論文 - 鳴海　覚志

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

Csillag B, Ilencikova D, Meissl M, Webersinke G, Laccone F, Narumi S, Haas O, Duba HC

Pediatric blood & cancer 66 （ 4 ） e27589 2019年04月

査読有り,  ISSN  1545-5009

　概要を見る

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年04月

ISSN  0029-0661

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

Yoshizaki K, Hachiya R, Tomobe Y, Kaku U, Akiba K, Shima H, Narumi S, Hasegawa Y

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

査読有り,  ISSN  0918-5739

　概要を見る

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.

Takagi M, Shimomura S, Fukuzawa R, Narumi S, Nishimura G, Hasegawa T

Journal of human genetics 63 （ 12 ） 1277 - 1281 2018年12月

ISSN  1434-5161

　概要を見る

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.

Higuchi S, Takagi M, Takeda R, Yoshihashi H, Narumi S, Hasegawa T

Clinical case reports 6 （ 12 ） 2371 - 2375 2018年12月

査読有り,  ISSN  2050-0904

　概要を見る

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年12月

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年11月

査読有り,  ISSN  0006-4971

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

Igarashi M, Mizuno K, Kon M, Narumi S, Kojima Y, Hayashi Y, Ogata T, Fukami M

Asian journal of andrology 20 （ 6 ） 629 - 631 2018年11月

査読有り,  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年09月

ISSN  0896-6273

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Rare monogenic causes of primary adrenal insufficiency.

Narumi S

Current opinion in endocrinology, diabetes, and obesity 25 （ 3 ） 172 - 177 2018年06月

査読有り,  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.

Yamazaki F, Shima H, Osumi T, Narumi S, Kuroda T, Shimada H

Journal of pediatric hematology/oncology 40 （ 3 ） e195 - e197 2018年04月

査読有り,  ISSN  1077-4114

　概要を見る

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年04月

ISSN  0029-0661

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

Ushijima K, Fukami M, Ayabe T, Narumi S, Okuno M, Nakamura A, Takahashi T, Ihara K, Ohkubo K, Tachikawa E, Nakayama S, Arai J, Kikuchi N, Kikuchi T, Kawamura T, Urakami T, Hata K, Nakabayashi K, Matsubara Y, Amemiya S, Ogata T, Yokota I, Sugihara S, Japanese Study Group of Insulin Therapy for Childhood and Adolescent Diabetes

Pediatric diabetes 19 （ 2 ） 243 - 250 2018年03月

査読有り,  ISSN  1399-543X

　概要を見る

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.

Jeffries L, Shima H, Ji W, Panisello-Manterola D, McGrath J, Bird LM, Konstantino M, Narumi S, Lakhani S

American journal of medical genetics. Part A （Wiley-Liss Inc.）  176 （ 2 ） 415 - 420 2018年02月

査読有り,  ISSN  1552-4825

　概要を見る

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.

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

European journal of endocrinology （BioScientifica Ltd.）  178 （ 2 ） 137 - 144 2018年02月

査読有り,  ISSN  0804-4643

　概要を見る

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.

Shima H, Koehler K, Nomura Y, Sugimoto K, Satoh A, Ogata T, Fukami M, Jühlen R, Schuelke M, Mohnike K, Huebner A, Narumi S

Journal of medical genetics 55 （ 2 ） 81 - 85 2018年02月

査読有り,  ISSN  0022-2593

　概要を見る

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年01月

査読有り,  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.

Wilson DB, Bessler M, Ferkol TW, Shenoy S, Amano N, Ishii T, Shima H, Narumi S

Pediatric blood & cancer （WILEY）  65 （ 1 ） e26747 2018年01月

査読有り,  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年

ISSN  0485-1439

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MIRAGE syndrome is a rare cause of 46,XY DSD born SGA without adrenal insufficiency.

Shima H, Hayashi M, Tachibana T, Oshiro M, Amano N, Ishii T, Haruna H, Igarashi M, Kon M, Fukuzawa R, Tanaka Y, Fukami M, Hasegawa T, Narumi S

PloS one 13 （ 11 ） e0206184 2018年

査読有り

　概要を見る

BACKGROUND: MIRAGE syndrome, a congenital multisystem disorder due to pathogenic SAMD9 variants, describes a constellation of clinical features including 46,XY disorders of sex development (DSD), small for gestational age (SGA) and adrenal insufficiency (AI). It is poorly understood whether SAMD9 variants underlie 46,XY DSD patients born SGA (46,XY DSD SGA) without AI. This study aimed to define the frequency and phenotype of SAMD9 variants in 46,XY DSD SGA without AI. METHODS: Forty-nine Japanese patients with 46,XY DSD SGA (Quigley scale, 2 to 6; gestational age-matched birth weight percentile, <10) without history of AI were enrolled. The single coding exon of SAMD9 was PCR-amplified and sequenced for each patient. Pathogenicity of an identified variant was verified in vitro. Placenta tissues were obtained from the variant-carrying patient, as well as from another previously described patient, and were analyzed histologically. RESULTS: In one 46,XY DSD SGA patient, a novel heterozygous SAMD9 variant, p.Phe1017Val, was identified. Pathogenicity of the mutant was experimentally confirmed. In addition to DSD and SGA, the patient had neonatal thrombocytopenia, severe postnatal grow restriction, chronic diarrhea and susceptibility to infection, all features consistent with MIRAGE, leading to premature death at age 14 months. The patient did not have any manifestations or laboratory findings suggesting AI. Placenta tissues of the two variant-carrying patients were characterized by maldevelopment of distal villi without other findings of maternal underperfusion. CONCLUSIONS: MIRAGE syndrome is a rare cause of 46,XY DSD SGA without AI. This study exemplifies that AI is a common feature of MIRAGE syndrome but that the absence of AI should not rule out a diagnosis of the syndrome.

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