The Neurofibromatoses

Abstract

Background: Neurofibromatosis of types 1 and 2 (NF1, NF2) and schwannomatosis are the diseases that make up the neurofibromatosis spectrum. With respective incidences of 1 in 3000, 1 in 33 000, and 1 in 60 000 births, they form part of the group of rare tumor-suppressor syndromes. They give rise to a greater tumor burden for the nervous system than any other type of neoplastic disease. New approaches to symptomatic treatment are emerging.

Methods: This review is based on articles retrieved by a selective literature search on the pathogenesis, diagnosis, and treatment of the neurofibromatoses.

Results: NF1 and NF2 are monogenic diseases, while the genetics of schwannomatosis is complex. The three entities are clinically and pathophysiologically distinct. An important aspect of their tumor biology is the alternation of growth phases and growth pauses. Correlations between genotypes and phenotypes are variable, while new mutations and genetic mosaics are common. Ninety-nine percent of patients with NF1 have six or more café-au-lait spots by the age of 12 months; 90-95% of patients with NF2 develop bilateral vestibular schwannomas. In schwannomatosis, pain is the most prominent symptom; two-thirds of those affected develop spinal schwannomas. The severity and prognosis of these disorders are not closely correlated with the radiological findings; rather, neurologic deficits, malignant transformation, and psychosocial stress are of greater clinical importance. Advances in knowledge of pathophysiology have led to the development of targeted treatment approaches. Examples include the off-label treatment of vestibular schwannomas with bevacizumab and of plexiform neurofibromas with MEK inhibitors.

Conclusion: Patients with neurofibromatoses need individualized care. They should be treated in centers of expertise where interdisciplinary consultation is available and new types of pharmacotherapy can be provided.

Figure 1:

Features of type 1 neurofibromatosis (NF1) a) There are small, nodular cutaneous neurofibromas (arrows) and changes of skin pigmentation. A large plexiform neurofibroma (*) extends across the right side of the neck to the back and arm. Scoliosis (arrowheads) and café-au-lait spots (star) are also seen, but are not specific and occur in other genetic syndromes as well (Silver–Russell syndrome, multiple endocrine neoplasia type IIb [MEN IIb], Legius syndrome, McCune–Albright syndrome, etc.). b) MRI reveals the nodular-infiltrative growth pattern of the plexiform neurofibroma (PNF). Further tumor manifestations are seen around the thoracic and abdominal organs.

Figure 2

Clinical features of type 2 neurofibromatosis: bilateral vestibular nerve schwannomas are pathognomonic.

Figure 3

Typical MRI findings: bilateral vestibular nerve schwannomas (VS) in a patient with type 2 neurofibromatosis. Collision of a VS with a meningioma, as seen here on the patient’s left side, is also not unusual.

eFigure

Treatment options for vestibular nerve schwannomas (VS) in type 2 neurofibromatosis (NF2). Possible constellations in the management of VS in NF2, depending on tumor size and residual auditory function: a) large tumor on both sides b) asymmetrical tumor distribution A “sleeper” is an inactive brainstem implant that is only activated in the event that the patient also loses hearing in the other ear. ABI, Auditory brainstem implant