Dysembryoplastic neuroepithelial tumors in two children with neurofibromatosis type 1

Dysembryoplastic neuroepithelial tumors (DNT) occur mainly in children and are always clinically associated with intractable complex partial seizures. In the first report, which included 39 cases, the patients had no neurological deficit and no stigmata of phacomatosis. In contrast, we observed a DNT in 2 children with a neurofibromatosis type 1. The first patient developed intractable complex partial seizures at age 9 years and was operated at the age of 13 years. Neuroimaging study showed multifocal involvement with three separated lesions in the frontal, parietal and temporal lobes. The second patient was a 16-year-old boy with 5-year history of severe and refractory epilepsy. Magnetic resonance imaging identified a right temporal lesion and the patient underwent a right temporal lobectomy. This unusual association of two cases of DNT with neurofibromatosis type 1 raises the question of whether this association is specific or fortuitous.     

Loss of neurofibromatosis 1 (NF1) gene expression in NF1-associated pilocytic astrocytomas

The critical role of the neurofibromatosis 1 (NF1) gene as a tumour suppressor has been clearly demonstrated for malignancies arising in NF1 patients. However, little is known about the more common benign tumours, such as the pilocytic astrocytoma. Most NF1-associated astrocytomas are benign and clinically non-progressive, though aggressive tumours are occasionally encountered. In this study, eight pilocytic astrocytomas from six individuals affected with NF1 were analysed for NF1 expression. All eight tumours demonstrated loss of neurofibromin expression by immunohistochemistry, which was confirmed in one case using Western blot analysis. Microsatellite analysis showed loss of a single NF1 allele (LOH) in two of four NF1-associated tumours. These results demonstrate that, in contrast to sporadic astrocytomas, loss of NF1 expression is an important primary genetic event in the pathogenesis of NF1-associated pilocytic astrocytomas.     

Fatal glioblastoma multiforme in a patient with neurofibromatosis type I: the dilemma of systematic medical follow-up

Introduction Neurofibromatosis type I (NF1) is one of the most prevalent genetic diseases of the nervous system. Although the majority of NF1 patients are only mildly affected, the risk of developing malignancies is significantly increased in this population. Case report Here, we present a 9-year-old girl with clinical stigmata of NF1 and a rapidly evolving glioblastoma multiforme. Molecular genetic analysis uncovered a novel missense mutation in Exon 32 of the NF1 gene [c.6032C>A(p.Ala2011Glu)]. Discussion The girl’s death 3 days after diagnosis of the brain tumor exemplifies that NF1 still is a life-threatening disease despite its generally benign course in most patients. However, it remains questionable if a fatal course as reported here can be prevented by routine MRI screening.     

Glioblastoma in adults with neurofibromatosis type I: A report of two cases

Neurofibromatosis type I (NF1) is a familial tumor syndrome with an autosomal‐dominant inheritance. NF1‐associated tumors often include neurofibromas, malignant peripheral nerve sheath tumors and pilocytic astrocytomas of the optic nerve. The presentation of NF1 patients with glioblastoma is a rare occurrence, with only a handful of cases reported in the literature. We report two cases of glioblastomas occurring in adults with NF1 and briefly review the relevant literature.     

Evaluation of the prognostic potential of EGFL7 in pilocytic astrocytomas

Pilocytic astrocytoma (PA) is the most frequent solid neoplasm in childhood. It has a good 5‐year overall survival (90% in childhood and 52% in adults). However, up to 20% of patients experience residual tumor growth, recurrence, and death. Although the main genetic alteration of PAs, including KIAA1549:BRAF fusion, involves chromosome 7q34, we previously found frequent loss in chr9q34.3 locus in a small subset of these tumors. Among the genes present in this locus, EGFL7 is related to poor prognosis in several tumor types. In this study, we aimed to assess EGFL7 expression through immunohistochemistry, and to evaluate its prognostic value in a series of 64 clinically and molecularly well‐characterized pilocytic astrocytomas. We found high expression of EGFL7 in 71.9% of patients. Low EGFL7 expression was associated with older patients, the mean age mainly older than 11 years (P = 0.027). EGFL7 expression was not associated with presence of KIAA1549:BRAF fusion, BRAF mutation, FGFR1 mutation, nor FGFR1 duplication. Moreover, high EGFL7 expression was associated with high FGFR1 (P = 0.037) and 5′‐deoxy‐5′‐methyltioadenosine phosphorylase (MTAP) (P = 0.005) expression, and with unfavorable outcome of patients (P = 0.047). Multivariate analysis revealed low EGFL7 expression related to older patients and high EGFL7 expression related to retained expression of MTAP. In addition, we found a borderline significance of unfavorable outcome and high EGFL7 expression. Finally, EGFL7 expression was not associated with overall or event‐free survival of PA patients. Our findings point to EGFL7 expression as a novel candidate prognostic marker in PA, which should be further investigated.     

A case of Miller-Dieker syndrome in a family with neurofibromatosis type I

The Miller-Dieker syndrome (type I lissencephaly) is a neuronal migration disorder which is associated with microdeletions in the short arm of chromosome 17. Neurofibromatosis type I (NF1) is an autosomal dominant condition associated with mutations in the long arm of chromosome 17, and characterised by neurofibromas, café-au-lait spots and axillary freckling. The neonatal period for a female infant born at 39 weeks gestation by emergency Caesarean section was complicated by frequent epileptic seizures as well as hypotonia. A computed tomography scan revealed evidence of lissencephaly, and chromosomal analysis showed a microdeletion on the short arm of chromosome 17 (17p13.3), confirming the diagnosis as Miller-Dieker syndrome. The child died at the age of 4 years and examination of the brain confirmed lissencephaly with a thickened cortex, deficient white matter, and grey matter heteropias. The mother had café-au-lait spots, and axillary freckling. In addition, the mother’s and maternal grandmother’s genetic analysis showed identical mutations in the neurofibromatosis I gene on the long arm of chromosome 17, confirming the diagnosis of NF1. The child did not possess the mutation. This case illustrates a rare neuronal migration disorder appearing in a child from a family with a history of NF1. Received: 15 April 1999 / Revised, accepted: 30 July 1999     

Spontaneous regression of optic pathways gliomas in three patients with neurofibromatosis type I and critical review of the literature

Case reports The authors report their experience about three children (two girls, one boy; average age 1.6 years) with a spontaneous regression of optic gliomas. All of them had a previous diagnosis of neurofibromatosis type 1 (NF 1). None of them underwent surgery or biopsy nor received chemotherapy or radiotherapy. The complete regression was documented by MRI scans performed during a mean follow-up of 6.3 years.Literature review Moreover, the authors analyze the features of the 16 cases previously reported in English literature of spontaneously regressed optic gliomas with an overview of the different therapeutic strategies. The knowledge that this kind of tumor, particularly in young patients, may regress is important in the decision of the best therapeutic approach.     

Laryngeal plexiform schwannoma as first symptom in a patient with neurofibromatosis type 2

Neurofibromatosis type 2 (NF2) is an autosomal dominant disorder characterized by bilateral vestibular schwannomas. The initial symptoms of NF2 are usually hearing loss and tinnitus caused by vestibular schwannomas. Although other intracranial, spinal, or skin tumors also occur in NF2, laryngeal lesions are very rare. We report a rare case of NF2 with laryngeal plexiform schwannoma as first symptom. A 38-year-old man presented with a smooth-surfaced submucosal supraglottic mass. Two round masses in the left chest wall and left supraclavicular fossa were noted incidentally during investigation of the laryngeal mass. Magnetic resonance imaging (MRI) findings for these masses were identical to those of the laryngeal mass. No typical symptoms related to NF2 were identified. Histologically, the laryngeal tumor represented plexiform schwannoma. We thus considered that the two round masses in the left chest wall and left supraclavicular fossa might also represent plexiform schwannomas. NF2 was suspected, as a high incidence of multiple plexiform schwannomas has been suggested for patients with NF2. MRI of brain lesions demonstrated bilateral vestibular schwannomas and multiple meningiomas. Finally, NF2 with laryngeal plexiform schwannoma was diagnosed. Recognizing that multiple plexiform schwannomas could be associated with NF2 is important.     

Hippocampal sclerosis and associated focal cortical dysplasia-related epilepsy in neurofibromatosis type I

Neurofibromatosis type I (NF1) is a relatively common disorder associated with a range of neurologic sequelae. Refractory epilepsy occurs in 4–13% of NF1 patients. Hippocampal sclerosis and focal cortical dysplasia, both well-defined epilepsy-related entities, have been described in a subset of cases. To our knowledge, there has been only one other series describing coexistent focal cortical dysplasia and hippocampal sclerosis in the setting of NF1. We report two such patients who presented with intractable seizures requiring epilepsy surgery. Histologically, the hippocampal sclerosis specimen met criteria for the International League Against Epilepsy (ILAE) hippocampal sclerosis subtypes Ia and II respectively. The associated focal cortical dysplasia observed within the resected temporal lobe were both consistent with ILAE focal cortical dysplasia type IIIa (e.g. associated with a secondary lesion). Post-operatively, both patients had recurrence of habitual seizures, with one case continuing to have intractable seizures following two subsequent temporal lobectomies. Although hippocampal sclerosis association with focal cortical dysplasia is well document in epilepsy, it has been rarely described in the setting of neurofibromatosis type I. Although prior surgical series have shown good epilepsy surgery outcomes within neurofibromatosis type I, these two cases did not.     

Circle of Willis abnormalities in children with neurofibromatosis type 1

Background and purposeThe aim of the study was to assess anatomical variants and abnormalities in cerebral arteries on magnetic resonance angiography in 67 children with neurofibromatosis type 1 (NF1).Materials and methodsThe study included 67 children aged 9 months to 18 years (mean 6.6 years). Control group comprised 90 children aged 2–18 years (mean: 11.8 years). All patients were examined at 1.5 T scanner.ResultsWe found cerebral arteriopathy (moyamoya disease) in one child (1.5%) in the study group. No aneurysms were found. Twenty-nine NF1 children (43.3%) had arterial anatomical variants. In 13 of them, more than one variant was diagnosed (44.8% of group with variants, 19.4% of study group). In control group, 19 children (21.1%) had variants, including four children with more than one variant (21% of group with variants, 4.4% of control group). Arterial variants were more common in NF1 patients compared with control group (p = 0.026, binomial test for two proportions). Percentage of multiple variants was higher in study group than in control group, but this difference was not significant. Variants were more frequent on left side than on the right one (significant difference in control group; p = 0.022, McNemara test). In study group, the number of left-sided anomalies (25) was similar to that of right-sided ones (22). There was no correlation between gender and variants, unidentified bright objects and variants or between optic gliomas and variants.ConclusionsOccurrence of arterial variants in NF1 patients was twofold higher than in control group. Multiple variants were more frequent in the study group although the difference did not reach statistical significance. Features of cerebral arteriopathy were found in one child with NF1.     

Long-term functional outcome of surgical treatment of juvenile pilocytic astrocytoma of the cerebellum in children

Purpose  Increasing incidence of pediatric brain tumors and improving survival rates encouraged us to assess long-term functional outcome of patients with cerebellar juvenile pilocytic astrocytoma (JPA). Materials and methods  Our study encompassed 105 children treated since 1980–2005 and consisted in analysis of mailed, custom-designed questionnaires. Results  Mean follow-up time was 8.3 years. Sixty out of 104 patients presented permanent neurological deficits and 47/104 presented significant behavioral disorders. Eighty-nine children continued their education at primary, secondary or high school level. Most patients and their parents were satisfied with treatment outcome. Patients’ and parents’ notes were usually concordant. Conclusions  Long-term functional treatment outcome of cerebellar JPA is relatively favorable, in spite of permanent neurological deficits and emotional disorders in over half of the patients. Vermian tumors are associated with worse long-term functional outcome. Neurological deficits and emotional disorders do not preclude further education and independent functioning.     

Functional MRI of visual-spatial processing in neurofibromatosis, type I

Visual-spatial impairment and neuroanatomical abnormalities are considered hallmark features of neurofibromatosis, type I (NF-I). Numerous studies have demonstrated visual-spatial deficits in children with NF-I, but few relations between these deficits and neuroanatomical abnormalities have been identified. We compared the functional neuroanatomy of cerebral regions involved in the spatial transformation of alphanumeric stimuli in individuals with NF-I and healthy control participants using functional magnetic resonance imaging (fMRI). Given the prevalence of visual pathway abnormalities and visual-spatial deficits in NF-I, we hypothesized that less neuronal hemodynamic activity would be found in occipital and parietal cortices in this group compared with controls. However, NF-I participants relied to a greater degree than controls on posterior cortex (including occipital, parietal, and middle temporal cortices) relative to lateral and inferior frontal regions during visual-spatial analysis. This pattern was significantly related to their behavioral performance on the fMRI task, which in turn was also positively correlated with reading scores. These findings support evidence of frontal cortical anomalies in NF-I and may provide a pathophysiological basis for cognitive deficits in NF-I.     

Malignant intracerebral giant nerve sheath tumor in a 14-month-old girl with neurofibromatosis type 1: a case report

Introduction  Malignant intracerebral nerve sheath tumor (MINST) is extremely rare and the origin is still unclear. The authors present the clinical, radiological, and pathological features of a malignant intracerebral giant nerve sheath tumor. Case report  A giant tumor in the right frontotemporoparietal lobes causing a midline shift was detected in a 14-month-old girl who presented with developmental delay, vomiting, and lethargy. The physical examination was consistent with neurofibromatosis type 1 (NF-1). Subtotal resection was performed and the histopathological examination revealed the diagnosis of MINST. Discussion  There are only six cases of malignant intracerebral nerve sheath tumor in the literature. The presented case is the youngest and the occurrence of MINST in a 14-month-old girl may support the hypothesis of multipotent mesenchymal stem cell origin; however, the tumors which arise from multipotent mesenchymal stem cells may be seen in later stages of life. Another important feature of the presented case is the occurrence of MINST in NF-1. Conclusion  MINSTs are extremely rare tumors with unknown origin. The location, the degree, and the size of the tumor and the general condition of the patient are prognostic factors in MINSTs, like in other malignant tumors.     

Activity and participation in children with neurofibromatosis type 1

We describe activity and participation in children and youth with neurofibromatosis type 1 (NF1), and compared an intervention and control group after a strengthening program using the Pediatric Outcomes Data Collection Instrument (PODCI) and the Children's Assessment of Participation and Enjoyment (CAPE). Questionnaires were filled out by parents at baseline, 12-weeks, and 1-year. The intervention group performed a strengthening program twice a week for ten weeks, followed by a 9-month independent program. Thirty-six participants (18 control, 18 intervention) between the ages of 5- and 18-years (mean 10.6 years, SD 4.6 years) were enrolled, and 34 completed the 1-year assessment. There were significant differences between formal and informal participation (p < 0.0001) in baseline CAPE scores for the entire cohort. At 12 weeks, PODCI upper extremity function improved in intervention and decreased in controls (p = 0.040), while happiness declined in intervention and increased in control (p = 0.003). There were no significant differences between control and intervention groups in any of the CAPE or PODCI change scores from baseline to 1-year. Upper extremity function, sport and physical function, comfort/pain and happiness PODCI scores were lower than normative values. The NF1 cohort had low participation in formal active physical and skill-based activities. The companionship and location dimensions suggest participation occurs with family and other relatives in the home or a relative's home and reflects a pattern of social isolation from peers.     

Cerebral vasculopathy in a Chinese family with neurofibromatosis type I mutation

Neurofibromatosis type I (NF1) is a hereditary, autosomal dominant, neurocutaneous syndrome that is attributed to NF1 gene mutation. NF1 has been associated with scoliosis, macrocephaly, pseudoarthrosis, short stature, mental retardation, and malignancies. NF1-associated vasculopathy is an uncommon and easily-overlooked presentation. Examination of a Chinese family affected by NF1 combined with cerebral vessel stenosis and/or abnormality suggested a possible relationship between NF1 and vessel stenosis. To determine which NF1 gene mutation is associated with vascular lesions, particularly cerebral vessel stenosis, we examined one rare family with combined cerebral vessel lesions or maldevelopment. Vascular lesions were detected using transcranial Doppler sonography and digital subtraction angiography in family members. Next, denaturing high-performance liquid chromatography and sequencing were used to screen for NF1 gene mutations. The results revealed a nonsense mutation, c.541C>T, in the NF1 gene. This mutation truncated the NF1 protein by 2659 aminoacid residues at the C-terminus and co-segregated with all of the patients, but was not present in unaffected individuals in the family. Exceptionally, three novel mutations were identified in unaffected family members, but these did not affect the product of the NF1 gene. Thus the nonsense mutation, c.541C>T, located in the NF1 gene could constitute one genetic factor for cerebral vessel lesions.     

Pulmonary meningioma and neurinoma associated with multiple CNS tumours in a patient with neurofibromatosis type 2

Objective

Neurofibromatosis type 2 (NF2) is a common neurocutaneous disorder that exhibits an autosomal dominant inheritance, with a mutation at chromosome 22q12.2. Two forms can be distinguished: the Wishart-phenotype with an early and aggressive course and the Feiling–Gardner-phenotype with a less dramatic presentation. In general, patients present bilateral vestibular schwannomas, meningiomas and neurinomas of the central and peripheral nervous system as well as neurofibromas and gliomas. There is no reported case of pulmonary meningiomas and neurinomas associated with NF2 until now.

Patient and methods

Here, we present a 16-year-old girl with NF-2 associated to CNS and pulmonary tumours and we discuss the case in the backlight of the literature.

Results

The reported patient presented a de novo NF2 germline mutation (R341X) and displayed the Wishart-type of NF-2 since she is 11 years old, with a huge anaplastic biparietal falx meningioma and a tentorium meningioma and a tumour-associated parietal mass as well as hypacusis starting at the infant age of 3 years. Multiple cranial and spinal tumours with extra- and intramedullary localization were also found. Moreover, recurrent pulmonary tumours developed and were classified as benign meningiomas and a single neurinoma. No direct evidence concerning a relationship between the pulmonary and cerebral tumours could be drawn.

Conclusion

This rare case extends our knowledge of NF2 and also raises interesting questions about the pathogenesis of meningiomas outside the CNS.     

Brain gliomas,hydrocephalus and idiopathic aqueduct stenosis in children with neurofibromatosis type 1

PurposeTo evaluate the incidence and clinical importance of brain gliomas – optic pathway gliomas (OPGs) and especially gliomas outside the optic pathway (GOOP) for children with neurofibromatosis type 1 (NF1), additionally, to assess the causes of obstructive hydrocephalus in NF1 children with an emphasis on cases caused by idiopathic aqueduct stenosis.Subjects and methodsWe analysed data from 285 NF1 children followed up on our department from 1990 to 2010 by the same examination battery.ResultsWe have found OPGs in 77/285 (27%) children and GOOPs in 29/285 (10,2%) of NF1 children, of who 19 had OPG and GOOP together, so the total number of brain glioma was 87/285 (30,5%). GOOPs were significantly more often treated than OPGs (p > 0.01). OPGs contain clinically important subgroup of 14/285 (4.9%) spreading to hypothalamus. Spontaneous regression was documented in 4/285 (1.4%) gliomas and the same number of NF1 children died due to gliomas.Obstructive hydrocephalus was found in 22/285 (7.7%) patients and 14/22 cases were due to glioma. Idiopathic aqueduct stenosis caused hydrocephalus in 6/22 cases and was found in 2.1% of NF1 children. Two had other cause.ConclusionsThe total brain glioma number (OPGs and only GOOPs together) better reflected the overall brain tumour risk for NF1 children. However, GOOPs occur less frequently than OPGs, they are more clinically relevant. The obstructive hydrocephalus was severe and featuring frequent complication, especially those with GOOP. Idiopathic aqueduct stenosis shows an unpredictable cause of hydrocephalus in comparison with glioma and is another reason for careful neurologic follow up.