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PubMed1997

Paternal age and sporadic neurofibromatosis 1: a case-control study and consideration of the methodologic issues.

Sporadic neurofibromatosis 1 (NF1) occurs in the absence of a family history of the disease and usually results from a new mutation in the germ cell of one of the parents, most commonly the father. Older paternal age may increase the risk for a new germinal NF1 mutation, but the results of studies to address this question conflict. We investigated paternal age in sporadic NF1 by using a case-control study design. Patients who were seen at two specialty NF clinics in Houston, Texas, born between 1970 and 1992 and living in the Houston area and surrounding counties, were studied. Birth certificates with information on the father were found for 89 cases. For each case, two birth certificates were chosen at random from the same year and county of birth. In this way, the control group of 178 individuals was formed. Fathers of patients with NF1 were 1.5 years older than fathers of control subjects at the birth of the child, but the difference was only of borderline statistical significance (P = 0.07). This paternal age difference was not changed by adjustment for socioeconomic status or maternal age. These and previous data are consistent with either a small paternal age effect in sporadic NF1 or a bias such as that resulting from the selection of cases and/or controls.

Adult↗
PubMed2000

Parents' responses to their child's diagnosis of neurofibromatosis 1.

Eighteen unaffected families with an affected child were interviewed in their homes to chronicle the experiences of parents in receiving their child's diagnosis of neurofibromatosis (NF) 1. Families were recruited through NF support groups and the Genetics Departments of two metropolitan hospitals in Northern California. Characteristics of disclosures were often at variance with suggestions made in recent years for the giving of "bad news." Disclosures typically were made "helter-skelter" during regular examinations. Parents in 16 of the families described shock, upset, and subsequent depression as their responses to the diagnosis. The overriding issues, which dominated in the disclosure, were the uncertainty of the condition, the possibility of many diverse symptoms, and its historic misdiagnosis as "The Elephant Man's Disease." However, physicians' attention to the setting and style of disclosure, imparting appropriate and positive information, allowance of additional time for careful explanation, and rescheduling a follow-up appointment, may be able to more effectively assist parents in receiving and more positively adapting to their child's diagnosis.

Adaptation, Psychological↗
PubMed2000

Magnetic resonance findings and ophthalmologic abnormalities are correlated in patients with neurofibromatosis type 1 (NF1).

In subjects with neurofibromatosis type 1 (NF1), we show that a reduction in the visual field is the most sensitive indicator of gliomas along the optic pathway. Therefore, we conclude that a visual field evaluation is the most sensitive clinical test among those evaluated to predict the presence of optic pathway pathology on an MRI examination. These data may contribute to the establishment of more precise guidelines for the evaluation and treatment of children with NF1.

Adolescent↗
PubMed2000

Neurofibromatosis type 1.

Neurofibromatosis 1 (NF1) is an autosomal dominant neurocutaneous disorder with an incidence of approximately 1 in 4000. Cognitive deficits and academic learning difficulties are the most common neurological 'complication' of NF1 in childhood and can be responsible for significant lifetime morbidity. The NF1 gene is usually classified as a tumor suppressor gene, but it is not yet known how NF1 gene mutations cause many of the non-tumor manifestations of the disorder. The NF1 protein, neurofibromin is expressed early during embryonic development with high levels of expression in the brain, suggesting that it plays an important role in regulating the orderly differentiation of central nervous system neurons. The mouse model for NF1 demonstrates behavioral abnormalities which bear striking similarity to the cognitive phenotype observed in humans with NF1. This review summarises our current understanding of the function of the NF1 gene, the nature of cognitive deficits in this disorder and correlations between neuroradiological, pathological and neuropsychological findings and animal studies which provide an insight into the pathogenesis.

Animals↗
PubMed2001

Cardiac findings in an individual with neurofibromatosis 1 and sudden death.

Vascular lesions in neurofibromatosis 1 (NF1) are infrequently recognised as manifestations of the disease, yet they can produce serious complications. Most individuals with NF1 vasculopathy are asymptomatic, which may contribute to underestimation of its frequency. A recent study indicates that vascular changes in individuals with NF1 contribute to mortality at younger ages. We report the sudden death of a young man with NF1. On autopsy examination there was evidence of an intramyocardial vasculopathy characteristic of the vascular pathology previously described in NF1. Other cardiac findings included non-specific cardiomyopathic changes, myocardial fibrosis, and a "floppy" mitral valve.

Adult↗
PubMed2001

A man who inherited his SRY gene and Leri-Weill dyschondrosteosis from his mother and neurofibromatosis type 1 from his father.

We report on a man with neurofibromatosis type 1 (NF1) and Leri-Weill dyschondrosteosis (LWD). His father had NF1. His mother had LWD plus additional findings of Turner syndrome (TS): high arched palate, bicuspid aortic valve, aortic stenosis, and premature ovarian failure. The proband's karyotype was 46,X,dic(X;Y)(p22.3;p11.32). Despite having almost the same genetic constitution as 47,XXY Klinefelter syndrome, he was normally virilized, although slight elevation of serum gonadotropins indicated gonadal dysfunction. His mother's karyotype was mosaic 45,X[17 cells]/46,X,dic(X;Y)(p22.3;p11.32)[3 cells].ish dic(X;Y)(DXZ1 +,DYZ1 + ). The dic(X;Y) chromosome was also positive for Y markers PABY, SRY, and DYZ5, but negative for SHOX. The dic(X;Y) chromosome was also positive for X markers DXZ1 and a sequence < 300 kb from PABX, suggesting that the deletion encompassed only pseudoautosomal sequences. Replication studies indicated that the normal X and the dic(X;Y) were randomly inactivated in the proband's lymphocytes. LWD in the proband and his mother was explained by SHOX haploinsufficiency. The mother's female phenotype was most likely due to 45,X mosaicism. This family segregating Mendelian and chromosomal disorders illustrates extreme sex chromosome variation compatible with normal male and female sexual differentiation. The case also highlights the importance of karyotyping for differentiating LWD and TS, especially in patients with findings such as premature ovarian failure or aortic abnormalities not associated with isolated SHOX haploinsufficiency.

Adult↗
PubMed1984

Paraganglioma of the duodenum in association with congenital neurofibromatosis. Possible relationship.

A case of a duodenal paraganglioma in a patient with von Recklinghausen's disease is presented, along with a review of the common clinical features of the 26 cases of duodenal paraganglioma and related neurogenic tumors reported in the literature. There was no reported evidence of recurrence or metastasis. Local excision was the most commonly employed method of treatment. It is proposed that duodenal paraganglioma with its admixed components and variable histologic features may represent hamartomatous hyperplasia of the paraganglia and the supporting neuroid tissue in this area. This would explain the benign behavior of these tumors as compared with carcinoids. Its association, in this case, with neurofibromatosis supports the neural crest origin of duodenal paragangliomas.

Cytoplasmic Granules↗
PubMed1986

Neurofibromatosis and childhood tumors.

Although tumors are a known complication of von Recklinghausen's neurofibromatosis (NF), they often develop after the second decade and their characteristics in the pediatric population are unclear. To define the frequency and distribution of tumor types in children with NF, the authors reviewed the experience at Children's Hospital of Pittsburgh between 1953 and 1984. During that time, 121 children younger than 18 years with documented NF were seen. Three patients (2.5%) developed locally extensive, unresectable sarcomas, two of which were clearly neural in origin. Two other children died from complications of highly cellular but not histologically malignant neurofibromas. Seventeen patients (14%) had brain tumors, of which 3 (2.5%) were malignant astrocytomas and 9 were optic gliomas. Two children had acute myelogenous leukemia. Although it has been said that patients with NF are particularly susceptible to the oncogenic effects of radiation, 12 children were treated with a median of 5000 rad to their tumor bed. Follow-up after radiation in that small cohort of patients ranged from 6 months to 12 years (mean, 6 years). Eleven of 12 patients experienced adequate local control. During the follow-up period, none developed a second tumor outside or within the radiation port that could be related to radiation. The authors conclude that clinically significant tumors in children with NF, not all of which are histologically malignant, are not rare. Although more prospective information is needed on response to and sequelae from therapy, the data in this report suggest no contraindication to aggressive therapy.

Adolescent↗
PubMed1989

Concomitant occurrence of an adrenal ganglioneuroma and a contralateral pheochromocytoma in a patient with von Recklinghausen's neurofibromatosis. An immunocytochemical study.

This report presents concomitant occurrence of an adrenal ganglioneuroma and a contralateral pheochromocytoma in a patient with von Recklinghausen's disease. The patient's daughter also has cutaneous neurofibromatosis and an adrenal medullary tumor indicating that the observed "three component disease" may represent an inherited neurocristopathy. Immunocytochemically the ganglioneuroma showed a positive reaction with a tyrosinhydroxylase antiserum, but a negative reaction with a dopamine-beta-hydroxylase antiserum, suggesting the capacity of dopamine synthesis. Frequent ganglion cells were immunopositive against neuropeptide Y, but occasional ganglion cells were also positive against enkephalin and substance P. Adrenergic nerve fibers were abundant in the Schwann cell portion of the tumor, but peptide containing nerve cell processes were also demonstrated.

Adrenal Gland Neoplasms↗
PubMed1989

Neurofibromatosis and acute monocytic leukemia in adults.

A patient with nonfamilial peripheral neurofibromatosis (NF) (von Recklinghausen's disease) is reported who contracted acute monocytic leukemia at 60 years of age. In the course of the illness, myelonecrosis developed and the patient died 4 months later due to a therapy-resistant bone marrow relapse. This association of the two illnesses would appear to confirm reports on an increased incidence of nonlymphatic leukemia and NF. Such an association is seen during childhood as juvenile chronic leukemia, but it is uncommon in adulthood.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1993

Loss of heterozygosity on chromosome arm 17p in small cell lung carcinomas, but not in neurofibromas, in a patient with von Recklinghausen neurofibromatosis.

BACKGROUND: It has been suggested that the genetic abnormality responsible for von Recklinghausen neurofibromatosis (NF1) increases a patient's risk of various kinds of malignancies. The incidence of small cell lung carcinoma (SCLC) as a complication of NF1, however, is rare. To clarify the relationship between NF1 and SCLC, possible loss of heterozygosity of chromosome 17 in a patient with SCLC combined with NF1 was analyzed. METHODS: Possible loss of heterozygosity for chromosome 17 was analyzed by a molecular genetic approach using several chromosome 17-specific polymorphic DNA markers. RESULTS: In both primary tumor and metastatic tumors of SCLC, loss of heterozygosity was detected on chromosome arm 17p, but not on 17q. Loss of heterozygosity, however, was detected on neither 17p nor 17q in neurofibromas and normal tissue. CONCLUSIONS: The formation of SCLC may result from several genetic alterations, including inactivation of tumor-suppressor gene on chromosome 17p, most likely P53, although it still is unknown whether or not a mutation of the NF1 gene on 17q was involved in the development of SCLC in this patient.

Alleles↗
PubMed1993

Neurofibromatosis type 1 and childhood cancer.

BACKGROUND: Patients with neurofibromatosis type 1 (NF1) are prone to develop malignancy, particularly malignant schwannoma and glioma in adults. METHODS: To assess the risk for childhood malignancy in NF1, 26,084 patients with cancer younger than 15 years of age registered from 1969 to 1989 in the Japan Children's Cancer Registry were reviewed. The incidence of NF1 in each type of cancer was compared with that in the Japanese population. RESULTS: Fifty-six children with cancer had NF1 in the national registry. The incidence of NF1 (0.21%) was 6.45 times that of the expected estimated rate of 1 per 3000 in the Japanese population. These tumors tended to be type and site specific. The NF1 incidence was extremely high in optical nerve glioma (12.5%), other central nervous system gliomas (0.9%), and malignant schwannoma (31.4%). For nonneural tumors, NF1 incidence was increased in rhabdomyosarcoma (1.36%), particularly those in urogenital organs, and in myelogenous leukemia (0.27%). Epithelial carcinomas were not observed in the group of patients with NF1. CONCLUSION: The risk for glioma and malignant schwannoma increases in children and adults with NF1. Moreover, the risk for two childhood malignancies, myelogenous leukemia and rhabdomyosarcoma, increases in children with NF1. The NF1 gene seems to increase the risk not only for neural tumors but also for some non-neural tumors in an age-specific, organ-dependent pattern of carcinogenesis.

Adolescent↗
PubMed2000

Three different premature stop codons lead to skipping of exon 7 in neurofibromatosis type I patients.

Neurofibromatosis type 1 (NF1) is an autosomal dominant genetic disorder affecting one in 3,500 individuals. The mutation rate in the NF1 gene is one of the highest known for human genes. Compared to other methods, the protein truncation test (PTT) provides improved efficiency in detecting NF1 mutations which are dispersed throughout the gene which spans 350 kilobases of genomic DNA. We have applied the PTT and subsequent sequence analysis of cloned cDNA to identify mutations in NF1 patients. We report here the identification of two novel (W336X and Q315X), and one recurrent (R304X) mutation located in exon 7 and show that all three premature termination codons lead to skipping of exon 7 in a proportion of the transcripts derived from the mutated allele. Possible mutation-induced alterations of the RNA secondary structure and their impact on skipping of exon 7 of the NF1 gene are explored and discussed.

Base Sequence↗
PubMed2000

Associations of clinical features in neurofibromatosis 1 (NF1).

Neurofibromatosis 1 (NF1), an autosomal dominant disease, exhibits extreme clinical variability. This variability greatly increases the burden for affected families and impairs our ability to understand the pathogenesis of NF1. Recognition of heterogeneity within a disease may provide important pathogenic insights, therefore we tested clinical data from three large sets of NF1 patients for evidence that certain common features are more likely to occur in some NF1 patients than in others. Clinical information on 4,402 patients with NF1 was obtained from three independent databases. We examined associations between pairs of clinical features in individual affected probands. We also examined associations between the occurrence of individual features in affected relatives. Associations were summarized as odds ratios with 95% confidence intervals. We found associations between several pairs of features in affected probands: intertriginous freckling and Lisch nodules, discrete neurofibromas and plexiform neurofibromas, discrete neurofibromas and Lisch nodules, plexiform neurofibromas and scoliosis, learning disability or mental retardation and seizures. We also found associations between the occurrence of Lisch nodules, macrocephaly, short stature, and learning disability or mental retardation as individual features in parents and children with NF1. Our observations suggest that, contrary to established belief, some NF1 patients are more likely than others to develop particular manifestations of the disease. Genetic factors appear to determine the development of particular phenotypic features.

Adult↗
PubMed2001

Neoplasms in neurofibromatosis 1 are related to gender but not to family history of cancer.

The risk of malignancies among persons with neurofibromatosis 1 (NF1) is higher than in the general population, but the excess risk has not been precisely estimated. The effects of gender and inheritance pattern on cancer risk are unclear. Therefore, we conducted a historical cohort study to determine cancer risk factors by contacting 138 Caucasian NF1 patients originally seen at Baylor College of Medicine (BCM) in Houston between 1978 and 1984. A total of 304 patients of all ethnic groups were evaluated at BCM during this period. We successfully located 173 patients, 138 of who were Caucasian. We computed standardized incidence ratios (SIRs) with the age-, gender-, and time period-specific rates from the Connecticut Tumor Registry for 2,094 person-years of observation (median follow-up = 16 years). Eleven incident tumors were reported. Females were at much higher risk of cancer than males (SIR = 5.6, 95% confidence interval (CI) 2.7-10.3 and SIR = 0.6; 95% CI, 0.0-3.0, respectively). We found no elevated cancer risk in unaffected first-degree relatives, regardless of whether the proband had cancer or not (SIR = 1.1 95% CI, 0.6-1.8 and SIR = 1.0, 95% CI, 0.6-1.5, respectively). Our results suggest that malignancy in the proband is not the result of a modifying gene that has a significant impact on general cancer risk.

Adolescent↗
PubMed2001

Hemarthrosis: an unusual complication of type 1 neurofibromatosis.

Type 1 neurofibromatosis is one of the most common autosomal-dominant disorders and often includes orthopedic manifestations. We report the case of a 48-year-old woman with hemarthrosis caused by a popliteal cyst infiltrated by a diffuse neurofibroma associated with angiodysplasia. Surgical resection of this tumor was followed by postoperative hemorrhagic complications.

Female↗
PubMed1999

Developmental regulation of a neuron-specific neurofibromatosis 1 isoform.

We have identified a protein isoform of the neurofibromatosis 1 (NF1) gene (neurofibromin) containing the alternatively spliced exon 9a that is expressed in forebrain neurons. Exon 9a neurofibromin is localized in the cytoplasm, sediments in a P100 fraction, and is expressed throughout the soma and processes in cortical neurons in vitro. Expression of exon 9a neurofibromin is developmentally regulated, with expression first detected after postnatal day 2. The identification of this novel protein isoform with restricted neuronal expression suggests novel functions for neurofibromin in the postmitotic brain that are perhaps relevant to the learning disabilities observed in children with NF1.

Alternative Splicing↗