Papers - Narumi, Satoshi

A patient with Pendred syndrome whose goiter progressed with normal serum thyrotropin and iodine organification

Asakura Y, Narumi S, Muroya K, Fujita K, Aida N, Hasagawa T, Adachi M.

American Journal of Medical Genetics Part A (WILEY-LISS)  152A ( 7 ) 1793-1797 - 1797 2010.07

Research paper (scientific journal), Joint Work, Accepted,  ISSN  1552-4825

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Biallelic mutations of SLC26A4 (encoding pendrin) cause Pendred syndrome (PS), an autosomal recessive genetic disorder with deafness and goiter. The mechanism underlying the development of the goiter is unknown. Here, we report clinical and molecular findings of a patient with PS. This 27-year-old woman was born to nonconsanguineous healthy parents. She was seen at our hospital due to hearing loss at age 3 years, and subsequently developed goiter at age 10 years. From age 15 years, her thyroid gland showed progressive enlargement accompanied by elevation of serum thyroglobulin reaching 10-fold the normal amount. Thyroidal iodine uptake was also increased during goiter progression ((123)I uptake at 24 hr: 20.2% at age 17 years; 69.4% at age 24 years; reference, 8-40), while serum thyrotropin (TSH) levels and iodine organification (examined by the per-chrolate or thiocyanate discharge test) remained normal. We sequenced SLC26A4 using standard PCR-based technique, and found one novel (p.T537P) and one recurrent (p.H723R) mutations in a compound heterozygous state. Expression experiments using COS-7 cells showed that the two mutants were entrapped in the endoplasmic reticulum and were poorly localized at the plasma membrane. In summary, a molecularly confirmed PS patient showed goiter progression accompanied by elevated serum thyroglobulin and increased thyroidal iodine uptake, but normal serum TSH levels and normal iodine organification. This implies that some pendrin mutations may involve direct stimulation of thyroid cell proliferation with no TSH hyperstimulation and no iodine organification defect. (C) 2010 Wiley-Liss, Inc.

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Cbln1 is a ligand for an orphan glutamate receptor delta2, a bidirectional synapse organizer.

Matsuda K, Miura E, Miyazaki T, Kakegawa W, Emi K, Narumi S, Fukazawa Y, Ito-Ishida A, Kondo T, Shigemoto R, Watanabe M, Yuzaki M

Science (New York, N.Y.) 328 ( 5976 ) 363 - 8 2010.04

ISSN  0036-8075

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Transcription factor mutations and congenital hypothyroidism: systematic genetic screening of a population-based cohort of Japanese patients

Narumi S, Muroya K, Asakura Y, Adachi M, Hasegawa T.

Journal of Clinical Endocrinology and Metabolism (ENDOCRINE SOC)  95 ( 4 ) 1981-1985 - 5 2010.04

Research paper (scientific journal), Joint Work, Accepted,  ISSN  0021-972X

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Context: Gene mutations of transcription factors that are predominantly expressed in the thyroid gland cause congenital hypothyroidism (CH). The prevalence of CH due to transcription factor mutations remains undetermined.
Objective: This study was designed to define the prevalence of CH due to mutations of PAX8, NKX2-1 [encoding thyroid transcription factor (TTF)-1], FOXE1 (encoding TTF-2), and NKX2-5 among patients with permanent primary CH and in the general population in Japan.
Subjects and Methods: We enrolled 102 CH patients that represent 353,000 newborns born in Kanagawa prefecture from October 1979 to June 2006. We sequenced PAX8, NKX2-1, FOXE1, and NKX2-5 using PCR-based methods. Additionally, deletion/duplication of PAX8, NKX2-1, and FOXE1 was screened by multiplex ligation-dependent probe amplification. Molecular functions of putative mutations were verified in vitro.
Results: We identified a novel small duplication of PAX8 (p.K80_A84dup) in two half-sibling patients with thyroid hypoplasia. We also found a novel NKX2-1 variation (p.H60W) in a sporadic nonsyndromic CH patient. In vitro experiments showed that K80_A84dup PAX8 had impaired transactivation of the thyroglobulin promoter. H60W TTF-1 exhibited a comparable transactivating capacity with wild-type TTF-1, suggesting a benign variation. We estimate the prevalence of PAX8 mutations to be 2.0% (two in 102) among Japanese CH patients and one in 176,000 (two in 353,000) in the general Japanese population.
Conclusions: Using a population-based sample, we confirmed that a minor subset of CH patients has transcription factor mutations, but they are rare. In our cohort, PAX8 mutations were the leading cause of such a rare condition. (J Clin Endocrinol Metab 95: 1981-1985, 2010)

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Various types of LRP5 mutations in four patients with osteoporosis-pseudoglioma syndrome: identification of a 7.2-kb microdeletion using oligonucleotide tiling microarray

Narumi S, Numakura C, Shiihara T, Seiwa C, Nozaki Y, Yamagata T, Momoi MY, Watanabe Y, Yoshino M, Matsuishi T, Nishi E, Kawame H, Akahane T, Nishimura G, Emi M, Hasegawa T.

American Journal of Medical Genetics Part A (WILEY-LISS)  152A ( 1 ) 133-140 - 40 2010.01

Research paper (scientific journal), Joint Work, Accepted,  ISSN  1552-4825

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Osteoporosis-pseudoglioma syndrome (OPS; OMIM 259770) is an autosomal-recessive genetic disorder characterized by severe osteoporosis and visual disturbance from childhood. Biallelic mutations in the low-density lipoprotein receptor-related protein 5 gene (LRP5) have been frequently detected, while a subset of patients had only one or no detectable mutation. We report on the clinical and molecular findings of four unrelated Japanese patients with the syndrome. The four patients had typical skeletal and ocular phenotypes of OPS, namely severe juvenile osteoporosis and early-onset visual disturbance, with or without mental retardation. We undertook standard PCR-based sequencing for LRP5 and found four missense mutations (p.L145F, p.T244M, p.P382L, and p.T552M), one nonsense mutation (p.R1534X), and one splice site mutation (c.1584+1G>A) among four OPS patients. Although three patients had two heterozygous mutations, one had only one heterozygous splice site mutation. In this patient, RT-PCR from lymphocytic RNA demonstrated splice error resulting in 63-bp insertion between exons 7 and 8. Furthermore, the patient was found to have only mutated RT-PCR fragment, implying that a seemingly normal allele did not express LRP5 mRNA. We then conducted custom-designed oligonucleotide tiling microarray analyses targeted to a 600-kb genome region harboring LRP5 and discovered a 7.2-kb microdeletion encompassing exons 22 and 23 of LRP5. We found various types of LRP5 mutations, including an exon-level deletion that is undetectable by standard PCR-based mutation screening. Oligonucleotide tiling microarray seems to be a powerful tool in identifying cryptic structural mutations. (C) 2009 Wiley-Liss, Inc.

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Ruvalcaba syndrome revisited

Masanori Adachi, Koji Muroya, Yumi Asakura, Kenji Kurosawa, Gen Nishimura, Satoshi Narumi, Tomonobu Hasegawa

American Journal of Medical Genetics, Part A (Wiley-Liss Inc.)  152 ( 7 ) 1854 - 1857 2010

Accepted,  ISSN  1552-4833

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【小児内分泌学の進歩2009】家族性先天性甲状腺機能低下症の臨床的・分子遺伝学的検討

長崎 啓祐, 鳴海 覚志, 浅見 直, 小川 洋平, 菊池 透, 長谷川 奉延, 内山 聖

ホルモンと臨床 ((有)医学の世界社)  57 ( 12 ) 1001 - 1005 2009.12

ISSN  0045-7167

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病型別の家族性先天性甲状腺機能低下症(CH)の頻度、家族性CHの臨床的・分子遺伝学的特徴の解明を目的に、CHおよび一過性甲状腺機能低下症の患者264名について検討した。明確な家族歴を認めない例にも積極的に検索した。その結果、CHの家族歴を認めたのは17家系33名(12.5%)で、同胞例12家系、いとこを含む同胞例3家系、親子例1家系、罹患患者7名を含む家系1家系であった。甲状腺形態別の家族歴の頻度は、異所性甲状腺、甲状腺無形成の45名では0%で、正所性CH(低形成、正常大、腫大)174名中32名(18.4%)であった。家族性CHのうち14名の病型診断の結果、臨床的TSH不応症5家系、合成障害3家系、合成障害疑い6家系で、大半は軽症であった。遺伝子解析を行った9家系のうち、遺伝子変異を認めたのは1家系であった。以上より、CHの遺伝性の予測には甲状腺形態、TSH不応症の有無が有用な情報で、軽症CH発生は未知の遺伝子変異、環境要因の関与を示唆した。

TSHR mutations as a cause of congenital hypothyroidism in Japan: a population-based genetic epidemiology study.

Narumi S, Muroya K, Abe Y, Yasui M, Asakura Y, Adachi M, Hasegawa T.

Journal of Clinical Endocrinology and Metabolism (ENDOCRINE SOC)  94 ( 4 ) 1317-1323 - 23 2009.04

Research paper (scientific journal), Joint Work,  ISSN  0021-972X

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Context: The prevalence of congenital hypothyroidism (CH) associated with mutations in the TSH receptor gene (TSHR) has not been established.
Objective: We examined the frequency of TSHR mutations among patients with permanent primary CH and in the general population in Japan.
Subjects and Methods: We enrolled 102 patients with permanent primary CH [70 with "moderate to severe CH" (TSH, >= 10 mU/liter) and 32 with "mild CH" (TSH, 5-10 mU/liter)], who were identified through newborn screening among 353,000 newborns born in Kanagawa prefecture from October 1979 to June 2006. These subjects were tested for TSHR mutations by PCR-based direct sequencing. We further characterized molecular functions of identified mutant TSHRs in vitro.
Results: We found three patients with moderate to severe CH who had biallelic mutations in TSHR and three patients with mild CH who had monoallelic mutations. Observed mutations included one previously characterized mutation (p.R450H) and three uncharacterized mutations (p.G132R, p.A204V, and p.D403N). In vitro experiments confirmed loss of functions of these four mutants. Among four mutations, p.R450H was particularly frequent: six of nine mutant alleles harbored p.R450H. All six alleles with p.R450H commonly carried a minor single nucleotide polymorphism, suggesting a founder effect. We estimated the prevalence of biallelic TSHR mutations to be 4.3% (three in 70) in Japanese patients with moderate to severe CH, and 1 in 118,000 (three in 353,000) in the general Japanese population.
Conclusions: In Japan, TSHR mutations are relatively common among patients with CH, and a founder mutation (p.R450H) accounts for about 70% of mutants. (J Clin Endocrinol Metab 94: 1317-1323, 2009)

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The role of the CXCL10/CXCR3 system in type 1 diabetes.

Shimada A, Oikawa Y, Yamada Y, Okubo Y, Narumi S

The review of diabetic studies : RDS 6 ( 2 ) 81 - 4 2009

ISSN  1613-6071

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【小児内分泌学の進歩2008】先天性甲状腺機能低下症におけるTSH不応症の臨床的および遺伝学的検討

長崎 啓祐, 鳴海 覚志, 浅見 直, 菊池 透, 長谷川 奉延, 内山 聖

ホルモンと臨床 ((有)医学の世界社)  56 ( 12 ) 1213 - 1216 2008.12

ISSN  0045-7167

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小児科で先天性甲状腺機能低下症(CH)マススクリーニングのガイドラインに従い病型診断を行った症例のうち、臨床的にTSH不応症と診断した16例を対象に、臨床像と分子遺伝的特徴を検討した。全例にTRH負荷試験、血清Tg測定、甲状腺エコー、123I摂取率測定(摂取率20%以下の場合はパークロレイト放出試験)を行った。偽性副甲状腺機能低下症Ia型と臨床診断した1例ではGNAS1遺伝子解析を行い、残り15例にはTSH受容体遺伝子(TSHR)、PAX8、TITF1、FOXE1、NKX2-5の遺伝子解析を行った。いずれの遺伝子も翻訳領域をPCR-直接シーケンス法で解析した。その結果、TSH高値・fT4正常範囲の軽症11例、TSH高値・fT4低値の顕性5例で、重症度はさまざまであった。血清Tg値は1例を除き高値、甲状腺サイズは正常8例、低形成8例、123I摂取率は5例が40%以上と高値であった。7例にCHの家族歴があった。遺伝子解析では、TSHR複合へテロ接合性変異を1例、TSHRへテロ接合性変異を1例、TITF1へテロ接合性変異を1例に認め、偽性副甲状腺機能低下症Ia型の症例ではGNAS1遺伝子変異は認めなかった。

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

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

Endocrine Journal (JAPAN ENDOCRINE SOC)  55 ( 5 ) 875-878 - 878 2008.10

Research paper (scientific journal), Joint Work, Accepted,  ISSN  0918-8959

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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, lie 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 (Delta FT3, 0.4 pg/ml; Delta T3, 13 ng/dl; and Delta TSH, 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.

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先天性甲状腺機能低下症におけるTSH不応症の臨床像及び遺伝学的検討

長崎 啓祐, 鳴海 覚志, 浅見 直, 小川 洋平, 菊池 透, 長谷川 奉延, 内山 聖

日本内分泌学会雑誌 ((一社)日本内分泌学会)  84 ( 2 ) 414 - 414 2008.09

ISSN  0029-0661

Radiological evolution in IMAGe association: A case report

Naoko Amano, Hori Naoaki, Tomohiro Ishii, Satoshi Narumi, Rumi Hachiya, Gen Nishiniura, Tomonobu Hasegawa

American Journal of Medical Genetics, Part A 146A ( 16 ) 2130 - 3 2008.08

Accepted,  ISSN  1552-4825

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IMAGe association is a recently recognized multi-system disorder of unknown etiology. IMAGe is a mnemonic acronym that stands for Intrauterine growth retardation, Metaphyseal dysplasia, adrenal hypoplasia congenita, and Genital anomalies (OMIM 300290). Suspicion for the disorder is readily raised by the distinctive clinical and endocrinological constellation, and radiological identification of metaphyseal dysplasia is crucial for the diagnosis. However, knowledge of the onset, evolution, severity, and variation of the metaphyseal dysplasia is currently limited. We illustrate the radiological evolution of an affected girl from her premature birth to early childhood. Her initial skeletal changes included thin ribs, delayed ossification of the juxtatruncal bones, and delayed epiphyseal ossification. The former two became less conspicuous during infancy. Metaphyseal dysplasia was not discerned at birth. However, mild metaphyseal cupping, sclerosis and longitudinal striations became manifest in late infancy, and then progressed with age. It is thought that the skeletal alterations in IMAGe association encompass retarded endochondral ossification normalized later on and mild metaphyseal dysplasia of postnatal onset. © 2008 Wiley-Liss, Inc.

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Correspondence between computed tomography and endoscopy in Menetrier's disease

Narumi S, Omori T, Mitamura K, Yamashita Y, Nakao A, Cho H.

Pediatrics International (BLACKWELL PUBLISHING)  50 ( 2 ) 245-247 - 247 2008.04

Research paper (scientific journal), Joint Work, Accepted,  ISSN  1328-8067

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A Novel Mutation of Androgen Receptor Gene in Complete Androgen Insensitivity Syndrome

Narumi S, Amano N, Hachiya R, Ishii T,Hasegawa T.

Clinical Pediatric Endocrinology 16 ( 2 ) 59-61 - 61 2007.03

Research paper (scientific journal), Joint Work, Accepted,  ISSN  0918-5739

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Growth failure in an infant with congenital nephrogenic diabetes insipidus during sodium restriction

Goro Sasaki, Tomohiro Ishii, Naoko Amano, Rumi Hachiya, Satoshi Narumi, Tomonobu Hasegawa

Clinical Pediatric Endocrinology 16 ( 4 ) 95 - 8 2007

Accepted,  ISSN  0918-5739

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Congenital nephrogenic diabetes insipidus (CNDI) is an inherited disorder characterized by renal tubular insensitivity to antidiuretic hormone, resulting in an inability to concentrate urine. We report on an infant boy with CNDI who showed growth failure during treatment with sodium restriction. At the age of 4 mo, he was diagnosed as having CNDI, judging from fever with hypernatremia (serum Na 153 mEq/L), diluted urine (urine osmolarity 193 mOsm/kg), high antidiuretic hormone (plasma antidiuretic hormone 53 pg/mL), and normal renal function (serum creatinine 0.3 mg/dL). His length and weight were mean +0.4 and -1.1 SD, respectively, at that time. He was treated with sodium restriction (sodium intake
0.53 mEq/kg/day) using low sodium formula in addition to trichlormethiazide, spironolactone, and mefenamic acid. Growth failure developed: his length and weight were mean -2.4 and -3.3 SD, respectively, at the age of 10 mo. After withdrawal of sodium restriction to 1.5 mEq/kg/day of sodium intake without any change of caloric intake and medication, catch-up growth was observed. At the age of 39 mo, the patient's height and weight were mean -0.8 and -0.6 SD, respectively. We conclude that excessive sodium restriction can cause growth failure in infants with CNDI. Copyright© 2007 by The Japanese Society for Pediatric Endocrinology.

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[11Beta-hydroxylase deficiency].

Narumi S, Hasegawa T

Nihon rinsho. Japanese journal of clinical medicine Suppl 1   699 - 701 2006.05

ISSN  0047-1852

Growth-chart-based qualitative evaluation of height growth after hematopoietic stem cell transplantation.

Narumi S, Shimada H, Shimasaki N, Takahashi T, Hasegawa T, Mori T.

Pediatric Transplantation (BLACKWELL PUBLISHING)  10 ( 1 ) 26-31 - 31 2006.02

Research paper (scientific journal), Joint Work, Accepted,  ISSN  1397-3142

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Growth failure is one of the most common late complications in children undergoing hematopoietic stem cell transplantation (SCT). The present report describes a qualitative method of evaluating height growth after SCT, using a growth chart. The patients were divided into three groups according to the shape of their growth chart: the normal growth chart group, the early-onset growth retardation group (E-group), in which a decreased growth rate was seen during the first year after SCT, and the late-onset growth retardation group (L-group), in which a decreased growth rate was seen more than 1 yr after the SCT. In the E-group, total body irradiation and prolonged steroid therapy were thought to contribute to the growth failure, whereas in the L-group, impaired pubertal development was thought to be responsible. The growth pattern in the L-group may, therefore, be of particular clinical importance, because the final stature of the subjects in this group can be improved by pharmacological adjustment of pubertal onset. Although limited by the small size and heterogeneous nature of the sample, our results suggest that growth-chart-based evaluation may provide important information to stratify subjects showing inadequate growth after SCT into two groups whose follow-up and treatment should be individualized.

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Significance of serum CXCL10/IP-10 level in type 1 diabetes.

Shigihara T, Oikawa Y, Kanazawa Y, Okubo Y, Narumi S, Saruta T, Shimada A

Journal of autoimmunity 26 ( 1 ) 66 - 71 2006.02

ISSN  0896-8411

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CXCL10 DNA vaccination prevents spontaneous diabetes through enhanced beta cell proliferation in NOD mice.

Shigihara T, Shimada A, Oikawa Y, Yoneyama H, Kanazawa Y, Okubo Y, Matsushima K, Yamato E, Miyazaki J, Kasuga A, Saruta T, Narumi S

Journal of immunology (Baltimore, Md. : 1950) 175 ( 12 ) 8401 - 8 2005.12

ISSN  0022-1767

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CXC chemokine ligand 10 neutralization suppresses the occurrence of diabetes in nonobese diabetic mice through enhanced beta cell proliferation without affecting insulitis.

Morimoto J, Yoneyama H, Shimada A, Shigihara T, Yamada S, Oikawa Y, Matsushima K, Saruta T, Narumi S

Journal of immunology (Baltimore, Md. : 1950) 173 ( 11 ) 7017 - 24 2004.12

ISSN  0022-1767

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