1 Neurofibromatosis Type 1: Diagnostic and Therapeutic Radiologic Imaging Elizabeth Brouillette
2
Abstract
Neurofibromatosis Type 1, also called von Recklinghausen’s Disease, is an
autosomal dominant genetic disorder that involves tumors along the nerves and affects
multiple systems throughout the body. The areas most prominently affected include the
skeletal, cardiovascular, neurological, endocrine, and ocular systems with some of the
most common clinical features of NF1 being short stature and macrocephaly. The tumors
can be malignant or benign and result in a variety of symptoms. A diagnosis requires the
presence of two or more major following clinical manifestations: six or more café-au-lait
spots on the skin (must be at least 0.5 cm in diameter in pre-pubertal individuals and 1.5
cm in post-pubertal patients), axillary or inguinal freckling, two or more cutaneous
neurofibromas, one plexiform neurofibroma, characteristic bony lesions, an optic glioma,
two or more iris Lisch nodules, or a first-degree relative with NF1. In order to aid in the
diagnosis process and therapeutic treatments, genetic testing and numerous radiologic
imaging modalities are utilized. Radiography, Computed Tomography, and Magnetic
Resonance Imaging help with the diagnosis and regular monitoring of tumors, whereas
Radiation Therapy can be an appropriate treatment.
3
Introduction
Neurofibromatosis Type 1 (NF1) is an autosomal dominant genetic disorder that
affects multiple systems throughout the human body and involves benign or malignant
tumors along the nerves. NF1, also called von Recklinghausen’s Disease, occurs in
approximately 1 in 3,000-4,000 people worldwide and an estimated 100,000 Americans
have this condition.1 NF1 results in a variety of clinical manifestations and multiple
criteria must be met before there is a true diagnosis of NF1. Patients undergo genetic
testing and radiologic imaging exams to aid in the diagnostic process, to regularly
monitor the tumors, and for potential treatment procedures. With a diagnosis by the
average age of ten, patients with NF1 are exposed to numerous imaging procedures at a
young age and continue to have these exams done throughout their lifetime.2
Methodology
Research was obtained through literature databases and online search engines. A
majority of the information came from 15 journal articles through electronic literature
databases. Primary databases utilized were Medline via PubMed and EBSCO, Cochrane
Library, and CINAHL. Other online sources and journal articles were retrieved using
Google Scholar and one book and four websites were used for their information. The key
search subject was “Neurofibromatosis Type 1” and primary search terms included: “NF1
and neurofibromas,” “NF1 and etiology,” “NF1 and diagnostic criteria,” “NF1 and
symptoms,” “NF1 and genetic testing,” “NF1 and radiologic imaging,” “NF1 diagnosed
on radiographic films,” “NF1 and Computed Tomography,” “NF1 and Magnetic
Resonance Imaging,” “NF1 and prognosis,” “NF1 and treatment,” “NF1 and Radiation
4
Therapy,” and “NF1 and mortality.” Most of the searches were refined to less than 10
years, however four of the cited sources used were written in the early 2000’s and one in
1998 and were therefore older than the 10-year mark.
Discussion
Neurofibromatosis is the general term for a nervous system disorder in which
normal cell growth is disrupted and the result is the formation of tumors on nerve tissue.
NF1, Neurofibromatosis Type 2 (NF2), and Schwannomatosis are three distinct disorders
that are categorized as forms of neurofibromatosis.2 All of the tumors originate in the
supporting cells that make up the nerve and myelin sheath that protects the nerves, rather
than the cells that actually transmit information. Each of these three disorders involves
tumor growth in the nervous system, but the type of tumor depends on which cells are
affected. Neurofibromas, which are tumors of the peripheral nerves, are most commonly
associated with NF1 and usually are located on or just under the skin. Neurofibromas are
not encapsulated and can appear as solitary tumors or as part of neurofibromatosis when
there are many. These tumors show proliferation of nerve sheath cells intermixed with
thick, wavy collagen bundles and there may be signs of myxoid degeneration, which is
when surrounding connective tissue turns into a mucus-like substance. On the other hand,
Schwann cell tumors, known as schwannomas, are mostly identified with NF2 and
Schwannomatosis. These tumors tend to be encapsulated, with the nerve fibers stretched
around the tumor as opposed to nerve fibers running through neurofibromas in NF1. 3
A mutation in the neurofibromin 1 gene on chromosome 17 results in the
production of these nervous system-associated tumors. The NF1 gene provides
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instructions for making the protein, neurofibromin, which acts as a tumor suppressor and
prevents cells from growing too quickly or uncontrollably. When there is a defect in this
gene, the neurofibromas associated with NF1 can form throughout the body along the
nerves. This genetic mutated gene that results in NF1 has an autosomal dominant pattern
of inheritance. However unlike most other autosomal dominant conditions, two copies of
the NF1 gene must be altered to trigger tumor formation in NF1.1 People affected with
this disorder are born with one mutated copy of the NF1 gene in each cell while the
second mutated copy of the gene can occur spontaneously throughout a person’s lifetime
in the cells surrounding the nerves, resulting in the tumors in 50% of cases.4
The diagnosis of NF1 is based upon clinical manifestations and genetic testing.
Diagnosis requires the presence of two or more of the following major criteria: six or
more café-au-lait spots on the skin (must be at least 0.5 cm in diameter in pre-pubertal
individuals and 1.5 cm in post-pubertal patients), axillary or inguinal freckling, two or
more cutaneous neurofibromas, one plexiform neurofibroma, characteristic bony lesions,
an optic glioma, two or more iris Lisch nodules, or a first-degree relative with NF1.5 In
some situations, the diagnosis can be made at birth but it can take several years for
enough signs to emerge to confirm a diagnosis on other patients. NF1 is a progressive
condition therefore different complications occur at various times throughout lifetime and
some may become worse. The café-au-lait spots (see Figure 1) and cutaneous
neurofibromas occur in at least 95% of patients, whereas other features occur in less than
1%.6
6
Symptoms associated with the skin are often most noticeable at birth.
Neurofibromas become apparent between the ages of 10-15, whereas other symptoms
usually have typical onsets by a certain age (see Table 1).(7,8) For 15 percent of
individuals with NF1, the symptoms can be debilitating.8
Genetic testing is an alternative method used to diagnose NF1 and can be helpful
to achieve an early diagnosis. Testing during the prenatal period helps determine the
possibility of developing NF1 based on family history of the disorder. However, genetic
testing is not able to predict the severity of NF1. Genetic testing is performed by either a
direct gene mutation analysis and/or a linkage analysis. The direct gene mutation analysis
tries to identify the particular gene change that causes NF1. If this test does not provide
enough information, then a linkage analysis is performed. This analysis involves testing
blood from family members to track the chromosome that carries the disease-causing
gene through two or more generations. Linkage testing is approximately 90 percent
accurate and the mutation analysis is 95 percent accurate in finding a mutation for NF1.8
Figure 1. Café-au-lait spots on the skin of NFI patient.6
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Clinical manifestation Frequency (%) Age of onset
Café-au-lait patches >99 Birth to 12 y
Skin-fold freckling 85 3 y to adolescence
Lische nodules 90-95 >3 y
Cutaneous neurofibromas >99 >7 y (usually late adolescence)
Plexiform neurofibromas 30 (visible) - 50 (on imaging) Birth to 18 y
Disfiguring facial plexiform neurofibromas 3-5 Birth to 5 y
Malignant peripheral nerve sheath tumour 2-5 (8-13% lifetime risk) 5-75 y
Scoliosis 10 Birth to 18 y
Scoliosis requiring surgery 5 Birth to 18 y
Pseudarthrosis of tibia 2 Birth to 3 y
Renal artery stenosis 2 Lifelong
Phaeochromocytoma 2 >10 y
Severe cognitive impairment (IQ < 70) 4-8 Birth
Learning problems 30-60 Birth
Epilepsy 6-7 Lifelong
Optic pathway glioma 15 (only 5% symptomatic) Birth to 7 y (up to 30 y)
Cerebral gliomas 2-3 Lifelong
Sphenoid wing dysplasia <1 Congenital
Aqueduct stenosis 1.5 Lifelong
General symptoms for those affected by NF1 can cause many abnormalities in
various systems of the body. The areas most prominently affected include the skeletal,
cardiovascular, neurological, endocrine, and ocular systems with some of the most
common clinical features of NF1 being short stature and macrocephaly. Along with these,
there is increased occurrence of hypertension, central precocious puberty, diencephalic
syndrome, growth hormone deficiency, and growth hormone hypersecretion.9 Other
features range from scoliosis and bone dysplasia in the skeletal system to blood vessel
dysplasia and cognitive learning problems. Learning disabilities and Attention Deficit
Hyperactivity Disorder occur in 60% of all patients but overall intelligence is usually
normal with less than 3% with mental retardation.8 Vision is also commonly affected in
Table 1. Frequency and age of onset of major clinical manifestations of NF1.7
8
NF1 with optic gliomas in 15% of patients.10 In addition, recent studies have shown that
Lisch nodules and choroidal abnormalities are becoming new diagnostic signs for NF1 in
children. According to a recent study published in 2015, 72 out of 140 pediatric patients
already diagnosed with NF1 also had an abnormality in their eye.11 With this early
detection, a NF1 diagnosis can be made before many other symptoms appear.
Besides noticeable symptoms and genetic testing, imaging plays a vital role in the
diagnosis of NF1. Neurofibromas, or benign tumors, are a major component of NF1 and
can be seen on radiograph if they involve the bone. They may appear as a lucent lesion
within the bone and usually have well defined margins (see Figure 2).12
In addition to the tumors themselves, spinal deformities occur in up to 50% of
patients with NF1 with scoliosis affecting 21% and being the most common
complication.12 Both scoliosis and kyphosis can easily be viewed on radiographs of the
spine and produce the short stature. Most common osseous spinal manifestations
associated with NF1 are vertebral body wedging and scalloping, pedicle erosion, foramen
Figure 2. Lucent lesions on anteriorposterior (AP) radiograph of
bilateral knees of patient with NF1.12
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enlargement, and penciling and spindling of transverse processes and ribs (see Figure
3).(13, 14)
In addition to abnormalities in the spine region, evidence of mesodermal dysplasia
that ultimately results in deficient bone formation in the pectoral and pelvis girdles and
bones of extremities can be seen on radiographs. Mesodermal dysplasia causes bowing of
long bones, pseudoarthrosis, and fibrocystic lesions that are common in NF1 patients.
Anterolateral bowing of the lower leg along with pseudarthrosis, a fracture that cannot
heal without intervention, can lead to a diagnosis of NF1. However, unlike the usual
diagnostic criteria of cortical thinning, recent studies have noted that bowed bones
associated with NF1 instead have cortical thickening and medullary narrowing when
viewed on radiograph (see Figure 4).15 Bowing typically occurs in the tibia as one of the
earliest signs of NF1 and results in limb shortening and eventually fracture.
Figure 3. AP radiograph of upper chest wall demonstrating rib
penciling.14
10
Radiography is not the only form of imaging that is used for diagnosis of NF1.
Computed Tomography (CT) and Magnetic Resonance Imaging (MRI) provide more
sensitive diagnostic pictures for NF1 than plain radiography, with MR imaging being the
best option. These types of imaging are utilized most often when looking for peripheral
tumors, tumors in abdominal organs, and lesions in the spine or brain to help define the
boundaries of the tumor and vascular supply.6 However, CT scans are most useful for
finding issues within the bone while MRI has better capabilities to see pathology with
greater soft tissue contrast resolution. Higher doses of ionizing radiation given to the
patient during a CT scan must be taken into account as well, as many NF1 patients will
receive numerous imaging exams throughout their lifetime. MRI on the other hand has
Figure 4. AP and lateral radiographs of the bowing of lower leg with the
appearance of cortical thickening with medullary canal narrowing.15
11
the added advantage of using magnets and radio waves to produce images of the body
and does not involve the possible harmful effects of ionizing radiation.
On CT scans, neurofibromas have a homogenous, smooth, round appearance with
distinct outlines and lower attenuation values of 20-25 Hounsfield units (HU) on
unenhanced scans and 30-50 HU on contrast-enhanced scans (see Figure 5).3 Studies
suggest that the amount of lipid-rich Schwann cells, adipocytes, fat, and collagen are the
reasoning as to why neurofibromas show up differently on scans with contrast and ones
without.3 CT is often used to look for NF1 complications within the thoracic, abdominal,
and pelvic regions of the body. In addition, neurofibromas may look different on each
scan due to the ubiquity of peripheral nerves within these areas. Neurofibromas can easily
be mistaken as other pathology processes on CT scans. For example, neurofibromas in
the mediastinum can resemble lymphoma, tuberculosis, and metastatic testicular cancer
while an intercostal neurofibroma in the ribs can mimic pulmonary or metastatic
adenocarcinoma or a pulmonary infection.4 For reasons like this, other tests and criteria
must be met before a true diagnosis of NF1 is confirmed.
12
MRI is useful as well for diagnostic imaging of NF1 with the ability to pinpoint
masses, tumors, deeper neurofibromas, and lesions associated with this disease. MRI is
argued to do the best job out of the other imaging options as far as searching for
pathology, especially in the brain and within the ocular pathway. T1 and T2 weighted
scans in multiple projections are used to aid with diagnosis. One of the indications of
NF1 that could potentially be seen on a T2 weighted brain MRI is a hyperintense lesion,
or what is also known as an unidentified bright object. These lesions are not one of the
main clinical manifestations used for diagnoses as mentioned previously, but they are
becoming more prevalent in patients diagnosed with NF1.16 Although a brain MRI is not
a routine exam for NF1 diagnosis, it has assisted in the identification of asymptomatic
structural abnormalities and have given a greater definition of the symptomatic structural
abnormalities.17 According to one study, these unidentified bright objects are typically
found in the brain stem, thalamus, and cerebellar peduncles on brain MRI scans (see
Figure 6).18
Figure 5. Contrast enhanced CT scan showing low-attenuation
in nodular lesions with scalloping of the vertebral body.3
13
Also, a target sign on a scan indicates a plexiform neurofibroma which is one of
the diagnosis criterion for NF1. This appearance is due to a central fibrocollagenous core
(T2-hypointense) surrounded by myxomatous tissue (T2-hyperintense) (see Figure 7).18
Once a patient has been diagnosed with
NF1 and their symptoms are under control, their prognosis is only slightly lower than the
normal person. Studies have shown that there is an 8-15 year decrease in life expectancy
for NF1 patients and there are excess deaths due to malignancy before the age of 50.(19, 20)
While there is only an estimated 3 to 5 percent chance that one of the benign tumors
becomes malignant, unusual tumors are more likely to occur with increased frequency of
NF1.2 Carcinoid, pheochromocytoma, brain tumors, chronic myeloid leukemia, and
Figure 6. Unidentified bright objects appearing on brain MRI on both
sides of the thalamus and left globus pallidus.18
Figure 7. Target-like appearance associated with plexiform neurofibromas
on brain MRI.18
14
malignant peripheral nerve sheath tumors all have been known to occur, as well as
common tumors such as breast, lung, kidney, color, and prostate.6 Other problems that
can lead to early death in NF1 patients include acute hydrocephalus, severe seizures,
progressive spinal cord intrusion by plexiform neurofibromas, unstable scoliosis, and
complications from hypertension.20
Not only does radiologic imaging aid in the diagnosis of NF1, but radiation
therapy can be a treatment option as well. Although there is no specific treatment yet for
NF1, surgery is most commonly recommended in addition to radiation therapy and
chemotherapy to remove and shrink tumors. Only the tumors that are painful, result in a
loss of function, or have grown quickly are likely removed during surgery. Even though
radiation therapy is not the first line of treatment for NF1, it can still be utilized to shrink
tumors. Many studies have shown that radiation therapy is most effective at relieving
symptoms and is used in conjunction with other treatment methods.21
However, it has been argued as to how beneficial radiation therapy really is for
treating NF1. Some studies claim that therapy should only be performed on malignant
tumors in fear that it could stimulate the growth of plexiform lesions.6 Other studies have
been constructed to look at how radiation therapy specifically affects children with NF1
too. Optic pathway gliomas associated with NF1 are known to greatly affect vision and
often undergo radiation therapy treatment to shrink these tumors. However, some results
show a significantly increased risk of secondary nervous system tumors in patients who
received radiation therapy treatment for optic pathway gliomas during childhood.22 Due
to these results and mixed outcomes from other studies in regards to the actual benefits of
radiation therapy, this treatment tends to be avoided unless absolutely necessary.
15
Conclusion
Although Neurofibromatosis Type 1 is a genetic disorder that involves multiple
symptoms and parts of the body, radiologic imaging still plays a crucial part in numerous
stages of this disorder. From radiographs, CT, and MRI scans throughout the diagnosis
process to radiation therapy during treatment, patients with NF1 become quite familiar
with many imaging modalities. Without imaging, the pathology and neurofibromas that
comprise most of this disorder would not be easily diagnosed and NF1 may not be caught
as early. Radiation therapy may not be the sole treatment for NF1 but radiologic imaging
as a whole can help these patients in more than one way. Not only are radiologic imaging
exams vital at the beginning stages of diagnosis and during treatment, but also to
continuously check the progress of tumors throughout the body during the patient’s
lifetime.
16
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