama M

    Hypertension research : official journal of the Japanese Society of Hypertension   28 ( 1 )   51 - 7   2005年1月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    This study aimed 1) to investigate the relationship between serum adiponectin levels and metabolic disorders and 2) to clarify the usefulness of serum adiponectin level as a diagnostic marker of metabolic syndrome in obese Japanese children. One hundred obese boys aged 8 to 13 years were examined. Serum adiponectin levels were measured by radioimmunoassay using a commercial kit. Abdominal fat thickness (maximum preperitoneal fat thickness: P(max); minimum subcutaneous fat thickness: S(min)) was measured by ultrasonography. The relationships between adiponectin and clinical characteristics were analyzed by simple regression. The relationships between anthropometric measurements and metabolic disorders were analyzed among three groups divided according to adiponectin percentile. The prevalence of metabolic syndrome was also analyzed, with metabolic syndrome defined as the presence of three or more complications of obesity. The criteria for metabolic syndrome by adiponectin were subjected to a receiver operating characteristic (ROC) analysis. Body weight, waist circumference, P(max), alanine aminotransferase and fasting serum insulin were all inversely correlated with adiponectin. There were significant differences in the prevalence of severe obesity, the accumulation of visceral adipose tissue, hyperinsulinemia, high serum low density lipoprotein-cholesterol, the number of complications of obesity and the prevalence of metabolic syndrome among the three groups. The area under the ROC curve for adiponectin was 0.672 +/- 0.055 and the cut-off value was 6.65 microg/ml. Hypoadiponectinemia was associated with visceral fat accumulation and metabolic syndrome in obese Japanese boys. Evaluation of adiponectin might contribute to an early intervention for obese children with metabolic syndrome.

    DOI: 10.1291/hypres.28.51

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  • Neonatal Identification of Congenital Hypopituitarism with an Invisible Pituitary Stalk and Pituitary Aplasia: Usefulness of Early Growth Hormone Replacement

    Nagasaki Keisuke, Ohashi Tsukasa, Hiura Makoto, Kikuchi Toru, Suda Masashi, Uchiyama Makoto

    Clinical Pediatric Endocrinology   14 ( 24 )   S24_93 - S24_96   2005年

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    記述言語:英語   出版者・発行元:The Japanese Society for Pediatric Endocrinology  

    We report a case of male neonatal onset congenital hypopituitarism with an invisible pituitary stalk and pituitary aplasia. He had a micropenis at birth and experienced multiple episodes of apnea, cyanosis, hypotonia and hypothermia, associated with severe hypoglycemia during the first few days of life. He was diagnosed as having congenital hypopituitarism due to the findings of low serum GH and cortisol levels during hypoglycemia, low free T4 and pituitary magnetic resonance imaging findings. He was started on hydrocortisone and levothyroxine at 12 d of life and GH replacement at 1 mo of life. Early GH replacement is effective not only for stabilizing blood glucose but also for improving the quality of life.<br>

    DOI: 10.1297/cpe.14.S24_93

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  • Clinical assessment and mutation analysis of Kallmann syndrome 1 (KAL1) and fibroblast growth factor receptor 1 (FGFR1, or KAL2) in five families and 18 sporadic patients. 査読

    Sato N, Katsumata N, Kagami M, Hasegawa T, Hori N, Kawakita S, Minowada S, Shimotsuka A, Shishiba Y, Yokozawa M, Yasuda T, Nagasaki K, Hasegawa D, Ogata T

    The Journal of clinical endocrinology and metabolism   2004年3月

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    掲載種別:研究論文(学術雑誌)  

    DOI: 10.1210/jc.2003-030476

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  • Virilizing Adrenocortical Carcinoma Invading the Right Atrium with Histological High-Grade Malignancy and p53 Mutation in a 3-Year-Old Child: Indication of Post Operative Adjuvant Chemotherapy. 査読

    Nagasaki K, Horikawa R, Nagaishi J, Honna T, Sekiguchi A, Tsunematsu Y, Tanaka T

    Clinical pediatric endocrinology : case reports and clinical investigations : official journal of the Japanese Society for Pediatric Endocrinology   2004年

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    掲載種別:研究論文(学術雑誌)  

    DOI: 10.1297/cpe.13.25

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  • The levels of serum low-density lipoprotein cholesterol using direct measurement in healthy Japanese school children. 査読

    Ogawa Y, Hiura M, Kikuchi T, Nagasaki K, Iwata Y, Uchiyama M

    Clinical pediatric endocrinology : case reports and clinical investigations : official journal of the Japanese Society for Pediatric Endocrinology   13 ( 1 )   55 - 8   2004年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    This study aimed to investigate the levels of serum low-density lipoprotein cholesterol (LDLC) using direct measurement in healthy Japanese school children. The subjects were 621 children (325 boys and 296 girls) aged 9 to 10 in the 4th grade, and 688 children (334 boys and 354 girls) aged 12 to 13 in the 7th grade. The levels of serum LDLC and high-density lipoprotein cholesterol were measured by direct determination (Cholestest LDL and Cholestest NHDL; Daiichi Pure Chemicals Co., Ltd., Tokyo, Japan). In boys in the 4th grade, the mean, the 75th, the 90th and the 95th percentiles of LDLC levels (mg/dl) were 91.6, 104, 124 and 134, respectively. In girls in the 4th grade, they were 92.8, 108, 122 and 130. In boys in the 7th grade, they were 83.4, 96, 113 and 123. In girls in the 7th grade, they were 93.0, 106, 126 and 137. Serum LDLC levels in boys in the 7th grade were lower than those of other groups. The direct measurement of serum LDLC level is useful for evaluation of dyslipidemia in healthy school children, because the method is applicable to non-fasting serum.

    DOI: 10.1297/cpe.13.55

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  • A case of female pseudohermaphroditism caused by aromatase deficiency. 査読

    Nagasaki K, Horikawa R, Fujisawa K, Hata I, Shigematsu Y, Tanaka T

    Clinical pediatric endocrinology : case reports and clinical investigations : official journal of the Japanese Society for Pediatric Endocrinology   13 ( 1 )   59 - 64   2004年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Female pseudohermaphroditism is caused by several etiologies. Here we report a case of aromatase deficiency who showed ambiguous genitalia and maternal virilization during pregnancy. The mother had noticed her own virilization from 16 wk of gestation without androgen exposure and had low urinary estriol levels (5~10 μg/ml at 35 wk of gestation). At birth, the patient presented severe virilization (Prader V), and was assigned as a male with a micropenis and unpalpable testes but the patient had a normal female karyotype and a uterus and cystic ovaries found by magnetic resonance imaging. The patient had a increase in serum 17α-hydroxy progesterone levels (basal 4.9 → 37 ng/ml after a single 0.25 mg/m(2) infusion of ACTH), but the increase in adrenal androgen was not sufficient to virilize the external genitalia. Dehydroepiandrosterone, 17α-hydroxy pregnenolone and deoxycorticosterone were within the normal ranges. These findings suggested a diagnosis of nonadrenal female pseudohermaphroditism. From the clinical features and biochemical data, we endocrinologically diagnosed her as having an aromatase deficiency. The aromatase gene is now under investigation for definite diagnosis. We finally agreed that aromatase deficiency should be suspected when both the mother and the newborn have been virilized.

    DOI: 10.1297/cpe.13.59

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  • Elevation of serum C-reactive protein levels is associated with obesity in boys. 査読 国際誌

    Makoto Hiura, Toru Kikuchi, Keisuke Nagasaki, Makoto Uchiyama

    Hypertension research : official journal of the Japanese Society of Hypertension   26 ( 7 )   541 - 6   2003年7月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    This study aimed to reveal the relationships among C-reactive protein (CRP), obesity, blood pressure (BP), and serum lipids in children. Eighty-six obese and 58 non-obese boys aged an average of 11.2 years were examined. Serum CRP levels were measured by high sensitivity latex turbidimetric immunoassay and subjects with CRP levels below 0.3 mg/dl were adopted. Comparisons of serum CRP levels, BP, and serum lipids levels between age-matched obese and non-obese groups were performed. A comparison of serum CRP levels among the percentage of relative weight quartiles and the relationships among percentage of relative weight, BP, and serum lipids in CRP quartiles were analyzed. The relationships between CRP and other parameters were analyzed by simple and stepwise multiple regressions. Obese children had significantly higher high-sensitivity CRP (hs-CRP) levels than their non-obese counterparts. The mean hs-CRP level was 5.5-fold higher in the top quartile of the percentage of relative weight than in the bottom quartile. In the top quartile of CRP, the percentage of relative weight, systolic BP, diastolic BP, pulse pressure, and low density/high density lipoprotein-cholesterol (LDL-C/HDL-C) were significantly higher than in the bottom quartile. The percentage of relative weight, BP, LDL-C, and apolipoprotein B (ApoB) showed positive correlations and HDL-C showed a negative correlation with log CRP by simple regression. Stepwise multiple regression analysis indicated that only the percentage of relative weight was strongly related to CRP. In conclusion, this study revealed a significant relationship between CRP and obesity in children. Obese children tended to have high CRP levels, BP elevation, and slight dyslipidemia. These results support the findings that CRP is one of the useful indices of childhood obesity that would affect the progression to future atherosclerotic disease. We consider that a strategy of preventing obesity from childhood would contribute to a drop in the future incidence of metabolic syndromes.

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