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

Abstract

Spinal neurofibromas are found in up to 38% of NF1 patients. However, they cause clinical implications only in about 5% of the patients. In contrast, multiple symptomatic spinal neurofibromas are the main clinical finding in patients with familial spinal neurofibromatosis. Familial spinal neurofibromatosis has been considered to be a distinct clinical form of neurofibromatosis. Linkage analysis in two families and identification of a NF1 gene mutation in a third family strongly associate spinal neurofibromatosis with the NF1 gene. We describe a NF1 patient who satisfies the NIH diagnostic criteria and has severe spinal involvement with bilateral spinal root neurofibromas at every level. A recurrent splice site mutation (IVS19b-3C4G) was identified in the NF1 gene in the patient. We discuss the possibility that the clinical picture of this patient represents an additional example of spinal neurofibromatosis. By comparison of the clinical expression of NF1 in this patient and that in another patient with the identical mutation the hypothesis that spinal neurofibromatosis is associated with a particular mutation is highly unlikely. The involvement of other genes linked to the NF1 gene or modifying genes is currently the most likely explanation for the clinical phenotype of spinal neurofibromatosis.

Evaluation of genotype-phenotype correlations in neurofibromatosis type 1

“…46 A recurrent NF1 splice site mutation (IVS19b-3 CRG) was identified in a patient with spinal neurofibromatosis. 47 In the present study, patients with spinal neurofibromatosis also had different types of mutations. These findings indicate that specific NF1 gene mutations are not associated with spinal neurofibromatosis.…”

Can the diagnosis of NF1 be excluded clinically? A lack of pigmentary findings in families with spinal neurofibromatosis demonstrates a limitation of clinical diagnosis

“…Conversely, multigenerational familial clustering of the spinal NF1 phenotype with few cutaneous features is well recognised,17 suggesting that individuals carrying mutations causing this phenotype may be more likely than the NF1 population in general to have children. Missense mutations have been highly overrepresented in the variants reported in association with spinal NF1 (nine of 15 mutations included in the human genome mutation database18), and a significant further proportion have been substitutions affecting splicing 13 19 20. It has therefore been postulated that the different clinical phenotype observed in these families could be a result of milder molecular effects of these mutations,17 but tissue specific effects may also be of importance.…”

Benign Tumors of the Spine

“…Fewer than 5% of patients with NF1 have symptomatic spinal involvement, whereas up to 38% may have asymptomatic lesions diagnosed by MRI. 28 Spinal involvement is more common in patients with NF2 than in those with NF1.…”