Neurofibromatosis is a group of heterogeneous conditions. According to the National Institutes of Health (NIH) only two types of neurofibromatosis are defined: neurofibromatosis type 1 (NF1) also called von Recklinghausen’s disease; and neurofibromatosis type 2 (NF2) or bilateral eighth nerve schwannomas syndrome. The definition of “peripheral” and “central” neurofibromatosis, referred in the past to NF1 and NF2, respectively, has now been abandoned since the two conditions often have central and peripheral manifestations together.
Neurofibromatosis Type 1 (NF1)
NF1 is an autosomal dominant disorder with high penetrance but variable expressivity.
The gene responsible is on the long arm of chromosome 17 and normally acts as a tumour-suppressor oncogene. The lack of both copies of the gene induces the growth of a variety of neoplasms and non-neoplastic lesions. The major target organs are both peripheral (PNS) and central (CNS) nervous system and the skin, but virtually widespread multiple organ system involvement occurs. NF1 is far more common than NF2 and affects approximately 1 in every 2,000 – 3,000 births.
The diagnosis is based on physical examination, neuroimaging of the brain (and probably of the spine), slit-lamp examination of the eyes and genetic testing.
In most individuals the cutaneous findings are prominent and include caf-au-lait spots (CAL), usually becoming evident during the first year of life, superficial neurofibromas, which begin to appear at puberty, and axillary or inguinal freckling. Lisch nodules that represent iris hamartomas start to appear in childhood and are found in almost all adult patients on slit-lamp examination.
CNS characteristic manifestations, well documented by MR, include true neoplasms (all coming from astrocytes and neuronrs), as well as dysplastic and hamartomatous/heterotopic lesions. The most common CNS tumours are optic nerve, tectal plate and brain stem gliomas (usually pilocytic astrocytoma or low-grade glioma). In one third of patients, neurofibromas affecting intraorbital and facial branches of the cranial nerves (III – VI) and/or diffuse plexiform neurofibroma of the face and eyelids is present.
Intracranial dysplastic lesions appear as multiple bright foci on T2-weighted MR images in the brain stem, cerebellar white matter, dentate nucleus, basal ganglia, periventricular white matter, optic nerve, and optic radiations. They most probably represent either abnormal myelination or hamartomas. Unlike neoplasms these lesions do not show mass effect, oedema, contrast enhancement or haemorrhage on MR images. Basal ganglia T1-weighted hyperintensities seem to represent ectopic Schwann cells. Other classic features of NF1 are benign peripheral nerve sheath tumours (spinal root/dumb-bell neurofibromas), kyphoscoliosis, lateral thoracic meningocele, dysplastic enlargement of spinal foramina, sphenoid wing dysplasia that is one of the “distinctive bone lesions” of the disease and causes pulsatile exophthalmos in 5 – 10% of patients, pseudarthrosis, thinning of long bone cortex, macrocephaly, vascular dysplasias and endocrine tumours.
The diagnosis of NF1 is established when two or more of the anomalies listed in Table I are present.
|1.||Six or more caf-au-lait spots > 5 mm|
|2.||Two or more neurofibromas of any type or one plexiform neurofibroma|
|3.||Two or more Lisch nodules (iris hamartomas)|
|4.||Freckling in the axillary or inguinal areas|
|5.||Optic nerve glioma|
|6.||A distinctive bone lesion such as sphenoid wing dysplasia|
|7.||First degree relative with NF1|
Neurofibromatosis Type 2 (NF2)
NF2 is an autosomal dominant disorder with high penetrance due to a defect of chromosome 22. Its frequency is approximately 1 in 35,000 births. Clinical manifestations develop only in the second or third decade of life. Cutaneous manifestations are much less frequent in NF2 than in NF1. CNS lesions that develop in nearly all affected individuals include: intracranial tumours of schwann cells and meninges, nontumoral intracranial calcifications (choroid plexus), and spinal cord and nerve root neoplasms (mainly ependymomas, schwannomas and meningiomas).
Bilateral acoustic schwannomas are present in about 95% of affected patients and are considered the hallmark of the disease. They are seen on both CT and MR containing cystic degeneration and calcifications. On MR schwannomas are hypo-isointense on T1-weighted and hyperintense on T2-weighted images with strong, inhomogeneous enhancement after contrast administration. All the other cranial nerves (except the olfactory and optic nerves) can be involved by schwannomas, most frequently the trigeminal nerve.
Spinal cord ependymomas, multilevel spine meningiomas and schwannomas along the exiting nerve roots are nicely visualized by MR. Peripheral nerve roots schwannomas appear as well encapsulated masses, isointense on T1-weighted and hyperintense on T2-weighted images, with typical contrast enhancement. Spinal bony abnormalities secondary to tumours are reported in NF2, e.g. posterior vertebral scalloping and enlargement of neural foramina. No dural dysplasia are found, contrary to NF1. Other reported anomalies are: presenile posterior subcapsular/capsular cataracts (85%), peripheral cortical lens opacities and agenesis of the internal carotid artery.
|1.||Bilateral eighth nerve masses at imaging studies|
|2.||Unilateral eighth nerve mass plus two of the following:|
|meningioma, schwannoma of any cranial neves, presenile posterior subcapsular/capsular cataracts|