NF1 is a progressive multisystem disorder, which includes some features that occur early in life and others that do not appear until later. It displays a wide range of variable expression, including differences within the same family. The hallmark feature is the neurofibroma, a benign tumor that arises from the nerve sheath. There are two major types of neurofibromas: focal growths and plexiform neurofibromas. Focal neurofibromas arise as discrete nodules at some point along a nerve. They may occur at the nerve root, along the length of a nerve, or at a nerve ending. They may be visible as growths that protrude above the surface of the skin, or cause a swelling due to subcutaneous growth. Dermal neurofibromas often present with a purplish discoloration to the overlying skin. They are soft and painless, but may have significant cosmetic impact. Internal neurofibromas are usually asymptomatic, but some can cause symptoms of nerve compression such as pain or sensory loss, or may invade the spinal canal and cause cord compression. Focal neurofibromas are rarely present in young children, but gradually increase in number over the years. Tumors often first appear or grow during puberty, or in women, during pregnancy. The numbers of neurofibromas vary widely in individuals, from a few small tumors to uncountably many.
Plexiform neurofibromas consist of a diffuse enlargement of multiple fascicles of a nerve. Some extend over a considerable distance and include multiple nerve branches. Plexiform neurofibromas may be associated with overgrowth of soft tissues, causing significant cosmetic deformity and functional impairment. Most, if not all, occur congenitally. The tumors tend to grow during the early childhood years, and often remain static in size thereafter. Plexiform neurofibromas that occur near the surface of the body may invade the skin, causing thickening and palpable cords of tumor. Some are associated with irregular hyperpigmentation of the overlying skin.
NF1 usually presents with pigmentary features. Multiple cafe-au-lait macules begin in early childhood, and skin-fold freckles appear between 3 and 5 years of age. Iris Lisch nodules are melanocytic hamartomas that are useful in diagnosis but are clinically silent. Other common nontumor manifestations include skeletal dys-plasia, macrocephaly, vascular dysplasia, and learning disabilities. Skeletal dysplasia most often affects long bones, particularly the tibia. Tibial dysplasia presents in infancy and creates risk of fracture. Orbital dysplasia occurs in association with trigeminal plexiform neurofi-broma. Children with NF1 tend to be short and have relative or absolute macrocephaly. Vascular dysplasia consists of nodular proliferation within the arterial wall and may cause arterial stenosis or hemorrhage due to dissection. Learning disabilities occur in at least 50% of affected individuals and include both verbal and nonverbal problems. There may also be attention deficit disorder and neuromotor problems.
Individuals with NF1 are at increased risk for malignant neoplasms. The most common is optic glioma, affecting approximately 15%. Most of these tumors are asymptomatic, but progressive growths can impair vision or cause neuroendocrine disturbance. Gliomas can occur elsewhere in the brain, especially the brainstem. Malignant peripheral nerve sheath tumors are sarcoma-like lesions that arise from neurofibromas (usually plexiform neurofibromas), with a lifetime risk around 10%. Other malignancies that are associated with NF1 include juvenile myelomonocytic leukemia and rhabdomyosarcoma.
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