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INTRODUCTION

KEY POINTS

  • Neurofibromatosis type 1 (NF1) is a neurocutaneous genetic disorder caused by mutation of the NF1 gene on chromosome 17q11.2, whereas neurofibromatosis type 2 (NF2) is a genetically distinct disorder caused by mutation of the gene on chromosome 22q12.2 encoding merlin.

  • The worldwide prevalence of NF1 is approximately 1 in 3000 individuals with no relation to race.

  • NF1 is characterized by café-au-lait spots, freckling, neurofibromas, Lisch nodules, cerebral tumors, and osseous abnormalities.

  • Clinical manifestations of NF1 are variable in each individual, and the overall degree of severity and complications are not predictable.

  • Patients with NF1 have increased risk of malignancies.

  • Age-specific annual monitoring and treatment of complications by appropriate specialists are important for management of NF1.

Neurofibromatosis type 1 (NF1; Online Mendelian Inheritance in Man [OMIM] #162200), also known as von Recklinghausen disease, is one of the most common neurocutaneous genetic disorders.1 NF1 is characterized by café-au-lait spots, freckling, neurofibromas, Lisch nodules, cerebral tumors, and osseous abnormalities. Clinical manifestations are variable even within the same family members. However, it has been estimated that two-thirds of patients with NF1 have a relatively mild phenotype without life-threatening complications.

Neurofibromatosis type 2 (NF2; OMIM #101000) is a genetically distinct disorder caused by mutation of the gene on chromosome 22q12.2 encoding merlin.2 NF2 is much less common than NF1 with an incidence of 1 in 25,000 live births (prevalence of 1 in 100,000 individuals).3 NF2 is characterized by tumors of the central nervous system (vestibular schwannomas, meningioma, and glioma), schwannoma of the peripheral nervous system, and juvenile posterior subcapsular lenticular opacities/juvenile cortical cataract.4 Cutaneous tumors are seen in 59% to 68% of patients and are usually schwannomas (not neurofibromas). Although pigmented spots are seen in 33% to 48% of patients, they are often singular and are not typical features of NF2. Therefore, pigmented spots are not included in the diagnostic criteria for NF2.

The primary emphasis of this chapter is the more common NF1.

EPIDEMIOLOGY

The worldwide prevalence of NF1 is approximately 1 in 3000 individuals with nearly 100% penetrance.5 The birth incidence of NF1 is similar to its prevalence. No racial predilection has been reported for NF1. About half of NF1 cases are nonfamilial sporadic cases. Mosaic NF1 (segmental neurofibromatosis) is characterized by a regionally limited distribution of the features of NF1. The estimated incidence of mosaic NF1 is approximately 1 in 36,000 to 40,000 individuals (0.003%) in the general population.6

The overall risk of malignancies in patients with NF1 is 36% by the age of 70 years, being 2.7 times higher than that in the general population in the United Kingdom.7 The most common associated malignancies in NF1 are malignant peripheral nerve sheath tumor (MPNST) (14% risk; standardized incidence ratio [SIR], 122) and brain tumors (7.9% risk; SIR, 22.6). In addition, women with NF1 (<50 years old) ...

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