Spinal neurofibromatosis without cafe-au-lait macules in two families withnull mutations of the NF1 gene

Spinal neurofibromatosis (SNF) is considered to be an alternative form of n eurofibromatosis, showing multiple spinal tumors and cafe'-au-lait macules. Involvement of the neurofibromatosis type 1 (NF1) locus has been demonstra ted, by linkage analysis, for three families with SNF. In one of them, a co segregating frameshift mutation in exon 46 of the NF1 gene was identified. In the present study, we report four individuals from two families who carr y NF1 null mutations that would be expected to cause NF1. Three patients ha ve multiple spinal tumors and no cafe'-au-lait macules, and the fourth has no clinical signs of NF1. In the first family, a missense mutation (Leu2067 Pro) in NF1 exon 33 was found, and, in the second, a splice-site mutation ( IVS31-5A -->G) enlarging exon 32 by 4 bp at the 5' end was found. The latte r mutation has also been observed in an unrelated patient with classical NF 1. Both NF1 mutations cause a reduction in neurofibromin of similar to 50%, with no truncated protein present in the cells. This demonstrates that typ ical NF1 null mutations can result in a phenotype that is distinct from cla ssical NF1, showing only a small spectrum of the NF1 symptoms, such as mult iple spinal tumors, but not completely fitting the current clinical criteri a for SNF. We speculate that this phenotype is caused by an unknown modifyi ng gene that compensates for some, but not all, of the effects caused by ne urofibromin deficiency.