藤井 克則

【目的】重症筋無力症(MG)や慢性炎症性脱髄性多発根ニューロパチー(CIDP)をはじめとする免疫性神経筋疾患の治療は長期にわたるため、小児では成長や発達に配慮したきめ細かな日常生活上の管理が必要である。しかし、その具体策についてはエビデンスが不明確であり、担当医は疑問を抱えながら診療している。診療の標準化を図る目的で、多施設の状況について調査し検討した。【方法】2017年2月、小児免疫性神経筋疾患研究会会員(研究時の会員82名67施設)に対し、アンケートを行い解析した。【結果】15施設から回答を得た。各施設で平均5.5(中央値4)名のMG患者と0.3名のCIDP患者を診療中であった。易感染性や消化性潰瘍、骨粗鬆症など副腎皮質ステロイド薬の副作用への対策や、予防接種基準、眼科診察などについて、施設間での相違が明らかとなった。特に、MGにおいて禁忌であるベンゾジアゼピン系薬剤の、けいれんや鎮静の際の使用については様々な対応が見られた。【結論】小児の免疫性神経筋疾患患者における日常生活管理の基準は施設ごとに異なっており、経験する患者数の少なさもその一因であると考えられた。この結果と各種ガイドラインおよび文献を参考に、小児の日常生活指導案をまとめた。これらをもとに多施設での経験を集積し、より有用な基準の策定が望まれる。(著者抄録)

上斜筋麻痺では斜視、複視、頭位異常などの症状が出現する。診断にはParks-Bielschowsky three-step testが使われるが、3 stepsを満たさない場合や所見の評価が難しい場合もある。斜視、頭位異常が軽微の場合には所見として認識されず、複視の原因となる他の全身性疾患の鑑別が必要となることもあり、上斜筋麻痺の診断に苦慮する場合がある。今回、複視で発症した上斜筋麻痺に対して、単眼視による頭部傾斜変化が他覚的診断に有用であったため報告する。症例は13歳女子。2年前より複視を自覚、増悪し受診した。右眼はわずかに外上方の斜位で、眼球運動9方向に制限はなかったが全方向に複視を認めた。眼瞼下垂はなかったが、夕方に増悪する日内変動があった。血液検査、脳MRI検査、神経伝導検査、テンシロン試験に異常はなく、重症筋無力症、脳腫瘍、Fisher症候群などは否定された。左右の単眼視で頭部傾斜を比較すると、健側である左単眼視で頭位は正中であるのに対し、右単眼視で健側に頸部を傾ける代償性頭位の所見が顕著となり、上斜筋麻痺と診断した。眼科手術により複視は著明に改善した。斜視、頭位異常が軽微で上斜筋麻痺の診断に苦慮する場合には、単眼視による頭部傾斜変化がBielschowsky徴候を強調し、他覚的な診断に有用となりうると考えられた。(著者抄録)

上斜筋麻痺では斜視、複視、頭位異常などの症状が出現する。診断にはParks-Bielschowsky three-step testが使われるが、3 stepsを満たさない場合や所見の評価が難しい場合もある。斜視、頭位異常が軽微の場合には所見として認識されず、複視の原因となる他の全身性疾患の鑑別が必要となることもあり、上斜筋麻痺の診断に苦慮する場合がある。今回、複視で発症した上斜筋麻痺に対して、単眼視による頭部傾斜変化が他覚的診断に有用であったため報告する。症例は13歳女子。2年前より複視を自覚、増悪し受診した。右眼はわずかに外上方の斜位で、眼球運動9方向に制限はなかったが全方向に複視を認めた。眼瞼下垂はなかったが、夕方に増悪する日内変動があった。血液検査、脳MRI検査、神経伝導検査、テンシロン試験に異常はなく、重症筋無力症、脳腫瘍、Fisher症候群などは否定された。左右の単眼視で頭部傾斜を比較すると、健側である左単眼視で頭位は正中であるのに対し、右単眼視で健側に頸部を傾ける代償性頭位の所見が顕著となり、上斜筋麻痺と診断した。眼科手術により複視は著明に改善した。斜視、頭位異常が軽微で上斜筋麻痺の診断に苦慮する場合には、単眼視による頭部傾斜変化がBielschowsky徴候を強調し、他覚的な診断に有用となりうると考えられた。(著者抄録)

Mitochondrial diseases (MDs) are occasionally difficult to diagnose. Growth differentiation factor 15 (GDF15) has been reported as a biomarker useful for not only diagnosing MDs, but also evaluating disease severity and therapeutic efficacy. To enable the measurement of serum GDF15 concentrations at medical institutions, we developed a new latex-enhanced turbidimetric immunoassay (LTIA) as an automated diagnostic indication test for MDs. We also examined the equivalency of specificity and sensitivity in measuring serum GDF15 concentrations between a commercially available enzyme-linked immunosorbent assay (ELISA) kit and a novel LTIA device in patients with MDs, disease controls, and healthy controls. A clinical performance study used a newly developed LTIA device and an existing ELISA kit to measure the concentrations of GDF15 in 35 MD patients, 111 disease controls, and 86 healthy controls. The median (first quartile-third quartile) of serum GDF15 concentrations measured with the LTIA device was significantly higher (P < .001) in MD patients (1389.0 U/mL [869.5-1776.0 U/mL]) than in healthy controls (380.5 U/mL [330.2-471.8 U/mL]); the interquartile ranges did not overlap between MD patients and healthy controls. The areas under the curve in disease and healthy controls were 0.812 (95% confidence interval [CI]: 0.734-0.886) and 0.951 (95% CI: 0.910-0.992), respectively. The automated, high-throughput technology-based LTIA device has definite advantages over the ELISA kit in shorter processing time and lower estimated cost per sample measurement. The LTIA device of GDF15 may be a sufficiently reliable, frontline, diagnostic indicator of individuals with suspected MDs in the general population.

BACKGROUND: Peripheral nerve imaging is increasingly recognized as a powerful tool to evaluate nerve hypertrophy in chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) and Charcot-Marie-Tooth diseases (CMT), whereas data in pediatric patients are limited. CASE DESCRIPTION: We describe the case of a 15-year-old Japanese girl with asymmetric demyelinating polyneuropathy, who, at the age of 10 years, was initially diagnosed with a demyelinating form of CMT. Fluorescence in situ hybridization for peripheral myelin 22 was negative, and already-known pathogenic variants were not detected by whole-genome sequencing, and nerve conduction studies revealed multifocal conduction blocks. Over the next 5 years, the patient showed gradual improvement in muscle weakness and sensory disturbance without immunological treatment and was referred to our hospital. RESULTS: At the age of 15 years, magnetic resonance (MR) neurography showed asymmetric multifocal fusiform enlargement of nerve roots, brachial and lumbosacral plexuses, and intermediated nerve trunks, as well as cranial nerves. Based on the MR neurography findings and multifocal nerve conduction blocks, she was diagnosed as having multifocal CIDP (multifocal demyelinating sensory and motor neuropathy [MADSAM]) according to the European Federation of Neurological Societies/Peripheral Nerve Society diagnostic criteria. DISCUSSION: Clinical diagnosis of childhood CIDP is challenging because its neurological manifestations and nerve conduction study findings occasionally resemble those of inherited demyelinating neuropathies. MR neurography is helpful for the assessment of patterns of nerve hypertrophy; MADSAM-CIDP is characterized by multiple fusiform nerve enlargement, whereas CMT shows symmetric and diffuse nerve hypertrophy. CONCLUSION: The MR neurography patterns would help in diagnosing pediatric demyelinating neuropathies.

Superior oblique palsy causes deviation, diplopia, and abnormal head posture. The Parks-Bielschowsky three-step test is used for diagnosis however. we experience cases that do not meet these 3 steps, or whose findings are difficult to evaluate. We were unable to detect findings in cases where deviation and abnormal head posture were mild. As we have to consider differential diagnoses, including systemic disorders causing diplopia, diagnosis is occasionally difficult. Here, we report the usefulness of the change of head tilt with monocular vision in the objective diagnosis of superior oblique palsy associated with diplopia. A 13-year-old Japanese girl experienced diplopia 2 years ago and presented to our hospital with exacerbated diplopia. She showed subtle right exotropic hypertropia and omnidirectional diplopia while her eye movements were preserved in 9 directions. She did not present with ptosis, but complained about circadian changes in diplopia that worsened in the evening. Blood examination, brain magnetic resonance imaging, a nerve conduction test, and a Tensilon test yielded normal results. Diagnosis of Myasthenia gravis, brain tumor, and Fisher syndrome was excluded. While comparing head tilt with the patient's right monocular vision to her left, we identified that head posture with left monocular vision, or the unaffected side was vertical. Alternatively, head posture with the patient's right monocular vision and the affected side revealed a compensating head posture. In this regard, the patient was diagnosed with superior oblique palsy. Diplopia was responsive to ophthalmic surgery. We conclude that the change of head tilt with monocular vision highlights the Bielschowsky sign and can be useful for objective diagnosis.

<p>日齢27に発熱より発症し，汎血球減少，肝機能障害，フェリチン高値を呈し血球貪食性リンパ組織球症（hemophagocytic lymphohistiocytosis, HLH）として当院に搬送，呼吸・循環不全のために集学的治療が必要であった．PRF1遺伝子解析においてc.1090_1091delCTとc.658G>Aの複合ヘテロ接合体と判明し家族性血球貪食性リンパ組織球症（familial HLH, FHL）type2と確定診断した．c.1090_1091delCTは既知の変異であった．c.658G>Aは現時点では病的意義は不明とされているが，ホモ接合体でperforin発現が欠損し，FHL2を発症した例も報告がある．c.1090_1091delCTとヘテロ接合体でFHL2を発症する遺伝子変異の組み合わせとして本症例は初報告であった．またc.658G>Aを伴うFHL2は本邦初の症例であった．本症例では非骨髄破壊的前処置による臍帯血移植を実施したが，合併症や移植時点での高い疾患活動性のため移植後間もなく死亡した．FHLは非常に稀な疾患であり，新規遺伝子変異に関する報告を蓄積し病的変異として広く認識されることが望まれる．</p>

BACKGROUND: Nevoid basal cell carcinoma syndrome (NBCCS) is a neurocutaneous disease, characterized by tumorigenesis and developmental anomalies due to aberrant sonic hedgehog (Shh) signaling. Patients with NBCCS typically appear calm and carefree, suggesting that the specific personality in these patients may be associated with an enhanced hedgehog pathway. Our study aimed to determine the personality type in these patients. METHODS: We enrolled 14 mentally normal patients with genetically-confirmed NBCCS (7 males and 7 females; mean age = 25.2 years) and 20 controls (10 males and 10 females; mean age = 27.9 years). The patients were assessed with the Japanese version of the Temperament and Character Inventory, based on the seven-dimensional model of temperament and character, and their clinical symptoms were evaluated. The amygdala volumes of 6 patients with NBCCS were measured using magnetic resonance imaging with an image processing software. RESULTS: Patients with NBCCS scored significantly lower on harm avoidance (0.89) than controls (1.00; p = 0.0084). Moreover, patients with NBCCS having developmental malformations such as rib anomalies, who may have experienced Shh signaling enhancement from the prenatal period, scored significantly lower on harm avoidance (0.80 [p = 0.0031]). The left amygdala volume was also significantly reduced in patients with NBCCS (p = 0.0426). CONCLUSIONS: Patients with NBCCS who experienced increased Shh signaling from the prenatal period showed significantly lower harm avoidance relate to serotonin. The left amygdala volume was significantly reduced in these patients. Our results indicate that Shh signaling may influence the human personality.

Parvalbumin-positive (PV+ ) fast-spiking interneurons are essential to control the firing activity of principal neuron ensembles, thereby regulating cognitive processes. The high firing frequency activity of PV+ interneurons imposes high-energy demands on their metabolism that must be supplied by distinctive machinery for energy generation. Exploring single-cell transcriptomic data for the mouse cortex, we identified a metabolism-associated gene with highly restricted expression to PV+ interneurons: Cox6a2, which codes for an isoform of a cytochrome c oxidase subunit. Cox6a2 deletion in mice disrupts perineuronal nets and enhances oxidative stress in PV+ interneurons, which in turn impairs the maturation of their morphological and functional properties. Such dramatic effects were likely due to an essential role of COX6A2 in energy balance of PV+ interneurons, underscored by a decrease in the ATP-to-ADP ratio in Cox6a2-/- PV+ interneurons. Energy disbalance and aberrant maturation likely hinder the integration of PV+ interneurons into cortical neuronal circuits, leading to behavioral alterations in mice. Additionally, in a human patient bearing mutations in COX6A2, we found a potential association of the mutations with mental/neurological abnormalities.

The non-encapsulated Streptococcus pneumoniae (NESp) has emerged and increased in the clinical setting. The majority of NESp strains have been isolated from the nasopharynxes of healthy carriers and from respiratory specimens of patients with otitis media. NESp strains were shown to be more effective than encapsulated counterparts at forming biofilms. Therefore, NESp should become one of the leading causes of emerging refractory respiratory disease after the introduction of pneumococcal conjugate vaccines. We report the first case of multidrug-resistant - including fluoroquinolone-resistant - NESp isolated from the intrabronchial aspirate of a patient with pneumonia. Drug-resistant NESp infections can possibly emerge as a clinical problem and thus the continuous monitoring of NESp infections is of utmost importance.

Gorlin syndrome is a rare autosomal dominant hereditary disease with a high incidence of tumors such as basal cell carcinoma and medulloblastoma. Disease-specific induced pluripotent stem cells (iPSCs) and an animal model have been used to analyze disease pathogenesis. In this study, we generated iPSCs derived from fibroblasts of four patients with Gorlin syndrome (Gln-iPSCs) with heterozygous mutations of the PTCH1 gene. Gln-iPSCs from the four patients developed into medulloblastoma, a manifestation of Gorlin syndrome, in 100% (four out of four), of teratomas after implantation into immunodeficient mice, but none (0/584) of the other iPSC-teratomas did so. One of the medulloblastomas showed loss of heterozygosity in the PTCH1 gene while the benign teratoma, i.e. the non-medulloblastoma portion, did not, indicating a close clinical correlation between tumorigenesis in Gorlin syndrome patients and Gln-iPSCs.

BACKGROUND: Non-paraneoplastic limbic encephalitis is characterized by attention deficit, loss of emotion control, and impaired memory. Viral infection can cause acute encephalitis in children, occasionally exhibiting clinical features of limbic dysfunction. However, how viral infection affects the limbic system remains to be elucidated. CASE DESCRIPTION: A 5-year-old Japanese boy was admitted to our hospital because of high fever and status epilepticus. After seizures were controlled by diazepam, he exhibited attention deficit, loss of emotion control, and impaired memory, suggesting acute limbic encephalitis. Since titers of antibodies against Coxsackie virus A10 were significantly elevated in the serum, we diagnosed him with non-paraneoplastic limbic encephalitis associated with the viral infection. Brain magnetic resonance imaging demonstrated involvement of anterior cingulate cortex as well as white matter of the frontal lobe in the acute period. After steroid pulse therapy, these brain lesions subsequently disappeared in a time-dependent manner, beginning with the frontal lobe white matter and extending to the anterior cingulate cortex, and his psychological symptoms also disappeared. CONCLUSION: To the best of our knowledge, this is the first report to show the involvement of the region from the anterior cingulate cortex to the frontal lobe white matter. Clinical features such as seizures, attention deficit, loss of emotion control, and impaired memory suggest that this viral limbic encephalitis possibly extended from the frontal white matter to the anterior cingulate cortex via inter-neuronal connections in a time-dependent manner.

BACKGROUND: Japanese encephalitis is a flavivirus that can cause pandemic encephalitis, and is prevalent in Southeast Asia and Australia. Brain images of patients with Japanese encephalitis are characterized by thalamic lesions, distinct from those seen in viral encephalopathies caused by the herpes simplex virus and West Nile virus. AIM: Herein, we describe for the first time a time-dependent magnetic resonance imaging pattern in Japanese encephalitis in a 10-month-old Japanese boy. CASE: The patient was a previously healthy 10-month-old Japanese boy, who exhibited acute-onset flaccid tetraplegia and loss of tendon reflexes. RESULTS: Brain MRI showed characteristic thalamic changes on diffusion weighted images from spotty to uniform and from the left to the right side, associated with low apparent diffusion coefficient maps. These images suggest that the Japanese encephalitis virus may first affect the unilateral thalamus, possibly expanding to the other side, with characteristic patterns changing from spotty to uniform in a manner consistent with the presentation of cytotoxic edema. CONCLUSION: This report first showed longitudinal magnetic resonance changes in Japanese encephalitis, which may help in accurate diagnosis and in discrimination from other etiologies.

Gorlin syndrome (GS) is a hereditary disorder with tumorigenicity, caused by constitutive hyperactivity of hedgehog signaling. Smoothened (SMO) antagonists have been effectively used in the clinical treatment of hedgehog signaling-related cancer. However, these treatments have led to problematic side effects, including severe adverse reactions and drug resistance from additional somatic mutations. We profiled microRNAs in GS fibroblasts to explore a novel therapeutic target for controlling hyper-activated hedgehog signaling. To identify GS-related microRNAs, we analyzed dermal fibroblasts from five patients with GS and three normal controls. We used microarray comparative genomic hybridization to screen 632 human microRNAs in GS fibroblasts. We identified 16 down- and 19 upregulated microRNAs with over twofold change in expression. We validated the increased expression of four microRNAs, confirming hsa-miR-196a-5p downregulation and hsa-miR-4485 upregulation using real-time PCR. Moreover, hsa-miR-196a-5p is complementary to sites in the 3' UTR of MAP3K1, which exhibits upregulated expression at mRNA and protein levels in GS fibroblasts. In addition, hedgehog signal induction with exogenous components decreased miR-196a-5p expression and increased map3k1 expression in a mouse mesenchymal cell line. Given that MAP3K1 has been reported to activate hedgehog signaling, hsa-miR-196a-5p may contribute to the positive feedback loop in this pathway.

BACKGROUND: Peripheral facial nerve palsy is characterized by unilateral facial paresis due to ipsilateral facial nerve dysfunction. Most cases are idiopathic; however, some have specific etiologies, such as herpesvirus infection, immunological disorders, and hypertension. Atomoxetine is a norepinephrine reuptake inhibitor that is used in the treatment of attention deficit hyperactivity disorder (ADHD). This drug is known to cause adverse effects, such as nausea, appetite loss, headache, insomnia, and hypertension. CASE DESCRIPTION: We herein describe a case of sudden-onset right peripheral facial palsy in a 9-year-old Japanese boy. The patient's systolic blood pressure was as high as 200 mmHg, and he was therefore admitted to our hospital for investigation. Extensive surveillance including blood examination; endocrinological testing; imaging studies such as computed tomography, magnetic resonance imaging, and renography; and renal biopsy did not reveal any abnormalities. The patient had ADHD and was under treatment with atomoxetine. We discontinued treatment with atomoxetine; the patient showed gradual improvement. His hypertension and facial palsy resolved. We therefore diagnosed the patient with peripheral facial palsy associated with atomoxetine-induced hypertension. CONCLUSION: Although peripheral facial nerve palsy is usually benign and self-limiting, blood pressure should be monitored in children under treatment with atomoxetine and the possibility of drug-induced hypertension should be considered in order to prevent palsy associated with hypertension.

Basal cell nevus syndrome (BCNS) is a rare, multisystem, autosomal dominant disorder that is characterized by various phenotypes, including multiple basal cell carcinomas of the skin, odontogenic keratocysts of the jaws, and occasionally cleft lip and/or palate. In this report, we describe a 6-year-old Japanese girl with a novel heterozygous nonsense mutation in PTCH1 who exhibited rare craniofacial phenotypes, such as oligodontia and a short-tooth root.

OBJECTIVE: To examine the efficacy and safety of the therapeutic regimen using oral and intravenous L-arginine for pediatric and adult patients with mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS). METHODS: In the presence and absence of an ictus of stroke-like episodes within 6 h prior to efficacy assessment, we correspondingly conducted the systematic administration of oral and intravenous L-arginine to 15 and 10 patients with MELAS in two, 2-year, prospective, multicenter clinical trials at 10 medical institutions in Japan. Subsequently, patients were followed up for 7 years. The primary endpoint in the clinical trial of oral L-arginine was the MELAS scale, while that for intravenous L-arginine was the improvement rates of headache and nausea/vomiting at 2 h after completion of the initial intravenous administration. The relationships between the ictuses of stroke-like episodes and plasma arginine concentrations were examined. RESULTS: Oral L-arginine extended the interictal phase (p = 0.0625) and decreased the incidence and severity of ictuses. Intravenous L-arginine improved the rates of four major symptoms-headache, nausea/vomiting, impaired consciousness, and visual disturbance. The maximal plasma arginine concentration was 167 μmol/L when an ictus developed. Neither death nor bedriddenness occurred during the 2-year clinical trials, and the latter did not develop during the 7-year follow-up despite the progressively neurodegenerative and eventually life-threatening nature of MELAS. No treatment-related adverse events occurred, and the formulations of L-arginine were well tolerated. CONCLUSIONS: The systematic administration of oral and intravenous L-arginine may be therapeutically beneficial and clinically useful for patients with MELAS.

Pallister-Killian syndrome (PKS) is rare genetic disorder caused by tetrasomy 12p mosaicism with supernumerary isochromosome 12p that manifests with intellectual disability, craniofacial dysmorphism, and epilepsy. Although PKS presents as a multisystem morphological defect, respiratory system involvement is rare, except for diaphragmatic hernia. We are the first to report a case of PKS with progressive subglottic stenosis. Subglottic stenosis is a potentially lethal condition due to severe respiratory obstruction and difficult intubation; therefore, further accumulation of cases is required to assess the causal link between PKS and subglottic stenosis.

Benign hereditary chorea (BHC) is a rare autosomal dominant disease that is characterized by non-progressive chorea with early-childhood-onset, congenital hypothyroidism, and neonatal respiratory distress. Although tetrabenazine and levodopa are partly effective for chorea and drop attacks in some patients, there is no standard treatment option. We herein describe a childhood case of BHC that presented with L-thyroxine-responsive drop attacks. A genetic analysis revealed an interstitial deletion that included two enhancer regions of NKX2-1, providing genetic confirmation of BHC. This is the first report to inform the connection between thyroid function and drop attacks in BHC. Moreover, our findings identify L-thyroxine as a therapeutic option for the management of drop attacks in BHC.

Background: Guillain-Barré syndrome is an acute immune-mediated peripheral polyneuropathy. Neuroimaging findings from patients with this syndrome have revealed gadolinium enhancement in the cauda equina and in the anterior and posterior nerve roots, but intra-spinal lesions have never been described. Aim: Herein, we report, for the first time, bilateral spinal anterior horn lesions in a patient with an acute motor axonal neuropathy form of Guillain-Barré syndrome. Case: The patient was a previously healthy 13-year-old Japanese girl, who exhibited acute-onset flaccid tetraplegia and loss of tendon reflexes. Results: Nerve conduction studies revealed motor axonal damage, leading to the diagnosis of acute motor axonal neuropathy. Notably, spinal magnetic resonance imaging revealed bilateral anterior horn lesions on T2-weighted imaging at the Th11–12 levels, as well as gadolinium enhancement of the cauda equina and anterior and posterior nerve roots. The anterior horn lesions were most prominent on day 18, and their signal intensity declined thereafter. Although intravenous treatment with immunoglobulins was immediately administered, the motor function was not completely regained. Conclusion: We propose that anterior spinal lesions might be responsible for the prolonged neurological disability of patients with Guillain-Barré syndrome, possibly produced by retrograde progression from the affected anterior nerve roots to the intramedullary roots, and the anterior horn motor neurons.

Moyamoya syndrome is a progressive cerebrovascular disease that is characterized by stenosis of the terminal portion of the internal carotid artery and its main branches, in combination with an accompanying disease. We herein describe an 8-year-old boy exhibiting transient loss of consciousness, who had recurrent seizures in infancy with progressive brain calcification. On admission, he was alert but magnetic resonance angiography showed bilateral stenosis of the whole internal carotid artery and proliferation of vascular collaterals, and brain CT revealed calcification on bilateral putamen. Given that this fulfilled diagnostic criteria, we finally diagnosed him as having moyamoya syndrome, though the etiology was unclear. Interestingly, a whole vessel survey revealed vascular stenosis of abdominal aorta and renal arteries, in which the former has not been reported in moyamoya syndrome. We considered that brain calcification was gradually formed by decreased cerebral vascular flow from infancy, and stenosis of abdominal aorta was possibly extended from renal arteries. This is, moyamoya syndrome with brain calcification and stenosis of abdominal aorta, suggesting that morphological screening of whole vessels containing cerebral and abdominal arteries should be considered in cases of slowly progressive brain calcification. (C) 2017 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.

Background Nevoid basal cell carcinoma syndrome (NBCCS) is an autosomal dominant disorder characterised by developmental defects and tumorigenesis, such as medulloblastomas and basal cell carcinomas, caused by mutations of the patched-1 (PTCH1) gene. In this article, we seek to demonstrate a mosaicism containing double mutations in PTCH1 in an individual with NBCCS. Methods and results A de novo germline mutation of PTCH1 (c.272delG) was detected in a 31-year-old woman with NBCCS. Gene analysis of two out of four induced pluripotent stem cell (iPSC) clones established from the patient unexpectedly revealed an additional mutation, c.274delT. Deep sequencing confirmed a low-prevalence somatic mutation (5.5%-15.6% depending on the tissue) identical to the one found in iPSC clones. Conclusions This is the first case of mosaicism unequivocally demonstrated in NBCCS. Furthermore, the mosaicism is unique in that the patient carries one normal and two mutant alleles. Because these mutations are located in close proximity, reversion error is likely to be involved in this event rather than a spontaneous mutation. In addition, this study indicates that gene analysis of iPSC clones can contribute to the detection of mosaicism containing a minor population carrying a second mutation.

Background: Anti-NMDA-R receptor encephalitis occurs predominantly in younger women and is often comorbid with ovarian teratoma, a feature that is often absent in children. Here, we report our experience with two pediatric patients, in whom no tumors were present during treatment for encephalitis, but in whom ovarian teratomas developed without encephalitis relapse after treatment was completed. Cases: Patient 1 was a 14-year-old girl who was diagnosed due to characteristic symptoms and anti-NMDA-R antibody. MRI scanning during treatment revealed no ovarian tumors, but a tumor developed in the right ovary 10 months after onset. Another tumor developed in the left ovary 3 years after onset, and a mature ovarian teratoma was confirmed after bilateral partial ovariectomy. Patient 2 was an 11-year old girl who was also diagnosed due to characteristic symptoms and anti-NMDA-R antibody. Imaging during treatment revealed no ovarian tumors, but a 2.5-cm tumor mass was found in the left ovary 10 months after onset, and a mature ovarian teratoma was confirmed after partial ovariectomy. Discussion: This case report suggests the need for regular tumor screening after treatment for anti-NMDA receptor encephalitis because of potential subsequent tumor development, even in pediatric patients who initially present with no comorbid tumors. No analysis of relapse risk has yet been reported in cases of tumor development after treatment, and at this point, whether or not resection is needed to prevent relapse remains unclear. However, because teratomas usually grow, have an associated risk of torsion, and can be malignant, tumor removal should be considered. (C) 2016 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.