Autopsy report of a 7-year old patient with the mosaic trisomy 13.

We present here a long survival case of a patient with the mosaic form of trisomy 13 who died of aspiration pneumonia at the age of 7 years and 4 months. The autopsy revealed olfactory aplasia and fenestration of the septum pellucidum, and dilated lateral ventricles and atrophic hippocampus. Furthermore, there were numerous "torpedos" (i.e., swollen fusiform Purkinje cell axons), mostly in the granular layer underneath the Purkinje cell layer, and, occasionally, in the granular layer. Similar neuropathological findings have been reported in elderly cases of essential tremor, Parkinson's disease, or Alzheimer's disease. Precise mechanism for this axonal change is still unclear. These pathological changes have never previously been reported in the literature on trisomy 13, and the present patient is one of the oldest autopsied individuals with the mosaic trisomy 13.

[Changes in treatment, symptoms and QOL of pediatric asthma patients at different ages for 7 years in Tochigi].

BACKGROUND: A 7-year analysis of pediatric asthma in Tochigi was performed with the aim of improvement of future treatment. METHODS: Self-administered questionnaires were completed by pediatric asthma patients and their parents who visited pediatric clinics or hospitals in Tochigi at the same period of year in 2002, 2006, and 2008. Changes in asthma symptoms and in the QOL of the patients and their parents were analyzed. Data on the background and treatment of the patients were obtained from doctors. RESULTS: The questionnaires were answered by 1487, 1058, and 1014 patients or parents in 2002, 2006, and 2008, respectively. The results showed significant increases in the use of ICS and LTRA (p< 0.001, for each.) and significant decreases in the use of theophylline, DSCG, and LABA (p< 0.001, for each.). Frequency of wheezing, cough and sputum were significantly reduced in all age groups (p< 0.01, for each.). There were significant reductions of frequency of wheezing in patients under 2 years old; in wheezing and cough in patients aged 2-5 years old; and in wheezing, cough and sputum in patients aged 6-15 years old (p< 0.05 for each.). The QOL of the patients and their parents was significantly improved in all age groups (p< 0.05 for each.). CONCLUSION: These findings suggest that increased use of anti-inflammatory agents such as LTRA and ICS have contributed to a reduction in asthma symptoms and an improvement in the QOL of the pediatric patients and their parents, but more widespread use of these agents are still needed for residual uncontrolled asthma patients.

Acute infantile encephalopathy predominantly affecting the frontal lobes.

To establish a novel subtype of acute infantile encephalopathy, the clinical and radiologic features of nine infants with acute encephalopathy involving the bilateral frontal lobes were examined. These patients had convulsive status epilepticus with hyperpyrexia followed by a prolonged impairment of consciousness for 2-20 days. After the recovery of consciousness, all the patients manifested regression of verbal function and lack of spontaneity. Some of them also exhibited stereotypic movements, instability of mood, or catalepsy. Transient postictal edema in both frontal lobes was suggested by diffusion-weighted magnetic resonance imaging. Attenuated cerebral perfusion in the frontal lobes was demonstrated by single-photon emission computed tomography at the tenth day after onset or subsequently. Serial studies disclosed atrophic changes in the frontal lobes. All patients manifested regression or retardation of motor and verbal functions. The recovery of intellectual deficit was slower and less prominent than that of motor dysfunction. These unique features suggest that the frontal lobes are the focus of this novel subtype of acute encephalopathy, which we propose to call acute infantile encephalopathy predominantly affecting the frontal lobes.

An analysis of epilepsy with chromosomal abnormalities.

We retrospectively reviewed the medical records of neonates with chromosomal abnormalities and epilepsy who had been admitted to the neonatal intensive care unit (NICU) and followed up at the outpatient clinic of Dokkyo University School of Medicine. Chromosomal anomalies were diagnosed in 128 of 5789 patients admitted from 1978 through 2001. Seventy-one neonates had trisomy 21, 29 had trisomy 18, 8 had trisomy 13, and 20 had other chromosomal anomalies. Seizures occurred in five patients with trisomy 21 and in one patient each with trisomy 18, 6q-, 13q-, 21q-, and mosaicism trisomy 13. Two patients with 4p- [Wolf-Hirschhorn syndrome] were admitted to the NICU, but were not followed up at our outpatient clinic. The boy with 6q- (46,XY,-6, +der(6)t(6;11)(q25.1;q23.3)mat) had agenesis of the corpus callosum and multiple congenital anomalies as well as intractable epilepsy. The girl with 13q- (46, XX, t(2,4)(q24.2;p14), del (13)(q21.2q31.2)) had infantile spasms at 12 months, which were well controlled with nitrazepam and vitamin B6. The girl with mosaic trisomy 8q; (46, XX, der(8) (qter-->q11.2::p23.3-->qter)/46, XX), was not born at our hospital, but showed unique clinical features. She had intractable epilepsy characterized by episodes of vomiting and staring with astatic seizures. Computed tomography of the brain revealed bilateral calcification in the globus pallidus, associated with bursts of high-amplitude slow waves on electroencephalography. One of the two patients with del(15)(q12)[Angelman syndrome] had giant-amplitude visual evoked potential, suggesting hyperexcitability of the visual cortex.

Degeneration of monoaminergic fibers in the aged micrencephalic rat.

Age-related changes in the monoaminergic neuron systems in the brains of methylazoxymethanol acetate (MAM)-induced micrencephalic rats were studied. Neurochemical analysis revealed high levels of serotonin, norepinephrine and associated metabolites in several brain areas of MAM-treated rats. In particular, serotonin levels in the frontal cortex, cingulate cortex and hippocampus of 12-month-old (12 M) MAM-treated rats were significantly higher than in corresponding age-matched controls. Immunohistochemical analysis demonstrated numerous aberrant serotonin-immunoreactive fibers and small numbers of aberrant tyrosine hydroxylase-immunoreactive fibers in the septum, caudate putamen, thalamus, cerebral cortex, hippocampus and midbrain tegmentum of 12 M MAM-treated rats. Aberrant monoaminergic fibers characterized by swollen varicosities and thickening of intervaricose segments were common compared to 12 M control rats. In the cortex and hippocampus of 12 M MAM-treated rats, aberrant fibers were observed near cortical heterotopic tissue. These results indicate early onset of age-related degeneration of monoaminergic fibers in micrencephalic rats. Aged MAM-treated rats may thus offer a good model for studying age-related monoaminergic changes in the cortical heterotopic tissue of human cortical malformations.

gamma-Globulin-induced modulation with necrotic-like morphology of peripheral blood neutrophils.

To determine the effect of intravenous immunoglobulin-administration on neutrophil function, we obtained neutrophils from patients with an acute phase of Kawasaki disease. In vitro IgG-induced modulation of neutrophils into Annexin-V-positive and propidium iodide-negative cells was observed in 20 of 28 patients in the presence of more than 300 microg/ml IgG and showed necrosis-like changes in morphologic features. However, we could not find any patients showing promotion of the sub-G1 cell fraction on DNA content analysis. The modulatory effect of in vitro IgG was not observed in neutrophils from healthy volunteers and was significantly correlated with the antifebrile effect of in vivo IgG.

Suppressive effect of intravenous immunoglobulin on peripheral blood neutrophil count in patients with idiopathic thrombocytopenic purpura.

PURPOSE: To determine the effect of intravenous immunoglobulin (IVIG) on neutrophil count, the authors studied patients with idiopathic thrombocytopenic purpura (ITP). PATIENTS AND METHODS: Thirty-one of 40 patients with ITP were treated with an IVIG regimen (400 mg/kg/daily for 5 days), while the other 9 were observed without any medications. Peripheral samples were examined during the clinical course. RESULTS: The absolute neutrophil count in 22 patients with no fever as a side effect decreased significantly by day 2 after the start of IVIG, but in most patients it began to increase soon after the last IVIG. There was also a significant difference between the decreased level of the absolute neutrophil count in patients with and without IVIG. However, re-administration of IVIG within 2 weeks did not significantly suppress the neutrophil count. In contrast, the neutrophil count increased in every patient with a fever as a side effect of IVIG. CONCLUSIONS: IVIG induced a decrease in peripheral blood neutrophil count in patients with ITP.

[Long-term remission in an acute monoblastic leukemia patient with down syndrome after cord blood transplantation].

A 4-year-old boy with Down syndrome (DS) was diagnosed as having acute monoblastic leukemia (AML-M5a). Leukemic cells were CD33+, CD56+ and CD4+, with t(9;11) on cytogenetic analysis and MLL gene rearrangement. After 2 courses of induction therapy using an AML 99-Down protocol failed to obtain complete remission, the patient received cord blood transplantation from an HLA-matched donor (CBT) following a conditioning regimen comprising total body irradiation and cyclophosphamide. Only cyclosporin A was used for graft-versus-host disease prophylaxis. Stem cell transplantation may not be indicated for AML patient with DS in first remission, who display a high rate of life-threatening and fatal toxicity on therapy. This patient remained well controlled in complete remission for 4 years, representing a rare case of DS with chemotherapy-resistant AML successfully treated with a CBT.

Anti-apoptotic effect of nerve growth factor is lost in congenital insensitivity to pain with anhidrosis (CIPA) B lymphocytes.

Congenital insensitivity to pain with anhidrosis (CIPA) is identified as a genetic disorder of mutations in the human TrkA known as high affinity receptor of nerve growth factor (NGF). NGF signal through TrkA promotes anti-apoptotic activity in hematopoietic cells including B lymphocytes. Here we studied the effect of NGF on anti-apoptotic activity by using human EBV-immortalized B lymphoblastoid cell lines (EB-LCLs) derived from a patient with CIPA and the associated carriers of CIPA. The TrkA(mt/mt) EB-LCL derived from the CIPA patient and the TrkA(wt/mt) EB-LCL derived from the carrier with the heterozygous TrkA mutation did not show any responses to NGF on anti-apoptotic activity. We concluded that this phenomenon is one of the pathogeneses of CIPA.

Reversible altered consciousness with brain atrophy caused by valproic acid.

A 5-year-old female developed alteration of consciousness during 3 days of long-term treatment with valproic acid for localization-related epilepsy. Computed tomography revealed cerebral atrophy, and electroencephalography presented slow background activity. Consciousness cleared only 12 hours after valproic acid was discontinued, and normal electroencephalography results were evident 1 week later. Cerebral atrophy was nonexistent 2 months later. This rapidly developing but reversible alteration of consciousness in parallel with brain atrophy is recognized as a rare idiosyncratic adverse effect of valproic acid.

Fusion of an AF4-related gene, LAF4, to MLL in childhood acute lymphoblastic leukemia with t(2;11)(q11;q23).

We showed that the LAF4 gene on 2q11.2-12 was fused to the MLL gene on 11q23 in a pediatric patient with CD10 positive acute lymphoblastic leukemia (ALL) having t(2;11)(q11;q23). The LAF4 gene, which encodes a lymphoid nuclear protein of 1227 amino acids with transactivation potential, is thought to have a role in early lymphoid development. The LAF4 protein was homologous to AF4 and AF5q31 proteins that are fused to MLL in infant early pre-B ALL and the breakpoint of LAF4 was located within the region homologous to the transactivation domain of AF4 and AF5q31. Expression of the 8.5-kb LAF4 transcript was detected in the adult heart, brain, and placenta and in the fetal brain. LAF4 expression was found to be higher in ALL cell lines than in AML and Epstein-Barr virus-transformed B-lymphocyte cell lines. These findings suggest that LAF4, AF4 and AF5q31 might define a new family particularly involved in the pathogenesis of 11q23-associated ALL.

[Lineage switch on recurrence from minimally differentiated acute leukemia (M0) to acute megakaryocytic leukemia (M7)].

Phenotypic switch in acute leukemia is a rare phenomenon. We report on a female infant with minimally differentiated acute leukemia (M 0) which underwent a lineage switch on relapse. In March 1997, a 1-year-8-month old girl was admitted to our hospital with a high-grade fever and generalized purpura. Bone marrow showed 84% blasts. The blasts were negative for peroxidase, periodic acid-Schiff and alpha-naphthyl butyrate esterase. Immunophenotypic analyses of the blast cells were positive for CD 13, CD 33 antigens, as well as CD 34. Lymphoid markers all were negative. Though some blasts morphologically demonstrated cytoplasmic blebs, CD 41 was negative and ultrastructural platelet peroxidase was absent. Based on these hematological features, the patient was diagnosed as having AML-M 0. She was treated according to the Children's Cancer and Leukemia Study Group schedule and a complete remission was achieved 1.5 months after starting induction therapy. However, she relapsed in spite of continued chemotherapy in July 1997, when the cytomorphological pattern changed and the patient was diagnosed both morphologically and immunologically as having M 7. Electron microscopy revealed platelet peroxidase (+) and CD 41 (+). Cytogenetic studies on relapse demonstrated inv(3) (q 21 p 25). We attempted aggressive reinduction therapy, but without effect. The patient simultaneously developed severe pneumonia and died in February, 1998. A lineage switch on relapse and resistance to chemotherapy may be associated with the occurrence of genetic aberration.

X-linked thrombocytopenia in a girl.

We report X-linked thrombocytopenia (XLT) in a 6-year-old girl with petechiae and thrombocytopenia from the age of 3 months. Her 2-year-old brother was also diagnosed with XLT. The Wiskott-Aldrich syndrome protein (WASP) gene was detected as a replacement of +5th G to Aon intron 6 using sequence analysis, and the WASP expression levels in this patient were one-third those of a healthy control. The X-inactivation analysis of the patients lymphocytes showed a random pattern of X-chromosome inactivation. To our knowledge, this is the first confirmed report of XLT in a female.

Ultrastructural and cytochemical characterization of human cord blood cells.

As part of a study to identify the characteristics of cord blood cells, we examined their morphological features by electron microscopy. Additionally, we cultured CD34-positive cells derived from cord blood and from bone marrow to perform morphological observations, as well as cytochemical examinations following the peroxidase reaction. Compared with normal peripheral blood cells, cord blood cells frequently showed immature morphology and a unique ultrastructure, such as nuclear pockets in neutrophils, several crystalloids in a single eosinophilic granule, and deformed nuclei in lymphocytes. In contrast to bone marrow cells, cord blood cells yielded a large number of cells of immature myelo-monocytic lineages in cell culture, and demonstrated a weaker peroxidase reaction. We identified that cord blood cells were different from normal peripheral blood cells and bone marrow cells, confirming the functional differences that were previously assumed.

Congenital bilateral perisylvian syndrome associated with congenital constriction band syndrome.

We report a 7-year-old boy with congenital bilateral perisylvian syndrome and congenital constriction band syndrome. The former is a congenital neurologic syndrome characterized by pseudobulbar palsy, mental retardation, epilepsy, and bilateral perisylvian polymicrogyria The latter is a malformative disorder with digital ring constrictions and amputations, probably caused by early amnion rupture resulting in entanglement of fetal parts by amniotic strands. We believe that the combination of these two malfornative disorders was not coincidental; instead, fetal circulatory disturbance related to chronic abruptio placentae could account for this combination.

Burkitt lymphoma associated with large gastric folds, pancreatic involvement, and biliary tract obstruction.

Large gastric folds in adults are seen in many benign and malignant conditions, but they are rare in children with malignant diseases such as non-Hodgkin lymphoma. The authors report a patient with non-Hodgkin lymphoma who had large gastric folds and jaundice as the initial symptoms. A 14-year-old boy was referred to the authors' hospital with upper abdominal pain and jaundice. A standard barium upper gastrointestinal series showed large gastric folds in the entire stomach. Magnetic resonance imaging showed a typical diffuse infiltrating type of pancreatic lymphoma. Because complete bilateral lower limb paralysis developed as a result of the epidural soft tissue mass, laminectomy and tumor resection were performed and a diagnosis of disseminated Burkitt lymphoma was established. After completing 6 months of chemotherapy, the patient has been disease-free without neurologic complications for 2.5 years.