Neurofibromatosis type 1 pathophysiology

Neurofibromatosis type 1 is an autosomal syndrome caused by a mutation in gene NF1 of chromosome 17, wich leads to a defective neurofibromin 1 protein. This mutation constitutes a phenotype with very pathognomonic features that are not always present; among them are the presence of Lisch nodules, neurofibromas, scoliosis, cognitive disabilities, vision disorders, multiple café au lait spots and epilepsy.

• Neurofibromin 1 (NF1) gene, is a large multi-domain protein, of approximately 250 KDa, containing 2,818 amino acids,^[1][2] located in chromosome 17,^[3] codes for the GTPase-activating protein, neurofibromin.^[4][5] This protein, is a tumor suppressor expressed in many cells, primarily in neurons, glial, immune cells, endothelial cellls of the adrenal medulla, Schwann cells and early in melanocyte development.^[6][7]
• Neurofibromin works by downregulating the RAS/MAPK pathway, by accelerating hydrolisis and preventing cell proliferation.^{[5][6] [8][9]}
• Neurofibromin interacts cytoskeletal microtubular and microfilaments for proper neuronal development.^[1][10]
  

• Neurofibromatosis type 1 is an autosomal syndrome, although, roughly 50% of gene mutations arise from de novo events.^[1]
• The large size of the NF1 gene (350 kb with 60 exons) predisposes to a high mutation rate, with approximately one mutation occurring per 10,000 gametes.^[11]
• NF1 mutations lead to protein truncation (loss of neurofibromin expression), which in turn produces increased cell growth and survival through expression of RAS to ultimately increase chances for malignant transformation.^[7][12][1]
• More than 3,000 NF1 gene mutations have been recognised.^[7]
• Loss of neurofibromin leads to formation of skin lesions, tumours and skeletal abnormalities.^[7]
• Patients with neurofibromatosis type 1 syndrome have a higher incidence of GI, liver, lung, bone, thyroid, breast and ovarian cancers.^[1][13]
• Nerve sheath tumours can arise from benign neurofibromas and these compose the first cause of death in individuals with neurofibromatosis type 1.^[1]
• Patients with neurofibromatosis type 1 can present a wide variability of clinical features, even in the same family since mutation mechanisms are so vast. Interestingly, patients can present traits limited to a part of their body (mosaicism).^[7]
• Therapies are focused to inhibit RAS phenylation to block oncogenic RAS signalling.^[1]
  

• Neurofibromatosis type 2 is a genetic condition which may be inherited or may arise spontaneously. It is caused by NF2 gene(Merlin gene) mutation in chromosome 22 and presents with bilateral vestibular schwannomas(acoustic neuromas).^[14]
• Neurofibromatosis type 1 is part of the group of neurocutaneous disorders called phakomatoses, some of the most famous conditions from this group are:
  • Tuberous sclerosis
  • Sturge-Weber
  • Von Hippel-Lindau disease
  • Ataxia telangiectasia

• The most common non-­neoplastic manifestations are cafe-au-lait macules, which is a very sensitive finding when they appear in large quantities.^[7][15][16]
• Dysplasia of the long bones and sphenoid wings, fractures, and pseudoarthrosis are common findings in patients with neurofibromatosis type 1.^[16][17] They occur due to osteoblastic and osteoclastic dysfunction which lead to decreased mineralization.^[7]
• The defects in bone observed in individuals with neurofibromatosis type 1 are due to the loss of both copies of NF1 in osteoclasts and/or osteoblasts.Osteoblast dysfunction following NF1 loss results in an increased generation of pyrophosphate, which inhibits bone mineral (hydroxyapatite) production and bone mineralization, causing reduced bone density and a higher risk of bone fracture.^[7][18]
• Lisch nodules are hyperpigmented hamartomas of the iris, which are seen in 95–100% of adults with neurofibromatosis type 1.^[16][17]
• Neurofibromas are benign peripheral nerve sheath tumors that arise from Schwann cells, and represent the most frequent type of tumors in patients with neurofibromatosis type 1; they can be divided as dermal and plexiform neurofibromas.^[7][19]
• Optic gliomas are the most common brain tumors in neurofibromatosis type 1, they are observed in 15–20% of children younger than 7 years.^[16][20]
• Several types of cerebrovascular disease, including stenotic or occlusive disease, vascular dilatation or aneurysm, arteriovenous fistula, moyamoya syndrome, or vascular proliferation have been consistently found in biopsies of patients with neurofibromatosis type 1.^[16][21]
  

• Cafe au-lait macules consist of a dense population of melanocytes with biallelic NF1 inactivation.^[7][15]
• Neurofibromas are benign peripheral nerve sheath tumors composed of neoplastic Schwann cells, fibroblasts, blood vessels, and mast cells.^[16]
• Optic pathway gliomas are composed of astrocytes, oligodendrocytes, neurons, microglia and progenitor or stem cells.^[7][22]
  

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