論文 - 鳴海　覚志

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年

査読有り,  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年12月

ISSN  0045-7167

　概要を見る

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

The Journal of clinical endocrinology and metabolism （ENDOCRINE SOC）  94 （ 4 ） 1317-1323 - 23 2009年04月

研究論文（学術雑誌）, 共著,  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年

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年12月

ISSN  0045-7167

　概要を見る

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年10月

研究論文（学術雑誌）, 共著, 査読有り,  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年09月

ISSN  0029-0661

Radiological evolution in IMAGe association: a case report.

Amano N, Naoaki H, Ishii T, Narumi S, Hachiya R, Nishimura G, Hasegawa T

American journal of medical genetics. Part A 146A （ 16 ） 2130 - 3 2008年08月

査読有り,  ISSN  1552-4825

　概要を見る

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年04月

研究論文（学術雑誌）, 共著, 査読有り,  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 : case reports and clinical investigations : official journal of the Japanese Society for Pediatric Endocrinology 16 （ 2 ） 59-61 - 61 2007年03月

研究論文（学術雑誌）, 共著, 査読有り,  ISSN  0918-5739

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

Sasaki G, Ishii T, Amano N, Hachiya R, Narumi S, Hasegawa T

Clinical pediatric endocrinology : case reports and clinical investigations : official journal of the Japanese Society for Pediatric Endocrinology 16 （ 4 ） 95 - 8 2007年

査読有り,  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年05月

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年02月

研究論文（学術雑誌）, 共著, 査読有り,  ISSN  1397-3142

　概要を見る

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年02月

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年12月

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年12月

ISSN  0022-1767

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Two cases of "fulminant" type 1 diabetes suggesting involvement of autoimmunity.

Nakagawa Y, Shimada A, Oikawa Y, Irie J, Shigihara T, Tsumura K, Narumi S, Saruta T

Annals of the New York Academy of Sciences 1005   359 - 61 2003年11月

ISSN  0077-8923

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T-cell function in anti-GAD65(+)diabetes with residual beta-cell function.

Suzuki R, Shimada A, Maruyama T, Funae O, Morimoto J, Kodama K, Oikawa Y, Kasuga A, Matsubara K, Saruta T, Narumi S

Journal of autoimmunity 20 （ 1 ） 83 - 90 2003年02月

ISSN  0896-8411

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Elevated serum IP-10 levels observed in type 1 diabetes.

Shimada A, Morimoto J, Kodama K, Suzuki R, Oikawa Y, Funae O, Kasuga A, Saruta T, Narumi S

Diabetes care 24 （ 3 ） 510 - 5 2001年03月

ISSN  0149-5992

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MIRAGE Syndrome.

Adam MP, Feldman J, Mirzaa GM, Pagon RA, Wallace SE, Amemiya A, Tanase-Nakao K, Olson TS, Narumi S

（University of Washington, Seattle）  1993年

　概要を見る

CLINICAL CHARACTERISTICS: MIRAGE syndrome is an acronym for the major findings of myelodysplasia, infection, restriction of growth, adrenal hypoplasia, genital phenotypes, and enteropathy. Cytopenias are typically seen soon after birth; Thrombocytopenia is the most common followed by anemia and pancytopenia. Recurrent infections from early infancy include pneumonia, urinary tract infection, gastroenteritis, meningitis, otitis media, dermatitis, subcutaneous abscess, and sepsis. Reported genital phenotypes in those with 46,XY karyotype included hypospadias, microphallus, bifid shawl scrotum, ambiguous genitalia, or complete female genitalia. Hypoplastic or dysgenetic ovaries have been reported in females. Gastrointestinal complications include chronic diarrhea and esophageal dysfunction. Moderate-to-severe global developmental delay is reported in most affected individuals. Autonomic dysfunction and renal dysfunction are also reported. DIAGNOSIS/TESTING: The diagnosis of MIRAGE syndrome is established in a proband with suggestive findings and a heterozygous germline gain-of-abnormal-function pathogenic variant in SAMD9 identified by molecular genetic testing. MANAGEMENT: Treatment of manifestations: Individuals with severe anemia and thrombocytopenia due to bone marrow failure should be treated with standard transfusion approaches; bacterial infection prevention including antibiotic prophylaxis and fever precautions in individuals with severe neutropenia. Individuals with severe neutropenia and chronic transfusion requirements, along with individuals who develop monosomy 7 myelodysplastic syndrome should be considered for hematopoietic stem cell transplantation. Standard treatment of infections with antibiotics, antiviral or antifungal agents as needed; consider prophylactic intravenous immunoglobulin if endogenous immunoglobulin levels are low; management by nutritionist to ensure adequate caloric intake and to assist with elemental diet for chronic diarrhea; hydrocortisone and fludrocortisone as needed for adrenal hypoplasia; surgical removal of dysgenetic gonads or surgical intervention may be considered for those with external genital anomalies; consider duodenal tube feeding in those with recurrent aspiration pneumonia; early intervention with occupational, physical, speech and feeding therapy for developmental delay; artificial tear solutions and treatment per ophthalmologist for ocular manifestations of autonomic dysfunction such as hypolacrima; management of ambient temperature for those with temperature instability; management of renal dysfunction per nephrologist. Surveillance: Complete blood count with differential every four to six months; annual bone marrow aspirate and biopsy (with analysis for somatic alterations including chromosome 7 abnormalities) in those with cytopenias including anemia, thrombocytopenia, or neutropenia; at least annual assessment of height, weight, head circumference, physical examination for features of adrenal hypoplasia, and measurement of serum sodium, potassium, glucose, cortisol, and ACTH. Assess for diarrhea, feeding issues, and esophageal dysfunction as needed; monitor developmental milestones every three to six months in the first year of life and at least annually thereafter; assess for keratoconjunctivitis sicca, corneal ulcer, and temperature instability as needed; at least annual measurement of serum creatinine, blood urea nitrogen, and urinalysis to evaluate renal function. Evaluation of relatives at risk: It is appropriate to clarify the genetic status of apparently asymptomatic at-risk relatives of an affected individual in order to identify as early as possible those who would benefit from evaluation for myelodysplasia. GENETIC COUNSELING: MIRAGE syndrome is an autosomal dominant disorder typically caused by a de novo pathogenic variant. Rarely, individuals diagnosed with MIRAGE syndrome have the disorder as the result of a variant inherited from a heterozygous parent with no apparent features of MIRAGE syndrome. If the proband has an SAMD9 pathogenic variant that is not detected in the leukocyte DNA of either parent, the recurrence risk to sibs is slightly greater than that of the general population because of the possibility of parental germline mosaicism or the possibility of a false negative result in a parent due to preferential loss of the chromosome with the SAMD9 pathogenic variant. Once the SAMD9 pathogenic variant has been identified in an affected family member, prenatal and preimplantation genetic testing are possible.