Papers - Narumi, Satoshi

Somatic mosaic monosomy 7 and UPD7q in a child with MIRAGE syndrome caused by a novel SAMD9 mutation.

Bernhard Csillag, Denisa Ilencikova, Manfred Meissl, Gerald Webersinke, Franco Laccone, Satoshi Narumi, Oskar Haas, Hans-Christoph Duba

Pediatric blood & cancer 66 ( 4 ) e27589 2019.04

Accepted,  ISSN  1545-5009

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MIRAGE syndrome caused by mutations in SAMD9 is associated with potential loss of chromosome 7 (-7/7q-) and an increased risk to develop myelodysplastic syndrome (MDS). We report a case of MIRAGE syndrome, caused by a novel SAMD9 mutation p.Leu641Pro, leading to characteristic clinical features as well as to the coexistence of cells with monosomy 7 (20%) and with uniparental disomy of long arm of chromosome 7 (UPD7q). In contrast to previously reported MIRAGE patients with -7/7q- developing MDS, our patient achieved complete cytogenetic remission of monosomy 7. As UPD7q remained unchanged, it seems to be a protective factor against MDS.

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新たに発見された変異TBL1X遺伝子の機能解析

高見澤 哲也, 鳴海 覚志, 杉澤 千穂, 谷山 松雄, 錦戸 彩加, 岡村 孝志, 土岐 明子, 石田 恵美, 松本 俊一, 堀口 和彦, 中島 康代, 登丸 琢也, 石井 角保, 小澤 厚志, 渋沢 信行, 石塚 高広, 佐藤 哲郎, 長谷川 奉延, 山田 正信

日本内分泌学会雑誌 ((一社)日本内分泌学会)  95 ( 1 ) 397 - 397 2019.04

ISSN  0029-0661

MIRAGE syndrome with recurrent pneumonia probably associated with gastroesophageal reflux and achalasia: A case report.

Kanako Yoshizaki, Rumi Hachiya, Yutaro Tomobe, Uiko Kaku, Kazuhisa Akiba, Hirohito Shima, Satoshi Narumi, Yukihiro Hasegawa

Clinical pediatric endocrinology : case reports and clinical investigations : official journal of the Japanese Society for Pediatric Endocrinology 28 ( 4 ) 147 - 153 2019

Accepted,  ISSN  0918-5739

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Aspiration pneumonia is a common complication of myelodysplasia, infection, restriction of growth, adrenal hypoplasia, genital phenotypes, and enteropathy (MIRAGE) syndrome. However, the detailed clinical course of aspiration pneumonia in neonates and infants diagnosed with this disorder remains unclear. We report a case of a 2-yr-old girl diagnosed with MIRAGE syndrome during the early neonatal period. The patient developed 3 episodes of aspiration pneumonia until 4 mo of age, and this complication was attributed to esophageal hypoperistalsis secondary to achalasia and gastroesophageal reflux. Enteral feeding via a duodenal tube effectively prevented further episodes of aspiration pneumonia in this patient.

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A novel truncating mutation in MYH3 causes spondylocarpotarsal synostosis syndrome with basilar invagination.

Masaki Takagi, Satoshi Shimomura, Ryuji Fukuzawa, Satoshi Narumi, Gen Nishimura, Tomonobu Hasegawa

Journal of human genetics 63 ( 12 ) 1277 - 1281 2018.12

ISSN  1434-5161

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Spondylocarpotarsal synostosis syndrome (SCT) is a rare group of skeletal dysplasias, characterized by disproportionate short stature with a short trunk, abnormal segmentation of the spine with vertebral fusion, scoliosis and lordosis, carpal and tarsal synostosis, and mild facial dysmorphisms. While the majority of the cases show autosomal recessive inheritance, only a few cases of vertical transmissions, with MYH3 mutations, have been reported. Here we report a case with typical SCT, carrying a novel heterozygous mutation in MYH3. This observation supports the hypothesis of a pathogenic link between autosomal dominant SCT and heterozygous mutations in MYH3. Of note, our case showed basilar invagination on brain magnetic resonance imaging at the age of 10 years. Basilar invagination could be a rare complication of both autosomal recessive and dominant SCT, indicating that prompt investigation are warranted for SCT patients.

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An association with hypopituitarism and 9q subtelomere deletion syndrome.

Shinji Higuchi, Masaki Takagi, Ryojun Takeda, Hiroshi Yoshihashi, Satoshi Narumi, Tomonobu Hasegawa

Clinical case reports 6 ( 12 ) 2371 - 2375 2018.12

Accepted,  ISSN  2050-0904

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Hypopituitarism could have been overlooked so far in the patients with 9q subtelomere deletion syndrome (9qSTDS); thus, further investigations or reevaluation of clinical information, especially hormonal evaluations, are warranted to determine whether hypopituitarism is a rare or relatively common presentation in patients with 9qSTDS.

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中枢性先天性甲状腺機能低下症男児における新規TBL1X変異の同定と機能解析

杉澤 千穂, 志賀 健太郎, 菅原 秀典, 大杉 康司, 谷山 松雄, 長谷川 奉延, 高見澤 哲也, 石井 角保, 佐藤 哲郎, 山田 正信, 鳴海 覚志

日本内分泌学会雑誌 ((一社)日本内分泌学会)  94 ( 4 ) 1228 - 1228 2018.12

ISSN  0029-0661

Germline loss-of-function SAMD9 and SAMD9L alterations in adult myelodysplastic syndromes.

Nagata Y, Narumi S, Guan Y, Przychodzen BP, Hirsch CM, Makishima H, Shima H, Aly M, Pastor V, Kuzmanovic T, Radivoyevitch T, Adema V, Awada H, Yoshida K, Li S, Sole F, Hanna R, Jha BK, LaFramboise T, Ogawa S, Sekeres MA, Wlodarski MW, Cammenga J, Maciejewski JP

Blood 132 ( 21 ) 2309 - 2313 2018.11

Accepted,  ISSN  0006-4971

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GATA4 mutations are uncommon in patients with 46, XY disorders of sex development without heart anomaly

Igarashi Maki, Mizuno Kentaro, Kon Masafumi, Narumi Satoshi, Kojima Yoshiyuki, Hayashi Yutaro, Ogata Tsutomu, Fukami Maki

ASIAN JOURNAL OF ANDROLOGY 20 ( 6 ) 629 - 631 2018.11

Accepted,  ISSN  1008-682X

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Optogenetic Control of Synaptic AMPA Receptor Endocytosis Reveals Roles of LTD in Motor Learning.

Kakegawa W, Katoh A, Narumi S, Miura E, Motohashi J, Takahashi A, Kohda K, Fukazawa Y, Yuzaki M, Matsuda S

Neuron 99 ( 5 ) 985 - 998.e6 2018.09

ISSN  0896-6273

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Rare monogenic causes of primary adrenal insufficiency

Narumi Satoshi

Current Opinion in Endocrinology & Diabetes and Obesity 25 ( 3 ) 172 - 177 2018.06

Accepted,  ISSN  1752-296X

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Nodular Lymphocyte-predominant Hodgkin Lymphoma in a 15-Year-Old Boy With Li-Fraumeni Syndrome Having a Germline TP53 D49H Mutation.

Fumito Yamazaki, Haruko Shima, Tomoo Osumi, Satoshi Narumi, Tatsuo Kuroda, Hiroyuki Shimada

Journal of pediatric hematology/oncology 40 ( 3 ) e195 - e197 2018.04

Accepted,  ISSN  1077-4114

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Germline mutations in TP53 are the primary cause of Li-Fraumeni syndrome (LFS). Most mutations are reported within the DNA-binding domain. We report a case of a 15-year-old boy with LFS who developed early-stage nodular lymphocyte-predominant Hodgkin lymphoma, a rare subtype of Hodgkin lymphomas. His sister was diagnosed with embryonal rhabdomyosarcoma at the age of 1.5 years. Sequence analysis revealed a germline mutation in the transactivation domain of TP53, c.145G>C (p.D49H), in the patient, his sister, and father. One family with LFS with a germline TP53 D49H mutation has previously been reported. This report supports the pathogenicity of this mutation.

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胎児甲状腺腫性甲状腺機能低下症を呈し胎内治療を行うも幼児期に軽快したDUOXA2異常症 世界初の報告例

宮田 市郎, 寺内 綾子, 齋藤 真希, 和田 誠司, 岩橋 めぐみ, 中尾 佳奈子, 鳴海 覚志

日本内分泌学会雑誌 ((一社)日本内分泌学会)  94 ( 1 ) 333 - 333 2018.04

ISSN  0029-0661

Comprehensive screening for monogenic diabetes in 89 Japanese children with insulin-requiring antibody-negative type 1 diabetes.

Kikumi Ushijima, Maki Fukami, Tadayuki Ayabe, Satoshi Narumi, Misako Okuno, Akie Nakamura, Toshikazu Takahashi, Kenji Ihara, Kazuhiro Ohkubo, Emiko Tachikawa, Shoji Nakayama, Junichi Arai, Nobuyuki Kikuchi, Toru Kikuchi, Tomoyuki Kawamura, Tatsuhiko Urakami, Kenichiro Hata, Kazuhiko Nakabayashi, Yoichi Matsubara, Shin Amemiya, Tsutomu Ogata, Ichiro Yokota, Shigetaka Sugihara

Pediatric diabetes 19 ( 2 ) 243 - 250 2018.03

Accepted,  ISSN  1399-543X

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BACKGROUND: Mutations in causative genes for neonatal diabetes or maturity-onset diabetes of the young have been identified in multiple patients with autoantibody-negative type 1 diabetes (T1D). OBJECTIVES: We aimed to clarify the prevalence and phenotypic characteristics of monogenic abnormalities among 89 children with autoantibody-negative insulin-requiring T1D. METHODS: Mutations in 30 genes were screened using next-generation sequencing, and copy-number alterations of 4 major causative genes were examined using multiplex-ligation-dependent probe amplification. We compared the clinical characteristics between mutation carriers and non-carriers. RESULTS: We identified 11 probable pathogenic substitutions (6 in INS , 2 in HNF1A , 2 in HNF4A , and 1 in HNF1B ) in 11 cases, but no copy-number abnormalities. Only 2 mutation carriers had affected parents. De novo occurrence was confirmed for 3 mutations. The non-carrier group, but not the carrier group, was enriched with susceptible HLA alleles. Mutation carriers exhibited comparable phenotypes to those of non-carriers, except for a relatively normal body mass index (BMI) at diagnosis. CONCLUSIONS: This study demonstrated significant genetic overlap between autoantibody-negative T1D and monogenic diabetes. Mutations in INS and HNF genes, but not those in GCK and other monogenic diabetes genes, likely play critical roles in children with insulin-requiring T1D. This study also suggests the relatively high de novo rates of INS and HNF mutations, and the etiological link between autoimmune abnormalities and T1D in the non-carrier group. Carriers of monogenic mutations show non-specific phenotypes among all T1D cases, although they are more likely to have a normal BMI at diagnosis than non-carriers.

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A novel SAMD9 mutation causing MIRAGE syndrome: An expansion and review of phenotype, dysmorphology, and natural history

Lauren Jeffries, Hirohito Shima, Weizhen Ji, David Panisello-Manterola, James McGrath, Lynne M. Bird, Monica Konstantino, Satoshi Narumi, Saquib Lakhani

American Journal of Medical Genetics, Part A (Wiley-Liss Inc.)  176 ( 2 ) 415 - 420 2018.02

Accepted,  ISSN  1552-4825

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Germline gain-of-function variants in SAMD9 have been associated with a high risk of mortality and a newly recognized constellation of symptoms described by the acronym MIRAGE: Myelodysplasia, Infection, Restriction of growth, Adrenal insufficiency, Genital phenotypes, and Enteropathy. Here, we describe two additional patients currently living with the syndrome, including one patient with a novel de novo variant for which we provide functional data supporting its pathogenicity. We discuss features of dysmorphology, contrasting with previously described patients as well as drawing attention to additional clinical features, dysautonomia and hearing loss that have not previously been reported. We detail both patients’ courses following diagnosis, with attention to treatment plans and recommended specialist care. Our patients are the oldest known with arginine-substituting amino acid variants, and we conclude that early diagnosis and multidisciplinary management may positively impact outcomes for this vulnerable group of patients.

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Association between monoallelic TSHR mutations and congenital hypothyroidism: A statistical approach

Kiyomi Abe, Satoshi Narumi, Ayuko S. Suwanai, Masanori Adachi, Koji Muroya, Yumi Asakura, Keisuke Nagasaki, Takayuki Abe, Tomonobu Hasegawa

European Journal of Endocrinology (BioScientifica Ltd.)  178 ( 2 ) 137 - 144 2018.02

Accepted,  ISSN  0804-4643

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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.

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Two patients with MIRAGE syndrome lacking haematological features: role of somatic second-site reversion SAMD9 mutations.

Hirohito Shima, Katrin Koehler, Yumiko Nomura, Kazuhiko Sugimoto, Akira Satoh, Tsutomu Ogata, Maki Fukami, Ramona Jühlen, Markus Schuelke, Klaus Mohnike, Angela Huebner, Satoshi Narumi

Journal of medical genetics 55 ( 2 ) 81 - 85 2018.02

Accepted,  ISSN  0022-2593

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BACKGROUND: Myelodysplasia, infection, restriction of growth, adrenal hypoplasia, genital phenotypes and enteropathy (MIRAGE) syndrome is a recently described congenital disorder caused by heterozygous SAMD9 mutations. The phenotypic spectrum of the syndrome remains to be elucidated. METHODS AND RESULTS: We describe two unrelated patients who showed manifestations compatible with MIRAGE syndrome, with the exception of haematological features. Leucocyte genomic DNA samples were analysed with next-generation sequencing and Sanger sequencing, revealing the patients to have two de novoSAMD9 mutations on the same allele (patient 1 p.[Gln695*; Ala722Glu] and patient 2 p.[Gln39*; Asp769Gly]). In patient 1, p.Gln695* was absent in genomic DNA extracted from hair follicles, implying that the non-sense mutation was acquired somatically. In patient 2, with the 46,XX karyotype, skewed X chromosome inactivation pattern was found in leucocyte DNA, suggesting monoclonality of cells in the haematopoietic system. In vitro expression experiments confirmed the growth-restricting capacity of the two missense mutant SAMD9 proteins that is a characteristic of MIRAGE-associated SAMD9 mutations. CONCLUSIONS: Acquisition of a somatic nonsense SAMD9 mutation in the cells of the haematopoietic system might revert the cellular growth repression caused by the germline SAMD9 mutations (ie, second-site reversion mutations). Unexpected lack of haematological features in the two patients would be explained by the reversion mutations.

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Poor outcome with hematopoietic stem cell transplantation for bone marrow failure and MDS with severe MIRAGE syndrome phenotype

Sarthy J, Zha J, Babushok D, Shenoy A, Fan JM, Wertheim G, Himebauch A, Munchel A, Taraseviciute A, Yang S, Shima H, Narumi S, Meshinchi S, Olson TS

Blood Advances 2 ( 2 ) 120 - 125 2018.01

Accepted,  ISSN  2473-9529

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Comment on: Acquired monosomy 7 myelodysplastic syndrome in a child with clinical features of dyskeratosis congenita and IMAGe association

David B. Wilson, Monica Bessler, Thomas W. Ferkol, Shalini Shenoy, Naoko Amano, Tomohiro Ishii, Hirohito Shima, Satoshi Narumi

PEDIATRIC BLOOD & CANCER (WILEY)  65 ( 1 ) e26747 2018.01

Accepted,  ISSN  1545-5009

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[Association between SAMD9/SAMD9L and hematological malignancies].

Narumi S, Hasegawa T

[Rinsho ketsueki] The Japanese journal of clinical hematology 59 ( 11 ) 2475 - 2480 2018

ISSN  0485-1439

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Molecular and Clinical Analyses of Two UPD(16)Mat Patients Detected by Screening of 94 Silver-Russell Syndrome Patients Without Known Etiology

Inoue Takanobu, Yagasaki Hideaki, Nishioka Junko, Nakamura Akie, Matsubara Keiko, Narumi Satoshi, Nakabayashi Kazuhiko, Yamazawa Kazuki, Fuke Tomoko, Oka Akira, Ogata Tsutomu, Fukami Maki, Kagami Masayo

HORMONE RESEARCH IN PAEDIATRICS 90   122 - 123 2018

Accepted,  ISSN  1663-2818