7.2.2.2 Optic Pathway Glioma

Optic pathway gliomas (OPG) are low-grade pilocytic astrocytomas seen in 15–20% of NF1 patients (Fig. 7.2). They usually present as unilateral lesions and bilateral involvement is believed to be pathognomonic of NF1 [17]. OPGs typically involve the optic nerve, but affect the chiasm and postchiasmal regions in 40–70% of patients [18, 19–22]. Tumors arising in the orbit typically result in proptosis, visual loss, visual field defects, relative afferent papillary defect, optic-disk edema or atrophy, and strabismus [22, 23]. Precocious puberty and neurological defects may be associated with chiasmal and postchiasmal OPGs encroaching on the hypothalamus and adjacent brain tissue. Tumors of the optic nerve are more indolent and less symptomatic than those involving the chiasm and postchiasmal visual pathway. In comparison to 30% of patients with optic nerve glioma, 60% of patients with chiasmal and postchiasmal OPGs develop visual loss and field defects [23, 24]. Radiographic progression of OPGs is also more commonly seen in chiasmal and postchiasmal tumors. However, the largest retrospective study to date found no correlation between tumor location and an increased risk for future treatment [22].

7.2.2.3 Neurofibroma of the Eyelid and Orbit

Solitary and plexiform neurofibromas of the eyelid are typical cutaneous manifestations of NF1. Depending on localization and size, eyelid neurofibromas may lead to ptosis of the upper eyelid, which in turn may

Fig. 7.2 Computerized tomogram scan of a typical optic nerve glioma. Reproduced with permission from: Singh et al. [228]

cause visual impairment and amblyopia in children. Orbital neurofibromas may cause proptosis and may be combined with the anomalous development of the sphenoid bone, presenting as pulsating exophthalmus. Symptomatic plexiform neurofibroma in adult NF1 patients has been shown to be less than 2%.

7.2.3 Systemic Manifestations

7.2.3.1 Café-au-lait Spot

Café-au-lait spots present as flat cutaneous hyperpigmentation on the eyelids, around the neck, under the breasts, and in the axilla and groin. They are often the earliest clinical signs of NF1 and are usually noticeable at birth. These lesions increase in number and size during childhood such that virtually all NF1 patients are affected by age 3. Other cutaneous lesions include axillary and intertriginous freckling.

7.2.3.2 Neurofibroma

Neurofibromas are the hallmark finding of NF1. They arise from the endoneurium of the peripheral nerve sheath and present as multiple, discrete tumors on the face, hands, and trunk. Based on their appearance and extent of involvement, neurofibromas can be classified as cutaneous, subcutaneous, and nodular or diffuse plexiform. Cutaneous neurofibromas usually emerge in adolescence and increase during pregnancy. These soft tumors are mostly asymptomatic but can itch and sting occasionally. Subcutaneous neurofibromas are firm, cause pain and neurological deficits, and can undergo malignant transformation. Plexiform lesions consist of a network of neurofibroma tissue that grows along the length of nerves and often involves multiple nerve fascicles, branches, and plexi [25]. Nodular plexiform lesions are confined to the nerve, but may encroach on the surrounding soft tissue. Diffuse plexiform neurofibromas are usually congenital or appear in early childhood, whereas nodular lesions develop later in life. Growth of neurofibromas is characterized by rapid enlargement in early childhood and adolescence, followed by periods of quiescence. Transformation of subcutaneous and plexiform neurofibromas to