Optic glioma and precocious puberty in a girl with neurofibromatosis type 1 carrying an R681X mutation of NF1: case report and review of the literature (original) (raw)

The Genetic Aspects of Neurofibromatosis

Annals of the New York Academy of Sciences, 1986

Neurofibromatosis (NF) is one of the most common, potentially serious, autosomal dominant conditions in man. Crowe estimated the prevalence to be one in 2500 to 3300 and from this figure calculated a mutation rate of 1 X per gamete per generation, long considered the highest in humans.' The phenotypic manifestations consist of cutaneous pigmentary changes and multiple benign neurofibromas; affected individuals are at risk for a diverse array of osseous, central nervous system, and neoplastic complications. There is marked variability in clinical involvement, making N F a prototypic condition for the study of the biologic mechanisms of variable expressivity in autosomal dominant disorders? Because of the diversity of clinical manifestations, presentation can range from the child with a multiple congenital anomaly /dysplasia syndrome to the adult with a solid tumor malignancy. Various authors have labeled NF as a phacomatosis, a hamartomatous disorder, a neurocutaneous condition, and most recently a neuro~ristopathy.~ Despite the recent increased interest in this genetic disorder, many unanswered questions about the clinical and biologic aspects of NF remain obvious and emphasize the need for this symposium.

A point mutation associated with a severe phenotype of neurofibromatosis 2

Annals of Neurology, 1996

Neurofibromatosis 2 (NF2) is an autosomal dominant disease characterized by bilateral vestibular schwannomas and other nonmalignant tumors of the brain, spinal cord, and peripheral nerves. Although the average age of onset of NF2 is 20 years, some individuals may become symptomatic in childhood. We studied 5 unrelated NF2 patients who became symptomatic before age 13. All 5 had multiple tumors in addition to vestibular schwannoma, and none had a positive family history. Sequence analysis of the NF2 gene revealed identical nonsense mutation of exon 6 in 3 patients. Because this mutation destroys a restriction enzyme recognition site, genomic DNA from the 2 other children was directly tested for this change and identical alterations were detected. Although the work of our laboratory and others has not, in general, detected identical mutations in unrelated patients, this mutation seems to occur particularly frequently in the pediatric population and thus may be associated with an especially severe phenotype. Restriction analysis in children with NF2 may be a cost effective way of identifying their mutation. Further work is needed to characterize the effects of this change on the NF2 protein product and its relationship to this severe phenotype.

The parental origin of new mutations in neurofibromatosis 2

neurogenetics, 2000

from new mutations at the NF2 locus. Loss of heterozygosity (LOH) in tumor specimens due to deletions covering the normal NF2 allele can be used to infer the haplotypes surrounding underlying mutations and determine the allelic origin of new mutations. We studied 71 sporadic NF2 patients using both LOH and pedigree analysis and compared the parental origin of the new mutation with the underlying molecular change. In the 45 informative individuals, 31 mutations (69%) were of paternal and 14 (31%) were of maternal origin (Pp0.016). Comparison with corresponding constitutional mutations revealed no correlation between parental origin and the type or location of the mutations. However, in 4 of 6 patients with somatic mosaicism the NF2 mutation was of maternal origin. A slight parent of origin effect on severity of disease was found. Further clinical and molecular studies are needed to determine the basis of these unexpected observations.

Characterization of NF1 frameshift mutations in pediatric patients with neurofibromatosis type I

Genetics and Molecular Research, 2015

Neurofibromatosis type I is an autosomal dominant disease with complete penetrance and variable age-dependent expressivity. It is caused by heterozygous mutations in neurofibromin 1 (NF1). These occur throughout the length of the gene, with no apparent NF1 frameshift mutations in children with NF1 ©FUNPEC-RP www.funpecrp.com.br Genetics and Molecular Research 14 (3): 8326-8337 (2015) hotspots. Even though some mutations have been found repeatedly, most have been observed only once. This, along with the variable expressivity, has made it difficult to establish genotype-phenotype correlations. Here, we report the clinical and molecular characteristics of four pediatric patients with neurofibromatosis type I. Patients were clinically examined and DNA was extracted from peripheral blood. The whole coding sequence of NF1, plus flanking intronic regions, was examined by Sanger sequencing, and four frameshift mutations were identified. The mutation c.3810_3820delCATGCAGACTC was observed in a familial case. This mutation occurred within a sequence comprising two 8-bp direct repeats (GCAGACTC) separated by a CAT trinucleotide, with the deletion leading to the loss of the trinucleotide and the 8-bp repeat following it. The deletion might have occurred due to misalignment of the direct repeats during cell division. In the mutation c.5194delG, the deleted G is nested between two separate mononucleotide tracts (AAAGTTT), which could have played a role in creating the deletion. The other two mutations reported here are c.4076_4077insG, and c.3193_3194insA. All four mutations create premature stop codons. In three mutations, the consequence is predicted to be loss of the GAP-related, Sec14 homology, and pleckstrin homology-like domains; while in the fourth, only the latter two domains would be lost.

Further genotype – phenotype correlations in neurofibromatosis 2

Clinical Genetics, 2010

Neurofibromatosis 2 (NF2) is caused by mutations in the NF2 gene predisposing carriers to develop nervous system tumours. Different NF2 mutations result in either loss/reduced protein function or gain of protein function (abnormally behaving mutant allele i.e. truncated protein potentially causing dominant negative effect). We present a comparison between the clinical presentations of patients with mutations that are predicted to produce truncated protein (nonsense/frameshift mutations) to those that results in loss of protein expression (large deletions) to elucidate further genotype-phenotype correlations in NF2. Patients with nonsense/frameshift mutations have a younger age of diagnosis and a higher prevalence/proportion of meningiomas (p = 0.002, p = 0.014), spinal tumours (p = 0.004, p = 0.004) and non-VIII cranial nerve tumours (p = 0.006, p = 0.003). We also found younger age of diagnosis of vestibular schwannomas (p = 0.007), higher mean numbers of cutaneous lesions (p = 0.003) and spinal tumours (p = 0.006) in these patients. With respect to NF2 symptoms, we found younger age of onset of hearing loss (p = 0.010), tinnitus (p = 0.002), paraesthesiae (p = 0.073), wasting and weakness (p = 0.001) and headaches (p = 0.049) in patients with nonsense/frameshift mutations. Our comparison shows, additional, new correlations between mutations in the NF2 gene and the NF2 disease phenotype, and this further confirms that nonsense/frameshift mutations are associated with more severe NF2 symptoms. Therefore patients with this class of NF2 mutation should be followed up closely.

Germline loss-of-function mutations in SPRED1 cause a neurofibromatosis 1–like phenotype

Nature Genetics, 2007

We report germline loss-of-function mutations in SPRED1 in a newly identified autosomal dominant human disorder. SPRED1 is a member of the SPROUTY/SPRED family 1 of proteins that act as negative regulators of RAS-RAF interaction and mitogenactivated protein kinase (MAPK) signaling 2 . The clinical features of the reported disorder resemble those of neurofibromatosis type 1 and consist of multiple café-au-lait spots, axillary freckling and macrocephaly. Melanocytes from a café-au-lait spot showed, in addition to the germline SPRED1 mutation, an acquired somatic mutation in the wild-type SPRED1 allele, indicating that complete SPRED1 inactivation is needed to generate a café-au-lait spot in this syndrome. This disorder is yet another member of the recently characterized group of phenotypically overlapping syndromes caused by mutations in the genes encoding key components of the RAS-MAPK pathway 3,4 . To our knowledge, this is the first report of mutations in the SPRY (SPROUTY)/SPRED family of genes in human disease.