The Adult with Neurofibromatosis
by Beth A. Pletcher, MD, May 1999

Although the estimated incidence of neurofibromatosis type 1 (classic NF) is felt to be 1:3000, the actual incidence is probably quite a bit higher due to ascertainment bias and mildly symptomatic patients. In infancy and early childhood the primary clinical features are multiple café-au-lait spots (CALS) and gradual appearance of axillary and/or inguinal freckles. Even though subcutaneous and cutaneous neurofibromas can appear at any age, puberty is a typical time for these benign lesions to first appear. Plexiform neurofibromas can also occur at any age and more often present as diffuse and less firm subcutaneous lesions with or without overlying hyperpigmentation. During pregnancy many women with NF1 note increasing numbers of neurofibromas or increasing size of pre-existing lesions. Optic gliomas occur in about 10-15% of children (more common in Caucasians), rarely present after the age of ten and most often before age five. Also, long bone lesions (pseudarthroses) are more often diagnosed in infancy or childhood but can lead to long term disability following casting, bracing and in severe cases, amputation. Conservative orthopedic management in recent years has decreased the need for amputation and many more limb sparing procedures are now clinically available.

• Cutaneous neurofibromas are often cosmetically worrisome but rarely present serious medical concerns. However, a painful or rapidly growing neurofibroma deserves prompt medical attention and resection should be considered in these cases. Because neurofibromas can undergo malignant transformation, patients should be cautioned to seek care if there is a sudden change in any lesion. Neurofibromas located on the scalp, buttocks, back or thorax, because of continual pressure or irritation, can cause significant discomfort and may need to be removed as well.

• Plexiform neurofibromas can occur anywhere and tend to extend locally along tissue planes and may even invade other soft tissues and bone. They are much more difficult to resect and also generally cause greater disability and discomfort than discreet neurofibromas. Plexiform neurofibromas have a predilection to appear in the upper eyelid, along the extremities and may even be seen on the soles of the feet. Periorbital plexiform neurofibromas may lead to visual loss due to obstruction of the pupil from ptosis and retro-orbital extension can lead to proptosis and/or optic nerve compression. Large plexiform neurofibromas occurring in the mediastinum and along extremities may undergo malignant degeneration with neurosarcomas representing a significant cause of mortality in young adults with NF.

• Paraspinal masses, extradural and intradural spinal tumors are not uncommon in adults with NF. Symptoms of weakness, pain or sensory changes should alert the clinician to possible problems in this area. MRI represents the mainstay of diagnostic testing with decisions about surgical intervention made in consultation with neurologic and neurosurgical specialists. Weakness, paraplegia or even quadriplegia may progress rather rapidly and should prompt immediate evaluation.

• Hypertension in adults with NF poses a more difficult diagnostic dilemma. While essential hypertension occurs in many adults with NF, two additional causes of hypertension must always be considered. First, pheochromocytomas are a rare cause of hypertension in the general population but are not rare in patients with NF. Many adults with NF (particularly those with a slightly younger age of onset of hypertension) have a pheo rather than run of the mill essential hypertension. Such patients are more likely to have intermittent hypertension that is difficult to control and responds only transiently to pharmacologic agents. Work-up for a pheo would include initial screening for catecholamines, metanephrines and vanillylmandelic acid (VMA) in a 24 hour urine collection. If a pheo is then suspected, a more thorough search can be done looking for adrenal and/or extra-adrenal lesions using a combination of MRI and nuclear scanning methods. Second, renal artery stenosis frequently associated with the pathologic finding of fibromuscular dysplasia is also common in individuals with NF and should be considered in both younger and older patients with hypertension. Lesions are most often located in the proximal renal arteries with renal artery aneurysms or abdominal aorta coarctation also seen on occasion. Renal arteriography remains the mainstay of diagnosis with selective renal vein measurements of renin often helpful in localization. Management should be individualized and both medical and surgical intervention may be considered. There are reports of great success in treating these lesions with angioplasty in selected cases although some patients may be managed with pharmacologic agents alone.

• Intracranial tumors (excluding optic gliomas in children) are relatively rare in adults with a lifetime incidence probably under 5%. That being said, patients with NF need to be monitored more carefully and should have head imaging studies (i.e. MRI with contrast) if they develop symptoms of increasing frequency or severity of headaches, headaches occurring in the morning with or without emesis, or headaches associated with other neurologic symptoms. Because migraines may also occur in individuals with NF, history should include items used to elicit such a diagnosis since evaluation and treatment for this entity would differ considerably.

• Scoliosis is a common clinical finding in NF and may be associated with severe and rapidly progressive curves requiring surgical intervention. The majority of patients with clinically significant scoliosis will present before adulthood and progression will generally cease once bony epiphyses have closed. Occasionally severe kyphosis can result in paraplegia. Spinal fusion for NF patients with significant curves presents an additional operative challenge and may require a more aggressive surgical approach for optimal results.