Neurofibromatosis (NF) is an autosomal dominant disorder, probably of neural crest origin, that affects all 3 germinal layers; therefore, it can involve any organ system. NF is not a single entity but a group of heterogeneous multisystemic neurocutaneous disorders involving both neuroectodermal and mesenchymal derivatives (see the images below). The National Institutes of Health (NIH) Consensus Development Conference has defined 2 distinct types: neurofibromatosis type 1 (NF1; previously known as von Recklinghausen disease or generalized neurofibromatosis), which affects 85% of patients, and neurofibromatosis type 2 (NF2; previously known as central or bilateral acoustic neuromas/vestibular schwannomas), which affects 10% of patients.
Frontal skull radiograph in a patient with NF1 shows asymmetry of the orbits but a normal sphenoid ridge.
Plain radiograph in a patient with NF1 shows a left lambdoid defect (same patient as in the previous image).
Neurofibromas may affect any organ in the body. Discrete cutaneous and subcutaneous neurofibromas may develop at any time in life, but they occur infrequently before puberty. The total number of neurofibromas seen in adults with NF1 varies from a few to hundreds or even thousands. Additional cutaneous and subcutaneous neurofibromas continue to develop throughout life, although the rate of appearance may vary greatly from year to year.
Patients with NF1 are at increased risk of several malignancies, including gastrointestinal stromal tumors and malignant peripheral nerve sheath tumors.
Many women experience a rapid increase in the number and size of neurofibromas during pregnancy. Although the course of the pregnancy is normal in most women with NF1, serious complications can occur. Hypertension may first become symptomatic or, if preexisting, may become greatly exacerbated during pregnancy. Large pelvic or genital neurofibromas can complicate delivery, and cesarean delivery appears to be necessary more often in women with NF1 than in other women.
Hypertension is frequent in patients with NF1 and may develop at any age. In most patients, the hypertension is essential, but vascular dysplasia can occur in association with NF1 and may produce renal artery stenosis, coarctation of the aorta, or other vascular lesions associated with severe hypertension in adult patients with NF1.
Pheochromocytoma can cause severe hypertension in patients with NF1. Malignant neoplasms can occur in patients with NF1 at any age.
Intracranial manifestations of NF1 include development of optic pathway gliomas,
cerebral gliomas, hydrocephalus, schwannomas of the cranial nerves, vascular dysplasias, hamartomas, craniofacial plexiform neurofibromas, and spongiotic myelinopathy. NF1 can involve the spine, musculoskeletal system, and the gastrointestinal (GI) tract,
and NF1 is associated with neural crest tumors.
Multisystemic involvement is common, and a variety of problems may present in childhood,
including seizures and intellectual compromise, optic and acoustic involvement, intracranial and spinal tumors, and an increased incidence of malignancies, osseous defects and congenital dislocations, oral pathology, endocrine disorders, autonomic involvement, GI tract involvement, hypertension, and vascular anomalies.
The NIH has developed criteria for the diagnosis of NF1 and NF2.
The criteria for the diagnosis of NF1 are met in an individual if 2 or more of the following signs are found:
Six or more café au lait macules larger than 5 mm in the greatest diameter in prepubertal children and larger than 1.5 cm in postpubertal individuals
Two or more neurofibromas of any type or 1 plexiform neurofibroma
Multiple freckles (Crowe sign) in the axillary or inguinal region
A distinctive osseous lesion, such as sphenoid dysplasia or thinning of long bone cortex, with or without pseudoarthrosis
Two or more iris hamartomas (Lisch nodules) seen on slitlamp or biomicroscopy examination
A first-degree relative (parent, sibling, offspring) with NF1, as diagnosed by using the above criteria.
However, the NIH criteria are often insufficient for diagnosis of NF1 in young children who have multiple café au lait spots, no other NF1 features, and no family history of NF1. The overwhelming majority of these children later are diagnosed with NF1 because many of the features are rare in infancy but increase in frequency with age.
The preferred examination depends on the clinical problem to be investigated and the organ involved. Although plain radiographs may be sufficient for evaluating skeletal lesions, sonography and MRI may be the investigation of choice for peripheral nerve tumors and tumors of solid intra-abdominal organs or for associated renal artery stenosis. CT and MRI are preferred with spinal or intracranial lesions. Radionuclide scans are useful when functional imaging is needed in associated tumors such as a pheochromocytoma.
Whole-body MRI is the reference standard to identify nerve sheath tumors in NF1, because it provides a comprehensive characterization of the growth pattern, growth dynamics, and extent of nerve sheath tumors. For detection of malignant transformation of nerve sheath tumors, FDG PET/CT has a sensitivity of up to 100% and a specificity of 77-95%.
Plain radiographs are excellent at showing skeletal abnormalities of both the axial and appendicular skeleton. Similarly, chest radiography remains a useful technique for demonstrating thoracic cage abnormalities and pulmonary fibrosis. For intracranial, intrathoracic, or intra-abdominal pathology, cross-sectional imaging is more appropriate, and the modality chosen is tailored to the problem.
Radiographic findings of NF1 are nonspecific, but a fairly confident diagnosis can be made in the appropriate clinical setting when the index of clinical suspicion is high. Many neurofibromas may not be depicted on plain radiographs. NF shares many skeletal abnormalities with other syndromes; therefore, the differential diagnosis is extensive.