Michinori Funato

Clinical improvement of diffuse lymphangiomatosis with pegylated interferon alfa-2b therapy: case report and review of the literature.

Diffuse lymphangiomatosis is a very rare congenital disease, characterized by diffuse or multifocal lymphangioma in the skeletal tissue, spleen, liver, mediastinum, and/or lung. The prognosis is usually poor, especially for children with thoracic lesion, and treatments for the disease are controversial. The authors report a 9-year-old boy with diffuse lymphangiomatosis involving the thorax with pleural effusions, the spleen, and systemic bone. The patient was treated with pegylated interferon alfa-2b, and achieved good clinical and radiological improvement.

Progressive multifocal leukoencephalopathy in a patient with X-linked agammaglobulinemia.

To our knowledge, this is the first case report describing progressive multifocal leukoencephalopathy (PML) associated with X-linked agammaglobulinemia. The JC virus was confirmed at autopsy and PML was diagnosed. Humoral immunodeficiency with normal cellular immunity could be infected with JCV.

Changes of autonomic nervous system function in patients with breath-holding spells treated with iron

To evaluate the autonomic nervous system of patients with breath-holding spells after iron treatment, we attempted to determine whether a dysregulation of the autonomic nervous system reflexes exists in children with severe cyanotic breathholding spells. An electrocardiogram for each subject was recorded for 24 hours in the subjects home and parasympathetic activity was investigated by the fast Fourier transform method. Hematologic data and clinical symptoms of all three patients treated with iron improved and attacks of severe breath-holding spells disappeared. After iron treatment was started, the heart rate variability increased during sleep. It appears that supplementation of iron is effective in improving the dysregulation of autonomic nervous system reflexes. (J Child Neurol 2002;17:337-340).

Acute cerebellitis associated with rotavirus infection.

BackgroundRotavirus infection is occasionally associated with central nervous system involvement, including cerebellitis. However, the precise clinical sequelae of central nervous system disorders and the usefulness of neuroradiological examination for clinical therapies, such as steroid pulse therapy, have not been clarified.MethodsWe present a case of rotavirus cerebellitis examined by magnetic resonance imaging (MRI), magnetic resonance spectroscopy, and single photon emission computed tomography.ResultsMRI demonstrated abnormal intensities in the right cerebellum on fluid attenuated inversion recovery images and, much more obviously, on diffusion-weighted images, but not on T1- or T2-weighted images. Single photon emission computed tomography showed only mild hypoperfusion in the right cerebellum on the 15th day, while 4 weeks later the image showed remarkably low perfusion in the right cerebellum.ConclusionThe findings of the reported case suggest the importance of performing radiological examinations at early phases of the disease, especially by new modalities such as diffusion weighted imaging, to make timely and appropriate therapeutic decisions.

Reversible cerebrospinal fluid edema and porencephalic cyst, a rare complication of ventricular catheter

Cerebrospinal fluid (CSF) edema and porencephaly are rare postoperative complications of a ventricular shunt that result from obstruction of the distal catheter, especially in children with taut ventricles. We report a 10-year-old male with cerebellar germinoma complicated by obstructive hydrocephalus. Ventriculopuncture was performed and an Ommaya reservoir was implanted at the right frontal horn. A distal catheter was initially attached to the reservoir for drainage of hydrocephalus but was later removed. After surgery, multi-agent chemotherapy and radiation therapy, a brain MRI showed CSF edema and porencephaly in the right frontal white matter. These lesions were reduced by prompt removal of the ventricular catheter. It is important to recognize such complications and to remove the catheter as soon as possible, because the brain tissue affected by massive edema may develop irreversible changes. Advanced MRI techniques, including fluid-attenuated inversion recovery (FLAIR) and diffusion-weighted imaging may be helpful for assessing this pathological condition and its prognosis.

A transient lesion in the corpus callosum during rotavirus infection.

To the Editor: Fukuda et al. [1] recently reported a case with a transient lesion in the corpus callosum during rotavirus infection. We have just encountered a similar case, and our review suggests the need to reevaluate the spectrum of central nervous system involvement in rotavirus infections. In March 2009, a 1-year-old girl was admitted to our hospital after three incidents of brief tonic convulsions with mild fever, as well as enterocolitis with vomiting and diarrhea for the previous three days. On admission, she was slightly drowsy as a result of diazepam treatment for her convulsions, but she quickly recovered to be fully conscious, engaging in fluent conversation with no evident neurological abnormal findings. Laboratory data including serum sodium (137 mEq/L) and analysis of cerebrospinal fluid were normal. Magnetic resonance imaging on admission showed a marked hyperintensity in the splenium of the corpus callosum on diffusion-weighted image; a slight abnormal was seen on T1or T2-weighted images (Fig 1). The hyperintensity in the splenium disappeared at 6 days after the first imaging (Fig 1). Initial electroencephalography on admission exhibited intermittent spikes and slowwaves in the right occipital region. The patient did not, however, experience any other seizures, and the abnormality was not evident on subsequent electroencephalograms 2 and 6 days after admission. No neurologic complications were evident upon discharge. Rotavirus antigen was detected in

Mutations of the GATA2 and CEBPA genes in paediatric acute myeloid leukaemia

Hereditary GATA2 mutations show predisposition to acute myeloid leukaemia (AML) and myelodysplastic syndrome (MDS) (Hahn et al, 2011). These mutations have also been reported in chronic myeloid leukaemia (Zhang et al, 2008) and monocytopenia and mycobacterial infection (MonoMAC) syndrome (Hsu et al, 2011). More recently, GATA2 mutations have been identified in de novo AML, especially in adult patients with biallelic CEBPA mutations (Greif et al, 2012; Green et al, 2013). GATA2 and CEBPA are transcription factors that are crucial for haematopoietic development. These findings prompted us to identify possible GATA2 and CEBPA mutations in patients with various paediatric leukaemias. Direct Sequencing of GATA2 was performed in 157 de novo AML patients, including 13 patients with acute promyelocytic leukaemia (APL; French–American–British type-M3) and 10 with Down syndrome (DS; Table S1), 22 secondary AML patients, 40 juvenile myelomonocytic leukaemia (JMML) patients, 50 acute lymphoblastic leukaemia (ALL) patients, 70 cell lines (25 B-cell precursor-ALL, 15 T-cell-ALL, 22 AML, and 8 neuroblastomas), and 60 healthy subjects. GATA2 mutation analysis was performed by direct sequencing for all coding exons (exons 2–6) using an ABI PRISM 3130 Genetic Analyser (Applied Biosystems, Branchburg, NJ, USA) (Table S2). For AML patients, CEBPA and NPM1 mutations were also examined. Mutational analyses of FLT3, KIT, WT1 and RAS genes in our AML patients was performed as described previously (Shimada et al, 2006). Informed consent was obtained from the patients or the patients’ parents according to guidelines based on the tenets of the revised Helsinki protocol. The institutional review boards of Gunma Children’s Medical Centre approved this project. GATA2 mutations were found in eight out of 157 AML patients (5 1%), including three APL patients (Fig 1A,B), but were absent in 18 patients with acute megakaryocytic leukaemia (FAB-M7; Table S3). Furthermore, there were no GATA2 mutations in patients with other leukaemias, in the cell lines, or in the 60 healthy subjects, suggesting that GATA2 mutations were indeed associated with leukaemogenesis in a subset of patients with de novo AML. Germline GATA2 mutations were also examined in five AML patients whose complete remission (CR) samples were available, and a germline mutation was identified in one patient. Furthermore, we performed GATA2 mutation analyses of the patient’s parents and two siblings, and identified the same GATA2 mutations in her father (II-4) and brother (III-1) but not in her mother (II-5) or sister (III-2) (Fig 1C). Her father and brother lacked abnormalities in their full blood cell counts, lymphocyte subsets, or episodes of opportunistic infections. The proband experienced severe mycotic pneumonia during induction chemotherapy. Remarkably, she has been in CR for more than 11 years, despite discontinuation of chemotherapy. Three patients, for whom CR samples were not available, had no history of MonoMAC syndrome. In addition, 16 CEBPA mutations (10 2%) and three NPM1 mutations (1 9%) were found in 157 paediatric AML patients. Thirteen (81 3%) of 16 patients with CEBPA mutations had been in CR for more than 4 years, suggesting that CEBPA mutations may be associated with favourable outcomes. Although most GATA2 mutations were found in patients with biallelic CEBPA mutations in adult AML (Greif et al, 2012; Green et al, 2013), only two of eight GATA2 mutation-positive patients had monoallelic CEBPA mutations in this study (Table I). We compared the clinical and molecular features between patients with and without GATA2 mutations. However, there were no significant differences in terms of age, initial white blood cell count, gender, and cytogenetics (Table S3). Of the eight patients with GATA2 mutations, one had a WT1 mutation, one had a KIT mutation, and two patients had RAS mutations (Table I). FLT3-internal tandem duplication, MLL-partial tandem duplication, and NPM1 mutations were not found in any patients with GATA2 mutations (Table S3). All of the GATA2 mutations were found in the intermediate risk subgroup or APL patients with t(15;17), whereas none were found in those with core-binding factor AML [i.e. t(8;21) and inv(16)]. GATA2 mutations were found in two patients with 11q23 translocations, including t(11;19) and t(7;11), and three patients with complex chromosomal abnormalities, whereas most GATA2 mutations were found in cytogenetically normal AML patients in previous reports (Table I) (Greif et al, 2012; Luesink et al, 2012). GATA2 mutations were previously reported in patients with M1, M2, and M4 subtypes of AML (Greif et al, 2012; Luesink et al, 2012), which is in accordance with our results. GATA2 mutations have not been previously reported in APL, but our study found these mutations in three APL patients. Of note, promyelocytic leukaemia protein has been shown to interact with GATA2 and potentiate its transactivation capacity (Tsuzuki et al, 2000). correspondence

Genetic variations in MyD88 adaptor-like are associated with atopic dermatitis

Toll-like receptors (TLRs) are important pathogen-associated molecular pattern recognition receptors involved in initiating immune responses. The adaptor protein MyD88 adaptor-like (Mal), involved in signaling downstream of TLRs, plays a crucial role in mediating NF-κB activation. The association of Mal polymorphisms with allergic diseases has not previously been defined. The objective of this study was to detect polymorphisms in the Mal gene and to investigate their association with allergic diseases. Mal gene polymorphisms were genotyped in 310 subjects. The functional effects of Mal variants were analyzed in vitro. One Mal polymorphism, c.303 G>A (Q101Q), was found at a significantly lower frequency in atopic dermatitis patients (p=0.016). Q101Q is in linkage disequilibrium with -103 A>G (rs1893352) and c.539 C>T (S180L) (rs8177374) in the HapMap database. The A allele of -103 A>G showed significantly reduced transcription of Mal compared with the G allele. In addition, three rare variants were identified in this study, c.394 G>A (E132K), c.428 G>A (R143Q) and c.570 G>C (E190D), and were shown to lead to loss-of-function of Mal. It is possible that gene polymorphisms in Mal could affect atopic dermatitis by influencing the innate immune system. We show that Q101Q, which is in linkage disequilibrium with -103 A>G and S180L, may play a protective role against atopic dermatitis. Furthermore, we propose that loss-of-function variants of Mal could predispose individuals to atopic dermatitis or other immunological disorders.

A family having type 2B von Willebrand disease with an R1306W mutation: Severe thrombocytopenia leads to the normalization of high molecular weight multimers.

In type 2B von Willebrand disease (2B VWD), abnormal von Willebrand factor (VWF) spontaneously binds to platelets. This leads to the clearance of the high molecular weight multimers (HMWM) of VWF and results in thrombocytopenia. Herein we report a family of 2B VWD with an R1306W mutation which caused thrombocytopenia with giant platelets. The most important finding in this study is dynamic changes in VWF values in association with platelet counts. When the proband (2 years of age) had severe thrombocytopenia, his HMWM were normal, however, hematological examination showed a low level of VWF and a lack of HMWM after platelet count recovered. His affected sister also exhibited similar phenomenona. These results suggest that the severe thrombocytopenia leads to decreased clearance of VWF HMWM and restoration of VWF HMWM in plasma. We must consider 2B VWD in the case of recurrent thrombocytopenia following infection or other stress condition.

Topical Review: Molecular and Neurologic Findings of Peroxisome Biogenesis Disorders:

Peroxisomal disorders, an expanding group of genetic disorders in humans, can be grouped into three categories: peroxisome biogenesis disorders, single peroxisomal enzyme deficiencies, and contiguous gene syndrome. At present, 13 complementation groups of peroxisome biogenesis disorders and their responsible genes have been identified, including our newly identified group with a PEX14 defect. We describe neuronal abnormalities related to deficiencies in peroxisomes and the phenotype-genotype relationship in peroxisome biogenesis disorders. We also identified 32 Japanese patients with peroxisome biogenesis disorders, subdivided into six complementation groups. Our institution acts as the only diagnostic center for studies on peroxisomal disorders in Japan. (J Child Neurol 2005;20:326—329).