Von Recklinghausen Disease Management

Once a patient has been diagnosed or is strongly suspected to have Von Recklinghausen disease (neurofibromatosis-1, NF-1), management should be under a team of pediatricians, neurologists, dermatologists, and genetic scientists.

At Each Visit

Disease evaluation should include:

• Visual evaluation especially in young children who may not realize or complain that their vision is affected
• Monitoring for signs of cognitive difficulty
• Monitoring on each follow-up visit for new symptoms and signs which might indicate complications, especially malignancies
• Yearly surveillance of pediatric patients who have uncomplicated NF-1

Older patients may choose to come in once a year for follow up, but for adults below 25 years old, psychological support and genetic counseling is highly advisable, as well as education about the course and prognosis of the condition.

If older adults are affected severely, lifelong monitoring in a special clinic will be necessary. Patients with mild NF-1 should know what complications may arise and be encouraged to come in for follow-up when they need to. They should have at least a yearly blood pressure check. They should also be aware of the symptoms of a malignant peripheral nerve sheath tumor and neurologic complications such as spinal cord compression. They may also be strongly encouraged to be part of a support group.

Specific Treatment

Neurofibromas are benign tumors of the peripheral nerve sheaths, usually occurring in late adolescence, and commonly remain asymptomatic by themselves. However, they may catch on clothing, become irritated, or sting, especially when the weather is hot or dry. Emollients and moisturizers may help with this problem, whereas antihistamines generally do not help nor mast cell inhibitors. Such symptoms may necessitate skilled cosmetic removal or laser ablation–the latter only for small growths because of the increased probability of hypertrophic scarring and of later recurrence.

If the neurofibroma is subcutaneous, it may be tender or cause tingling along the course of the nerve fibers of the nerve from which it arises. However, removal may require expert care to avoid damage to the underling nerve. These, like the cutaneous neurofibromas, rarely undergo malignant transformation.

Because laser ablation cannot be recommended at present, café-au-lait macules or freckles may be a source of emotional turmoil to some sensitive patients who may be advised to camouflage them. Hypopigmentation of skin patches may also occur in these patients and should be treated the same way. However, the nevus anemicus and Campbell de Morgan spots, or cherry angiomas, need no specific management.

Management of Plexiform Neurofibromas

Plexiform neurofibromas have a tendency to elongate along the course of the nerve of origin, including its branches. More than one tumor may grow along the same nerve trunk. They infiltrate underlying and surrounding soft tissue and may induce overgrowth of the bone. They are known to grow deep under the surface in some cases, but their presence is often indicated by a sizable pigmented area of skin over these tumors. They grow quite irregularly, and if on the face, they appear within three years of birth. Their removal is complicated by their propensity to encroach on neighboring soft tissue, including the blood vessels supplying the nerve itself. The removal of such could lead to dangerous bleeding.

Drug therapy is being explored to limit this dangerous surgical route in plexiform tumors. These include inhibitors of farnesyl transferase, drugs that inhibit angiogenesis, and fibroblast inhibitors. These therapeutic methods, however, are still under investigation. Radiation therapy is not recommended as it may trigger malignant change in these unpredictable tumors.

Malignant peripheral nerve sheath tumours (MPNST) may grow in 8–13% of NF-1 patients, usually between the ages of 20 and 35. They tend to remain hidden, may spread far and wide, and are difficult to treat. They arise most commonly from plexiform neurofibromas, and may cause any of the following disturbing symptoms:

• Pain which is sufficient to impair sleep, lasting more than a month, over a plexiform or subcutaneous neurofibroma
• Recent neurologic symptom or sphincter deficit
• Change from soft to hard tumor
• Rapid enlargement

Such symptoms in an NF-1 patient should be taken seriously even if no neurofibroma is palpable at that site, as the tumor may be deep-seated.

Surveillance should be especially meticulous in individuals who have any of the following risk factors:

• Personal history of cancer
• Family history of cancer
• History of radiation therapy
• Optic nerve or pathway glioma
• Deletion of the whole gene
• More than one subcutaneous neurofibroma
• Neuropathy due to neurofibromatosis

One tool that has proven its value in helping to distinguish between MPNST and benign plexiform neurofibromas is the fluorodeoxyglucose positron emission tomography (FDG-PET) which is based on the assessment of glucose metabolism within the cells.

Treatment of MPNST is by done complete excision, paying attention to obtaining tumor-free margins to prevent recurrence. For large tumors that are over 5 cm in diameter, adjuvant radiotherapy may help. It is also useful in preventing recurrence of high-grade lesions and lesions with tumor-positive margins. Chemotherapy may be used to reduce tumor size before surgery as well as for palliation in patients with metastasis.

Management of Other Complications

Any headache with vomiting or visual symptoms should be taken as a medical emergency; an intracranial catastrophe must be immediately ruled out. Intracranial tumors must be diagnosed and followed up according to their probable course. Optic pathway gliomas are usually treated with chemotherapy and sometimes surgical debulking to relieve pressure on the orbits or the optic chiasma.

Glomus tumors caused by arteriovenous anastomosis may occur in NF-1 patients and may cause great pain. Once they are diagnosed as such, local excision is curative.

Cognitive impairment should be monitored. Appropriate remedial teaching should be given, bearing in mind that a low IQ is common, as well as behavioral disturbances such as poor sleep, reduced socialization skills, attention deficit-hyperactivity disorder, and autism spectrum disorders. A baseline assessment of the child’s development is required at first contact, and then repeated yearly, with the findings being used to set up an action plan for the child.

Skeletal growth should be monitored annually for pseudoarthrosis, bowing of the legs, or kyphoscoliosis, especially if there are breathing problems such as sleep apnea or snoring. Bone abnormalities are increased in this group, and osteoporosis is more probable, making surgical management more taxing.

Other complications to be assessed include:

• Hypertension
• Renal artery stenosis
• Pheochromocytoma
• Gastrointestinal problems due to a gut neurofibroma, carcinoid tumors, and other stromal tumors
• Seizures which need to be controlled with medication. Such patients should be counseled before becoming pregnant and put on folic acid 5 mg a day before conception, with careful monitoring of the anticonvulsant medication in view of possible teratogenicity.

Any child born to a mother with NF-1 should be kept under observation for at least 5 years before concluding that there are no signs of the syndrome.