A Novel AICDA Splice-Site Mutation in Two Siblings with HIGM2 Permits Somatic Hypermutation but Abrogates Mutational Targeting.

Hyper-IgM syndrome type 2 (HIGM2) is a B cell intrinsic primary immunodeficiency caused by mutations in AICDA encoding activation-induced cytidine deaminase (AID) which impair immunoglobulin class switch recombination (CSR) and somatic hypermutation (SHM). Whereas autosomal-recessive AID-deficiency (AR-AID) affects both CSR and SHM, the autosomal-dominant form (AD-AID) due to C-terminal heterozygous variants completely abolishes CSR but only partially affects SHM. AR-AID patients display enhanced germinal center (GC) reactions and autoimmune manifestations, which are not present in AD-AID, suggesting that SHM but not CSR regulates GC reactions and peripheral B cell tolerance. Herein, we describe two siblings with HIGM2 due to a novel homozygous AICDA mutation (c.428-1G > T) which disrupts the splice acceptor site of exon 4 and results in the sole expression of a truncated AID variant that lacks 10 highly conserved amino acids encoded by exon 4 (AID-ΔE4a). AID-ΔE4a patients suffered from defective CSR and enhanced GC reactions and were therefore indistinguishable from other AR-AID patients. However, the AID-ΔE4a variant only partially affected SHM as observed in AD-AID patients. In addition, AID-ΔE4a but not AD-AID patients revealed impaired targeting of mutational hotspot motives and distorted mutational patterns. Hence, qualitative defects in AID function and altered SHM rather than global decreased SHM activity may account for the disease phenotype in these patients.

CDK5RAP2 expression during murine and human brain development correlates with pathology in primary autosomal recessive microcephaly.

Homozygous mutations in the cyclin-dependent kinase-5 regulatory subunit-associated protein 2 gene CDK5RAP2 cause primary autosomal recessive microcephaly (MCPH). MCPH is characterized by a pronounced reduction of brain volume, particularly of the cerebral cortex, and mental retardation. Though it is a rare developmental disorder, MCPH has moved into the spotlight of neuroscience because of its proposed central role in stem-cell biology and brain development. Investigation of the neural basis of genetically defined MCPH has been limited to animal studies and neuroimaging of affected patients as no neuropathological studies have been published. In the present study, we depict the spatiotemporal expression of CDK5RAP2 in the developing brain of mouse and human. We found intriguing concordance between regions of high CDK5RAP2 expression in the mouse and sites of pathology suggested by neuroimaging studies in humans and mouse. Our findings in human tissue confirm those in mouse tissues, underlining the function of CDK5RAP2 in cell proliferation and arguing for a conserved role of this protein in the development of the mammalian cerebral cortex.

Somatostatin receptor subtype 2 (sst2) is a potential prognostic marker and a therapeutic target in medulloblastoma.

INTRODUCTION: Neuroectodermal tumors in general demonstrate high and dense expression of the somatostatin receptor subtype 2 (sst2). It controls proliferation of both normal and neoplastic cells. sst2 has thus been suggested as a therapeutic target and prognostic marker for certain malignancies. METHODS: To assess global expression patterns of sst 2 mRNA, we evaluated normal (n = 353) and tumor tissues (n = 340) derived from previously published gene expression profiling studies. These analyses demonstrated specific upregulation of sst 2 mRNA in medulloblastoma (p < 0.001). sst2 protein was investigated by immunohistochemistry in two independent cohorts. RESULTS: Correlation of sst2 protein expression with clinicopathological variables revealed significantly higher levels in medulloblastoma (p < 0.05) compared with CNS-PNET, ependymoma, or pilocytic astrocytoma. The non-SHH medulloblastoma subgroup tumors showed particularly high expression of sst2, when compared to other tumors and normal tissues. Furthermore, we detected a significant survival benefit in children with tumors exhibiting high sst2 expression (p = 0.02) in this screening set. A similar trend was observed in a validation cohort including 240 independent medulloblastoma samples. CONCLUSION: sst2 is highly expressed in medulloblastoma and deserves further evaluation in the setting of prospective trials, given its potential utility as a prognostic marker and a therapeutic target.

Leptomeningeal neurons are a common finding in infants and are increased in sudden infant death syndrome.

Developmental abnormalities of the brain, in particular, the brainstem potentially affecting centers for breathing, circulation and sleep regulation, are thought to be involved in the etiology of sudden infant death syndrome (SIDS). In order to investigate whether leptomeningeal neurons could serve as morphological indicators for a developmental failure or retardation in cerebral maturation, we evaluated the density of isolated leptomeningeal neurons (without associated glia) in 15 brain regions of 24 SIDS and 8 control cases, representing part of the German Study on sudden infant death. Leptomeningeal neurons were encountered in 79% of SIDS and 68% of control cases. More leptomeningeal neurons in SIDS versus control cases were found in lower pons (p = 0.002), upper pons (p = 0.016), cerebellar hemispheres (p = 0.012), lower medulla oblongata (p = 0.039), and temporal lobe (p = 0.041). Summarizing the data according to gross anatomical region of origin (i.e., brainstem, cerebellum or cerebrum), higher numbers of leptomeningeal neurons in SIDS cases were only found in the brainstem (p = 0.006 vs. 0.13 and 0.19, respectively). Our data show that single leptomeningeal neurons are present in most normal infantile brains. The age-dependent increase of leptomeningeal neurons among SIDS cases may either (a) represent a delayed maturation or retardation, i.e., a later or slower reduction of neurons or a delayed peak in occurrence (shift toward an older age), or (b) may be interpreted as a generally increased occurrence of leptomeningeal neurons among SIDS cases as a result of a diffuse developmental abnormality during central nervous system maturation.

Primary pontomedullary germinoma in a 12 year old boy.

Primary intracranial germinomas are rare tumors, accounting for approximately 1-4% of all intracranial tumors. Intracranial germinomas are more commonly found in the suprasellar and pineal midline structures of the brain. Brainstem and posterior fossa germinomas are rarer still, with few reported cases in the literature, and little discussion of their presentation, management and clinical outcome. A unique case of pontomedullary germinoma, diagnosed in a 12-year-old boy, is described. Only six previous cases of lower brainstem germinoma have been reported, with varying modes of presentation and a lack of definitive management guidelines. Of these, all occurred in either females or a patient with Klinefelter's syndrome. We report the first case of a lower brainstem germinoma in a male without known genetic abnormality. Tumor remission was achieved with partial surgical resection, chemotherapy and radiotherapy.

Prognostic implications of atypical histologic features in choroid plexus papilloma.

The prognostic significance of atypical histologic features in choroid plexus tumors remains uncertain. Therefore, a series of 164 choroid plexus tumors was evaluated for the presence of atypical histologic features, including mitotic activity, increased cellularity, nuclear pleomorphism, blurring of papillary growth pattern, and necrosis. The impact of histopathologic and clinical features on the probability of recurrence and survival was investigated. Twenty-four tumors displaying frank signs of malignancy were diagnosed as choroid plexus carcinoma according to World Health Organization criteria. Of 124 choroid plexus papillomas that had not received adjuvant treatment, 46 tumors (37%) displayed at least one atypical feature, including increased cellularity (n = 25 [20%]), mitotic activity (> or =2 mitoses per 10 high-power fields; n = 19 [15%]), nuclear pleomorphism (n = 16 [13%]), solid growth (n = 15 [12%]), and necrosis (n = 5 [4%]). Only one tumor-related death, but 10 recurrences, were observed on a mean observation time of 58 months. On univariate analysis, incomplete surgical resection (p = 0.03) and mitotic activity (p < 0.001) were the only clinicopathologic factors associated with recurrence. Using a multivariate model, an independent effect of mitotic activity on the probability of recurrence could be confirmed (p = 0.001). Because mitotic activity is the sole atypical histologic feature independently associated with recurrence, we propose to define atypical choroid plexus papilloma by mitotic activity (> or =2 mitoses per 10 high-power fields) corresponding to World Health Organization grade II, thus adjoining other intermediate tumor entities associated with increased mitotic activity such as atypical meningioma. Close follow up of patients harboring atypical choroid plexus papillomas may be warranted.

Identification of novel diagnostic markers for choroid plexus tumors: a microarray-based approach.

To identify specific markers for the diagnosis of choroid plexus tumors, gene expression profiles of choroid plexus epithelial cells (n = 8) and ependymal cells (n = 6) microdissected from human autopsy brains as well as choroid plexus papilloma tissue were investigated using DNA microarrays. Protein expression of genes overexpressed in choroid plexus was evaluated in normal choroid plexus, choroid plexus papilloma, choroid plexus carcinoma, other primary brain tumors, and cerebral metastases. Forty-six genes found to be overexpressed in normal choroid plexus epithelial cells were also present in choroid plexus papilloma. Among those, 11 were further analyzed by immunohistochemistry. Expression of inward rectifier potassium channel Kir7.1 was confirmed in normal choroid plexus (34 of 35), choroid plexus papilloma (12 of 18), and choroid plexus carcinoma (5 of 5) but was not found in 100 other primary brain tumors and cerebral metastases. Similarly, stanniocalcin-1 stained normal choroid plexus (32 of 35), choroid plexus papilloma (16 of 18), and choroid plexus carcinoma (3 of 5), whereas staining was seen in only 2 of 100 other primary brain tumors and cerebral metastases. Transthyretin stained choroid plexus (33 of 35), choroid plexus papilloma (14 of 18), and plexus carcinoma (2 of 5), but its specificity was significantly lower. Antibodies directed against coagulation factor V, glutathione peroxidase 3, pigment epithelium derived factor, serotonin receptor 5-HTR2C, lumican, fibulin-1, plastin-1, and cytokeratin 18 revealed varying degrees of specificity and sensitivity. Our data suggest that antibodies directed against Kir7.1 and stanniocalcin-1 might serve as sensitive and specific diagnostic markers for choroid plexus tumors.

Cellular and reticular variants of hemangioblastoma differ in their cytogenetic profiles.

Capillary hemangioblastomas of the central nervous system are benign tumors and occur either sporadically or as a manifestation of von Hippel-Lindau disease. A rarer cellular and a more common reticular variant can be distinguished on the basis of the abundance of the stromal cell component, with the cellular variant being significantly associated with a greater probability of recurrence. To investigate whether these subtypes differ in their cytogenetic profile, a comparative genomic hybridization analysis of 10 cellular and 10 reticular hemangioblastomas was undertaken. Comparative genomic hybridization revealed DNA copy number changes in 14 of 20 cases (8 of 10 cellular and 6 of 10 reticular hemangioblastomas). The most common changes overall were losses of chromosomes 19 (35%), 6 (30%), and 22q (15%), whereas loss of 3 and gain of 4 were encountered in one case each (5%). The cellular variant showed losses of chromosomes 6 (60%), 22q and 19 (20% each), as well as gain of 4 (10%), whereas the reticular variant presented with losses of chromosomes 19 (50%), 22q and 3 (10% each). Loss of chromosome 6 was significantly associated with the cellular subtype (P < .005), whereas loss of 19/19p was found more frequently in the reticular variant, albeit not significantly (P = .16). In conclusion, our data may point toward different genetic pathways in the pathogenesis of the 2 histologic subtypes of capillary hemangioblastoma.

Somatostatin receptor subtype 2 is expressed by supratentorial primitive neuroectodermal tumors of childhood and can be targeted for somatostatin receptor imaging.

PURPOSE: Although gliomas predominate among central nervous system (CNS) neoplasms in adulthood, embryonal tumors are the most common malignant brain tumors in children. Despite novel treatment approaches, including improved radiotherapy and high-dose chemotherapy, survival rates remain unsatisfactory. The timely diagnosis of residual or recurrent embryonal CNS tumors and thus the earliest possible time point for intervention is often hampered by inaccuracies of conventional imaging techniques. Novel and refined imaging methodologies are urgently needed. EXPERIMENTAL DESIGN: We have previously demonstrated the use of somatostatin receptor imaging (SRI) in the diagnosis of recurrent and residual medulloblastomas. Here, we evaluated somatostatin receptor type 2 (sst(2)) expression using an antibody in an array of CNS tumors of childhood. Eight high-grade gliomas, 4 atypical teratoid/rhabdoid tumors, 7 supratentorial primitive neuroectodermal tumors (stPNET), 1 medulloepithelioma (ME), and 8 ependymomas were screened. Tumors positive in vitro were additionally analyzed in vivo using SRI. RESULTS: Abundant expression of somatostatin receptor type 2 in stPNET, a ME, and ependymomas warranted in vivo imaging of 7 stPNET, 1 rhabdomyosarcoma, 3 ependymomas, 1 ME, and 1 glioblastoma. Although SRI was positive in 6/7 stPNET, 1 rhabdomyosarcoma, and 1 ME, none of the ependymomas nor the glioblastoma could be imaged using SRI. In selected cases SRI was more sensitive in the detection of relapse than conventional imaging by magnetic resonance imaging and computed tomography. CONCLUSIONS: SRI should be considered in the evaluation of residual or recurrent embryonal CNS tumors, especially stPNET. The strengths of SRI lie in the differentiation of reactive tissue changes versus residual or recurrent tumor, the detection of small lesions, and possibly in the distinction of stPNET from gliomas.

Mature teratoma of the temporal bone in 3.5-month-old baby girl.

Mature teratoma is a benign germ cell tumor rarely located in the temporal bone. We are reporting a case of a mature teratoma of the temporal bone in a healthy borne 3.5-month-old baby girl with a 2-day suggestive history of otitis media and polypoidal mass expulsing from the external auditory canal of the left ear. A definitive diagnosis is made after complete excision and histological examination of the tissue. Total surgical excision of the tumor is the treatment of choice.

Prognosis-related molecular markers in pediatric central nervous system tumors.

In the wake of recent progress in understanding the genetic pathways involved in the development of brain tumors, a major goal is to correlate molecular data with clinical outcome, survival, and response to treatment modalities. This is of particular importance among the pediatric population. Reliable prognostic factors could potentially permit a tailoring of therapy in that only patients with the most aggressive tumors would receive the most intense treatments. A survey of publications about prognosis-related molecular features among pediatric brain tumors revealed 74 series, of which 46 presented statistically significant outcome-associated parameters as defined by a p value <0.05. Most investigations revealing significant prognosis-related features were performed on medulloblastomas (34 publications), followed by astrocytic tumors (6 publications) and ependymomas (5 publications). Promising approaches and molecular markers include gene expression profiles, DNA ploidy, loss of heterozygosity and chromosomal aberrations as detected by CGH and FISH (1q, 17p, 17q), as well as oncogenes/ tumor suppressor genes and their proteins (TP53, PTEN, c-erbB2, N-myc, c-myc), growth factor and hormonal receptors (PDGFRA, VEGF, EGFR, HER2, HER4, ErbB-2, hTERT, TrkC), cell cycle genes (p27) and cell adhesion molecules, as well as factors potentially related to therapeutic resistance (multi-drug resistance, DNA topoisomerase IIalpha, metallothionein, P-glycoprotein, tenascin). This review discusses the predictive potential of molecular markers for clinical outcome and their influence on therapeutic decision-making among children with brain tumors.

Comparative genomic hybridization in central and peripheral nervous system tumors of childhood and adolescence.

Brain tumors amount to less than 2% of all malignant neoplasms. However, they account for approximately 20% of all childhood cancers and are the leading cause of cancer mortality among children. Recently, enormous progress has been achieved in the field of pediatric neuro-oncology regarding the classification of children's brain tumors, as well as the understanding of the genetic events involved in their pathogenesis; thus leading to an emerging role of molecular diagnostic approaches using novel tools. Comparative genomic hybridization (CGH) is a technique that has revolutionized cytogenetic knowledge in the past decade. It permits the detection of chromosomal copy number changes without the need for cell culturing and gives a global overview of chromosomal gains and losses throughout the whole genome of a tumor. A survey of CGH-related publications on central and peripheral nervous system tumors in the pediatric and adolescent population revealed 884 cases. The CNS tumor groups most frequently examined by CGH were embryonal tumors (268 cases/30.3%) and ependymomas (241/27.2%), followed by astrocytic (163/18.4%), peripheral nerve (73/8.2%), choroid plexus tumors (56/6.3%), and craniopharyngiomas (38/4.3%). The most common CNS tumor entities were medulloblastomas (238/26.9%), classic ependymomas (160/18.1%), anaplastic ependymomas (70/7.9%), pleomorphic xanthoastrocytomas (53/6.0%), and pilocytic astrocytomas (50/5.6%). This article provides a short review of the CGH technique and its pitfalls, summarizes the current CGH-related data on pediatric brain tumors and muses on the future of CGH.

Cerebral vascular and metabolic response to sustained systemic inflammation in ovine traumatic brain injury.

Traumatic brain injury (TBI) is frequently accompanied by a systemic inflammatory response secondary to multiple trauma, shock, or infections. This study investigated the impact of sustained systemic inflammation on cerebral hemodynamics and metabolism in ovine traumatic brain injury. Fifteen sheep were investigated for 14 hours. Head injury was induced with a nonpenetrating stunner in anesthetized, ventilated animals. One group (TBI/Endo, n = 6) subsequently received a continuous endotoxin infusion for 12 hours, whereas a second group (TBI, n = 6) received the carrier. Three instrumented animals served as sham controls. Head impact significantly increased intracranial pressure from 9 +/- 4 mm Hg to 21 +/- 15 mm Hg (TBI/Endo) and from 10 +/- 3 mm Hg to 24 +/- 19 mm Hg (TBI) (means +/- SD). Internal carotid blood flow increased and cerebral vascular resistance decreased (P < 0.05) during the hyperdynamic inflammatory response between 10 and 14 hours in the TBI/Endo group, whereas these parameters were at baseline level in the TBI group. Intracranial pressure remained unchanged during this period, but increased during hypercapnia. The CMRO2, PaCO2, and arterial hematocrit values were identical among the groups between 10 and 14 hours. It is concluded that chronic endotoxemia in ovine traumatic brain injury was associated with cerebral vasodilation uncoupled from global brain metabolism. Different mechanisms appear to induce cerebral vasodilation in response to inflammation and hypercapnia.

Amniotic air insufflation during minimally invasive fetoscopic fetal cardiac interventions is safe for the fetal brain in sheep.

BACKGROUND: Amniotic air insufflation during experimental fetoscopic fetal cardiac interventions greatly improves the visualization of intra-amniotic contents. The purpose of this study was to assess any histologically discernible effects from this approach on the fetal brain after short-term studies and long-term survival in sheep. METHODS: Thirty pregnant ewes between 80 and 110 days of gestation underwent amniotic air insufflation during various fetoscopic fetal cardiac interventions. After 18 short-term and 12 long-term studies, the brains of the operated fetuses and-if available-their unoperated siblings were examined for hemorrhage, embolism, infarctions, inflammatory changes, and abnormal cortical maturation. RESULTS: Amniotic air insufflation during minimally invasive fetoscopic fetal cardiac interventions did not result in any histologically discernible damage to the brain in short-term and long-term studies in any but 2 sibling sheep. In the 2 affected siblings, a small area of chronic cortical frontal lobe infarction was observed after long-term survival. CONCLUSIONS: Amniotic air insufflation during minimally invasive percutaneous fetoscopic fetal cardiac interventions is safe for the fetal brain and does not compromise maternal hemodynamics in sheep. These findings encourage further investigation of the role this technique might play during fetoscopic fetal cardiac interventions in humans.

Prognostic significance of amino acid transport imaging in patients with brain tumors.

OBJECTIVE: To evaluate the prognostic significance of presence, intensity, and extent of amino acid uptake in patients with suspected primary or recurrent brain tumors. METHODS: We retrospectively analyzed 181 consecutive studies of amino acid uptake using single-photon emission computed tomography and the amino acid l-[3-(123)I]iodo-alpha-methyltyrosine (IMT). In a blinded analysis, all studies were evaluated for presence, maximal uptake (IMT(max)), and extent (IMT(ext)) of focal tracer uptake. RESULTS: The most frequent tumors were 53 astrocytomas (World Health Organization Grade I-III), 41 glioblastomas, 16 metastases, 13 oligodendrogliomas (Grade II-III), and 10 medulloblastomas. The other patients exhibited various parenchymal tumors or nonneoplastic lesions. IMT uptake was present in 69% of the patients with IMT(max) ranging from 1.4 to 6.2. IMT(max) and IMT(ext) were significant predictors of survival in the whole group. When the group was divided according to primary versus recurrent tumor, only the primary tumors achieved a high level of significance (P < 0.01). When patients without any IMT uptake were excluded from the analysis, statistical significance for both IMT(max) and IMT(ext) was lost. Multiple regression analysis, including IMT(max), IMT(ext), age, and tumor grade, revealed only extent of IMT uptake as an independent predictor of prognosis. CONCLUSION: Absence of IMT uptake is a significant predictor of long-term survival in patients with suspected primary or recurrent brain tumors. Only the extent of a given lesion provided minor supplementary prognostic information as compared with histopathology and age. These findings suggest caution in relating high amino acid uptake values to poor prognosis, despite the capability of amino acid imaging to help determine the presence and extent of gliomas.

Raine syndrome: report of a family with three affected sibs and further delineation of the syndrome.

We describe three affected sibs with Raine syndrome born to a consanguineous Turkish couple. Clinical findings and post-mortem assessment are presented. We have added previously unreported meso and severe telebrachyphalangy and urogenital anomalies to the clinical spectrum. Appositional new bone formation may be mistaken for fractures and callus formation--both prenatally by ultrasound and postnatally in radiographs. Further research is required to detect the underlying metabolic and molecular defects of this autosomal recessive syndrome.

Glioblastoma with adipocyte-like tumor cell differentiation--histological and molecular features of a rare differentiation pattern.

We report on three adult patients with primary glioblastomas showing prominent adipocytic (lipomatous) differentiation, hence referred to as "glioblastomas with adipocyte-like tumor cell differentiation." Histologically, the tumors demonstrated typical features of glioblastoma but additionally contained areas consisting of glial fibrillary acidic protein (GFAP)-positive astrocytic tumor cells resembling adipocytes, that is, containing large intracellular lipid vacuoles. Comparative genomic hybridization (CGH) and focused molecular genetic analyses demonstrated gains of chromosomes 7, losses of chromosomes 9 and 10, as well as homozygous deletion of p14(ARF) in one of the tumors. The second tumor showed gains of chromosomes 3, 4, 8q and 12 as well as losses of chromosomes 10, 13, 15q, 19 and 22. In addition, this tumor carried homozygous deletions of CDKN2A and p14(ARF) as well as point mutations in the TP53 and PTEN genes. The third tumor also had a mutation in the PTEN gene. None of the tumors demonstrated EGFR, CDK4 or MDM2 amplification. Taken together, our results define a rare glioblastoma differentiation pattern and indicate that glioblastomas with adipocyte-like tumor cell differentiation share common molecular genetic features with other primary glioblastomas.

Cortical dysplasia: neuropathological aspects.

INTRODUCTION: Malformations of the cerebral cortex are a frequent cause of pharmacoresistant epilepsies and developmental disorders. EPIDEMIOLOGY AND GENETICS: The incidence of cortical dysplasias in epilepsy surgical series varies from 12 to 40% and focal cortical dysplasias (FCD) are one of the most common neuropathological findings in resection specimens from pediatric patients undergoing cortical resections for the treatment of refractory epilepsy. MACROSCOPY AND HISTOPATHOLOGY: Surgical specimens in FCD may appear normal macroscopically, but in some cases, widening of the cortex with poor demarcation from the underlying white matter is noted. In milder dysplasias, the main pathological feature is disorganization of the cortical architecture ("dislamination") with less striking neuronal and glial cytopathology. Histopathology shows an excess of neurons in layer I, including Cajal-Retzius cells, clusters of neurons, marginal glioneuronal heterotopias, and a persistent subpial granule cell layer. The hallmarks of FCD are disorganization of the laminar architecture and of the cytology of individual neurons. In many cases, layer I remains hypocellular and distinct from deeper laminae, but lower cortical layers may be ill-defined or broken up by the presence of many large and randomly located abnormal and cytomegalic neurons; depending on their morphology, referred to as "giant neurons," "immature neurons," or "dysmorphic neurons." The other pathognomonic cell type associated with FCD is the "balloon cell." These cells were originally considered to be of astrocytic lineage; however, there is evidence that they are in effect "balloon neurons." IMMUNOHISTOCHEMISTRY AND STRUCTURAL FINDINGS: Immunohistochemistry is not essential in making the diagnosis of FCD or microdysgenesis but allows further characterization of cell types.

Cytogenetic features of ependymoblastomas.

Ependymoblastomas are very rare and highly malignant embryonal tumours of the central nervous system with distinctive multilayered rosettes being the main histopathological feature. They are a diagnostically challenging subtype of embryonal tumours, whose genetic features are unknown. Primary ependymoblastomas from four children (one boy, three girls; mean age 24.8 months, range 4-41 months) were investigated by comparative genomic hybridisation (CGH), to our knowledge constituting the only cohort of this entity studied by cytogenetic means. DNA copy number changes were found in each case, consisting mainly of gains of chromosome 2 as well as losses of chromosomes 6q and 13q (75% each). The tumours showed between one and five aberrations with a mean of 3.25 DNA copy number changes per case, with gains being less frequent than losses (1.25 gains vs 2 losses per case). The youngest patient showed the least imbalances (one), whereas the oldest child presented with the most aberrations (five). Clinical follow-up data were available for three of the four patients. All three had died of their disease after a post-operative survival of 9 months (range 6-14 months). Our CGH data suggest that ependymoblastomas show distinct and fairly consistent chromosomal aberrations.

Chromosomal imbalances in clear cell ependymomas.

Clear cell ependymoma is a rare and diagnostically challenging subtype of ependymoma, whose genetic features are essentially unknown. We studied 13 clear cell ependymomas (five cases WHO grade II, eight cases WHO grade III) by comparative genomic hybridization (CGH). Chromosomal imbalances were found in 12/13 cases. The most common aberrations overall were +1q (38%), -9 (77%), -3 (31%), and -22q (23%). Clear cell ependymomas of WHO grade II were characterized by -9 (40%), whereas WHO grade III cases mainly showed +1q (63%), and +13q (25%), as well as -9 (100%), -3 (38%), and -22q (25%). In contrast to other ependymal tumors, clear cell ependymomas of WHO grade II showed fewer imbalances than WHO grade III samples (1.4 vs 3.5 per case). Although some of the implicated chromosomes have previously been shown to be involved in other ependymoma variants, the striking frequency of +1q, -9, and -3 suggests that aberrations differ between clear cell and other types of ependymomas, in particular, for loss of chromosome 9 which can be regarded as the molecular hallmark of clear cell ependymomas.