Neurofibromatosis type I (NF1) is an autosomal dominant familial tumor syndrome 
characterized by the presence of multiple benign neurofibromas. In 95% of NF1 
individuals, a mutation is found in the NF1 gene, and in 5% of the patients, the 
germline mutation consists of a microdeletion that includes the NF1 gene and 
several flanking genes. We studied the frequency of loss of heterozygosity (LOH) 
in the NF1 region as a mechanism of somatic NF1 inactivation in neurofibromas 
from NF1 patients with and without a microdeletion. There was a statistically 
significant difference between these two patient groups in the proportion of 
neurofibromas with LOH. None of the 40 neurofibromas from six different NF1 
microdeletion patients showed LOH, whereas LOH was observed in 6/28 
neurofibromas from five patients with an intragenic NF1 mutation (P = 0.0034, 
Fisher's exact). LOH of the NF1 microdeletion region in NF1 microdeletion 
patients would de facto lead to a nullizygous state of the genes located in the 
deletion region and might be lethal. The mechanisms leading to LOH were further 
analyzed in six neurofibromas. In two out of six neurofibromas, a chromosomal 
microdeletion was found; in three, a mitotic recombination was responsible for 
the observed LOH; and in one, a chromosome loss with reduplication was present. 
These data show an important difference in the mechanisms of second hit 
formation in the 2 NF1 patient groups. We conclude that NF1 is a familial tumor 
syndrome in which the type of germline mutation influences the type of second 
hit in the tumors.