山岸 裕和

Menkes disease is an X-linked disorder of copper metabolism caused by mutations in the ATP7A gene, and female carriers are usually asymptomatic. We describe a 7-month-old female patient with severe intellectual disability, epilepsy, and low levels of serum copper and ceruloplasmin. While heterozygous deletion of exons 16 and 17 of the ATP7A gene was detected in the proband, her mother, and her grandmother, only the proband suffered from Menkes disease clinically. Intriguingly, X chromosome inactivation (XCI) analysis demonstrated that the grandmother and the mother showed skewing of XCI toward the allele with the ATP7A deletion and that the proband had extremely skewed XCI toward the normal allele, resulting in exclusive expression of the pathogenic ATP7A mRNA transcripts. Expression bias analysis and recombination mapping of the X chromosome by the combination of whole genome and RNA sequencing demonstrated that meiotic recombination occurred at Xp21-p22 and Xq26-q28. Assuming that a genetic factor on the X chromosome enhanced or suppressed XCI of its allele, the factor must be on either of the two distal regions derived from her grandfather. Although we were unable to fully uncover the molecular mechanism, we concluded that unfavorable switching of skewed XCI caused Menkes disease in the proband.

BACKGROUND: Niemann-Pick disease type C (NPC) is an autosomal recessive inherited and neurodegenerative disorder. Approximately 10% of NPC patients have acute liver failure and sometimes need liver transplantation (LT), and 7% reportedly develop inflammatory bowel disease (IBD). We report the case of a girl with NPC who had a re- accumulation of cholesterol in the transplanted liver and NPC-related IBD. CASE REPORT: The patient underwent living donor liver transplantation (LDLT) due to severe acute liver failure caused by an unknown etiology inherited from her father. At 1 year and 6 months (1Y6M), she developed neurological delay, catalepsy, and vertical supranuclear gaze palsy. The foam cells were found in her skin, and fibroblast Filipin staining was positive; hence, she was diagnosed with NPC. It was identified that her father had NPC heterozygous pathogenic variant. At 2 years, she had anal fissure, skin tag and diarrhea. She was diagnosed with NPC-related IBD, using a gastrointestinal endoscopy. Three years after LT, liver biopsy revealed foam cells and numerous fatty droplets. At 8 years, broken hepatocytes and substantial fibrosis were observed. She died from circulation failure due to hypoalbuminemia at 8Y2M. CONCLUSIONS: In NPC, load of cholesterol metabolism is suggested to persist even after LT. LDLT from NPC heterozygous variant donor was insufficient to metabolize cholesterol overload. In NPC patients, the possibility of cholesterol re-accumulation should be considered when LT is performed. NPC-related IBD should be considered when NPC patients have anorectal lesions or diarrhea.

Corona virus infectious disease, emerged in 2019(COVID-19)は、流行の主体が感染性の高いオミクロン変異株に置き換わり小児の感染者数が増加し、けいれん、意識障害、脳炎・脳症例も増加し、重症化する症例や後遺症を残す症例も報告されている。われわれが経験した小児COVID-19の出血性ショック脳症症候群や、片側けいれん・片麻痺・てんかん症候群を含む3症例の急性脳症を提示する。小児COVID-19の急性脳症はインフルエンザ脳症と同様、さまざまな臨床病型・重症度、そして予後をとりうる。(著者抄録)

BACKGROUND: Eight waves of the coronavirus disease 2019 (COVID-19) epidemic have been observed in Japan. This retrospective study was conducted to clarify the clinical characteristics of pediatric COVID-19 patients. METHODS: We studied 121 patients admitted to the Jichi Children's Medical Center Tochigi between April 2020 and March 2023. Incidence of pediatric COVID-19 in Tochigi Prefecture was used to examine hospitalization and severe illness rates. RESULTS: The mean age of the patients was 3 years and 8 months. One hundred and eleven patients (91.7%) were hospitalized after January 2022 (after the 6th wave), when the Omicron strain became endemic in Japan. Convulsions occurred in 30 patients (24.8%), all of whom were admitted after the 6th wave. Twenty-three of the 30 patients had no underlying disease. Eleven patients (9.1%) were diagnosed with acute encephalopathy. One patient died due to hemorrhagic shock and encephalopathy syndrome and two had sequelae after the 6th wave. The patient who died due to encephalopathy had hypercytokinemia. In the Tochigi Prefecture, the number of pediatric COVID-19 patients increased after the 6th wave, but the hospitalization rate declined. The rate of severe illness did not change before the end of 5th and after the 6th wave. CONCLUSION: Although the rate of severe illness in patients with pediatric COVID-19 did not increase after the 6th wave, some patients had complicated critical illnesses. Systemic inflammatory reaction was considered to have been associated with the severe encephalopathy.

Abstract Background Infants with trisomy 13 have a very high mortality rate. However, aggressive interventions for their complications, can improve their prognosis and may, thereby, increase the number of long‐term survivors with trisomy 13. To date, there is no study on the psychomotor developmental progress of patients with trisomy 13. We conducted this survey to clarify the prognostic factors, living circumstances, and developmental status of infants the trisomy 13. Methods Patients with trisomy 13 who were admitted to the Department of Pediatrics, Jichi Medical University Hospital were enrolled. Their clinical data were investigated retrospectively using clinical records. Results Nine patients with trisomy 13 were enrolled and divided into the early death (died at <1 year) and long‐term survival (survived for >1 year) groups. All the early death group patients had severe congenital heart disease. Heart failure at under 1 year of age was associated with early death. All the long‐term survival group patients underwent operations (e.g. tracheostomy or gastrostomy) and all used home nursing and/or a social care service. Three patients used home mechanical ventilation. None of the patients was able to stand alone or speak intelligible words. Two patients without severe brain anomalies were able to roll over, sit up, and smile by 3 years of age. Conclusions Long‐term survivors with trisomy 13 require extensive nursing and medical care. It is important to provide medical and welfare services to reduce the burden on families. In patients without severe brain anomalies, psychomotor development may be expected. However, no clear developmental prognostic factors were found.

OBJECTIVES: We aimed to validate a newly developed antigen-detecting rapid diagnostic test (Ag-RDT) for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) using anterior nasal specimens. METHODS: Between February 12 and September 30, 2021, 16 patients (age range, <1 month-76 years) were enrolled, and samples were collected simultaneously from anterior nasal and nasopharyngeal sites continuously during hospitalization. The primary endpoints were the diagnostic accuracy of the Ag-RDT and utility of anterior nasal specimens. RESULTS: In total, 226 sets of paired samples were obtained. In 88.2% of specimens, the viral load was high at the nasopharyngeal site. The mean cycle threshold (Ct) values for the anterior nasal and nasopharyngeal sites were 32.4 and 29.9, respectively. Using the real-time polymerase chain reaction results as a reference, the Ag-RDT showed 100% sensitivity up to day 6 of the illness using specimens with moderate or high viral load (Ct <30) from either site. From day 7, the sensitivity was 70.4-90.6% and 83.9-84.6% for the anterior nasal and nasopharyngeal sites, respectively. The specificity remained at 100%. CONCLUSIONS: Our novel Ag-RDT meets the World Health Organization criteria and provides stable sensitivity and specificity and accurate results with anterior nasal specimens.

新型コロナウイルス感染症診断のための迅速抗原検査キットであるPanbio COVID-19 Antigenラピッドテスト(以下、Panbio)は、わが国では体外診断薬として承認されているが、国内での実臨床における検討はまだ報告されていない。本研究では、有症状者の鼻咽頭ぬぐい液および鼻腔ぬぐい液を用いて、リアルタイムRT-PCR結果を基準としたPanbioの臨床的評価を行った。対象は、第9病日以内の患者に限定した。鼻咽頭ぬぐい液における感度は97.2%(35/36)、特異度100%(45/45)であった。鼻腔ぬぐい液における感度は90.9%(20/22)、特異度100%(19/19)であった。ウイルス量が100copies/5μL以上あれば、感度は100%(55/55)であった。発症からの経過日数が短い症例ほどウイルス量が多く、鼻咽頭ぬぐい液に比して鼻腔ぬぐい液のウイルス量は少ない傾向が認められた。リアルタイムRT-PCR陽性、Panbio陰性である、すなわち偽陰性の3検体は、鼻咽頭ぬぐい液の第9病日検体、鼻腔ぬぐい液の第7、8病日検体であった。発熱や呼吸器症状などの有症状者であり、かつ第9病日以内の患者において、Panbioは鼻咽頭ぬぐい液で高い感度・特異度を有することが確認された。また、検体採取がより簡便な鼻腔ぬぐい液であっても、特に発症後6日目以内で有用であると思われた。(著者抄録)

BACKGROUND: LAVV have historically been avoided in children after solid organ transplantation. However, it has been reported that post-transplant, children without severe immunosuppression can generate anti-varicella antibody after immunization but the duration of the response is not clear. Furthermore, the origin of the varicella virus in immunosuppressed patients who develop varicella after vaccination is often unclear. CLINICAL PROGRESS: A female child received LAVV 30 months after a living donor liver transplant at the age of 2 months. Varicella rash appeared on the trunk 16 days after vaccination and gradually spread over the body. The patient was treated with intravenous acyclovir followed by oral therapy and recovered fully. The virus detected in blisters was derived from the vaccine-type strain. Paired sera before and after the onset of varicella showed an increase in antibody titer. However, 2 years after onset, the antibody titer decreased to undetectable again. CONCLUSIONS: This was an informative case of varicella due to vaccine strain attenuated virus. Antibody levels were not maintained over many years. Although varicella was caused by the vaccine-type strain, repeated vaccinations may be necessary for post-transplant patients who develop varicella.

BACKGROUND: The incidence of cerebral palsy (CP) is influenced by perinatal medicine and regional medical systems. We investigated the recent incidence of CP and the current problems of children with CP in living at home under an advanced perinatal medical system in Tochigi Prefecture, Japan. METHODS: A clinical datasheet survey was performed among 13 hospitals and six rehabilitation facilities treating children with CP born in Tochigi Prefecture to estimate the incidence of CP among children born between 2009 and 2013. The severity of motor and intellectual impairment, presumed causal factors, complications, and provided medical interventions were investigated and compared between preterm and term-born children with CP. RESULTS: The incidence of CP was 1.6 per 1000 live births. Shorter gestation period and lower birthweight were associated with a higher incidence of CP. Fifty-one percent of children with CP were non-ambulatory and 55% had severe to profound intellectual impairment. Episodes of neonatal asphyxia and periventricular leukomalacia were the most frequent causal factors; both were significantly more frequent in preterm than in term-born children. Approximately 30% of children with CP had respiratory disorders, dysphagia, or epilepsy; 62% received medical interventions, including medication, mechanical ventilation, oxygen therapy, tube feeding, and intraoral/intranasal suction. CONCLUSION: We found the incidence of CP to be lower in comparison to previous Japanese studies. However, the motor and intellectual impairments were severe, and many children with CP and their families were burdened by daily medical care. Public support systems should be developed, as well as the perinatal medical system.

Ring chromosome 20 syndrome is an epileptic and neurodevelopmental encephalopathy that occurs in children, characterised by a triad of refractory frontal lobe seizures, recurrent non-convulsive status epilepticus and frontal lobe-dominant paroxysmal discharges. However, details of other clinical features associated with ring chromosome 20 syndrome remain unknown. Here, we report two patients with ring chromosome 20 syndrome who had praxis-induced reflex seizures. Case 1 was an 11-year-old girl who presented with seizures triggered by specific activities such as mental and written calculations, writing, decision-making, recall, sudden changes in routine or ambient temperature and bathing. During calculations, left frontal lobe-dominant, 3-Hz slow-wave bursts were observed on EEG. Lacosamide effectively suppressed her tonic seizures. Case 2 was a six-year-old boy who presented with seizures triggered by specific activities such as calculations, recall and bathing. During calculations, frontal lobe-dominant, 3-Hz spike and slow-wave bursts were observed on EEG. Although his epilepsy was refractory, gabapentin reduced the frequency of focal seizures. In both cases, the hyperexcitability in the frontal lobe may have spread to the motor cortex and precipitated praxis-induced seizures. Therefore, in addition to the known characteristic triad, praxis-induced reflex seizures may also be a feature of ring chromosome 20 syndrome.

&lt;p&gt;ペランパネル（PER）は、AMPA受容体を非競合的に阻害する新規の抗てんかん薬である。日本国内の使用実績の報告は少ない。今回、知的障害者や12歳未満の小児を含む難治性てんかんの33例について、PERの治療効果と副作用を検討した。発作が50%以上減少した症例を「有効」とし、両側性けいれん性発作への進展を含む焦点発作（Fs）と全般発作のうち強直、間代発作（GTCS）に対する有効率を検討した。FsおよびGTCSに対しては50%の症例で有効であった。全体では52%の症例に有効であった。12歳未満でも12歳以上と同等の有効率が得られた。併用薬剤別では、有意差は得られなかったものの、KBrを併用した2症例でともに有効であった。CBZやPHTといったCYP3A4を誘導する薬剤との併用例の有効率はそれぞれ30%、18%と低い傾向があった。副作用の出現率は55%で、情緒・行動面の異常が30%、傾眠・眠気が18%、めまいが15%であった。若年者や知的障害者では情緒・行動面の異常が出やすく、注意を要する。&lt;/p&gt;

日本小児感染症学会若手研修会夏季セミナーに参加した産科医21名と小児科医41名に対してGBS母子感染予防に関するアンケートを行った。産科医に対する質問は「母体のGBSスクリーニング実施時期」「スクリーニングにおける検体の採取部位と使用する培地」「予防的抗菌薬の使用法」とし、小児科医に対する質問は「GBS陽性母体から出生した児の管理方法」「GBS感染予防に関する知識」とした。産科医アンケートの結果、母体のGBSスクリーニング実施時期は、日本産婦人科学会のガイドラインで示されている「妊娠33〜37週」と回答した人が86%を占めたが、米国CDCのガイドラインで推奨されている「35週以降」は52%にとどまった。小児科医アンケートの結果、CDCのガイドラインにGBS陽性母体から出生した児に対する二次予防のためのアルゴリズムがあることを「知らない」と答えた人が46%存在した。

胆道閉鎖症による肝不全に対して生体肝移植を施行し，免疫抑制療法としてタクロリムスを内服中に川崎病を発症した１歳女児例を経験した。血液検査上，白血球の増加がなくCRP の上昇も軽度で，診断に苦慮した。炎症反応の上昇が軽度であった理由として，タクロリムス内服による炎症性サイトカインの抑制が推測される。また，川崎病が原因と考えられる門脈吻合部狭窄の増悪を認めた。川崎病の剖検例では血管壁の炎症により門脈の拡大が生じると報告されているが，本症例では門脈吻合部の線維化のため内径が拡大せず，門脈域の細胞浸潤を伴った炎症と浮腫により吻合部狭窄が生じたと推測される。Here we report a case of Kawasaki disease（ KD） in a 1-year-old female patient treated with tacrolimus（ FK506） following liver transplantation for hepatic failure secondary to congenital biliary atresia. At the onset of KD, laboratory data included a normal white blood cell count and slightly increased C reactive protein, making the diagnosis of KD difficult. This mild inflammatory reaction could have been due to cytokine suppression by FK506. The portal vein became stenotic, possibly due to KD-associated phlebitis. Portal vein dilatation caused by inflammation in KD patients was previously reported; however, to our knowledge, there is no previous report of the occurrence of portal vein stenosis in this setting. In patients who have undergone liver transplantation, the anastomosis site can become non-elastic due to fibrosis, which, in the setting of KD-induced inflammation of the vein, can lead to portal vein stenosis.