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PubMed1989

Experimental model of tumors associated with neurofibromatosis.

Four groups of animals, each composed of 22 pregnant Wistar rats, were used in this study. Single intraperitoneal (IP) injections of ethylnitrosourea (ENU) at a dose of 15 mg/kg body weight (BW) were given to the animals of two groups on days 15 and 21 of pregnancy, respectively. The progeny of a third group received by subcutaneous injection (SC) the same dose of ENU, 15 mg/kg BW, on day 1 postnatally. The descendants of the fourth group served as untreated controls. The most striking findings were observed in the progeny of the mothers treated on day 15 of pregnancy, in which group 64 of 180 descendants developed peripheral nervous system (PNS) tumors, 30% of which had plexiform pattern. One hundred fifteen of the 180 descendants developed central nervous system (CNS) gliomas, mainly oligodendrogliomas, and five animals presented with Wilms' tumors. No tumors of these types were observed in the untreated controls. Although descendants of mothers treated on day 21 of pregnancy had the highest number of PNS tumors (130 of 172 animals), only 21% of these tumors were plexiform; CNS gliomas were observed in 78 animals and Wilm's tumors in one animal. The lowest percentage of PNS tumors with plexiform pattern (16%) was found in the group of 157 descendants treated postnatally on day 1, in which 88 animals developed PNS tumors, 76 developed CNS gliomas, and no animals developed Wilms' tumors. The higher percentage of plexiform PNS tumors found in the descendants treated prenatally on day 15 of pregnancy was statistically significant (P less than 0.05) when compared with the percentage found in the group treated postnatally. This significance was also valid for the plexiform tumors that developed selectively from branches of the trigeminal nerves (of the PNS tumors from this location, 48% showed a plexiform pattern), but only in the progeny exposed to ENU on day 15 of pregnancy. This same progeny also had the highest numbers of CNS and Wilms' tumors. Because in humans, plexiform neurofibromas are considered to be the neoplastic markers of neurofibromatosis, and CNS gliomas as well as Wilms' tumors are associated with this disease, it is suggested that exposure to ENU on day 15 of pregnancy, under the experimental conditions described here, may offer a model for investigating tumors associated with neurofibromatosis, as well as aspects of the spontaneous, noninherited forms of this disease.

Animals↗
PubMed2000

Behavioral phenotype of neurofibromatosis, type 1.

Neurofibromatosis, type 1 (NF1) is a very common inherited disorder that was first described in the late 19th century. NF1 is associated with a myriad of behavioral manifestations in addition to its frequent and often severe medical and physical complications. Learning disability, cognitive impairment, emotional and psychosocial difficulties have been reported so frequently in neurofibromatosis that these are often considered hallmarks. This report briefly introduces the medical and physical characteristics of NF1. We then detail the behavioral manifestations of NF1 with additional discussion of possible etiologies for the high incidence of these behavioral difficulties. MRDD Research Reviews 2000;6:117-124.

Attention Deficit Disorder with Hyperactivity↗
PubMed1985

Neurofibromatosis and fragile-X syndrome in the same patient.

We report on an 11 1/2-year-old boy with neurofibromatosis and the fragile-X syndrome. Clinical manifestation of neurofibromatosis include multiple cafe-au-lait spots, axillary freckles, congenital glaucoma, relative macrocephaly, radiologic findings of overtubulation of the long bones, and precocious puberty. The fragile-X syndrome manifests itself as mental retardation with behavior problems, macro-orchidism, and specific cytogenetic findings. The boy has normal serum hormone levels, but a greatly elevated FSH on a first morning void, which contains the nocturnally secreted gonadotropins. This seems to be the first reported occurrence of the fragile-X syndrome with another inherited disease.

Child, Preschool↗
PubMed1991

Galactose metabolism and reproductive history in women with type 1 neurofibromatosis.

To explore a possible relationship between neurofibromatosis and abnormalities of galactose metabolism, we examined the activity and characteristics of red cell galactokinase and galactose-1-phosphate uridyl transferase in 14 white women with type 1 neurofibromatosis and in 28 control women. Women with NF1 had a significantly lower activity of galactokinase and were more likely to have the 3-band pattern on electrophoresis of their transferase enzyme known as the Duarte variant. In addition, we found that women with NF1 were more likely to have reproductive histories suggestive of hypogonadism, including irregular menses, infertility, ovarian cysts, and early menopause. We conclude that abnormalities of galactose metabolism may be linked to abnormalities of both germ cell and neural crest development.

Adult↗
PubMed1993

Autosomal dominant multiple café-au-lait spots and neurofibromatosis-1: evidence of non-linkage.

Multiple café-au-lait spots have been observed in successive generations of several families without any other manifestations of neurofibromatosis (NF) or any other systemic disorder. The café-au-lait spots in these families segregate as an autosomal dominant trait. The relationship (if any) between the gene for this trait and the NF-1 gene has previously been unknown. We describe a family with five individuals spanning four generations with dominantly inherited café-au-lait spots, without any other stigmata of NF-1. Linkage analysis with probes proximal, distal, and within the NF-1 gene indicate that the trait in this family is not linked to NF-1. We propose that this condition be called Familial Café-Au-Lait Spots (FCAL) to distinguish it from the neurofibromatosis syndromes.

Alleles↗
PubMed1993

Reproductive failure in a patient with neurofibromatosis-Noonan syndrome.

We report on a 39-year-old man with neurofibromatosis-Noonan syndrome and long-standing infertility. Comprehensive testing did not uncover any significant endocrine abnormalities, but the testicular seminiferous epithelium was found to be severely compromised. While the occasional association of neurofibromatosis with signs of Noonan syndrome has been reported, reproductive failure has not been previously described in this condition.

Adult↗
PubMed1994

Diffusion of information about neurofibromatosis type 1 DNA testing.

There is little information available as to how individuals with genetic disorders receive information about the availability of DNA tests and what effect this has on their utilization. The purpose of this study was to survey centers where some individuals with neurofibromatosis type 1 (NF 1) are cared for, to establish how this type of information was disseminated. In 1990 announcement of the availability of testing for familial NF 1 was published in a newsletter of the National Neurofibromatosis Foundation (NNFF) and sent to individuals with NF 1 or NF 2 and their families, professionals, and NF centers in North America. Two years later these centers were surveyed to determine whether they had notified their patients of test availability. Of the 46 responding centers, 65% indicated they had attempted to notify their patients. The majority (80%) notified patients on an individual basis in clinic. The rest did so either on an individual basis in the clinic or by telephone or by letter or by a combination of these. Based on a survey response rate of 56% and approximately 1,000 enquiries received by the NNFF from families and physicians, it is concluded that 1) factors other than knowledge of test availability determined whether DNA testing for NF 1 was utilized; 2) some centers used testing more frequently than others; 100% of the referrals came from 40% of the centers, with 15% of referrals coming from a single center; 3) a significant percentage (35%) of NF centers did not inform their patients that DNA testing was available.

DNA↗
PubMed1995

Clitoromegaly in neurofibromatosis.

Genitourinary neurofibromas are rare and clitoral involvement in neurofibromatosis (NF) has been reported infrequently. However, when it occurs, clitoromegaly is often the presenting sign. In many cases, it is congenital. In 236 families with type 1 neurofibromatosis (NF-1) evaluated through the USF Regional Genetics Program between January 1982 and September 1993, four patients had clitoral involvement. In three, involvement was limited to the clitoris. Biopsy/surgical excision in two of them showed a neurofibroma in one and non-specific hamartomatous soft tissue overgrowth in the other. In the fourth patient, the involvement was asymmetric and extended to the labia majora and mons pubis. Endocrine studies and chromosomes in all patients were normal; there was no exposure to androgens, progestins, or coumadin. There was no gestational history of maternal luteomas. Review of the literature documented 26 patients with NF and clitoral involvement. Clitoral involvement in NF-1 appears to be more common than previously reported and the differential diagnosis of ambiguous genitalia should include clitoromegaly due to NF. Pathogenesis of clitoral lesions appears similar to other lesions of NF. Biopsy of such lesions appears to be justified only when malignancy is suspected.

Child↗
PubMed2003

Different mutations in the NF1 gene are associated with Neurofibromatosis-Noonan syndrome (NFNS).

The association of the Noonan phenotype with neurofibromatosis type 1 (NF1) was first noted by Allanson et al. [Am J Med Genet 1985;21:457-462.] and 30 further cases have subsequently been reported. It has been suggested that this phenotype is more common than previously appreciated, as Colley et al. [Clin Genet 1996;49:59-64.] examined 94 sequentially identified patients with NF1 from their genetic register and found Noonan features in 12. A 3-bp deletion of exon 17 of the NF1 neurofibromin gene was described in one family by Carey et al. [Proc Greenwood Genet Center 1997;17:52-53]. However, it remains unclear whether Neurofibromatosis-Noonan syndrome (NFNS) represents a form of NF1 (with mutations in the NF1 neurofibromin gene) or a separate syndrome. We have used a new, rapid sequence analysis technique-comparative sequence analysis (CSA)-to examine the NF1 gene in six patients with NFNS. None of the six patients had the previously identified mutation, nor did we observe other mutations within this exon. However, two other mutations were found: in exon 25, a 3-bp deletion 4312 del GAA, and in exon 23-2, a 2-bp insertion 4095 ins TG. The PTPN11 gene, now known to cause over 50% of Noonan syndrome was also examined in four cases of NFNS, and no mutations were found. These results show that NFNS can in some cases result from different mutations in the NF1 gene and therefore represents a variant form of NF1.

Adolescent↗
PubMed2004

Outcomes of systematic screening for optic pathway tumors in children with Neurofibromatosis Type 1.

Optic pathway tumors (OPT) occur in about 15% of individuals with Neurofibromatosis Type 1 (NF1) and may effect substantial visual loss. Because their growth is not predictable at the time of discovery, neuroimaging for OPT in asymptomatic NF1 patients remains controversial. We evaluated the outcomes of systematic screening by both MRI and ophthalmic examinations for OPT in young children with NF1 seen at multi-disciplinary clinics for Neurofibromatosis and Genetics at one institution between 1996 and 2001. We report on 84 children who presented with NF1 under age 6 years, of whom 13 children presented with either known OPT or abnormal MRI findings and 11 children had OPTs identified by neuroimaging, including two children with abnormal eye examinations at presentation (one with strabismus and one with optic atrophy). Nine OPTs were detected in asymptomatic subjects with normal ophthalmic examinations. Three children with chiasmal lesions enlarging on subsequent MRI were treated with carboplatin and vincristine. After treatment, the vision in each involved eye was intact. In contrast, the 13 children with OPT diagnosed outside of screening guidelines included five children with substantial visual loss. Our observations suggest that early recognition of NF1 promotes appropriate surveillance and allows early intervention to reduce complications of OPT. This analysis supports prospective studies to compare the outcomes of systematic screening with neuroimaging to screening with ophthalmic examinations alone in children with NF1.

Child↗
PubMed2005

Subcutaneous neurofibromas are associated with mortality in neurofibromatosis 1: a cohort study of 703 patients.

Neurofibromatosis 1 (NF1) is a common genetic disorder with an autosomal dominant mode of inheritance, an increased morbidity and mortality, and a shorter lifespan. Although the disease is fully penetrant by the age of 8, the variability in symptoms and complications is high, even among members of the same family. The aim of this study was to identify easily recognizable clinical features that may be associated with mortality in a cohort of patients affected with NF1. We used prospectively collected data from the Neurofibromatosis Institute Database (NFID) and included in our analysis 703 patients who fulfilled the NIH diagnostic criteria for NF1. Clinical, especially dermatological features were tested as potential factors associated with mortality. Among the patients, 405 (57.6%) were children and 298 (42.4%) were adults. The mean follow-up was 2.4 years (median = 0.98, range: 0-15.3 years). Forty patients died during follow-up, mostly due to tumor development such as sarcoma (n = 18). In the adult population, subcutaneous neurofibromas (odds ratio [OR] = 3.6, 95% confidence interval (CI): [1.2-11.3], P = 0.02) and male gender (OR = 5.6, [1.5-20.9], P = 0.004) were independent predictors of mortality after adjustment for age. Among children, the presence of facial plexiform neurofibromas and pruritus were significantly associated with mortality in univariate analysis. Our study describes independent risk factors of mortality in a large cohort of adult and pediatric patients. Close follow-up should be obtained for patients presenting with subcutaneous neurofibromas.

Adolescent↗
PubMed2005

Neurofibromatosis-Noonan syndrome: molecular evidence of the concurrence of both disorders in a patient.

Noonan syndrome (NS) is an autosomal dominant disorder characterized by short stature, facial anomalies, webbed neck, sternal deformity, heart defects, and, in males, cryptorchidism. PTPN11 encodes SHP2, an important component of several signal transduction pathways that acts as a positive regulator of RAS-mitogen activated protein kinase signaling. Neurofibromatosis type 1 (NF1) is another autosomal dominant disorder characterized by hamartomas in multiple organs. The NF1 gene encodes a GAP-related protein, which acts as a negative regulator of the Ras-mediated signal transduction pathway. Clinical overlap between both syndromes, neurofibromatosis-Noonan syndrome (NFNS) is well known. We studied a female patient with typical findings of NFNS and found two mutations: a novel PTPN11 transversion, 1909A --> G, resulting in Gln510Arg, and an NF1 transversion, 2531A --> G, resulting in Leu844Arg. She inherited the PTPN11 mutation from her father and had a de novo NF1 mutation. This is the first report of molecular concurrence of both disorders in the same patient.

Abnormalities, Multiple↗
PubMed2004

Blood expression profiles for tuberous sclerosis complex 2, neurofibromatosis type 1, and Down's syndrome.

Blood gene expression profiling has been applied to a variety of hematological malignancies, autoimmune disorders, and infectious diseases. This study applies this approach to genetic diseases without obvious blood phenotypes. Three genetic diseases including tuberous sclerosis complex 2, neurofibromatosis type 1, and Down's syndrome were compared with a group of healthy controls. RNA from whole blood was surveyed using Affymetrix U133A arrays. Each disease was associated with a unique gene expression pattern in blood that can be accurately distinguished by a classifier. Genes on chromosome 21 were overexpressed in Down's syndrome, and genes controlling cell cycle and proliferation were associated with tuberous sclerosis complex type 2 or neurofibromatosis type 1. A subset of genes involved in cardiac development or remodeling were overexpressed in patients with Down's syndrome and congenital heart defects. These findings suggest that blood gene expression profiling on a broader basis might be useful for genetic disease screening/diagnosis and might help elucidate mechanisms and pathways that lead to genotype-phenotype differences.

Cluster Analysis↗
PubMed1984

Serum neuronal growth factor levels in von Recklinghausen's neurofibromatosis.

A single neuronal cell biological assay was used to quantitate neuronal growth factors in 87 serum samples from 69 patients in 48 families with von Recklinghausen's neurofibromatosis, plus 16 samples from 16 comparison subjects. Mouse nerve growth factor was used as a standard for the bioassay, and results of serum assays were expressed as nerve growth factor equivalents. Antiserum to mouse nerve growth factor inhibited fractionally serum-induced neurite outgrowth, while kinetics of neurite outgrowth and maximal cellular response to serum differed from those induced by mouse nerve growth factor. The mean values (+/- SD) of neuronal growth factors for the patients were 20.5 +/- 15.7 pg/mg serum protein, while mean values for the comparison group as a whole were 22.3 +/- 15.6 pg/mg serum protein. Sex, race/ethnicity, patient age, and date of sample collection did not significantly influence serum levels among patients or comparison subjects. Three to six serial samples taken from women before pregnancy, during the course of pregnancy, during delivery, and in the postpartum period did not show significant differences from one period to another. These data suggest that human serum does contain non-nerve-growth-factor neuronal growth factors, but that levels of the factors do not contribute to the identification of patients with von Recklinghausen's neurofibromatosis.

Adolescent↗
PubMed1976

Gastric lesions in generalized neurofibromatosis.

A patient with dyspepsia and multiple gastric polyps associated with generalized neurofibromatosis is described, and the English literature on generalized neurofibromatosis with gastric involvement is reviewed. Nine patients with gastric neurofibromas have been reported and 2 with one and two gastric polyps respectively, but none with multiple gastric polyps. The commonest presentation has been dyspepsia suggestive of a peptic ulcer.

Aged↗
PubMed2002

Management issues in massive pediatric facial plexiform neurofibroma with neurofibromatosis type 1.

BACKGROUND: Plexiform neurofibroma is a relatively common but potentially devastating manifestation of neurofibromatosis type 1 (NF1). Surgical management is the mainstay of therapy, but within the head and neck region it is limited by the infiltrating nature of these tumors, inherent operative morbidity, and high rate of regrowth. METHOD: We describe a case of a 7-year-old girl with neurofibromatosis type 1 and a massive facial plexiform neurofibroma with the aim of emphasizing the treatment and timing issues involved in the management of this difficult problem. A MEDLINE search (1966 through December 2000) was carried out, and pertinent literature on the subject was reviewed. RESULT: The patient described in this case report was carefully observed for a period of 6 years from diagnosis before surgical excision of the tumor was undertaken with an uneventful recovery. CONCLUSION: Surgical management remains the mainstay of treatment for these locally invasive tumors, but functional disturbances are almost inevitable in resecting substantial tumors involving the head and neck region. The indication and timing of surgery in pediatric patients therefore needs to be carefully weighed against the physical and psychologic consequences of treatment.

Child↗
PubMedDate not supplied

Neurofibromatosis of the head and neck.

Neurofibromatosis (von Recklinghausen's disease) is an autosomal dominant disease that affects one in 2,500-3,000 births. Because the head and neck is unique in its anatomical compartmentalization of the central and peripheral nervous systems, the potential for involvement of these areas with neurofibromas is substantial and accounts for a myriad of clinicopathologic presentations. In the present study, the incidence of involvement in the head and neck is 37%. We found 81% of the patients had café au lait spots, 63% had positive family histories, and 66% had multiple cutaneous nodules. An incidence of malignant transformation was documented in 3.5% of the cases. Management of benign neurofibromatosis must be individualized for each patient and ranges from incisional biopsy to wide local excision. In every case, the risk of severe neurologic deficit must be weighted against the benefits of surgical resection, which is usually incomplete. Genetic counseling is advised for all patients with this disease, since no cure is available.

Adolescent↗
PubMed1979

Malignant fibrous histiocytoma arising in a patient with multiple neurofibromatosis: a case report and a literature review.

A case report of a 56-year-old man with the characteristic clinical and histologic features of multiple neurofibromatosis is presented. This patient was also diagnosed as having a malignant fibrous histiocytoma involving the right thigh with metastasis to the lung. A definite association between Von Recklinghausen's disease and various sarcomas (most commonly neurofibrosarcomas) of the peripheral nerves and the somatic soft tissues is well-known. This is apparently the first report in the literature of a malignant fibrous histiocytoma arising in a patient with multiple neurofibromatosis. The phenomenon of sarcomatous change in Von Recklinghausen's disease and the clinical and pathologic features of malignant fibrous histiocytoma are also discussed.

Histiocytoma, Benign Fibrous↗