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NCI CANCERLIT^® Search: Neurofibromatosis 1 and 2 - August 2002

National Cancer Institute^®
Last Modified: August 1, 2002

Ten novel mutations in the human neurofibromatosis type 1 (NF1) gene in Italian patients.
Human genome epidemiologic reviews: the beginning of something HuGE.
NF1 gene and neurofibromatosis 1.
Quantification of NF1 transcripts reveals novel highly expressed splice variants.
Differential NF1, p16, and EGFR patterns by interphase cytogenetics (FISH) in malignant peripheral nerve sheath tumor (MPNST) and
Grouping of multiple-lentigines/LEOPARD and Noonan syndromes on the PTPN11 gene.
Orthopaedic manifestations of neurofibromatosis in children: an update.
Unequal meiotic crossover: a frequent cause of NF1 microdeletions.
The molecular and genetic basis of neurological tumours.

Table of Contents

1
UI - 12112660
AU - Origone P; De Luca A; Bellini C; Buccino A; Mingarelli R; Costabel S; La
TI - Rosa C; Garre C; Coviello DA; Ajmar F; Dallapiccola B; Bonioli E Ten novel mutations in the human neurofibromatosis type 1 (NF1) gene in Italian patients.
SO - Hum Mutat 2002 Jul;20(1):74-5
AD - Dipartimento di Oncologia, Biologia e Genetica, Universita di Genova, Genova, Italy. origone@unige.it
The entire NF1 coding region was analyzed for mutations in a panel of 108 unrelated Italian NF1 patients. Using PTT, SSCP, and DNA sequencing, we found 10 mutations which have never been reported before. Clinical diagnosis of NF1 was established according to the NIH consensus criteria in 100 individuals, while 8 were young children with only multiple cafe-au-lait spots. We detected 46 truncated fragments, and 24 of them were fully characterized by SSCP and direct sequencing. Of the 24, 14 were known mutations (R304X, R681X, Q682X, R1306X, R1362X, R1513X, R1748X, Q1794X, R1947X, Y2264X, R2237X, 2674delA, 6789delTTAC, 2027insC). The other 10 mutations represent novel changes that contribute to the germline mutational spectrum of the NF1 gene (K810X, Q2595X, 6772delT, 7190delCT, 7331delA, 1021insTT, 3921insT, 4106insTA, 7149insC, 2033insCG / 2034delA). PTT in a large number of Italian NF1 patients supports the usefulness of this method for characterization of mutations in disorders where the responsible gene is very large and the disease-causing mutations often create a stop codon. In agreement with previous reports, no mutational hotspots within the NF1 gene were detected. Copyright 2002 Wiley-Liss, Inc.

2
UI - 10625169
AU - Khoury MJ; Little J
TI - Human genome epidemiologic reviews: the beginning of something HuGE.
SO - Am J Epidemiol 2000 Jan 1;151(1):2-3

3
UI - 10625171
AU - Rasmussen SA; Friedman JM
TI - NF1 gene and neurofibromatosis 1.
SO - Am J Epidemiol 2000 Jan 1;151(1):33-40
AD - Centers for Disease Control and Prevention, Division of Birth Defects and Developmental Disabilities, Atlanta, GA 30341, USA.
Neurofibromatosis 1 (NF1), also known as von Recklinghausen disease, is an autosomal dominant condition caused by mutations of the NF1 gene, which is located at chromosome 17q11.2. NF1 is believed to be completely penetrant, but substantial variability in expression of features occurs. Diagnosis of NF1 is based on established clinical criteria. The presentation of many of the clinical features is age dependent. The average life expectancy of patients with NF1 is probably reduced by 10-15 years, and malignancy is the most common cause of death. The prevalence of clinically diagnosed NF1 ranges from 1/2,000 to 1/5,000 in most population-based studies. A wide variety of NF1 mutations has been found in patients with NF1, but no frequently recurring mutation has been identified. Most studies have not found an obvious relation between particular NF1 mutations and the resulting clinical manifestations. The variability of the NF1 phenotype, even in individuals with the same NF1 gene mutation, suggests that other factors are involved in determining the clinical manifestations, but the nature of these factors has not yet been determined. Laboratory testing for NF1 mutations is difficult. A protein truncation test is commercially available, but its sensitivity, specificity, and predictive value have not been established. No general, population-based molecular studies of NF1 mutations have been performed. At this time, it appears that the benefits of population-based screening for clinical features of NF1 would not outweigh the costs of screening.

4
UI - 12095621
AU - Vandenbroucke I; Vandesompele J; De Paepe A; Messiaen L
TI - Quantification of NF1 transcripts reveals novel highly expressed splice variants.
SO - FEBS Lett 2002 Jul 3;522(1-3):71-6
AD - Centre for Medical Genetics, Ghent University Hospital-0K5, De Pintelaan 185, Belgium.
Previously, we have shown that the NF1 gene gives rise to multiple novel splice variants. In the present study, nine NF1 variants were quantified by real-time PCR in various human tissues. Some of these variants were expressed at low to moderate low levels and possible implications of these findings are discussed. Interestingly, two variants (NF1-DeltaE4b and NF1-DeltaE43) were shown to be highly expressed in specific tissues. NF1-DeltaE43 lacks a nuclear targeting sequence and might be functionally different from full-length NF1. These novel NF1 splice variants might expand our understanding of the role of neurofibromin.

5
UI - 12152785
AU - Perry A; Kunz SN; Fuller CE; Banerjee R; Marley EF; Liapis H; Watson MA;
TI - Gutmann DH Differential NF1, p16, and EGFR patterns by interphase cytogenetics (FISH) in malignant peripheral nerve sheath tumor (MPNST) and morphologically similar spindle cell neoplasms.
SO - J Neuropathol Exp Neurol 2002 Aug;61(8):702-9
AD - Department of Pathology, Washington University School of Medicine, St Louis, Missouri 63110-1093, USA.
Malignant peripheral nerve sheath tumors (MPNSTs) are diagnostically challenging neoplasms for which sensitive and specific immunohistochemical markers are lacking. Although limited to date, previous studies have suggested that NF1 (17q), NF2 (22q), p16 (9p), and EGFR (7p) alterations may be involved in MPNST tumorigenesis. To determine whether specific genetic changes differentiate between MPNST and morphologically similar neoplasms, we assessed these chromosomal regions in 22 MPNSTs (9 NF1-associated, 13 sporadic), 13 plexiform neurofibromas, 5 cellular schwannomas, 8 synovial sarcomas, 6 fibrosarcomas, and 13 hemangiopericytomas by 2-color FISH. NF1 deletions, often in the form of monosomy 17, were found in MPNSTs (76%). neurofibromas (31%), hemangiopericytomas (17%), and fibrosarcomas (17%), but not in synovial sarcomas or cellular schwannomas. NF1 losses were encountered more frequently in MPNSTs versus other sarcomas (p < 0.001), as were p16 homozygous deletions (45% vs 0%; p < 0.001), EGFR amplifications (26% vs 0%; p = 0.006), and polysomies for either chromosomes 7 (53% vs 12%; p = 0.003) or 22 (50% vs 4%; p < 0.001). Hemizygous or homozygous p16 deletions were detected in 75% of MPNSTs, but not in benign nerve sheath tumors (p < 0.001). Thus, FISH analysis identifies relatively specific genetic patterns that may be useful in selected cases, for which the differential diagnosis includes low- or high-grade MPNST.

6
UI - 12058348
AU - Digilio MC; Conti E; Sarkozy A; Mingarelli R; Dottorini T; Marino B;
TI - Pizzuti A; Dallapiccola B Grouping of multiple-lentigines/LEOPARD and Noonan syndromes on the PTPN11 gene.
SO - Am J Hum Genet 2002 Aug;71(2):389-94
AD - Division of Medical Genetics, Bambino Gesu Hospital, Istituto di Ricovero e Cura a Carattere Scientifico, Rome, Italy.
Multiple-lentigines (ML)/LEOPARD (multiple lentigines, electrocardiographic-conduction abnormalities, ocular hypertelorism, pulmonary stenosis, abnormal genitalia, retardation of growth, and sensorineural deafness) syndrome is an autosomal dominant condition--characterized by lentigines and cafe au lait spots, facial anomalies, cardiac defects--that shares several clinical features with Noonan syndrome (NS). We screened nine patients with ML/LEOPARD syndrome (including a mother-daughter pair) and two children with NS who had multiple cafe au lait spots, for mutations in the NS gene, PTPN11, and found, in 10 of 11 patients, one of two new missense mutations, in exon 7 or exon 12. Both mutations affect the PTPN11 phosphotyrosine phosphatase domain, which is involved in <30% of the NS PTPN11 mutations. The study demonstrates that ML/LEOPARD syndrome and NS are allelic disorders. The detected mutations suggest that distinct molecular and pathogenetic mechanisms cause the peculiar cutaneous manifestations of the ML/LEOPARD-syndrome subtype of NS.

7
UI - 12151887
AU - Vitale MG; Guha A; Skaggs DL
TI - Orthopaedic manifestations of neurofibromatosis in children: an update.
SO - Clin Orthop 2002 Aug;(401):107-18
AD - Department of Orthopaedic Surgery, University of Southern California Keck School of Medicine and Childrens Hospital Los Angeles, Los Angeles, CA 90027-6062, USA.
Neurofibromatosis is one of the most common genetic disorders affecting mankind. Despite extensive basic science research, the diagnosis still is based largely on well-defined clinical criteria, which often present gradually during childhood. Approximately 50% of patients have significant musculoskeletal manifestations, with scoliosis and congenital pseudarthrosis of the tibia most common. Approximately 20% of children with Type I neurofibromatosis present with scoliosis with or without the classic dystrophic features, such as vertebral scalloping and rib penciling. Dystrophic curves portend rapid progression and require early fusion. Surgical treatment often is challenging because of the common presence of neurofibromas adjacent to the spinal cord, significant multiplanar deformity, and poor bone quality. Congenital pseudarthrosis of the tibia also continues to present significant difficulties. The use of a brace is the mainstay of early treatment, whereas intramedullary rodding commonly is used for operative fixation. Grafting of the free fibula and correction using techniques of distraction and compression histiogenesis with Ilizarov fixators have been reported for refractory cases with varying degrees of success. Multiple heroic, operative attempts may have a tremendous toll on the quality of life of affected children through their early childhood. In addition to these and other distinctive musculoskeletal lesions, affected children often suffer from various medical problems.

8
UI - 10775528
AU - Lopez Correa C; Brems H; Lazaro C; Marynen P; Legius E
TI - Unequal meiotic crossover: a frequent cause of NF1 microdeletions.
SO - Am J Hum Genet 2000 Jun;66(6):1969-74
AD - Center for Human Genetics, University Hospital Gasthuisberg, B-3000 Leuven, Belgium.
Neurofibromatosis type 1 is a common autosomal dominant disorder caused by mutations of the NF1 gene on chromosome 17. In only 5%-10% of cases, a microdeletion including the NF1 gene is found. We analyzed a set of polymorphic dinucleotide-repeat markers flanking the microdeletion on chromosome 17 in a group of seven unrelated families with a de novo NF1 microdeletion. Six of seven microdeletions were of maternal origin. The breakpoints of the microdeletions of maternal origin were localized in flanking paralogous sequences, called "NF1-REPs." The single deletion of paternal origin was shorter, and no crossover occurred on the paternal chromosome 17 during transmission. Five of the six cases of maternal origin were informative, and all five showed a crossover, between the flanking markers, after maternal transmission. The observed crossovers flanking the NF1 region suggest that these NF1 microdeletions result from an unequal crossover in maternal meiosis I, mediated by a misalignment of the flanking NF1-REPs.

9
UI - 12154354
AU - Zhu Y; Parada LF
TI - The molecular and genetic basis of neurological tumours.
SO - Nat Rev Cancer 2002 Aug;2(8):616-26
AD - Center for Developmental Biology and Kent Waldrep Foundation Center for Basic Research on Nerve Growth and Regeneration, University of Texas Southwestern Medical Center, Dallas, Texas 75390-9133, USA.
There are no effective therapies for many tumours of the nervous system. This is, in part, a consequence of their location within relatively inaccessible tissues. It is also likely, however, that the unique characteristics of the cells that give rise to these tumours create a set of conditions that facilitate tumour development. Here, we consider recent advances in molecular genetics, the development of mouse models and developmental neurobiology as they relate to tumours of neuroectodermal origin. It is likely that these advances will provide insight into underlying mechanisms and provide a rational framework for the development of effective interventions.

The above citations and abstracts reflect those newly added to CANCERLIT for the month and topic listed in the title. The citations have been retrieved from CANCERLIT using a predefined search strategy of indexed subject terms. Although the search strategy has been refined as best as possible, citations may appear that are not directly related to the topic, and occasionally relevant references may be omitted.

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