6.1.1 Neurofibromatosis

Autosomal dominant (57%) or sporadic (43%) neurocutaneous disease characterized by a predisposition to develop multiple benign mesenchymal tumors, esp. neurofibromas, and multi-organ involvement.

Mutations in suppressor genes.

NF1: Neurofibromin, an essential negative regulator of Ras cellular proliferation pathways (chromosome 17q11.2).

NF2: Merlin (or schwannomin), important in anchoring of the cytoskeleton to the cell membrane, the organization of cell membrane proteins and interaction with cytosolic proteins (chromosome 22q12).

NF1:

• Skin: cutaneous neurofibromas (localised, buttonhole phenomenon, 75-99%), plexiform neurofibromas (large nodular or diffuse tumors, 30%), café-au-lait macules (>5, larger than 1.5 cm, 86%), axillary and inguinal freckling (84%)

• Eyes: pigmented iris hamartomas (Lisch nodules) (40%)

• Skeletal system: kyphoscoliosis (25%), long-bone dysplasia (2%), sphenoid wing dysplasia (<1%)

• CNS: optic pathway glioma (13%), cerebral glioma (1%)

• Other organs: malignant peripheral nerve sheath tumor (6%), hydrocephalus (3%), renal artery stenosis (1%), pheochromocytoma (1%)

NF2:

• Vestibular schwannomas (usually bilateral; 95%)

• Schwannomas on other intracranial nerves and in the spinal compartment

• Meningiomas, ependymomas, and gliomas

Molecular classification

• NF1: skin findings (+/-), neurofibromas, Lisch nodules.

• NF2: bilateral acoustic schwannomas (rarely skin findings of NF1).

Severity classification (DNB classification)

Dermatological manifestations

D1 Pigmented macules and a few neurofibromas

D2 Pigmented macules and many neurofibromas

D3 Numerous neurofibromas (>1000 in number, >1 cm in size)

D4 Severe plexiform neurofibromas or malignant peripheral nerve sheath tumor

Neurological manifestations N0 No neurological symptoms

N1 Neurological symptoms (e.g. paralysis or pain) or/and abnormal neurological findings

N2 Severe or progressive neurological symptoms

Bone manifestations

B0 No bone lesion

B1 Mild or moderate bone lesion (deformity in spine or extremities that does not need treatment)

B2 Severe bone lesion (dystrophic type or spine deformity that needs surgical treatment (e.g. scoliosis or kyphosis), severe bone deformity in extremities (e.g. pseudarthrosis, fracture) or defect of the skull or facial bone.

Cutaneous neurofibroma: Non-encapsulated lesion in the dermis representing a proliferation of all elements of peripheral nerves. The cells have wavy serpentine nuclei and pointed ends. There is stromal mucin deposition and fibroplasia. Mast cells are easily recognisable. Axon course may be illustrated with immunohistochemical stains for neurofilament.

Plexiform neurofibroma: Tumour growth within and irregularly expanding over a nerve bundle.

The course of the disease is not predictable and depends on the individual organ manifestations and the severity grade. Cutaneous neurofibromas and café-au-lait macules can increase with progressing age but are always benign, whereas plexiform neurofibromas have a potential for malignant transformation into malignant peripheral nerve sheath tumors. Half of the patients with optic pathway glioma will develop visual symptoms. Long-bone dysplasia can result in pseudarthrosis.

NF1 life time risk for malignant nerve sheath tumor-associated mortality 8-13%. Significant excess mortality in the ages of 10-20 years (5.2x) and 20-40 years (4.2x), in females > males, mostly due to malignant nerve sheath tumors (60%).

The spectrum of complications in NF1 patients includes osteoporosis, learning disability, pregnancy and delivery complications, cardiovascular abnormalities, speech defects and cancer.

Rare complications (6%):

• Malignant transformation of plexiform neurofibromas (neurofibrosarcomas)

• Increased risk for lymphoma and leukemia

Genetic counselling.

Excision of disturbing or painful neurofibromas, which may also be destroyed with CO2 or Erb: YAG laser. Methylphenidate (0.5-0.8 mg/kg/d) has a short-term effectiveness in NF1 children with ADHD-like symptoms.

Chemotherapy does not reduce mortality in metastasized neurofibrosarcoma. Multidisciplinary approach to diagnosis and treatment.