Neurofibromatosis Type 1 Workup
- Author: David T Hsieh, MD, FAAP; Chief Editor: Amy Kao, MD more...
The diagnosis of NF1 is usually made clinically, however, molecular testing may be helpful for younger patients with a single clinical finding, such as multiple café-au-lait spots in the absence of a positive family history.
Sequencing of the neurofibromin gene offers the highest detection rate and may approach 95% in clinically affected individuals.
97% of patients with NF1 are expected to meet clinical diagnosis by the age of 8 years. For those not meeting clinical criteria or for those that overlap with Legius Syndrome, molecular testing can be useful for confirmation. 
Legius Syndrome should be suspected in patients with macrocephaly, café-au-lait spots and axillary freckling and no NF1 tumors (neurofibromas, lisch nodules, optic gliomas or plexiform neurofibromas). Given that NF1 is more common, testing should start with NF1 sequencing and reflexing to SPRED1 if negative.
Neurofibromatosis type 1 (NF1) may be diagnosed by either of 2 methods during the prenatal period.
In a family with multiple affected members, linkage analysis can track the NF1 gene through the generations to determine which chromosome 17 region the fetus received. However, with advances in molecular diagnosis, family studies are rarely necessary.
For a parent with NF1 who is the only affected family member, gene sequencing can be used to identify a specific gene mutation. Identification of the mutation in the affected parent would permit prenatal diagnosis via amniocentesis or chorionic villus sample (CVS).
When a specific mutation is known, preimplantation genetic diagnosis can also be offered to couples using in vitro fertilization with selection of unaffected embryos for transfer.
Urinary free catecholamines (norepinephrine and epinephrine) as well as their metabolites (normetanephrine, metanephrine and vanillyl-mandelic acid) measured on a 24-hour urine collection are good biochemical screening tests for a suspected pheochromocytoma.
Plasma catecholamines may also be measured using liquid chromatography. Measurement of free plasma metanephrine is more sensitive in detection of a pheochromocytoma than plasma catecholamines.
Plain films may detect a variety of subtle and not so subtle bony abnormalities associated with NF1. See the image below.
Radiographs should be obtained when clinical findings suggest possible modeling defects of the long bones or ribs, possible bony erosion secondary to an adjacent plexiform neurofibroma, signs of scoliosis, or bone pain.
MRI or CT scan
The use of routine screening brain neuroimaging in patients with NF1 is controversial. This is mainly due to the lack of evidence that early detection reduces the rate of vision loss and that identifying and repeating interval imaging of asymptomatic optic pathway gliomas that never progress exposes young children to repeated sedations.
Some clinicians prefer to perform a baseline CT scan or MRI in children or adults at the time of diagnosis, subsequently recommending another imaging study only if neurological problems arise. Other clinicians feel that baseline studies are of limited value, since detecting an asymptomatic optic nerve glioma would probably not prompt medical intervention.
MRI is the preferred diagnostic head imaging study in NF1.
These bright spots seen on T2-weighted images generally do not enhance, cause no mass effect, and often resolve as the individual gets older.
They are believed to represent benign hamartomas in NF1 and, in some reports, are seen more often in children with NF1-related learning disabilities.
Brain CT scan or MRI should be considered to evaluate ventricular size when increasing head circumferences is noted in an infant or young child. Rarely, hydrocephalus and/or a Chiari type 1 malformation are seen in children and even adults with NF1.
MRI is also a valuable tool in evaluating the optic nerves or optic chiasm. See the image below.
- It is indicated for patients with optic nerve pallor, visual changes, proptosis, or precocious puberty.
- Thin cuts through the orbits and optic nerves are an ideal way to identify subtle optic nerve pathology.
Brain MRI should be considered in patients with headaches that are changing in quality or are increasing in frequency or intensity.
MRI has proven useful in evaluating internal lesions such as mediastinal masses, spinal cord tumors, deep plexiform neurofibromas, neurofibromas of the brachial or sacral plexus, and abdominopelvic lesions. Short T1-inversion recovery MR images can be used to accurately estimate the volume of a plexiform neurofibroma, which can be useful for both diagnosis and follow-up. In adults, unlike children where continued growth of plexiform lesions is quite common, rapid growth of a plexiform neurofibroma may portend malignant transformation.  Although MRI is not always helpful in differentiating benign peripheral nerve lesions from malignant lesions, central hypointense areas within a lesion noted on T2-weighted images (the so-called target sign) is more suggestive of a benign lesion.  On the other hand, MRI evidence of intratumoral lobulation or T1 high signal intensity are much more suggestive of malignancy. 
Positron emission tomography: F-18 fluorodeoxyglucose (FDG) positron emission tomography (PET) may be used to stage and follow up MPNSTs before, during, and after therapy. 
Gallium-67 scintigraphy may be used as a screening tool for patients with NF, especially patients with a large plexiform neurofibroma when there is concern about 1 or more areas having undergone malignant transformation. 
Electroencephalogram (EEG) is indicated in patients with symptoms suggestive of seizures. Seizures are reported more often in patients with NF1 than in the general population, occurring in between 4 and 7%.
MRI alone is generally sufficient for medical and/or surgical decision making. Occasionally, myelography is needed to clarify the extent of a spinal cord tumor.
Slit-lamp examination by an experienced ophthalmologist can provide key diagnostic information in older children and adults who have only a single clinical criterion such as multiple café-au-lait spots.
The occurrence of Lisch nodules appears to be age dependent; more than 95% of NF1-affected individuals older than 10 years have this iris finding.
This examination is invaluable in determining if parents of an affected child carry the NF1 mutation, even when the parent has no other signs of the condition.
Neurofibromas are generally well-differentiated tumors that contain elongated spindle-shaped cells as well as pleomorphic fibroblast-like cells. Rarely, inflammatory cells may be seen in these otherwise benign-appearing lesions.
Optic gliomas also are indolent, generally very low-grade lesions. In fact, optic nerve lesions associated with NF1 are less aggressive and respond more favorably to current therapies than optic nerve tumors in the general population.
Occasionally, a neurofibroma (typically large or deep plexiform neurofibroma or peripheral nerve sheath tumor residing within the brachial or pelvic plexus) undergoes malignant transformation to a neurofibrosarcoma. Unlike benign neurofibromas, neurofibrosarcomas are characteristically hypercellular with giant cells, increased numbers of mitoses, and vascular proliferation.
Because collections of malignant cells may be present between larger masses of benign cells in a plexiform neurofibroma, examining a plexiform tumor carefully (ie, taking samples from multiple regions to confirm that it is indeed benign) is essential.
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