A Clinical Variant of Neurofibromatosis Type 1: Familial Spinal Neurofibromatosis with a Frameshift Mutation in the NF1 Gene

Abstract

Spinal neurofibromatosis (SNF) has been considered to be an alternative form of neurofibromatosis in which spinal cord tumors are the main clinical characteristic. Familial SNF has been reported, elsewhere, in three families-two linked to markers within the gene for neurofibromatosis type 1 (NF1) and the other not linked to NF1-but no molecular alterations have been described in these families. We describe a three-generation family that includes five members affected by SNF. All the affected members presented multiple spinal neurofibromas and café au lait spots, one member had cutaneous neurofibromas, and some members had other signs of NF1. Genetic analysis, performed with markers within and flanking the NF1 gene, showed segregation with the NF1 locus. Mutation analysis, performed with the protein-truncation test and SSCP/heteroduplex analysis of the whole coding region of the NF1 gene, identified a frameshift mutation (8042insA) in exon 46, which should result in a truncated NF1 protein. The 8042insA mutation was detected in all five family members with the SNF/NF1 phenotype. To our knowledge, this is the first time that a mutation in the NF1 gene has been associated with SNF. The clinical homogeneity in the severity of the disease among the affected members of the family, which is unusual in NF1, suggests that a particular property of the NF1 mutation described here, a gene closely linked to NF1, or posttranscriptional events are involved in this severe neurological phenotype.

A patient severely affected by spinal neurofibromas carries a recurrent splice site mutation in the NF1 gene

“…17 The splice mutation found in our patient has also been identified in a classic NF1 patient and her similarly affected father. 16 Spinal MRI of the latter patient did not reveal any evidence of spinal neurofibromas, hence demonstrating a lack of genotype-phenotype correlation with respect to this specific mutation.…”

Statistical Methods for Analysis of NF Clinical Data

“…In general, little evidence has been found of allele-phenotype correlations in NF1, although a more or less consistent phenotype occurs in association with deletions involving the entire NF1 gene (Tonsgard et al 1997;Dorschner et al 2000). Similar clinical features have been observed among affected members of a few families with the NF1 variants Watson syndrome (Allanson et al 1991), familial cafe-au-lait spots (Abeliovich et al 1995) or familial spinal neurofibromas (Pulst et al 1991;Poyhonen et al 1997;Ars et al 1998). This observation is consistent with an allele-phenotype correlation, but no consistent kind of NF1 mutation has been found in families with these or other phenotypic variants.…”

Clinical Risk Factors for Mortality in Patients With Neurofibromatosis 1

“…Affected patients may have typical cutaneous manifestations of NF1, although these are generally not severe. Ars et al 22 described a 3-generation family that includes 5 members affected by familial spinal NF; only 1 member had cutaneous neurofibromas. Poyhonen et al 23 described a family in which 7 members in 3 generations were affected; only 2 had possible dermal neurofibromas.…”