Neurofibromatosis 1 (NF1) is a multisystem disorder characterized by multiple café au lait macules, intertriginous freckling, multiple cutaneous neurofibromas, and learning disability or behavior problems. About half of people with NF1 have plexiform neurofibromas, but most are internal and not suspected clinically. Plexiform neurofibromas can cause pain, neurologic deficits, and abnormalities of involved or adjacent structures. Less common but potentially more serious manifestations include optic nerve and other central nervous system gliomas, malignant peripheral nerve sheath tumors, scoliosis, tibial dysplasia, vasculopathy, and gastrointestinal, endocrine, or pulmonary disease.

Neurofibromatosis 2 (NF2) is characterized by bilateral vestibular schwannomas with associated symptoms of tinnitus, hearing loss, and balance dysfunction. The average age of onset is 18 to 24 years. Almost all affected individuals develop bilateral vestibular schwannomas by age 30 years. Affected individuals may also develop schwannomas of other cranial and peripheral nerves, meningiomas, ependymomas, and, very rarely, astrocytomas. Because NF2 is considered an adult-onset disease, it may be underrecognized in children, in whom skin tumors and ocular findings (retinal hamartoma, thickened optic nerves, cortical wedge cataracts, third cranial nerve palsy) may be the first manifestations. Mononeuropathy that occurs in childhood is an increasingly recognized finding; it frequently presents as a persistent facial palsy or hand/foot drop.

Watson syndrome (WTSN) is an autosomal dominant disorder characterized by pulmonic stenosis, cafe-au-lait spots, decreased intellectual ability (Watson, 1967), and short stature (Partington et al., 1985). Most affected individuals have relative macrocephaly and Lisch nodules and about one-third of those affected have neurofibroma (Allanson et al., 1991).

Legius syndrome is characterized by multiple café au lait macules without neurofibromas or other tumor manifestations of neurofibromatosis type 1 (NF1). Additional clinical manifestations reported commonly include intertriginous freckling, lipomas, macrocephaly, and learning disabilities / attention-deficit/hyperactivity disorder (ADHD) / developmental delays. Current knowledge of the natural history of Legius syndrome is based on the clinical manifestations of fewer than 300 individuals with a molecularly confirmed diagnosis; better delineation of the clinical manifestations and natural history of Legius syndrome will likely occur as more affected individuals are identified.

A variant of neurofibromatosis type 1 characterized by the combination of features of neurofibromatosis type 1, such as café-au-lait spots, iris Lisch nodules, axillary and inguinal freckling, optic nerve glioma and multiple neurofibromas; and Noonan syndrome, with features such as short stature, typical facial features, congenital heart defects and unusual pectus deformity.

Approximately 5 to 20% of all patients with neurofibromatosis type I (162200) carry a heterozygous deletion of approximately 1.4 Mb involving the NF1 gene and contiguous genes lying in its flanking regions (Riva et al., 2000; Jenne et al., 2001), which is caused by nonallelic homologous recombination of NF1 repeats A and C (Dorschner et al., 2000). The 'NF1 microdeletion syndrome' is often characterized by a more severe phenotype than that observed in the majority of NF1 patients. In particular, patients with NF1 microdeletion often show variable facial dysmorphism, mental retardation, developmental delay, an excessive number of early-onset neurofibromas (Venturin et al., 2004), and an increased risk for malignant peripheral nerve sheath tumors (De Raedt et al., 2003).