Dissecting the clinical phenotype associated with mosaic type-2 NF1 microdeletions

Patients with large deletions of the NF1 gene and its flanking regions (termed NF1 microdeletions) generally exhibit more severe clinical manifestations of neurofibromatosis type-1 (NF1). Here, we have investigated the clinical phenotype displayed by eight patients harbouring mosaic type-2 NF1 microdeletions. These patients did not exhibit facial dysmorphism, attention deficit hyperactivity disorder, delayed cognitive development and/or learning disabilities, cognitive impairment, congenital heart disease, hyperflexibility of joints, large hands and feet, muscular hypotonia or bone cysts. All these features have previously been reported to be disproportionately associated with germline (i.e. non-mosaic) type-1 NF1 microdeletions as compared with the general NF1 population. Plexiform neurofibromas were also less prevalent in patients with mosaic type-2 NF1 microdeletions as compared with patients carrying constitutional (germline) type-1 NF1 microdeletions. Five of the eight patients with mosaic type-2 deletions investigated here had 20-250 cutaneous neurofibromas, but only one of them exhibited a high load of cutaneous neurofibromas (N > 1,000). By contrast, a previous study indicated a high burden of cutaneous neurofibromas (N > 1,000) in 50% of adult patients with germline type-1 NF1 deletions. Patients with germline type-1 NF1 microdeletions have been reported to have an increased lifetime risk of 16-26% for a malignant peripheral nerve sheath tumour (MPNST). In this study, one of the eight investigated mosaic type-2 microdeletion patients developed an MPNST. We conclude that patients with mosaic type-2 NF1 microdeletions may also be at an increased risk of MPNSTs despite their generally milder disease manifestations as compared with germline type-1 NF1 microdeletions.