藤井 克則

We described a 7-year-old girl with reversible cerebral vasoconstriction syndrome associated with brain parenchymal hemorrhage. She initially presented with high fever and pancytopenia, leading to a diagnosis of most severe type aplastic anemia. We treated her with cyclosporine, methylprednisolone and anti-thymocyte globulin. Thereafter she recurrently complained of a very severe headache called as thunderclap, and finally exhibited loss of consciousness. Brain imaging revealed massive parenchymal hemorrhage between the left occipital and parietal lobes on computed tomography, and diffuse cerebral vasoconstriction on magnetic resonance angiography. The cerebral vasoconstriction resolved within two months, and thus we diagnosed her as having reversible cerebral vasoconstriction syndrome associated with brain parenchymal hemorrhage. This syndrome has been frequently reported in adult females, but rarely in children. However, even in children, a so called thunderclap headache may become a clue for the diagnosis of reversible cerebral vasoconstriction syndrome, especially in cases taking immunosuppressive agents. Immediate magnetic resonance angiography is essential to diagnose this syndrome, and a prompt application of calcium channel inhibitors should be considered to resolve constriction of the vessels and to prevent subsequent brain damage. (C) 2011 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.

Acute disseminated encephalomyelitis (ADEM) is an immune-mediated inflammatory disorder of the central nervous system. We describe a previously healthy 2-year-old boy with ADEM, who exhibited high fever, lethargy, and recurrent seizures at 25 days after H1N1 influenza vaccination. To our knowledge, there has been only one report of ADEM following the 2009 H1N1 influenza vaccine, although such vaccination is accompanied with optic neuritis apart from this case. Thus, this is the first case of ADEM without optic neuritis, following the 2009 H1N1 influenza vaccination. Although vaccine-associated ADEM remains rare, the increasing number of influenza vaccinations might increase the incidence of ADEM. We still need to pay attention to the occurrence of ADEM and treat patients with steroid therapy.

Nevoid basal cell carcinoma syndrome (NBCCS) is an autosomal dominant disorder characterized by developmental defects and tumorigenesis. The gene responsible for NBCCS is PTCH1. The PTCH1 gene has five alternatively used first exons resulting in the translation of three isoforms of the PTCH1 protein; that is, PTCHL, PTCHM and PTCHS. However, the biological significance of each isoform is unclear. Here we show an individual with NBCCS carrying a nonsense mutation in PTCH1 exon2, c. 387G > A (p.W129X). As the mutation lay upstream of the ATG codon used for PTCHS translation, the mutant allele still expressed RNA isoforms that encode PTCHS. These results clearly demonstrate that a selective haploinsufficiency of longer isoforms of the PTCH1 protein, PTCHL and PTCHM, but not PTCHS is sufficient to cause NBCCS. Although mice selectively deficient in PTCHS isoforms are currently unavailable, this study sheds light on the complex in vivo roles of PTCH1 isoforms. Journal of Human Genetics (2012) 57, 422-426; doi:10.1038/jhg.2012.45; published online 10 May 2012

Nevoid basal cell carcinoma syndrome (NBCCS) is an autosomal dominant disorder characterized by developmental defects and tumorigenesis. The gene responsible for NBCCS is PTCH1. Using multiplex ligation-dependent probe amplification, we identified a heterozygous tandem duplication within the PTCH1 gene in a 14-year-old girl with typical NBCCS. We have sequenced the chromosomal breakpoint and determined the duplication as tandem in orientation and 18,814?bp in size. The fusion occurred between non-repetitive elements with an overlap of three nucleotides. The duplicated segment began at exon 10 and ended at intron 17. Subsequent analysis of cDNA from the patient showed the expression of mutant mRNA species containing a duplicated segment spanning exons 1117, resulting in a frameshift and premature stop codon. This is the first reported case of NBCCS due to a tandem multiexon duplication of PTCH1 representing a novel mechanism leading to the NBCCS phenotype, and highlights the importance of copy number analysis as an adjunct to exon sequencing in identifying infrequent mutational events in PTCH1. (C) 2012 Wiley Periodicals, Inc.

MicroRNAs (miRNAs) are small non-coding RNAs that inhibit gene expression by cleaving or hindering the translation of target mRNAs. We used microarray-based comparative transcriptome analysis to identify changes in miRNA expression and function between a human cell line, RSa, which is highly sensitive to HuIFN-β-mediated inhibition of cell viability, and its variant, the F-IFr cell line, which is relatively resistant to the cytokine. miR-431 expression was significantly higher in RSa cells compared with F-IFr cells. The addition of HuIFN-β to RSa cultures reduced cell viability, down-regulated expression of IGF1R and IRS2 (putative miR-431 target genes), and inhibited the PI3K-Akt and MAPK pathways. The survival of F-IFr cells was not reduced by HuIFN-β, but transient transfection with miR-431 precursors significantly decreased viability and concomitantly down-regulated IGF1R and IRS2 expression. In addition, the MAPK pathway, but not the PI3K-Akt pathway, was suppressed in F-IFr cells. Based on these results, we propose that, in RSa cells, HuIFN-β-induced miR-431 expression may down-regulate IGF1R and IRS2 expression, and consequently inhibit cell proliferation by suppressing the MAPK pathway.

We describe a 4-year-old boy with posterior reversible leukoencephalopathy syndrome associated with hemolytic-uremic syndrome. He exhibited bloody stool by Escherichia coli O157: H7 infection with acute renal failure. He subsequently presented high blood pressure, followed by visual disturbance and loss of consciousness. Brain MRI revealed bilateral occipital high intensities by T2-weighted images and high value by apparent diffusion coefficient map, thus we made a diagnosis of posterior reversible leukoencephaly syndrome associated with hemolytic-uremic syndrome. In spite of immediate blood pressure control, occipital lesions developed day by day, resulting in multiple subcortical cavitations. Although posterior reversible leukoencephalopathy syndrome is originally characterized by reversible vasogenic edema, this case rarely resulted in irreversible changes with cystic formation. We concluded that precipitating factors, i.e., clotting abnormalities, Shiga toxin, vasospasms and endothelial dysfunction might have synergistically induced irreversible brain infarcts, and caused unusual cavitations. © 2011 The Japanese Society of Child Neurology.

We describe a 4-year-old boy with posterior reversible leukoencephalopathy syndrome associated with hemolytic-uremic syndrome. He exhibited bloody stool by Escherichia coli O157:H7 infection with acute renal failure. He subsequently presented high blood pressure, followed by visual disturbance and loss of consciousness. Brain MRI revealed bilateral occipital high intensities by T2-weighted images and high value by apparent diffusion coefficient map, thus we made a diagnosis of posterior reversible leukoencephaly syndrome associated with hemolytic-uremic syndrome. In spite of immediate blood pressure control, occipital lesions developed day by day, resulting in multiple subcortical cavitations. Although posterior reversible leukoencephalopathy syndrome is originally characterized by reversible vasogenic edema, this case rarely resulted in irreversible changes with cystic formation. We concluded that precipitating factors, i.e., clotting abnormalities, Shiga toxin, vasospasms and endothelial dysfunction might have synergistically induced irreversible brain infarcts, and caused unusual cavitations. (C) 2011 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.

Nevoid basal cell carcinoma syndrome (NBCCS) is characterized by developmental defects and tumorigenesis. The clinical manifestations of NBCCS have been reported in large epidemiological studies from the United States, the United Kingdom, and Australia, but not from an Asian country. We conducted a nationwide survey and identified 311 NBCCS patients in Japan. We investigated the detailed clinical manifestations of 157 patients ranging in age from 9 months to 77 years old (mean: 33.1 years). We then compared the frequency and age of onset for various tumors developed in Japanese NBCCS patients with patients from the three countries listed above in which NBCCS studies were previously conducted. Our most significant finding was the low frequency of basal cell carcinoma (BCC) in Japanese patients. Frequency of BCC in patients over 20 years of age was 51.4%, a much lower rate compared to the United States, Australia, and the United Kingdom (91%, 85%, and 73%, respectively). The mean age of BCC onset was 37.4 years of age, a much older age compared to the above-mentioned countries. These findings suggest that differences in ethnicity and/or environmental factors affect the incidence of BCC. Because the age of BCC onset is generally higher in Japanese NBCCS patients, careful skin examination over a prolonged period of time is warranted. (C) 2012 Wiley Periodicals, Inc.

ヘッジホッグシグナルは、形態形成と細胞増殖において中核的な役割を果たし、特に髄芽腫や基底細胞癌などの腫瘍形成において治療標的となる重要な経路である。Gorlin症候群(母斑基底細胞癌症候群)は、ヘッジホッグ受容体であるPTCH遺伝子の異常により生じる先天性奇形症候群であり、肋骨異常、手掌足底小陥凹、大脳鎌の石灰化を主とした多彩な身体奇形と角化嚢胞性歯原性腫瘍、髄芽腫、基底細胞癌などの易腫瘍形成を特徴とする。Gorlin症候群では髄芽腫に対する全脊髄照射により二次性に基底細胞癌を生じるため注意が必要である。現在、同経路を阻害する低分子化合物の臨床応用が進んでおり、髄芽腫で効果が報告されている。したがって脳腫瘍の治療においてもヘッジホッグ経路を理解することが望ましい。(著者抄録)

Nevoid basal cell carcinoma syndrome (NBCCS) is a rare autosomal dominant disorder characterized by developmental abnormalities and a predisposition to cancers. Although multiple jaw tumors, such as keratocystic odontogenic tumors (KCOTs), are one of the most frequent complications in NBCCS, the molecular mechanism for how KCOTs develop in NBCCS is poorly understood. A 15-year-old girl with 2 jaw tumors was diagnosed as NBCCS according to the clinical criteria. The pathologic findings indicated that the 2 tumors were consistent with KCOTs. A PTCH1 mutation, c.1472delT, was detected in her peripheral blood as well as in the 2 tumors. Interestingly, an additional PTCH1 mutation, c. 264_265insAATA, that was not present in the peripheral blood, was found in the maxillary tumor but not the mandibular tumor. The Ki-67 labeling index was significantly higher in the maxillary KCOT (17.7%) than in the mandibular KCOT (14.3%). These findings indicate distinct molecular mechanisms of tumorigenesis in these KCOTs. (Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2010; 110: e41-e46)

Williams-Beuren syndrome (WBS) is a neuro-developmental disorder presenting with an elfin-like face, supravalvular aortic stenosis, a specific cognitive-behavioral profile, and infantile hypercalcemia. We encountered two WBS patients presenting with infantile spasms, which is extremely rare in WBS. Array comparative genomic hybridization (aCGH) and fluorescent in situ hybridization (FISH) analyses revealed atypical 5.7-Mb and 4.1-Mb deletions at 7q11.23 in the two patients, including the WBS critical region and expanding into the proximal side and the telomeric side, respectively. On the proximal side, AUTS2 and CALN1 may contribute to the phenotype. On the telomeric side, there are two candidate genes HIP1 and YWHAG. Because detailed information of them was unavailable, we investigated their functions using gene knockdowns of zebrafish. When zebrafish ywhag1 was knocked down, reduced brain size and increased diameter of the heart tube were observed, indicating that the infantile spasms and cardiomegaly seen in the patient with the telomeric deletion may be derived from haploinsufficiency of YWHAG. genesis 48:233-243,2010. (C) 2010 Wiley-Liss, Inc.

腸管出血性大腸菌 (enterohemorrhagic E. coli: EHEC) 感染症を契機に発症した溶血性尿毒症症候群 (hemolytic uremic syndrome: HUS) の重篤な合併症として，脳症がある。脳症の臨床像・病態生理は複雑である。今回われわれが経験したHUSに合併した脳症は，急性壊死性脳症 (acute necrotizing encephalopathy of childhood: ANE) に特徴的な画像所見を示していた。<br> こういった例はHUSに合併した脳症のなかでも，特に重篤な経過をたどりやすいようだ。また，サイトカインの関与も示唆された。HUSに対する既存の治療法では不十分であり，発症機序，管理・治療法に関するさらなる検討が必要と思われる。

The MR imaging finding of a reversible splenial lesion with transiently reduced diffusion has been reported in patients with clinically mild encephalitis/encephalopathy, leading to a new clinical-radiological syndrome, clinically mild encephalitis/encephalopathy with a reversible splenial lesion. We recently experienced a 3-year-old boy with clinically mild encephalitis with a splenial lesion exhibiting transient reduced diffusion on admission. He recovered completely with no particular treatment within 2 weeks. Though the splenial lesion decreased in size, it was detected for over 5 months in T2-weighted imaging. It is suggested that a splenial lesion with transiently reduced diffusion in clinically mild encephalitis/encephalopathy is not always reversible, and could result in gliosis. © 2008 Elsevier B.V. All rights reserved.

Nevoid basal cell carcinoma syndrome (NBCCS) is a rare autosomal dominant disorder characterized by developmental abnormalities and a predisposition to cancers. Two unrelated patients, 21- and 16-year-old males, with cleft lip and palate and multiple jaw cysts, were diagnosed according to clinical criteria. To confirm a diagnosis of NBCCS, we undertook a molecular genetic analysis of the PTCH gene. Their PTCH genes were analyzed by direct sequencing of the PCR product from their DNA, and previously unreported mutations were identified. A heterozygous duplication at the nucleotide position between 3325 and 3328 of the PTCH gene (c.3325-3328dupGGCG) was detected in the 21-year-old patient. It caused a frameshift mutation, resulting in a premature termination of the PTCH protein. A point mutation (G to C) in intron 7 of the PTCH gene (c.10671GC) was detected in the 16-year-old patient. This caused an aberrant splicing of PTCH. It is interesting to note that the non-canonical cryptic splice-donor site was activated, which did not conform to the GT-AG rule. © 2009 The Japan Society of Human Genetics.

Nevoid basal cell carcinoma syndrome (NBCCS) is a rare autosomal dominant disorder characterized by developmental abnormalities and a predisposition to cancers. Two unrelated patients, 21- and 16-year-old males, with cleft lip and palate and multiple jaw cysts, were diagnosed according to clinical criteria. To confirm a diagnosis of NBCCS, we undertook a molecular genetic analysis of the PTCH gene. Their PTCH genes were analyzed by direct sequencing of the PCR product from their DNA, and previously unreported mutations were identified. A heterozygous duplication at the nucleotide position between 3325 and 3328 of the PTCH gene (c.3325-3328dupGGCG) was detected in the 21-year-old patient. It caused a frameshift mutation, resulting in a premature termination of the PTCH protein. A point mutation (G to C) in intron 7 of the PTCH gene (c.10671GC) was detected in the 16-year-old patient. This caused an aberrant splicing of PTCH. It is interesting to note that the non-canonical cryptic splice-donor site was activated, which did not conform to the GT-AG rule. © 2009 The Japan Society of Human Genetics.

Nevoid basal cell carcinoma syndrome (NBCCS) is a rare autosomal dominant disorder characterized by developmental abnormalities and a predisposition to cancers. Two unrelated patients, 21- and 16-year-old males, with cleft lip and palate and multiple jaw cysts, were diagnosed according to clinical criteria. To confirm a diagnosis of NBCCS, we undertook a molecular genetic analysis of the PTCH gene. Their PTCH genes were analyzed by direct sequencing of the PCR product from their DNA, and previously unreported mutations were identified. A heterozygous duplication at the nucleotide position between 3325 and 3328 of the PTCH gene (c. 3325_3328dupGGCG) was detected in the 21-year-old patient. It caused a frameshift mutation, resulting in a premature termination of the PTCH protein. A point mutation (G to C) in intron 7 of the PTCH gene (c.1067+1G&gt;C) was detected in the 16-year-old patient. This caused an aberrant splicing of PTCH. It is interesting to note that the non-canonical cryptic splice-donor site was activated, which did not conform to the GT-AG rule. Journal of Human Genetics (2009) 54, 398-402; doi: 10.1038/jhg.2009.51; published online 12 June 2009

OBJECTIVE. We sought to clarify the features of kernicterus in preterm infants. METHODS. The subjects of this study were 8 preterm infants with athetoid cerebral palsy whose gestational ages were ≤34 weeks. We retrospectively investigated clinical, laboratory, MRI, and brainstem auditory evoked potential (BAEP) findings. RESULTS. Gestational age was ≤26 weeks in 6 of the 8 infants, and birth weight was &lt 1000 g in 5 infants. Serious postnatal complications with systemic deterioration were observed in 3 infants. Total bilirubin levels were measured frequently in the majority of infants peak values of &gt 15 mg/dL were observed in 3 infants. No infant showed neurologic symptoms characteristic of classical acute bilirubin encephalopathy during the neonatal period. Dystonic posture and abnormal muscle tone were first recognized within 6 months' corrected age in all patients. During infancy, MRI was performed in 7 infants. Abnormal high-intensity areas were observed in the bilateral globi pallidi in all 7 infants. However, MRI during the neonatal period or after 1 year's corrected age showed no abnormal findings. BAEP measurements were abnormal in 7 of the 8 infants. CONCLUSIONS. Preterm infants with athetotic cerebral palsy showed rather homogeneous features, similar to term infants with kernicterus, with marked hyperbilirubinemia. This combination of clinical, laboratory, neuroimaging, and neurophysiological data will contribute to the increased recognition of preterm infants with kernicterus. Copyright © 2009 by the American Academy of Pediatrics.

We report, for the first time, on a female Becker muscular dystrophy (BMD) patient with homozygous dystrophin deletion. The 14-year-old patient, product of consanguineous parents, presented with a 7-year history of exercise intolerance and recurrent myoglobinuria. Although CK was elevated to 1,800 U/L, no muscle weakness, atrophy, or hypertrophy was seen on examination. Muscle pathology demonstrated a minimal dystrophic change and faint dystrophin staining pattern. Semi-quantitative PCR of dystrophin revealed a homozygous dystrophin deletion of exons 45-55, which is predicted to remove 593 amino acids without frame shifting. Western blot analysis of skeletal muscle for dystrophin showed a 306 kDa band; thus, we made a diagnosis of female BMD. We confirmed identical deletion in both father and mother, in hemizygous and heterozygous modes, respectively. Neither female Duchenne muscular dystrophy (DMD) nor BMD due to homozygous dystrophin mutation has ever been identified although female DMD has been found in patients with Turner syndrome or unilateral parental disomy for X chromosome. Our results indicate that dystrophinopathy can also be caused in females by homozygosity, albeit rare.

We investigated the clinical manifestations of 25 Japanese patients with Gorlin syndrome. We revealed the frequencies of major five symptoms in Japanese Gorlin syndrome patients, i.e. basal cell carcinomas (BCCs) (20%), jaw cysts (80%), palmar and plantar pits (64%), calcification of the falx cerebri (64%), and rib abnormalities (44%). Compared with the previous studies in the United States, the United Kingdom, and Australia, Japanese Gorlin syndrome patients showed a significantly lower rate of BCCs, and no medulloblastomas in this study. We also revealed minor symptoms which were not included in the diagnostic criteria, i.e. empty sellas, lipomas, ulcerative colitis, dysgenesis of the corpus callosum, and cardiac fibromas. We conclude that clinical manifestations other than major symptoms are quite variable, and racial differences may influence the occurrence of BCCs in Gorlin syndrome patients.

Gorlin syndrome is an autosomal dominant disorder characterized by congenital anomalies and tumorigenesis. The gene responsible for Gorlin syndrome is PTCH1, a human homologue of the Drosophila segment polarity gene, patched. We analysed the PTCH1 gene in 25 patients in 22 families with Gorlin syndrome. We detected PTCH1 mutations in 22 patients in 19 families, including insertion/deletion mutations in 13 patients in 11 families (86%), chromosomal deletions in 4 patients in 3 families (16%), nonsense mutations in 2 patients in 2 families (11%), splicing mutations in 3 patients in 3 families (16%), and a missense mutation in 1 patient (5.3%). The sixteen mutations were distributed in extracellular loops (10 mutations: 63%), intracellular loops (four mutations: 25%), and transmembrane portions (two mutations: 13%). Our detection rate of PTCH1 mutations, i.e. 86%, was much higher than those previously reported from other countries. The differences may be derived either from ethnicity or the detection methods.

We describe a 10-year-old boy with an intracranial lipoma in the posterior fossa. The patient had a subcutaneous tumor of the posterior neck at birth, which was gradually growing and Subsequently accompanied by gait disturbance and ataxia. MR imaging revealed the intracranial lipoma in the posterior fossa extending into the cervical spinal canal and Subcutaneous space via a cranium bifidum. A surgical operation was performed, but the lipoma Could not be removed completely. He had had prominent obesity that might have caused not only enlargement of the intracranial lipoma but also neurological complications. Although intracranial lipomas are usually benign and asymptomatic, early detection of them is quite critical, and body weight control may help to prevent their progression. (c) 2008 Elsevier B.V. All rights reserved.