According to the National Institute of Health Consensus Development Conference6, at

least two of the following criteria must be present to make the diagnosis of NF-1:
1. Five or more cafe-au-lait spots larger than 5 mm in diameter in prepubertal patients; six or
more cafe-au-lait spots larger than 15 mm in diameter in postpubertal patients
2. Two or more neurofibromas of any type, or one plexiform neurofibroma
3. Axillary or inguinal freckling
4. Optic glioma
5. Two or more Lischs nodules
6. A distinctive osseous lesion (pseudoarthrosis of the tibia or sphenoid wing dysplasia)
7. A first-degree relative diagnosed with NF-1 in accordance with the above criteria
Cutaneous neurofibromas are present in almost all adult NF1 patients. Plexiform
neurofibromas (PNFs), a more diffuse type of tumour, are present in 3050 per cent of NF1
patients, and some 1015 per cent of these benign tumours are transformed to malignant
peripheral nerve sheath tumours (MPNSTs), the main cause of morbidity in NF1.
Inactivating mutations in the NF 1 and NF 2 genes, both, inherited and/or new germline
mutations, are responsible for the development of the phenotypes of the diseases. The NF1 gene,
located on 17q11.2, encodes for a protein also known as neurofibromin. Neurofibromin functions
as a tumor suppressor by negatively regulating mitogenic Ras signalling through a GTPase
activating protein (GAP), which is essential for NF 1-associated tumorigenesis. Particularly in
neurocutaneous tissues, loss-of-function mutations result in increased Ras activity, causing
increased proliferation and tumorigenesis.
The NF2 gene is located on 22q12.2 and encodes for merlin (schwannomin). The gene is
much smaller than neurofibromin, which explains the much lower mutation rate of NF2 as
compared to NF1. Merlin is considered to act as a regulator of growth, motility, and cellular
remodeling by inhibiting the transduction of extracellular mitogenic signals such as CD44mediated contact-dependent inhibition of proliferation. Correspondingly, Merlin has been shown
to prevent epidermal growth factor receptor (EGFR) signalling, known to induce cellular
proliferation