Papers - Narumi, Satoshi

Human Chorionic Gonadotropin Stimulation Test in Prepubertal Children with Micropenis Can Accurately Predict Leydig Cell Function in Pubertal or Postpubertal Adolescents

Tomohiro Ishii, Nobutake Matsuo, Seiji Sato, Tsutomu Ogata, Shinya Tamai, Makoto Anzo, Tsutomu Kamimaki, Goro Sasaki, Mikako Inokuchi, Naoaki Hori, Naoko Amano, Satoshi Narumi, Hironori Shibata, Tomonobu Hasegawa

HORMONE RESEARCH IN PAEDIATRICS (KARGER)  84 ( 5 ) 305 - 10 2015

Accepted,  ISSN  1663-2818

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Background/Aim: To evaluate the accuracy of the human chorionic gonadotropin (hCG) stimulation test in children with micropenis in predicting later Leydig cell function. Methods: We conducted a retrospective investigation of testosterone response to a 3-day hCG test (3,000 IU/m(2)/day) in prepuberty to indicate the need for hormone replacement therapy (HRT) in adolescence. Results: Fifty Japanese boys (range, 0.8-15.4 years of age; median, 8.9) with micropenis were enrolled. Thirty-four spontaneously developed puberty and preserved the ability of testosterone production (group 1), while 16 did not develop any pubertal signs without HRT (group 2). Serum testosterone levels after the hCG test (post-hCG T) in group 2 (range, <0.05-1.1 ng/ml; median, 0.24) were significantly lower than in group 1 (range, 0.5-8.7 ng/ml; median, 2.4; p < 0.0001). Based on true positives who required continuous HRT, the area under the receiver-operating characteristics curve for post-hCG T was 0.983 [95% confidence interval (CI), 0.90-1.00]. The post-hCG T cut-off level corresponding to the Youden index was 1.1 ng/ml (95% CI, 1.0-1.1), with a sensitivity of 100.0% (95% CI, 79.4-100.0) and a specificity of 94.1% (95% CI, 80.3-99.3). Conclusions: The hCG test in prepubertal children with micropenis can be useful for predicting Leydig cell function in pubertal or postpubertal adolescents. The post-hCG T cutoff level of 1.1 ng/ml is recommended to screen for those who will likely require HRT for pubertal development. (C) 2015 S. Karger AG, Basel

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TSH resistance revisited

Satoshi Narumi, Tomonobu Hasegawa

ENDOCRINE JOURNAL (JAPAN ENDOCRINE SOC)  62 ( 5 ) 393 - 8 2015

Accepted,  ISSN  0918-8959

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Genetic defects of hormone receptors are the most common form of end-organ hormone resistance. One example of such defects is TSH resistance, which is caused by biallelic inactivating mutations in the TSH receptor gene (TSHR). TSH, a master regulator of thyroid functions, affects virtually all cellular processes involving thyroid hormone production, including thyroidal iodine uptake, thyroglobulin iodination, reuptake of iodinated thyroglobulin and thyroid cell growth. Resistance to TSH results in defective thyroid hormone production from the neonatal period, namely congenital hypothyroidism. Classically, clinical phenotypes of TSH resistance due to inactivating TSHR mutations were thought to vary depending on the residual mutant receptor activity. Nonfunctional mutations in the two alleles produce severe thyroid hypoplasia with overt hypothyroidism (uncompensated TSH resistance), while hypomorphic mutations in at least one allele produce normal-sized thyroid gland with preserved hormone-producing capacity (compensated TSH resistance). More recently, a new subgroup of TSH resistance (nonclassic TSH resistance) that is characterized by paradoxically high thyroidal iodine uptake has been reported. In this article, the pathophysiology and clinical features of TSH resistance due to inactivating TSHR mutations are reviewed, with particular attention to the nonclassic form.

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Comprehensive Next-Generation Sequencing Analyses of Hypoparathyroidism: Identification of Novel GCM2 Mutations

Toshikatsu Mitsui, Satoshi Narumi, Mikako Inokuchi, Keisuke Nagasaki, Mie Nakazawa, Goro Sasaki, Tomonobu Hasegawa

JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM (ENDOCRINE SOC)  99 ( 11 ) E2421 - 8 2014.11

Accepted,  ISSN  0021-972X

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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.

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遷延する妊娠甲状腺中毒症に検出されたTSH受容体遺伝子変異

谷山 松雄, 杉澤 千穂, 百渓 尚子, 井上 ゆか子, 阿部 清美, 鳴海 覚志

日本内分泌学会雑誌 ((一社)日本内分泌学会)  90 ( 2 ) 506 - 506 2014.09

ISSN  0029-0661

変異TSH受容体V711FfsX18の機能解析 1塩基欠失によるたんぱく質不安定化シグナルの獲得

鳴海 覚志, 杉澤 千穂, 阿部 清美, 長谷川 奉延

日本内分泌学会雑誌 ((一社)日本内分泌学会)  90 ( 2 ) 528 - 528 2014.09

ISSN  0029-0661

奇異性123I摂取率高値を認めた両アリル性TSHR変異の一男児例 世界で5例目の非古典型TSH不応症

杉澤 千穂, 鳴海 覚志, 阿部 清美, 長谷川 奉延

日本内分泌学会雑誌 ((一社)日本内分泌学会)  90 ( 2 ) 507 - 507 2014.09

ISSN  0029-0661

TPO遺伝子異常による甲状腺腫性クレチン症の8歳女児例

福留 啓祐, 坂口 善市, 冨田 理絵, 藤岡 啓介, 阿部 容子, 木下 ゆき子, 市原 朋子, 藤井 笑子, 幸山 洋子, 関口 隆憲, 大原 克明, 鳴海 覚志, 阿部 清美, 長谷川 奉延

日本小児科学会雑誌 ((公社)日本小児科学会)  118 ( 7 ) 1126 - 1126 2014.07

ISSN  0001-6543

サイログロブリン著明高値、甲状腺腫大を契機に診断したDUOX2異常症の2例

後藤 元秀, 荒木 俊介, 久保 和泰, 川越 倫子, 山本 幸代, 楠原 浩一, 齋藤 玲子, 河田 泰定, 阿部 清美, 鳴海 覚志, 長谷川 奉延

日本小児科学会雑誌 ((公社)日本小児科学会)  118 ( 6 ) 1016 - 1016 2014.06

ISSN  0001-6543

新生児マススクリーニング(MS)で発見されなかった先天性甲状腺機能低下症の3例

上村 美季, 鳴海 覚志, 梅木 郁美, 箱田 明子, 菅野 潤子, 長谷川 奉延, 藤原 幾磨

日本小児科学会雑誌 ((公社)日本小児科学会)  118 ( 5 ) 875 - 875 2014.05

ISSN  0001-6543

4世代・世界最大のPAX8変異陽性家系からみえた甲状腺表現型の多様性 高齢PAX8変異保有者の臨床像

西岡 淳子, 阿部 清美, 鳴海 覚志, 長谷川 奉延, 八ツ賀 秀一, 佐々木 孝子, 片山 幸樹, 久野 建夫, 古賀 靖敏

日本内分泌学会雑誌 ((一社)日本内分泌学会)  90 ( 1 ) 296 - 296 2014.04

ISSN  0029-0661

IGSF1変異による中枢性先天性甲状腺機能低下症の3男児例

阿部 清美, 鳴海 覚志, 杉澤 千穂, 室谷 浩二, 朝倉 由美, 安達 昌功, 沼倉 周彦, 長谷川 奉延

日本内分泌学会雑誌 ((一社)日本内分泌学会)  90 ( 1 ) 271 - 271 2014.04

ISSN  0029-0661

Identification and Functional Characterization of Two Novel NPR2 Mutations in Japanese Patients With Short Stature

Naoko Amano, Tokuo Mukai, Yoshiya Ito, Satoshi Narumi, Toshiaki Tanaka, Susumu Yokoya, Tsutomu Ogata, Tomonobu Hasegawa

JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM (ENDOCRINE SOC)  99 ( 4 ) E713 - 8 2014.04

Accepted,  ISSN  0021-972X

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Context: C-type natriuretic peptide-natriuretic peptide receptor B (NPR-B) signaling is critical for endochondral ossification, which is responsible for longitudinal growth in limbs and vertebrae. Biallelic NPR2 mutations cause acromesomelic dysplasia, type Maroteaux, which is bone dysplasia characterized by severe short stature and short limbs. A monoallelic NPR2 mutation has been suggested to mildly impair long bone growth.
Objective: The goal of this study was to identify and characterize NPR2 mutations among Japanese patients with short stature.
Subjects and Methods: We enrolled 101 unrelated Japanese patients with short stature. NPR2 and NPPC were sequenced, and the identified variants were characterized in vitro.
Results: In two subjects, we identified two novel heterozygous NPR2 mutations (R110C and Q417E) causing a loss of C-type natriuretic peptide-dependent cGMP generation capacities and having dominant-negative effects. R110C was defective in trafficking from the endoplasmic reticulum to the Golgi apparatus. In contrast, Q417E showed clear cell surface expression.
Conclusions: We identified heterozygous NPR2 mutations in 2% of Japanese patients with short stature. Our in vitro findings indicate that NPR2 mutations have a dominant negative effect, and their dominant-negative mechanisms vary corresponding to the molecular pathogenesis of the mutations.

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A novel KAL1 mutation is associated with combined pituitary hormone deficiency

Masaki Takagi, Satoshi Narumi, Riku Hamada, Yukihiro Hasegawa, Tomonobu Hasegawa

Human Genome Variation (Nature Publishing Group)  1   14011 2014

ISSN  2054-345X

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Using a next-generation sequencing strategy, we identified a novel KAL1 missense mutation (p.His568Gln) in a patient with combined pituitary hormone deficiency, right microphthalmia, right renal aplasia and severe developmental delay. Our findings will provide additional evidence that KAL1 mutations are associated with hypopituitarism, in addition to luteinizing hormone, and follicle-stimulating hormone deficiencies, and improve our understanding of the phenotypic features and developmental course associated with KAL1 mutations.

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A Novel Mutation in SOX2 Causes Hypogonadotropic Hypogonadism with Mild Ocular Malformation

Masaki Takagi, Satoshi Narumi, Yumi Asakura, Koji Muroya, Yukihiro Hasegawa, Masanori Adachi, Tomonobu Hasegawa

HORMONE RESEARCH IN PAEDIATRICS (KARGER)  81 ( 2 ) 133 - 8 2014

Accepted,  ISSN  1663-2818

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Background: Heterozygous SOX2 mutations have been reported to cause isolated hypogonadotropic hypogonadism (HH) in addition to ocular and brain abnormalities. Objective: We report a novel missense SOX2 (Y110C) mutation in an HH patient with mild ocular malformation. Patients: The 20-year-old male was referred because of typical signs of complete hypogonadism, with small intrascrotal testes (2 ml), no pubic hair (P1), and a micropenis. Hormone assays revealed very low plasma testosterone levels and very low levels of plasma gonadotropin. He was found to have retinal detachment in his right eye and surgery was performed at the age of 14 years. Results: Using a next-generation sequencing strategy, we identified a novel heterozygous SOX2 mutation, c. 329A>G (p.Y110C). Y110C SOX2 had reduced transactivation and no dominant negative effect. Subcellular localization revealed no significant difference between wild-type and mutant SOX2. EMSA experiments showed that the Y110C SOX2 abrogated DNA-binding ability. Conclusion: The Y110C mutation affects a critical residue in the SOX2 protein. This study extends our understanding of the phenotypic features, molecular mechanism, and developmental course associated with mutations in SOX2. When multiple genes need to be analyzed for mutations simultaneously, targeted sequence analysis of interesting genomic regions is an attractive approach. (C) 2014 S. Karger AG, Basel

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新生児マス・スクリーニング検査でみつかったTPO異常症の2例

石津 桂, 森川 俊太郎, 鳴海 覚志, 長谷川 奉延, 田島 敏広

日本内分泌学会雑誌 ((一社)日本内分泌学会)  89 ( 3 ) 977 - 977 2013.12

ISSN  0029-0661

IGSF1遺伝子変異による中枢性甲状腺機能低下症の2家系 家族検索とPRL分泌能

松浦 信夫, 橘田 一輝, 阿部 清美, 小池 明美, 椿 淳子, 鳴海 覚志, 長谷川 奉延, 横田 行史, 大津 成之, 田久保 憲行, 柴山 啓子, 大山 宜秀

日本内分泌学会雑誌 ((一社)日本内分泌学会)  89 ( 2 ) 463 - 463 2013.09

ISSN  0029-0661

PAX8変異陽性甲状腺機能低下症の世界最大家系 甲状腺表現型の多様性

阿部 清美, 鳴海 覚志, 八ツ賀 秀一, 西岡 淳子, 久野 建夫, 長谷川 奉延

日本内分泌学会雑誌 ((一社)日本内分泌学会)  89 ( 2 ) 474 - 474 2013.09

ISSN  0029-0661

A report of two novel NR5A1 mutation families: possible clinical phenotype of psychiatric symptoms of anxiety and/or depression

Ayuko S. Suwanai, Tomohiro Ishii, Hidenori Haruna, Atsuyuki Yamataka, Satoshi Narumi, Ryuji Fukuzawa, Tsutomu Ogata, Tomonobu Hasegawa

CLINICAL ENDOCRINOLOGY (WILEY-BLACKWELL)  78 ( 6 ) 957 - 65 2013.06

Accepted,  ISSN  0300-0664

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Objective NR5A1 or steroidogenic factor 1 is a nuclear receptor that plays important roles in the hypothalamuspituitarysteroidogenic axis. The clinical phenotype of most 46,XY mutation carriers includes disorders of sex development (DSD) without adrenal insufficiency, whereas 46,XX mutation carriers have phenotypes ranging from no symptoms to ovarian insufficiency. Although genetically engineered ventromedial hypothalamus-specific Nr5a1 knockout mice show anxiety behaviour, no psychiatric symptoms have been reported in human NR5A1 mutation carriers. We report clinical and molecular findings for individuals (from two families) with NR5A1 mutations, showing psychiatric symptoms. Design and methods We screened for NR5A1 mutations in a cohort of 34 patients with 46,XY DSD using PCR-based sequencing. Psychiatric symptoms were assessed using mental health assessment tools and structured clinical interviews. Functional properties of detected mutant NR5A1s were studied in silico and in vitro, including three-dimensional (3D) mutation models, subcellular NR5A1 protein localization and transactivation assays. Results We found 2 (46,XY) patients with NR5A1 heterozygous novel mutations (p.D257fs and p.V424del), which were transmitted from their respective mothers. The patients' clinical findings indicated DSD without adrenal insufficiency. Both mothers showed psychiatric symptoms, including excessive anxiety and/or depression. The mother and grandmother of one patient had premature ovarian insufficiency. Functional studies showed altered 3D models of p.V424del and normal subcellular NR5A1 localization and impaired transcriptional activation without dominant-negative effects in both mutations. Conclusions We found 2 (46,XX) NR5A1 mutation carriers with excessive anxiety and/or depression. These results suggest that excessive anxiety and/or depression are possible clinical phenotypes of 46,XX NR5A1 mutations.

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Congenital hypothyroidism caused by a novel mutation of the dual oxidase 2 (DUOX2) gene

Atsuko Yoshizawa-Ogasawara, Sayaka Ogikubo, Mari Satoh, Satoshi Narumi, Tomonobu Hasegawa

JOURNAL OF PEDIATRIC ENDOCRINOLOGY & METABOLISM (WALTER DE GRUYTER GMBH)  26 ( 1-2 ) 45 - 52 2013.02

Accepted,  ISSN  0334-018X

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The dual oxidase 2 (DUOX2) mutation results in an impairment of the hydrogen peroxidase-generating system and is identified as a dyshormonogenic cause of congenital hypothyroidism (CH). Here, we describe two unrelated Japanese girls with CH due to a novel DUOX2 mutation. They had high serum thyrotropin levels and low free thyroxine/thyroxine concentrations during the neonatal period. A novel missense mutation with a transversion of G to A at position 1462 in exon 12 of the DUOX2 gene that caused a replacement of glycine (G) with arginine (R) at codon 488 of the protein (c.1462G>A, p.[G488R]) was identified. One patient was a compound heterozygote forp. [L479SfsX3] + [G488R]. The other was homozygous for p.[G488R]. This p. G488R substitution occurred in a highly conserved glycine residue of the mammalian DUOX2 protein. The two patients had different haplotypes, suggesting that the p. G488R alleles were the result of independent, recurrent mutations. Later in life, both patients were still euthyroid even after discontinuing thyroid hormone therapy. We conclude that this p. G488R missense mutation in the DUOX2 gene of the patients is associated with thyroid dysfunction that presents during the neonatal period.

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Delayed onset congenital hypothyroidism in a patient with DUOX2 mutations and maternal iodine excess

Toshihiko Kasahara, Satoshi Narumi, Keisuke Okasora, Ryuzo Takaya, Hiroshi Tamai, Tomonobu Hasegawa

AMERICAN JOURNAL OF MEDICAL GENETICS PART A (WILEY)  161A ( 1 ) 214 - 217 2013.01

Accepted,  ISSN  1552-4825

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Congenital hypothyroidism (CH), one of the most common congenital endocrine disorders, causes irreversible intellectual disability in untreated patients. Today, the vast majority of patients receive early diagnosis and treatment in the context of newborn screening for CH, and achieve satisfactory cognitive development. However, a subset of patients with delayed onset are undetectable by newborn screening, and miss benefit from early intervention. Here, we report on a delayed-onset CH patient that had two contributing factors in the pathogenesis of CH simultaneously, i.e., a genetic defect and iodine excess. The patient was exposed to excessive iodine in utero because her mother consumed massive amounts of seaweed during pregnancy. Surprisingly, the patient had a negative result in newborn screening, but developed overt CH at age 3 months. She received thyroxine supplementation until when normalization of the thyroid function was confirmed at age 3 years (i.e., transient CH). Mutation screening for DUOX2, a causative gene for transient CH, showed biallelic mutations (p.[E327X]?+?[H678R]). This report provides a new example of environmental modification of phenotypes of CH due to a genetic defect, which can potentially distort screening results. (c) 2012 Wiley Periodicals, Inc.

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