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Neurofibromatosis Type 1: Diagnostic and Therapeutic Radiologic Imaging

Elizabeth Brouillette

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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.

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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

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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

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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

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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

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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

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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.

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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

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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

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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.

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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.

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