Mitsuru Ikeno

Skin infiltration of CD56bright CD16- natural killer cells in a case of X-SCID with Omenn syndrome-like manifestations

We observed a patient with X‐linked severe combined immunodeficiency (X‐SCID) with Omenn syndrome‐like manifestations. X‐linked inheritance, absence of CD132 expression and impaired response to interleukin‐2 (IL‐2) indicated that the case is typical of X‐SCID due to γc defect. However, this case was unusual in that circulating natural killer (NK) cells were increased and nearly half of these NK cells exhibited the CD56bright CD16− phenotype. A missense mutation was found within exon 5 of the IL2RG gene. The identical mutation was detected within NK, CD4+ T and B cells. Engraftment of maternally derived NK cells or gene reversion was ruled out. The erythroderma‐like skin lesion was characterized by infiltration of the dermis by CD56bright NK cells admixed with CD1a+ dendritic cells (DC). Expression of mRNA for inflammatory cytokines was significantly enhanced within the skin. This may be the first human case to demonstrate that close cell‐to‐cell contact between DC and NK cells provides an effective alternative pathway for NK cell differentiation/activation in vivo.

De novo microdeletion of 5q14.3 excluding MEF2C in a patient with infantile spasms, microcephaly, and agenesis of the corpus callosum.

The 5q14.3 microdeletion syndrome has recently been recognized as a clinical entity manifesting as severe intellectual disability, epilepsy, and brain malformations. Analysis of the shortest region of overlap among patients with this syndrome and subsequent identification of nucleotide alterations in the coding region of myocyte enhancer factor 2C gene (MEF2C) have suggested MEF2C as the gene responsible for the 5q14.3 microdeletion syndrome. We identified a de novo 3.4‐Mb deletion of 5q14.3 in a patient with infantile spasms, microcephaly, and brain malformation. The deleted region in the present patient was positional toward the centromere, and MEF2C was not included in the deleted region. However the neurological and dysmorphic features of the present patient resembled those of patients with the 5q14.3 microdeletion syndrome. We consider that a positional effect is the likely explanation for this evidence. To study the precise mechanism of this positional effect, further information is required on patients showing atypical deletions neighboring MEF2C.

Glucose metabolism soon after birth in very premature infants with small- and appropriate-for-gestational-age birth weights

UNLABELLED The intrauterine environment affects the development of insulin resistance in adulthood. To determine the influence of foetal growth restriction on glucose metabolism, we assessed indices of insulin sensitivity soon after birth in very premature infants. Blood samples were collected at birth from 52 premature infants with a gestational age of ≤31 weeks, who were divided into a group whose birth weight was small for their gestational age (SGA group, n=19) and a group whose birth weight was appropriate for their gestational age (AGA group, n=33). Blood glucose, serum insulin and C-peptide immunoreactivity (CPR) levels were measured in both groups. Furthermore, the quantitative insulin check index (QUICKI) was also calculated. Correlations between these indices and glucose metabolism and the standard deviation (SD) score for birth weight were also determined. The levels of insulin and CPR were significantly (p<0.05) lower in the SGA group than in the AGA group. The QUICKI was significantly (p<0.05) higher in the SGA group compared with the AGA group. The SD score for birth weight was correlated with the QUICKI (p<0.01), the serum insulin level (p<0.05) and the CPR level (p<0.05) in all 52 infants. CONCLUSION In very premature infants, poor foetal growth may impair foetal insulin secretion and affect the QUICKI at birth.

Refractory neonatal epilepsy with a de novo duplication of chromosome 2q24.2q24.3

There are only two reports on epileptic patients associated with microduplication of 2q. We found a de novo duplication of chromosome 2q24.2q24.3 in another infant with neonatal epilepsy. The patient had refractory focal seizures since the third day of life. Her seizures were refractory against phenobarbital and levetiracetam, but were controlled by valproate. Array comparative genomic hybridization revealed a 5.3‐Mb duplication of 2q24.2q24.3, where at least 22 genes including a cluster of voltage‐gated sodium channel genes (SCN1A, SCN2A, SCN3A, SCN7A, and SCN9A) and one noncoding RNA are located.

A de novo TUBB4A mutation in a patient with hypomyelination mimicking Pelizaeus–Merzbacher disease

OBJECTIVE Hypomyelinating leukoencephalopathy is a heterogeneous disorder caused by mutations in several-different genes. Clinical entity of hypomyelination with atrophy of the basal ganglia and cerebellum (H-ABC) is one of them. METHOD A male patient showed pendular nystagmus, infantile hypotonia, an abnormal pattern of brain auditory evoked potential, and hypomyelination on brain magnetic resonance imaging, which suggested Pelizaeus-Merzbacher disease (PMD) as the candidate diagnosis; however, no abnormality was found in the proteolipid protein 1 gene (PLP1) that is responsible for PMD. Whole exome sequencing was performed to identify pathogenic mutations in this patient. RESULTS A de novo mutation was identified in the tubulin 4a gene (TUBB4A), which has been recently reported to be associated with H-ABC. Although the patient did not show any neurological features suggesting H-ABC, such as extrapyramidal or cerebellar signs, radiological findings demonstrated the finding of cerebellar atrophy at the age of 36months. CONCLUSION This study suggested us the difficulty of clinical diagnosis for H-ABC early in the life of the patient, which makes predication of prognosis and genetic counseling difficult.

Amplitude-integrated electroencephalography in patients with acute encephalopathy with refractory, repetitive partial seizures

We report amplitude-integrated EEG findings in two children with acute encephalopathy with refractory, repetitive partial seizures. Both patients had a febrile illness one week before the onset of seizure. They had reduction of consciousness and repetitive seizures refractory to first-line antiepileptic drugs. Seizure frequency rapidly increased and evolved into status epilepticus. Continuous seizure monitoring with amplitude-integrated EEG revealed frequent subclinical seizures which were missed by direct observation. In addition, the site of origin of seizures was multifocal, and seizure foci shifted from one hemisphere to the other. Their seizures were controlled after an administration of high-dose phenobarbital. Continuous seizure monitoring with amplitude-integrated EEG will contribute to correct estimation of seizure burden and efficacy of antiepileptic drugs in children with acute encephalopathy with refractory, repetitive partial seizures.

3p Interstitial Deletion Including PRICKLE2 in Identical Twins With Autistic Features

BACKGROUND Microdeletion and microduplication syndromes without characteristic dysmorphic features are difficult to diagnose without chromosomal microarrays. PATIENTS We describe the clinical course and genetic findings of monozygotic twins with intellectual disabilities and autistic features associated with mild facial dysmorphism and microdeletion of chromosome 3p14. RESULTS The postnatal course of the second twin was complicated by intestinal malrotation, whereas that of the first twin was unremarkable. Both twins had several mild dysmorphic features including upswept frontal hair, low-set posterior rotated ears, arched down-slanting eyebrows, prominent forehead, epicanthic folds, micrognathia, hypertelorism, broad nasal bridge, short philtrum, and camptodactyly of the bilateral fifth fingers. They had autistic features such as poor eye contact and no social smile, stereotyped behaviors, and preference for solitary play. Array comparative genomic hybridization analysis revealed de novo 6.88-Mb deletions of 3p14 (chr3: 60,472,496-67,385,119) involving 17 genes in both twins. The deleted region contained 17 genes, five of which are known or presumed to be related to central nervous system disorders: FEZF2, SYNPR, ATXN7, PRICKLE2, and MAGI1. CONCLUSIONS We consider that PRICKLE2 is the most likely causative gene for the autistic features exhibited by these individuals.

Whole-exome sequencing of a unique brain malformation with periventricular heterotopia, cingulate polymicrogyria and midbrain tectal hyperplasia

We report a case of an infant with unique and unreported combinations of brain anomalies. The patient showed distinctive facial findings, severe delay in psychomotor development, cranial nerve palsy and seizures. Brain magnetic resonance imaging performed at 5 days of age revealed complex brain malformations, including heterotopia around the mesial wall of lateral ventricles, dysmorphic cingulate gyrus, and enlarged midbrain tectum. The patient unexpectedly died at 13 months of age. Postmortem pathological findings included a polymicrogyric cingulate cortex, periventricular nodular heterotopia, basal ganglia and thalamic anomalies, and dysmorphic midbrain tectum. Potential candidate genes showed no abnormalities by traditional PCR‐based sequencing. Whole‐exome sequencing confirmed the presence of novel gene variants for filamin B (FLNB), guanylate binding protein family member 6, and chromosome X open reading frame 59, which adapt to the autosomal recessive mode or X‐linked recessive mode. Although immunohistochemical analysis confirmed the expression of FLNB protein in the vessel walls and white matter in autopsied specimens, there may be functional relevance of the compound heterozygous FLNB variants during brain development.

Synthetic MR Imaging in the Diagnosis of Bacterial Meningitis

1Department of Radiology, Juntendo University School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo 113-8421, Japan 2Department of Radiology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan 3Department of Radiological Sciences, Graduate School of Human Health Sciences, Tokyo Metropolitan University, Tokyo, Japan 4Department of Pediatrics, Juntendo University School of Medicine, Tokyo, Japan

Analyses of Genetic and Clinical Parameters for Screening Patients With Inherited Thrombocytopenia with Small or Normal-Sized Platelets

Childhood thrombocytopenias include immune thrombocytopenic purpura (ITP) and inherited thrombocytopenia; the former is caused by autoantibodies to platelets, whereas the latter can be distinguished by platelet size and underlying genetic mutations. Due to limited methods for the definite diagnosis of ITP, genetic and clinical parameters are required for diagnosing inherited thrombocytopenias with small or normal‐sized platelets.