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PubMed2003

Visual-spatial performance deficits in children with neurofibromatosis type-1.

Neurofibromatosis type-1 (NF1) is a common genetic disorder associated with a variety of medical complications, cognitive impairments, and behavioral problems including a high incidence of Attention Deficit Hyperactivity Disorder (ADHD). The current study examined the hypotheses that deficits in visual-spatial/motor abilities enable one to discriminate and classify children with NF1 (n = 101) compared to control children (n = 37), beyond effects secondary to parent reported ADHD symptomology. Discriminant analysis showed a multivariate combination of visual-spatial/motor ability tests (Judgment of Line Orientation, Block Design subtest of the WISC-III, Recognition-Discrimination Test, Beery Visual-Motor Integration Test) to be a significant predictor of NF1 diagnostic status (P = 0.0000004; canonical R(2) = 0.2306). A significantly greater degree of ADHD behavior was found in the NF1 group, and a discriminant analysis using ADHD residualized visual-spatial motor scores indicated that the combination of tests continued to be a significant predictor of group membership after the level of ADHD behavior was controlled (P = 0.00002 and a canonical R(2) = 0.1818). This combination of tests proved to be a strong discriminator of NF1. It correctly identified 90% of individuals with the diagnosis, and may be useful to educators to provide assistance and alternatives to minimize the impact of learning problems in those with either known or suspected NF1.

Analysis of Variance↗
PubMed2003

Optic pathway gliomas in neurofibromatosis type 1: the effect of presenting symptoms on outcome.

Children with neurofibromatosis type 1 (NF1) may present with optic pathway gliomas (OPG) that can progress to visual loss or other neurologic symptoms. These tumors may become evident either as a result of patient signs or symptoms or as an incidental finding on "baseline" neuroimaging studies. In an attempt to determine if there were differences between symptomatic and asymptomatic children with OPG, a retrospective cohort study of ninety children with NF1 and OPG was performed using data from two large NF1 referral centers. Age at diagnosis, presenting symptoms, tumor location, associated features, and clinical response were assessed for children who were initially symptomatic from their OPG (n = 51) and compared to similar data of asymptomatic children whose tumors were incidentally discovered by MRI (n = 39). There were no differences in age at presentation, tumor location, NF1-associated symptoms, or clinical response between the groups. Initially symptomatic children were much more likely to require treatment (OR: 14.8, 95% CI [1.9-116.7]) than those with incidentally discovered, asymptomatic OPG. Although 36% of OPG were diagnosed in children over the age of 6 years, none received prior neuroimaging and only two children had previously normal eye examinations, suggesting that the vast majority of OPG in this group were longstanding, undiagnosed tumors. Based on these findings, we do not advocate "baseline" MRI in children with NF1, but strongly recommend that all children of the age 10 years and younger with NF1 have complete annual ophthalmologic evaluations.

Child↗
PubMed2004

Analysis of neurofibromatosis 1 (NF1) lesions by body segment.

Café-au-lait spots and neurofibromas are defining features of neurofibromatosis 1 (NF1), but they vary greatly in number, size, and clinical importance from patient to patient. The cause of this variability is unknown. We tested the hypotheses that development of these lesions is influenced by local or familial factors. The presence or absence of café-au-lait spots, cutaneous neurofibromas, and diffuse plexiform neurofibromas was recorded for each of 10 divisions of the body surface in 547 NF1 patients, including 117 affected individuals in 52 families. We used stratified Mantel-Haenszel tests to look for local associations between the presence of diffuse plexiform neurofibromas, cutaneous neurofibromas, and café-au-lait spots in individual body segments of NF1 patients. We used a random effects model to obtain intrafamilial correlation coefficients for the age-adjusted number of body divisions affected with each of the three lesions. No significant association was observed between the occurrence of cutaneous and diffuse plexiform neurofibromas, between café-au-lait spots and cutaneous neurofibromas, or between café-au-lait spots and plexiform neurofibromas in the same body segment. The correlation among relatives in the number of body segments affected with café-au-lait spots was 0.45 (95% confidence interval [CI] = 0.18-0.71), with cutaneous neurofibromas, 0.37 (95% CI = 0.15-0.55), and with plexiform neurofibromas, 0.35 (95% CI = 0.15-0.57). We conclude that the development of café-au-lait spots, cutaneous neurofibromas, and plexiform neurofibromas are spatially independent in NF1 patients but that the development of all three lesions is influenced by familial factors.

Adolescent↗
PubMed2003

Is Jaffe-Campanacci syndrome just a manifestation of neurofibromatosis type 1?

This article describes four patients with non-ossifying fibromas (NOFs) and multiple café-au-lait spots. Two of the patients were diagnosed with NOFs when they presented with a femur fracture. The other two patients were diagnosed with NOFs because of complaints of leg problems. In addition, axillary freckles and Lisch nodules were present in all four patients and multiple cutaneous neurofibromas in two patients. These four patients fulfilled the diagnostic criteria for neurofibromatosis type 1 (NF1) and also have been diagnosed with Jaffe-Campanacci syndrome. We propose that Jaffe-Campanacci syndrome is a manifestation of NF1 and suggest that patients with NF1 should have more rigorous radiographic screening of the long bones during early adolescence or adulthood to determine the presence or absence of NOFs. Appropriate intervention (exercise restriction, bracing, and/or surgery) might decrease the long-term disability associated with Jaffe-Campanacci syndrome.

Adolescent↗
PubMed2004

Non-neurogenic sarcomas in four children and young adults with neurofibromatosis type 1.

It is well known that children and young adults with neurofibromatosis type 1 (NF1) have a higher risk for non-neurogenic sarcomas than the general population, in addition to an increased risk for malignant peripheral nerve sheath tumor. When non-neurogenic sarcomas occur in early childhood, a subsequent malignant peripheral nerve sheath tumor can occur as a second malignant neoplasm, especially after alkylating agent chemotherapy and irradiation. This report includes the clinicopathologic features of non-neurogenic sarcomas and secondary malignant peripheral nerve sheath tumor in the context of four cases of NF1. The purpose is to emphasize that early diagnosis of NF1 and recognition of potential manifestations of non-neurogenic sarcomas are important for clinical care of these patients and their families.

Adolescent↗
PubMed2004

Longitudinal evolution of unidentified bright objects in children with neurofibromatosis-1.

Neurofibromatosis type-1 (NF-1) is the most common autosomal dominant disorder affecting the central nervous system. Magnetic resonance imaging (MRI) has revealed distinctive T2-weighted hyperintense foci (termed unidentified bright objects, UBOs) which appear to represent spongiform changes in the white matter. Cross-sectional and longitudinal analyses suggest that UBOs disappear over time; however, none of these studies have examined comprehensively these foci. We conducted a quantitative MRI longitudinal study of number of affected regions, number of UBOs per region, and UBO volume per region, in a sample of 12 children with NF-1. We applied semi-automatic morphometric methods and comprehensive statistical approaches, within a detailed anatomical parcellation framework. Our data demonstrate that, despite a similar UBO regional distribution (e.g., prevalent globus pallidus/internal capsule (GP/IC) location), UBO evolution was more complex than previously reported. In some subjects, the total number of UBO-occupied locations demonstrated a decrease between approximately ages 7 and 12 years, followed by a progressive increase during adolescence. This pattern was also found for UBO number and/or volume for all regions, with the exception of the cerebellar hemispheres. This REGIONAL distinction may reflect differences in white matter structure between affected long tract fiber bundles and that of cerebral and cerebellar myelinated fibers. The findings are also discussed in the context of previous MR and behavioral studies. We conclude that studies like the present one, in association with other MR modalities, are necessary to characterize more completely the nature and evolution of UBOs and their role in the cognitive phenotype of NF-1.

Adolescent↗
PubMed2004

Unusual features in a patient with neurofibromatosis type 1: multiple subcutaneous lipomas, a juvenile polyp in ascending colon, congenital intrahepatic portosystemic venous shunt, and horseshoe kidney.

We report a case that draws attention to a hitherto undescribed association of neurofibromatosis type 1 (NF1) with juvenile polyp, congenital intrahepatic portosystemic venous shunt, multiple subcutaneous lipomas, and horseshoe kidney. Our patient has fulfilled the National Institutes of Health consensus conference criteria for NF1 by having neurofibromas, axillary freckling, Lisch nodules, and café-au-lait spots. There is no family history of NF1 and his 7-year-old son has no stigmata of NF1. On the other hand, the patient's family had a presumably dominant inheritance of horseshoe kidney: the father, proband, sister, and son of the other sister had a horseshoe kidney. The patient was investigated for mutations in the NF1 gene and PTEN, but no germline mutations were detected. The differential diagnosis for such a collection of hamartomatous, cutaneous, and vascular disorders includes the Proteus, Bannayan-Riley-Ruvalcaba, and Cowden syndromes. None of these diagnoses was convincingly confirmed in this patient.

Abnormalities, Multiple↗
PubMed2005

Frequency of incidental intracranial aneurysms in neurofibromatosis type 1.

Neurofibromatosis type 1 (NF1) is often mentioned among the heritable connective tissue disorders associated with intracranial aneurysms, but the association has not been firmly established. We therefore reviewed a contemporary series of hospitalized patients with NF1, many of whom underwent brain magnetic resonance imaging (MRI). We identified patients with NF1 who were hospitalized at Cedars-Sinai Medical Center, Los Angeles, California, between January 1, 1997 and December 31, 2001 through the hospital's centralized medical records system using DRG codes. The mean age of the 39 patients was 30.4 years, and 22 patients had undergone MRI of the brain for the evaluation of symptoms due to the presence of central or peripheral nervous system tumors. Incidental intracranial aneurysms were detected in 2 (5%) of the 39 patients. Limiting the patient population to the 22 patients who had undergone MRI examination, the detection rate was 9%. This was significantly (P < 0.005) higher than the aneurysm detection rate in a control population (0/526 [0%]) of patients hospitalized for primary or secondary brain tumors, all of whom had undergone MRI examination. Our study suggests that patients with NF1 are at an increased risk of developing intracranial aneurysms.

Adolescent↗
PubMed2005

Simultaneous occurrence of neurofibromatosis type 1 and tuberous sclerosis in a young girl.

Neurofibromatosis type 1 and tuberous sclerosis are the two most common neurocutaneous disorders in humans. Both are transmitted as autosomal dominant conditions with a high rate of new mutations and similar clinical features. However, the two disorders have distinct and well-delineated genetic, biochemical, and physical findings. Simultaneous occurrence of these two conditions is rare. We report on a young girl who inherited both disorders, review similar cases reported in the world literature, and discuss possible implications of the presence of NF1 and TSC in the same individual.

Child, Preschool↗
PubMed2005

Neurofibromatosis von Recklinghausen type I phenotype and early onset of cancers in siblings compound heterozygous for mutations in MSH6.

We report on a nonconsanguineous family in which two siblings with cutaneous manifestations leading to a diagnosis of neurofibromatosis type 1 (NF1) developed CNS tumors at an early age. In addition, one of them developed a T-cell lymphoma. Neither parent had NF1. The mother was known to be heterozygous for a MSH6 mutation, and the father was found to be heterozygous for a different MSH6 mutation. Screening of MSH2, MLH1, MSH6, PMS1, PMS2, and MLH3 in the affected children disclosed that they both were compound heterozygote for the MSH6 mutations of their parents. Most recently, about a dozen other cases of inherited bi-allelic deficiency of mismatch repair (MMR) genes associated with early onset CNS tumors, hematologic malignancy, gastrointestinal neoplasia, café-au-lait spots, and other NF1 features have been reported. In the present study, we summarize the clinical findings of 27 individuals homozygous or compound heterozygous for an MMR gene mutation reported in the medical literature. We suggest that biparentally inherited mutations of one of the MMR genes should be considered in children with multiple café-au-lait spots who have early-onset CNS tumors, hematologic malignancies, or early onset gastrointestinal neoplasia.

Age of Onset↗
PubMed2006

Non-random associations and vascular fields in neurofibromatosis 1: a pathogenetic hypothesis.

Neurofibromatosis type 1 (NF1) is an autosomal dominant disorder with highly variable expression generally ascribed to random factors. However, evidence is presented for patterns suggesting non-stochastic processes as follows: (1) We have seen a MZ twin pair concordant for renal vascular hypertension, and another for unilateral ptosis. Other concordances have been reported, including both malformations and tumors, and combinations as well. (2) Four children were seen with a distinct ipsilateral association of glaucoma or iris anomaly, optic glioma, plexiform neurofibromas arising from the trigeminal nerve and its branches, and sphenoid dysplasia. Other cases in the literature support milder forms of this association. (3) We saw six children with apparent gynecomastia or premature thelarche without endocrine abnormalities. Tissue samples from four of these showed an unusual fibrous plexiform neurofibroma. Interestingly, five of the six cases were African Americans, and constitutional factors affecting fibrous reactions may also be involved here.A tentative hypothesis is presented suggesting vascular fields involving defined areas that can: (1) Support tumor growth. They would be the "soil" determining the ability and the extent of growth. There would, however, still be a need for a "second hit" tumor transformation. (2) Affect blood supply to organs, creating structural anomalies. NF1 involves a vasculopathy, and would predispose to vulnerabilities of such fields. Genetic factors could induce superimposed susceptibilities of specific fields, leading to twin concordances. "Hits" affecting specific fields would increase the likelihood of multiple abnormalities that could include both tumors and structural findings. Finally, tumors may follow the contours of existing fields. The breast is an area normally primed for growth, and the observation of clitoromegally secondary to tumor involvement suggests that such fields exist elsewhere.

Child↗
PubMed2006

Impact of neurofibromatosis 1 on Quality of Life: a cross-sectional study of 176 American cases.

Neurofibromatosis 1 (NF1), a genetic condition most commonly characterized by the presence of dermal neurofibromas and café au lait macules, has a significant impact on Quality of Life (QoL). There is a wide range of phenotypic variability, so that affected individuals may have either medically devastating or relatively mild manifestations that do not impact their daily lives. In this study, the SF-36 and Skindex questionnaires were used to quantitatively investigate the impact of severity and visibility on QoL in an American population. Participants were recruited primarily through advertisements distributed by The Children's Tumor Foundation (CTF). The majority participated by completing a mailed questionnaire in which they rated themselves using Ablon's visibility and Riccardi's severity scales, and then completed the SF-36 and Skindex questionnaires. Participants with NF1 reported a significant impact in all aspects of skin-disease-specific QoL, but the emotional aspect demonstrated the greatest effect. Participants with more visible signs of NF1 reported significantly greater overall effects on their skin-disease-specific QoL than those whose manifestations were more subtle. All domains of general health QoL were affected as well, especially in participants who reported having severe complications. Interestingly, greater visibility was not found to be associated with a significant decrease in general health QoL. These findings are consistent with those found in a French cohort, and demonstrate the utility of incorporating tools designed for use in both the general population and for patients with skin disease in examining the impact of NF1 on QoL.

Adult↗
PubMed2007

A girl with neurofibromatosis type 1, atypical autism and mosaic ring chromosome 17.

We describe a girl with neurofibromatosis type 1 (NF1), mild dysmorphic features, growth and mental retardation, autism, and mosaicism of ring chromosome 17 and chromosome 17 monosomy. The extent of genetic material deleted from the ring chromosome was determined using a combination of classical cytogenetics, fluorescence in situ hybridization (FISH) and multiplex ligation-dependent probe amplification (MLPA) to be 0.6-2.5 Mb on 17p, and up to about 10 Mb on 17q. Based on our observations and on a review of the literature we argue that in addition to a universal "ring syndrome" which is based on ring instability and is less specific for the chromosome involved, various ring chromosomes underlie their own characteristic phenotypes. We propose that the symptoms leading to the diagnosis of NF1 in our patient could be attributed to mosaic hemizygosity for the NF1 gene in some of her somatic cells. A similar mechanism or a direct involvement of respective disease genes in the aberration could possibly influence also the development of autism and other symptoms. We raise a question if the loss of one copy of chromosome 17 from a substantial fraction of somatic cells can have specific consequences also for future risks of the patient, for example, due to the mosaic hemizygosity for the BRCA1 and TP53 genes.

Autistic Disorder↗
PubMed2004

Utility and limitations of genetic disease databases in clinical genetics research: a neurofibromatosis 1 database example.

Databases that collect clinical information on patients with particular genetic diseases can be used to investigate the clinical history of a disorder, its genetics, and genotype-phenotype correlations. A database can also serve as a valuable source of patients for studies of disease pathogenesis, variability, or treatment. We review the strengths and limitations of genetic disease databases in the context of our experience with the National Neurofibromatosis Foundation International Database (NNFFID). Genetic disease databases have been developed by individual investigators, scientific consortia, patient support organizations, and commercial enterprises. Databases vary from simple lists of affected individuals to comprehensive collections of detailed clinical and genetic information. Data may be obtained from people who volunteer to be included, systematic assessments of patients seen at participating medical centers, or population-based registries. Access to information may be highly restricted or widely available. These variables all affect the possible uses and usefulness of the data for research. Technical aspects of data entry, organization, storage, and retrieval, as well as issues related to data quality, confidentiality, and security, help determine how well a system actually functions. We discuss examples of research that have been accomplished with genetic disease databases and make recommendations regarding the organization and operation of these resources.

Biomedical Research↗
PubMed2005

Natural history of neurofibromatosis 1-associated optic nerve glioma in mice.

Children affected with the inherited tumor predisposition syndrome, neurofibromatosis 1 (NF1), are prone to the development of low-grade astrocytic optic pathway tumors (optic pathway glioma [OPG]). Previously, we developed a model of NF1-associated astrocytoma (GFAPCre; Nf1(flox/mut) mice) in which mice develop optic nerve and chiasm glioma. To define the molecular pathogenesis of OPG, we used this mouse model to study the natural history of OPG formation using immunohistological and radiographic approaches. We observed that whereas astrocyte hyperplasia is present in the optic nerves associated with gross optic nerve thickening at 3 weeks of age, overt neoplastic changes were not seen until 2 months of age. Astrocyte proliferation was maximal between 3 weeks and 2 months of age, suggesting that the most rapid period of growth occurs early. Mouse OPG tumors were detected by magnetic resonance imaging at 2 months of age and exhibited contrast enhancement, as seen in human OPG. In addition, the mouse OPG tumors exhibited expression of proteins associated with astroglial progenitors, including nestin and brain lipid binding protein. Last, we observed neovascularization and microglial cell infiltration by 3 weeks of age before overt neoplastic transformation, suggesting that these cellular changes participate in the early stages of tumor formation.

Age Factors↗
PubMed1980

Diminished epidermal growth factor binding by neurofibromatosis fibroblasts.

Neurofibromatosis (NF) is an autosomal dominant disease characterized by growth abnormalities of epithelial, mesothelial, and endothelial elements. We recently reported abnormal growth and morphology of NF fibroblasts in tissue culture. Because epidermal growth factor (EGF) is known to stimulate the growth of fibroblasts in tissue culture, we studied the binding of commercial iodine 125-labeled EGF to age- and passage-matched confluent NF (N = 6) and normal (N = 4) fibroblasts. Fibroblasts were maintained at 37 degrees C for 2, 30, 60, 120, and 240 minutes in a medium in which the cells grow slowly (Dulbecco's Eagle medium) and one in which they grow normally (Ham's F-12 medium). Binding assays were done in both serum-free media according to accepted procedures. The EGF binding did not differ in the two media, and pooled data are presented. These data demonstrate no significant differences in the early binding of EGF to normal and NF fibroblasts (4,682 +/- 1,092 versus 3,441 +/- 826 cpm/10(6) cells; 20,000 cpm/ng; p > 0.15 at 30 minutes). At one hour, however, differences suggestive of abnormal EGF binding become apparent (12,495 +/- 1,989 versus 3,172 +/- 853 cpm/10(6) cells; 20,000 cpm/ng; p < 0.0025). We conclude that there may be a membrane defect in NF which is reflected by diminished EGF binding.

Cells, Cultured↗
PubMed1984

Hypothalamic mass and gigantism in neurofibromatosis: treatment with bromocriptine.

A child with neurofibromatosis exhibited gigantism and acromegaly in association with a hypothalamic mass lesion. Bromocriptine, 5 mg daily, reduced somatic growth rate and restored biochemical homeostasis but had no effect on tumor growth. Radiation therapy arrested tumor enlargement and stabilized deteriorating visual function.

Acromegaly↗
PubMed1985

Tissue culture studies of neurofibromatosis: effects of axolemmal fragments and cyclic adenosine 3',5'-monophosphate analogues on proliferation of Schwann-like and fibroblast-like neurofibroma cells.

Six dermal neurofibromas obtained from 5 patients with neurofibromatosis were dissociated and the cells were plated on polylysine-coated glass. Two principal cell types were observed in the cultures: elongated and bipolar Schwann-like cells (SLCs), and polymorphic flattened fibroblast-like cells (FLCs). Indirect immunofluorescence demonstrated that SLCs expressed surface laminin but not surface fibronectin; FLCs expressed surface fibronectin but were only weakly positive for surface laminin. Tritiated thymidine autoradiography demonstrated that cultured SLCs proliferated slowly (labeling index, 0.7 to 4.0%), whereas FLCs divided more rapidly (labeling index, 7.5 to 26.4%). Axolemmal fragments prepared from human or rat central nervous system specimens adhered to SLCs derived from each of the 6 neurofibromas, but not to FLCs. Axolemmal fragments induced a marked proliferative response of SLCs from 2 of the 6 neurofibromas but had no effect on proliferation of SLCs from the other 4 neurofibromas or FLCs from any of the 6 neurofibromas. In one patient from whom 2 neurofibromas were obtained, SLCs from one neurofibroma responded to axolemmal fragments, while SLCs from the other did not. Treatment of the cultures with 0.1 mM cyclic adenosine 3'5'-monophosphate (cAMP) analogue, 8-bromo cAMP, caused marked inhibition of proliferation of both SLCs and FLCs derived from all 6 neurofibromas. The same concentration of another cAMP analogue, dibutyryl cAMP, inhibited proliferation of SLCs but not of FLCs.

Adult↗