The patches of cutaneous pigmentation, appearing shortly after birth and occurring anywhere on the body, constitute the most obvious clinical expression of the disease. They are approximately oval in shape and vary in size from a 1 to 2 mm to many centimeters, and in color from a light to dark brown (the term café-au-lait is applied) and are rarely associated with any other pathologic state (Fig. 37-8).
They do not appear to change in number as the patient ages, but they do enlarge during puberty and become more pigmented. In a survey of pigmented spots in the skin, Crowe and associates found that 10 percent of the normal population had one or more spots of this type; however, anyone with more than 6 such spots, some exceeding 1.5 cm in diameter in postpubertal individuals (bigger than 0.5 mm in prepubertal ones), nearly always proved to have neurofibromatosis. Of their 223 patients with NF, 95 percent had at least 1 spot and 78 percent had more than 6 large spots. Freckle-like or diffuse pigmentation of the axillae and other intertriginous areas (groin, under breast) and small, round, whitish spots are characteristic, as pointed out by Crowe; when coupled with café-au-lait patches, they are virtually pathognomonic of the disease.
The appearance of multiple cutaneous and subcutaneous tumors in late childhood or early adolescence is the other principal feature of the disease. The cutaneous tumors are situated in the dermis and form discrete soft or firm papules varying in size from a few millimeters to a centimeter or more (molluscum fibrosum; Fig. 37-9). They assume many shapes—flattened, sessile, pedunculated, conical, lobulated, and so on. They are flesh-colored or violaceous and often topped with a comedo. When pressed, the soft tumors tend to invaginate through a small opening in the skin, giving the feeling of a seedless raisin or a scrotum without a testicle. This phenomenon, spoken of as “buttonholing,” is useful in distinguishing the lesions of this disease from other skin tumors, for example, multiple lipomas. A patient may have anywhere from a few of these dermal tumors to hundreds.
The subcutaneous neural tumors, which are also multiple, take two forms: (1) firm, discrete nodules attached to a nerve or (2) an overgrowth of subcutaneous tissue, sometimes reaching enormous size. The latter, which are called plexiform neuromas (also pachydermatocele, elephantiasis neuromatosis, la tumeur royale), occur most often in the face, scalp, neck, and chest, and may cause severe disfigurement. When palpated, they feel like a bag of worms or strings; the bone underlying the tumor may thicken. Neurofibromas are easily distinguished from lipomas, which are soft, unattached to the skin or nerve, and not accompanied by any neurologic disorder. An exception to this last statement is the rare disease of multiple symmetrical lipomatosis with axonal polyneuropathy (Launois-Bensaude disease). As a rule, congenital neurofibromas tend to be highly vascular and invasive and are especially prominent in the orbital, periorbital, and cervical regions. They may be accompanied by hypertrophy of a segment of the body (a sign also seen in the arteriovenous malformation of Klippel-Trenaunay-Weber syndrome). When the hyperpigmentation lesion overlies a plexiform neurofibroma and extends to the midline, one should suspect an intraspinal neurofibroma tumor at that level.
Another unique finding is the Lisch nodule. This is a small whitish spot (actually a hamartoma) in the iris that was present in 94 percent of Riccardi’s type 1 cases, but was not found in patients with NF2 or in normal individuals (Fig. 37-10 and below).