Chapter 206: Neurofibromatosis

Patient Story

A 12-year-old asymptomatic girl was noted to have six café-au-lait macules (Figure 206-1A) and axillary freckles (Figure 206-1B) during a general physical examination. No neurofibromas were noted at the time. Although neither parent had neurofibromatosis, that diagnosis was entertained. She was referred to an ophthalmologist and monitored closely for scoliosis. In time, she began to develop neurofibromas and was eventually diagnosed with sporadic neurofibromatosis type 1 (NF-1).

Introduction

NF-1 is a common autosomal dominant disorder that predisposes to tumor formation. Café-au-lait spots are often the first clinical sign. Other clinical signs include neurofibromas, axillary or inguinal freckling, optic gliomas, Lisch nodules, and sphenoid bone dysplasia. Treatment at present is early recognition and monitoring for complications such as cognitive dysfunction, scoliosis or other orthopedic problems, tumor pressure on vital structures, or malignant transformation.

Synonyms

Café-au-lait spots and café-au-lait macules are synonyms.

Epidemiology

• NF-1 is relatively common—Birth incidence is 1 in 3000 and prevalence in the general population is 1 in 5000.¹

• Autosomal-dominant inheritance; however, up to 50 percent of cases are sporadic.¹

• Diagnosis is typically made during childhood.

Etiology and Pathophysiology

• Mutations in the NF-1 gene (on the long arm of chromosome 17) result in loss of function of neurofibromin, which helps keep protooncogene ras (which increases tumorigenesis) in an inactive form.

• Loss of neurofibromin results in increased protooncogene ras activity in neurocutaneous tissues, leading to tumorigenesis.¹

Risk Factors

A first-degree relative with NF-1.

Diagnosis

For a diagnosis of NF-1, patients need to have at least 2 of the following:²

• Two or more neurofibromas (Figures 206-2 and 206-3) or one or more plexiform neurofibromas (Figures 206-4 and 206-5).

• Six or more café-au-lait spots, 0.5 cm, or larger before puberty and 1.5 cm or larger after puberty (Figures 206-6 to 206-9).

• Axillary or inguinal freckling (Figures 206-1 and 206-9).

• Optic glioma.

• Two or more Lisch nodules (melanotic iris hamartomas; Figure 206-10).

• Dysplasia of the sphenoid bone or dysplasia/thinning of long bone cortex.

• A first-degree relative with NF-1.