Use of the National Institutes of Health Criteria for Diagnosis of Neurofibromatosis 1 in Children

DeBella, Kimberly; Szudek, Jacek; Friedman, Jan M.

doi:10.1542/peds.105.3.608

Cited by 494 publications

(395 citation statements)

References 13 publications

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“…21 These samples comprised 94 primary tumour samples taken from 43 patients, plus 15 Schwann cell lines cultured from individual neurofibromas excised from the remaining three patients. Primary tumour tissue was carefully macrodissected away from adjacent normal skin.…”

Section: Patient Samplesmentioning

confidence: 99%

Exploring the somatic NF1 mutational spectrum associated with NF1 cutaneous neurofibromas

et al. 2011

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Neurofibromatosis type-1 (NF1), caused by heterozygous inactivation of the NF1 tumour suppressor gene, is associated with the development of benign and malignant peripheral nerve sheath tumours (MPNSTs). Although numerous germline NF1 mutations have been identified, relatively few somatic NF1 mutations have been described in neurofibromas. Here we have screened 109 cutaneous neurofibromas, excised from 46 unrelated NF1 patients, for somatic NF1 mutations. NF1 mutation screening (involving loss-of-heterozygosity (LOH) analysis, multiplex ligation-dependent probe amplification and DNA sequencing) identified 77 somatic NF1 point mutations, of which 53 were novel. LOH spanning the NF1 gene region was evident in 25 neurofibromas, but in contrast to previous data from MPNSTs, it was absent at the TP53, CDKN2A and RB1 gene loci. Analysis of DNA/RNA from neurofibroma-derived Schwann cell cultures revealed NF1 mutations in four tumours whose presence had been overlooked in the tumour DNA. Bioinformatics analysis suggested that four of seven novel somatic NF1 missense mutations (p.A330T, p.Q519P, p.A776T, p.S1463F) could be of functional/clinical significance. Functional analysis confirmed this prediction for p.S1463F, located within the GTPase-activating protein-related domain, as this mutation resulted in a 150-fold increase in activated GTP-bound Ras. Comparison of the relative frequencies of the different types of somatic NF1 mutation observed with those of their previously reported germline counterparts revealed significant (P¼0.001) differences. Although non-identical somatic mutations involving either the same or adjacent nucleotides were identified in three pairs of tumours from the same patients (Po0.0002), no association was noted between the type of germline and somatic NF1 lesion within the same individual.

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Section: Patient Samplesmentioning

confidence: 99%

Exploring the somatic NF1 mutational spectrum associated with NF1 cutaneous neurofibromas

et al. 2011

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“…), which is characterized by a wide clinical expressivity (Riccardi, 1992;Huson, 1994). At the genetic level, NF1 is transmitted in an autosomal dominant pattern and mutations in the NF1 gene are considered almost fully penetrant at the age of 8 years (DeBella, et al, 2000). The NF1 gene Viskochil et al, 1990;Wallace et al, 1990) is located on chromosome 17 and consists of 57 constitutive and various alternative exons (Li et al, 1995;reviewed in Viskochil, 1998).…”

Section: Introductionmentioning

confidence: 99%

Nature and mRNA effect of 282 differentNF1point mutations: focus on splicing alterations

et al. 2008

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Neurofibromatosis type 1 (NF1) is a common autosomal dominant genetic disorder caused by mutations in the NF1 gene. In this paper we report our experience using the cDNA-SSCP/HD analysis as a mutational screening approach and the double characterization of all mutations at the DNA and RNA levels. Two hundred and eighty-two different mutations (in 374 independent patients) were identified, 140 of which were novel in our population. Most of these mutations are unique and distributed along the gene. However, we also detected 37 recurrent mutations. Our approach is limited with respect to the detection of single base substitutions, but it is highly effective in the detection of frameshift mutations and mutations that affect the correct splicing. Due to this bias we focus here in the characterization of these two types of mutations. Forty-seven percent of mutations found were frameshift mutations, with small deletions being 2.3 times more common than small insertions. At the mRNA level, 44% of mutations affected the correct splicing, 80% of them located in the consensus sequences, with the donor site being much more frequently involved. The remaining 20% consisted of mutations located in deep intronic sites and mutations located in the coding region. In general the latter group produces different types of mutated transcripts with specific proportions for each mutation. The double characterization of mutations at the DNA and RNA levels enables to detect a broader spectrum of mutations than any single level approach, and provides a greater understanding of their molecular pathogenesis.

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“…Neurofibromatosis 1 can be associated with optic gliomas, spinal and peripheral nerve neurofibromas, neurologic or cognitive impairment, scoliosis and other bone abnormalities, malignant tumors of the nerve sheath, pheochromocytoma, and vasculopathy. 3 The disease is fully penetrant by the age of 8 years, 4 but expressivity is variable. 5 Manifestations of NF1 vary at different times in an individual's life.…”

mentioning

confidence: 99%

Clinical Risk Factors for Mortality in Patients With Neurofibromatosis 1

Khosrotehrani¹,

Bastuji‐Garin²,

Zeller³

et al. 2003

Arch Dermatol

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Use of the National Institutes of Health Criteria for Diagnosis of Neurofibromatosis 1 in Children

Abstract: The diagnosis of NF1 cannot always be made in young children using the NIH Diagnostic Criteria. Modification of these criteria may be necessary for children under 8 years old.

Cited by 494 publications

References 13 publications

Exploring the somatic NF1 mutational spectrum associated with NF1 cutaneous neurofibromas

Exploring the somatic NF1 mutational spectrum associated with NF1 cutaneous neurofibromas

Nature and mRNA effect of 282 differentNF1point mutations: focus on splicing alterations

Clinical Risk Factors for Mortality in Patients With Neurofibromatosis 1

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