Neurofibromatosis Type 1

Definition

• Type of Neurofibromatosis
• Autosomal Dominant neurocutaneous condition that can involve almost any organ
  • Disease in which Schwann cells grow tumours in skin, skeleton and spinal nerve roots
• AD mutation in NF1 (tumour suppressor) gene, Ch17
  • Leads to loss of function of the protein product neurofibromin (a GTPase)
  • Leads to unopposed RAS activity & dysregulated cell proliferation

Clinical

• Café-au-lait macules
  • The presence of six or more café-au-lait macules is highly suggestive
• Neurofibromas
  • Benign tumors of peripheral nerve sheaths
  • Can become malignant Malignant peripheral nerve sheath tumor
• Freckling of groin and armpit
• Lisch spots
  • Pigmented spots (hamartomatous lesions) of the iris
• Optic Glioma / Meningiomas / Astrocytomas
• Pheochromocytoma (in 3-5% of pts)
• Sarcoma, GIST, Breast cancer
• Learning disabilities
• Pancreatic neuroendocrine neoplasms

Pathology

• 50% of patients present with new (rather than inherited) mutations
• Neurofibromas:
  • Composed of Schwann cells, Fibroblasts, Mast cells & vascular components
  • Can develop at any point along a nerve
• Types: Cutaneous, Subcutaneous & Plexiform
• On skin, appear: Brown, pink or skin coloured
• < 10% develop cancerous growths

Diagnosis

• Revised diagnostic criteria for neurofibromatosis type 1 (NF1)
  • A: The diagnostic criteria for NF1 are met in an individual who does not have a parent diagnosed with NF1 if 2 or more of the following are present:
    • ≥ 6 Café au lait spots

      • 5 mm if pre-puberty

      • 15 mm if post-puberty

    • Freckling in the axillary or inguinal region*
    • 2 or more neurofibromas of any type or 1 plexiform neurofibroma
    • Optic pathway glioma
    • 2 or more iris Lisch nodules
    • A distinctive osseous lesion such as sphenoid dysplasia, anterolateral bowing of the tibia, or pseudarthrosis of a long bone
    • A heterozygous pathogenic neurofibromin 1 (NF1) variant with a variant allele fraction of 50% in apparently normal tissue such as white blood cells
  • B: A child of a parent who meets the diagnostic criteria specified in A merits a diagnosis of NF1 if 1 or more of the criteria in A are present

Investigations

• Genetic testing 

Management

• The approach to treatment of the various tumors associated with NF1 depends upon the type of tumor, its effect on adjacent tissues, and related complications.
• Surgical treatment and pain management of plexiform neurofibromas (PNs) can be challenging.
• Surgical resection often is limited to debulking of a specific area of a large lesion.
• Progressive or symptomatic plexiform neurofibromas may be treated with mitogen-activated protein kinase kinase (MEK) inhibitors

Prognosis

• Estimated 3-15% lifetime risk of malignant disease
• Change in size / pain could be a sign of malignant transformation

Pictures

• Café-au-lait macules
• Lisch nodules (picture below)
• Subcutaneous neurofibromas