Language：English   Publishing type：Research paper (scientific journal)  

Pseudoachondroplasia (PSACH) is an autosomal dominant skeletal dysplasia caused by pathogenic variants of cartilage oligomeric matrix protein (COMP). Clinical symptoms of PSACH are characterized by growth disturbances after the first year of life. These disturbances lead to severe short stature with short limbs, brachydactyly, scoliosis, joint laxity, joint pain since childhood, and a normal face. Epimetaphyseal dysplasia, shortened long bones, and short metacarpals and phalanges are common findings on radiological examination. Additionally, anterior tonguing of the vertebral bodies in the lateral view is an important finding in childhood because it is specific to PSACH and normalizes with age. Here, we report five Japanese patients with PSACH, with one recurrent (p.Cys351Tyr) and four novel heterozygous pathogenic COMP variants (p.Asp437Tyr, p.Asp446Gly, p.Asp507Tyr, and p.Asp518Val). These five pathogenic variants were located in the calcium-binding type 3 (T3) repeats. In four of the novel variants, the affected amino acid was aspartic acid, which is abundant in each of the eight T3 repeats. We describe the radiological findings of these five patients. We also retrospectively analyzed the sequential changes in the vertebral body and epimetaphysis of the long bones from the neonatal to infantile periods in a patient with PSACH and congenital heart disease.

DOI： 10.1297/cpe.2023-0035

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Language：Japanese   Publisher：日本小児高血圧研究会  

酸化ストレスは、内部・外部刺激により生体内で活性酸素群(活性窒素も含む)が抗酸化システムで捕捉しきれないほど過剰に生じる状況である。酸化ストレス亢進は血管内皮障害と深く関連する。とりわけ、血管内皮での一酸化窒素(nitric oxide:NO)生成は生体のレドックス環境を保持するうえで必須である。酸化ストレス亢進はarginineを基質とするNO合成を抑制し、内因性NO合成酵素阻害因子であるasymmetric dimethylarginine(ADMA)の生成を刺激する。新生児の急速進行性疾患、慢性遷延性疾患ではしばしば酸化ストレスが増幅され、生体の構造や機能が酸化劣化を受けて、組織障害が不可逆的に進展する。これらの疾患の治療や管理において酸化ストレスを制御することは重要である。そのためには酸化ストレスの病態生理、それへの防御機制を把握し、特異的マーカーを用いて患者の酸化ストレス環境を非～低侵襲的に評価することが必要である。新生児医療の現場で実施される種々の治療は、酸化ストレス制御を目指すものでもある。その中で、母乳はNO、thioredoxin-1などの抗酸化因子を多量に含有し、酸化ストレス過剰病態の抑止に有効と推定される。今後は、"レドックス"に関連してより特異性の高い細胞機能修飾薬が開発され、それらが重症疾患への集学治療の中に組み込まれていくことが期待される。(著者抄録)

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Language：Japanese   Publisher：日本小児高血圧研究会  

【背景】一過性の著明な血圧上昇をきたし種々の身体症状を呈する症例において,褐色細胞腫の可能性は考慮する必要があるが,偽性褐色細胞腫との鑑別を要することもある.他方,その他の疾患と悩まれることは多くないが,今回我々は本態性高血圧に加えて精神的要因が関与したことにより褐色細胞腫に類似した症状を呈した症例を経験したため報告する.【症例】生来健康な男児で肥満はなかった.15歳時に学校で誘因なく発作的に胸部違和感を自覚した後上肢の脱力をきたし,更に意識混濁した.その際に保健室で測定された収縮期血圧は200mmHgを超えていた.同様のエピソードを反復したため当院に紹介された.来院時の血圧は140-150/70-80mmHg程度であった.問診では,学校生活での強い心理的ストレスの他,塩分摂取過多が疑われた.鑑別疾患として褐色細胞腫や偽性褐色細胞腫も考えられたが,意識混濁の身体症状を伴ったためてんかんの可能性も検討した.メタネフリンやカテコラミンの測定値や画像検査で異常はなく,上記エピソードが起こった際の心電図や脳波所見にも異常はなかった.他方,brachial-ankle Pulse Wave Velocityは両側とも高値であった.また,意識混濁を含む身体症状は精神科より解離性障害が疑われた.これらのことから,本態性高血圧が背景にあり,精神的要因が加わって一過性に高血圧になった可能性を考えた.食事指導とアムロジピンを少量から開始し増量した他,精神科からはクロチアゼパムが処方された.その後しばらくは,上記と同様のエピソードを繰り返し何度か当院に救急搬送されたが,次第に症状は落ち着いた.【考察】本症例は,褐色細胞腫に類似した症状を呈したが,身体症状として意識混濁を伴った点も特徴的であった.意識混濁は褐色細胞腫や偽性褐色細胞腫の身体症状としては考えにくく,てんかん性疾患も考えたが否定的であった.精神的要因で身体症状を伴って一過性に高血圧を呈することはあるが,その際の血圧上昇の程度は軽度とされている.このため,精神症状のみでは本症例の症状を説明できなかったが,本態性高血圧が背景にあり,解離様の精神症状が加わったことで褐色細胞腫類似の症状を呈したものと考えることで症状が説明づけられた.(著者抄録)

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DOI： 10.1038/s41598-022-11823-3

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Under normal conditions, fasting results in decreased protein disulfide isomerase (PDI) activity and accumulation of unfolded proteins, leading to the subsequent activation of the unfolded protein response (UPR)/autophagy signaling pathway to eliminate damaged mitochondria. Fasting also induces upregulation of thioredoxin-interacting protein (TXNIP) expression and mice deficient of this protein (TXNIP-KO mice) was shown to develop severe hypoglycemia, hyperlipidemia and liver steatosis (LS). In the present study, we aimed to determine the role of TXNIP in fasting-induced LS by using male TXNIP-KO mice that developed LS without severe hypoglycemia. In TXNIP-KO mice, fasting induced severe microvesicular LS. Examinations by transmission electron microscopy revealed mitochondria with smaller size and deformities and the presence of few autophagosomes. The expression of β-oxidation-associated genes remained at the same level and the level of LC3-II was low. PDI activity level stayed at the original level and the levels of p-IRE1 and X-box binding protein 1 spliced form (sXBP1) were lower. Interestingly, treatment of TXNIP-KO mice with bacitracin, a PDI inhibitor, restored the level of LC3-II after fasting. These results suggest that TXNIP regulates PDI activity and subsequent activation of the UPR/autophagy pathway and plays a protective role in fasting-induced LS.

DOI： 10.1038/s41598-022-08791-z

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Language：English   Publishing type：Research paper (scientific journal)  

High-dose steroids are required for the treatment of minimal change nephrotic syndrome (MCNS), especially for episodes of recurrence. Predicting and avoiding recurrence can help reduce the steroid dose, but prediction is currently difficult. We herein examined whether changes in laboratory data, especially the urinary protein- to-creatinine ratio (UTP/UCr), can predict clinical recurrence. We also assessed differences in clinical features between children and young adults. We included 36 patients with MCNS; for each case, we retrospectively studied laboratory data during stable remission and pre-recurrence, with the "stable" period defined as all but the 6 weeks before recurrence, and pre-recurrence defined as the 4±2 weeks before recurrence. UTP/UCr, serum albumin, etc. were measured every 5 years during stable periods. We divided patients into cohorts by age at recurrence, < 15 years and ≥ 15 years, and compared stable and pre-recurrence values for the two groups. UTP/UCr values during stable periods tended to be higher in younger patients. UTP/UCr and serum albumin showed statistically significant changes during pre-recurrence periods, but only in those aged ≥ 15 years. Thus, clinical features of recurrence differed depending on age. Signs of recurrence can be confirmed via UTP/UCr or serum albumin several weeks before recurrence in patients ≥ 15 years.

DOI： 10.18926/AMO/63207

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Language：Japanese   Publisher：(株)診断と治療社  

症例は全身性エリテマトーデスの18歳女性。タクロリムス(TAC)、ミコフェノール酸モフェチル(MMF)併用下に寛解状態にあった。急性胃腸炎を機に腎機能が低下し、いったん軽快した下痢の再燃および血球減少を認めた。TAC、MMF相互の副作用により両薬剤の血中濃度が上昇し有害事象が出現したと考えられ、TAC減量により症状は改善した。TAC、MMF2剤併用中に胃腸炎に罹患したときには、特異な血中濃度の変動に注意する必要がある。(著者抄録)

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Other Link： https://search.jamas.or.jp/default/link?pub_year=2022&ichushi_jid=J00642&link_issn=&doc_id=20220119040018&doc_link_id=%2Fae4shond%2F2022%2F008502%2F019%2F0253-0255%26dl%3D0&url=https%3A%2F%2Fwww.medicalonline.jp%2Fjamas.php%3FGoodsID%3D%2Fae4shond%2F2022%2F008502%2F019%2F0253-0255%26dl%3D0&type=MedicalOnline&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00004_2.gif

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Pathogenic-activating variants of interferon induced with Helicase C domain 1 (IFIH1) cause Singleton-Merten (S-M) syndrome, which accompanies acro-osteolysis, loss of permanent teeth, and aortic calcification, as well as causing Aicardi-Goutières (A-G) syndrome, which shows progressive encephalopathy, spastic paraplegia, and calcification of basal ganglia. Recently, patients with overlapping syndromes presenting with features of S-M syndrome and A-G syndrome were reported. However, progression of clinical features of this condition has not been fully understood. We report a Japanese boy with a novel pathogenic IFIH1 variant who presented with clinical features of S-M syndrome and A-G syndrome.

DOI： 10.1002/ajmg.a.62478

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Fibrodysplasia ossificans progressiva (FOP) is a rare skeletal disorder characterized by congenital malformation of the great toes and progressive heterotopic ossification. Malformation of the great toes appears at birth, while heterotopic ossification generally occurs during childhood and rarely occurs during infancy. Classical FOP results from the heterozygous p.Arg206His variant of the ACVR1 gene, which encodes Activin A receptor type 1. Recently, some atypical FOP patients with other ACVR1 gene variants and clinical features that are not observed in classical FOP patients have been reported. Herein, we describe a girl with severe FOP and multiple anomalies, including syndactyly of the hands and feet, nail agenesis, mandibular hypoplasia, heterotopic ossification occurring from infancy, and congenital cardiac malformation. In our patient, we identified de novo occurrence of the heterozygous p.Arg258Gly variant of ACVR1, which has previously been reported in only two severe FOP patients. Heterotopic ossification occurred earlier and more frequently compared with classical FOP patients. We present the time-series changes in heterotopic ossification in our patient and compare her clinical features with those of the previously reported patients with p.Arg258Gly. Our report deepens understanding of the clinical features in severe FOP with p.Arg258Gly and of FOP as a systemic disorder.

DOI： 10.1155/2022/5021758

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Language：English   Publishing type：Research paper (scientific journal)  

BACKGROUND: Renal calcified lesions are known as one of the complications during adrenocorticotropic hormone (ACTH) therapy for intractable epilepsy. However, laboratory changes during the therapy or laboratory features of high-risk cases with renal calcified lesions are yet to be clarified. METHODS: In this study, 43 patients with West syndrome aged ≤2 years were included. We retrospectively reviewed age and body mass index at the beginning of ACTH therapy, as well as the amount of fluid intake, daily urinary volume, and laboratory data during therapy. In addition, we studied the urinary sediment of the cases with renal calcified lesions diagnosed by computed tomography. RESULTS: After initiating ACTH treatment, urinary calcium (Ca)/creatinine ratio and urinary pH increased within 2 weeks. Urinary crystals and renal tubular epithelial cells (RTECs) in urinary sediment were frequently found in most cases. Urinary Ca levels, proteinuria or frequency of urinary crystals, and number of RTECs in the urinary sediment were significantly higher in patients with epithelial casts (ECs) or hematuria than in patients without these findings. Among the seven patients who underwent abdominal CT, ECs or hematuria were found only in those with renal calcified lesions. These findings suggested that patients with ECs or hematuria were more likely to have calcified lesions. CONCLUSIONS: The risk of renal calcified lesions increased after 2 weeks of ACTH treatment. Abnormal findings in urinary sediments might be an early sign of renal calcification during ACTH therapy.

DOI： 10.1111/ped.14158

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BACKGROUND: The initial presentation of acute encephalopathy with biphasic seizures and late reduced diffusion (AESD) is indistinguishable from that of complex febrile seizures (FS), which poses a great diagnostic challenge for clinicians. Excitotoxicity is speculated to be the pathogenesis of AESD. Vitamin B6 (VB6) is essential for the biosynthesis of gamma-aminobutyric acid, an inhibitory neurotransmitter. The aim of this study is to investigate our hypothesis that VB6 deficiency in the brain may play a role in AESD. METHODS: We obtained cerebrospinal fluid (CSF) samples from pediatric patients with AESD after early seizures and those with FS. We measured pyridoxal 5'-phosphate (PLP) and pyridoxal (PL) concentrations in the CSF samples using high-performance liquid chromatography with fluorescence detection. RESULTS: The subjects were 5 patients with AESD and 17 patients with FS. Age did not differ significantly between AESD and FS. In AESD, CSF PLP concentration was marginally lower (p = 0.0999) and the PLP-to-PL ratio was significantly (p = 0.0417) reduced compared to those in FS. CONCLUSIONS: Although it is impossible to conclude that low PLP concentration and PLP-to-PL ratio are causative of AESD, this may be a risk factor for developing AESD. When combined with other markers, this finding may be useful in distinguishing AESD from FS upon initial presentation.

DOI： 10.1016/j.braindev.2020.02.002

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Language：Japanese   Publisher：(一社)日本小児腎臓病学会  

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The characteristics of chordomas in children are distinct from those in adults. In particular, the prognosis of patients with INI1-negative chordoma is dismal. The standard treatment for localized chordoma, complete surgical resection with a wide margin, is seldom feasible for chordomas arising at the clivus in children, mainly due to associated complications. Therefore, other treatments for unresectable chordomas in children, including chemoradiotherapy, must be explored. Here, we report a 7-year-old girl with an INI1-negative chordoma of the clivus, who responded to conventional chemotherapy plus radiotherapy. Without surgical resection, she remains alive after 1 year and 7 months of the initial diagnosis.

DOI： 10.1097/MPH.0000000000001318

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BACKGROUND: Nonepileptic twilight state with convulsive manifestations (NETC) is a nonepileptic state following a febrile seizure (FS), which may be misdiagnosed as a prolonged seizure and result in overtreatment. We aimed to describe clinical manifestations of NETC and to determine characteristics that are helpful to distinguish NETC from other pathological conditions. METHODS: We conducted a retrospective chart review from January 2010 to December 2016 and selected the patients who presented with symptoms resembling status epilepticus with fever and a confirmed diagnosis using an electroencephalogram (EEG). We compared the NETC clinical features and venous blood gas analysis results with those of other conditions that mimic NETC. We also compared the characteristics of NETC with past reports. RESULTS: Our NETC patients presented with short durations of the preceding generalized convulsions followed by tonic posturing, closed eyes, no cyanosis, responsiveness to painful stimulation, and no accumulation of CO2 in the venous blood gas. Most of these characteristics were consistent with past reports. Prolonged FS or acute encephalopathy with biphasic seizures and late reduced diffusion (AESD) showed several of these features, but all the characteristics were not consistent with our study. CONCLUSIONS: Prolonged FS and AESD need to be differentiated from NETC, and close clinical observation makes it possible to partially distinguish NETC from the other conditions. EEG is recommended for patients with symptoms that are inconsistent with these features.

DOI： 10.1016/j.braindev.2018.05.014

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Cases of recurrent meningitis in elderly patients with a spontaneous cerebrospinal fistula have been reported, and in some of these patients, cystic lesions were thought to be the underlying cause. We report a case of recurrent meningitis in an 11-year-old Japanese girl with an arachnoid cyst in the petrous apex. Pulsation of the cystic lesion was thought to cause bone erosion, leading to the formation of a fistula. Magnetic resonance imaging was useful in evaluating the arachnoid cyst and fistula. During 2 years of follow-up, the osteolytic lesion enlarged and the rate of bone erosion was higher than expected.

DOI： 10.18926/AMO/56251

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Language：Japanese   Publisher：日本小児高血圧研究会  

【背景】腎血管性高血圧は小児高血圧の主要な原因の一つと言われているが、乳児例の報告は少なく、また診断に時間を要することが多い。今回、生後3ヵ月頃から網状チアノーゼの症状を認めたレニン依存性高血圧の男児例を経験した。【症例】周産期には異常なかったが1ヵ月健診で体重増加不良、3ヵ月健診で網状チアノーゼを指摘され、心エコーで拡張型心筋症が疑われていた。経過中に胃腸炎に罹患した際、心不全の状態となり、同時に高血圧も認められた。入院後、心機能改善に伴い高血圧が増悪したため、高血圧性心疾患として原因検索したところ、血漿レニン活性およびアルドステロン高値の状態であった。造影CTでは両側に複数腎動脈が認められ、局所的な狭窄はなかったが、いずれの腎動脈も全長にわたって狭小であり、これらの血管による腎灌流圧の低下が病態の本態と考えた。その後、降圧薬2剤で血圧は良好にコントロールできるようになり、現在外来で経過観察されている。【考察】本症例は、レニン依存性高血圧の状態であり、腎血管性が疑われた。本症例と同様に、乳児期の腎血管性高血圧の症例は、症状が非特異的であり、心不全の状態で診断されることも多いため、注意を要する。また、病態も局所的な腎血管狭窄に限らず、腎灌流圧の低下をきたしうる病変を幅広く検討する必要がある。(著者抄録)

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DOI： 10.1016/j.parkreldis.2016.04.021

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Since the introduction of the seven-valent pneumococcal conjugate vaccine (PCV7) in 2007, invasive pneumococcal disease has declined, but the incidence of Streptococcus pneumoniae serotype 19A has risen worldwide. The present study examined changes in the features of invasive pneumococcal disease since the introduction of the PCV7 in Kochi, Japan. Pediatric cases of invasive pneumococcal disease were investigated before and after vaccine introduction (January 2008 to December 2013). Cases of invasive pneumococcal disease tended to decrease after PCV7 introduction. In addition, before introduction of the vaccine, most serotypes causing invasive pneumococcal disease were those included in the vaccine. However, after the introduction, we found cases infected by serotypes not covered by vaccine. Penicillin-resistant S. pneumoniae was the predominant serotype causing invasive pneumococcal disease before introduction of the PCV7, and the susceptibility of this serotype to antibiotics improved after vaccine introduction. Serotype isolates identified after vaccine introduction were also relatively susceptible to antibiotic therapy, but decreased susceptibility is expected.

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Language：Japanese   Publisher：(一社)日本小児腎臓病学会  

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Language：Japanese   Publisher：(公社)日本小児科学会  

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Language：Japanese   Publisher：日本小児腎不全学会  

精神発達遅滞を伴った小児には、身体にテープを貼られたりカテーテルを留置されたりすることを拒絶する者がおり、腹膜透析(peritoneal dialysis:PD)の導入に難渋することがある。成人領域では認知症を伴った高齢者に肩甲骨部出口でPDを導入する報告がある。精神発達遅滞を伴う末期腎不全の小児に対し、工夫してPDを導入した症例を報告する。ジュベール症候群の男児が15歳で末期腎不全に至りPDを行って献腎移植を待機する方針を選択した。出口部保清を保つため肩甲骨部出口を採用し、ウルトラロングカテーテルを留置し、良好な注排液が得られた。この2点の工夫が精神発達遅滞を伴った小児におけるPD導入時の問題を軽減し、これまで導入をあきらめていた例でもPDが腎代替療法の選択肢になりうることが示唆された。(著者抄録)

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