INTRODUCTION

Neurofibromatosis is a group of genetic diseases that predispose to both benign and malignant tumors encompassing neurofibromatosis 1, 2, and Schwannomatosis (6). Neurofibromatosis type 1, otherwise known as von Recklinghausen’s Disease, is the most common of these diseases with a prevalence of approximately 1/1900-1/3000 (1, 33). Clinically, NF1 manifests as increased risk for an array of benign and malignant tumors, as well as pigmentary findings such as café-au-lait spots, intertriginous freckling, and lisch nodules (24). This condition is usually diagnosed clinically in childhood and has many manifestions (33). Individuals with NF1 have a decreased life expectancy and suffer from a range of NF1 related comorbidities into adulthood including vision deterioration, significant disfigurement, neuropathic pain, hypertension, vasculopathy, osteoporosis, other skeletal manifestations, impairments in cognition and mood, and a variety of potentially life-threatening malignancies (33).

We report on a 36-year-old female with history of NF1 who presented to neurology clinic for consultation regarding headaches and facial pain after being lost to follow-up for several years.

CASE PRESENTATION 

A 36-year-old female with history of neurofibromatosis type 1 presented to neurology clinic for consultation regarding headaches and facial pain. She had an approximately 1 year history of worsening headaches in the right frontal and temporal area. The headaches were severe, lasting for several hours, and the pain was not relieved by acetaminophen. Complete ROS positive for problems with vision in the right eye and shortness of breath with exertion.

Past medical history was significant for GERD, acute gastritis, esophageal ulcer, essential HTN, asthma, uterine fibroids, pulmonic valve regurgitation, and steatosis of the liver. Her history was also significant for admission to the ICU one year prior following MVA at which time she was treated for multiple orthopedic and facial fractures.

During her hospitalization the patient had an MRI demonstrating stable right optic glioma, scattered dermal lesions suggestive of neurofibromas, and STIR hyperintense signal and enhancement throughout the right masticator space with bony remodeling suggestive of plexiform neurofibromas.

Surgical history included uterine myomectomy, ORIF for malleolar fracture, and debridement of subglottic stenosis following endotracheal intubation. Social history notable for learning challenges in high school and middle school. The patient graduated high school and did one semester of college.

Physical exam showed multiple widespread neurofibromas and multiple café-au-lait spots. Facial asymmetry was also noted, with the patient’s orbital ridge higher on one side, and minimal, flat left nasolabial fold. Neurologic exam was notable for visual acuity of 20/15 in the left eye, but light perception only in the right eye. Examination of cranial nerves III-XII was unremarkable. Motor exam showed normal muscle bulk and tone, with absent pronator drift and 5/5 strength in the bilateral extremities. The patient’s gait was normal, as were finger-to-nose, heel-to-shin, and tandem walking. Reflexes were 2+ throughout. Mental status exam was unremarkable.

Treatment plan

View MRIs

An MRI brain and orbits with and without contrast was ordered to reassess the lesions noted on her last MRI, and she was referred to nephrology, ophthalmology, OB/GYN, and dermatology for further evaluation and screening. The patient was also instructed to keep a headache diary and a 3-month follow-up for further evaluation was scheduled. She was already followed by orthopedics for a previous left ankle fracture repaired with open reduction and internal fixation and had been referred to neurosurgery for excision of multiple facial NFs.

Repeat MRI showed T2 and T2 FLAIR hyperintensities in the anterior right frontal corona radiata that were not significantly changed from previous studies, as well as stable optic nerve glioma. The enhancement, deformity, and atrophy of the right mandibular ramus with atrophy of right medial and lateral pterygoids which was previously noted as suggestive of possible plexiform neurofibroma was again noted without significant change. Scalp nodules representing neurofibromas showed mild progression. Also noted were mild changes of acute sinus disease mostly involving the sphenoid sinus and right maxillary sinus.

DISCUSSION

Neurofibromatosis type I, otherwise known as von Recklinghausen’s Disease, is relatively rare genetic disease with a prevalence of approximately 1/1900-3000 (1). It is characterized by the development of benign peripheral nerve sheath tumors, pigmentary abnormalities, and increased risk for a spectrum of malignancies (24, 33). NF1 is usually diagnosed clinically during childhood, and confirmatory genetic testing is rarely needed (24, 33). The diagnosis of constitutional (germline) NF1 is made clinically when at least 2 of the diagnostic criteria are met, or 1 for the child of a parent with NF1. The clinical criteria include at least 6 café-au-lait macules, intertriginous freckling, 2 or more neurofibromas or 1 plexiform neurofibroma, 2 lisch nodules or choroidal abnormalities, optic pathway glioma, and distinctive osseous findings (24). Clinical diagnosis is complicated by the existence of clinically similar entities such as Legius syndrome, Noonan syndrome, and constitutional mismatch repair deficiency syndrome. However, though these entities may share pigmentary findings with NF1, they do not share any of its other diagnostic criteria, and sensitivity and specificity of the diagnostic criteria increase with age due to disease progression (24).

Although genetic testing is not often needed to confirm a diagnosis of NF1, it may be used in clinically equivocal cases. As knowledge of genotype-phenotype mutations advances, genetic testing may also be increasingly pursued to elucidate the mutation involved in a particular case to better understand prognosis and guide future therapy and screening (27).

The genetic basis for NF1 is well studied and understood to be due to a loss of function mutation in a single NF1 allele on chromosome 17q11.2 (6, 23). This gene encodes neurofibromin, a large protein which acts as a tumor suppressor via suppression of RAS. Elevated RAS activity causes downstream activation of MEK and AKT, which in turn result in elevated mTOR activity leading to increased cell growth and proliferation (3, 9, 44).

The inheritance pattern of NF1 is autosomal dominant with complete penetrance and variable expressivity. However, the NF1 gene has a very high spontaneous mutation rate, and thus approximately 50% of cases are sporadic (23). The high mutation rate of the NF1 allele is also responsible for frequent postzygotic mutations resulting in a mosaic form of NF1(29). Mosaic NF1 is characterized clinically by a segmental distribution of café-au-lait macules or neurofibromas with at least one other finding of NF1 (11, 24, 37). Although mosaic NF1 is usually not heritable, it is possible for the gonads to be affected, in which case the pathogenic variant can be passed on to offspring (8).

Of note, many sporadic cancers contain NF1 gene mutations. However, one study comparing mutations in sporadic cancers to those in constitutional NF1 found significant differences in cancer type, as well as class and location of mutations. Most mutations in sporadic cancer were not predicted to be pathogenic (5).

Tumors, both benign and malignant, are an important source of morbidity and mortality in NF1. The most common benign tumors in NF1 are cutaneous neurofibromas (17, 30). These tumors typically begin to appear during puberty and increase in size and number with age, with periods of rapid growth occur during puberty and pregnancy (30, 33). These tumors can be associated with bleeding, tenderness, and pruritis, and often are very concerning to patients from a cosmetic standpoint (30, 43). These lesions can be removed via electrodesiccation, surgical excision, or CO2 laser treatment if painful or disfiguring (27, 33). All 3 are associated with high patient satisfaction (33).

Another common benign tumor in NF1 is the Optic Pathway Glioma (OPG), which occurs between 5% and 25% of patients (20, 25, 26). OPGs are classified by the WHO as class I astrocytomas, (21) and can arise at any point in the visual pathway (20). Although the exact protocol for screening in childhood Is controversial, the American Academy of Pediatrics recommends yearly screening to age 8, and every 2 years to age 18 (16). Some practices continue to screen through adulthood. In addition, yearly screening for precocious puberty may be beneficial (27). The precise clinical presentation of an OPG depends on its location (20). Benign gliomas can also appear elsewhere in the CNS in NF1 patients and are often incidental findings on imaging studies (6).

Once an OPG has been diagnosed, the best way to follow tumor progression is using serial visual acuity testing (26). Because OPGs typically cause deterioration in color vision, color vision testing can be useful in distinguishing between amblyopia and OPG progression (2). Although MRI is the recommended imaging modality for evaluating extent and progression of OPG, the American Academy of Pediatrics does not recommend its use as a screening tool due to inconsistent evidence that early detection reduced the rate of vision loss (20).

Although there are no clear guidelines for when to treat OPGs, treatment is typically considered when there is documented evidence of clinical or radiographic progression. Currently, Vincristine and Carboplatin combination therapy is considered the standard of care (20).

Plexiform neurofibromas are another common benign tumor in NF1, affecting about 50% of patients (34). They are known to have a faster growth rate than other neurofibromas, especially in childhood, and can cause severe facial disfigurement and decreased visual acuity. Due to invasion of surrounding structures, surgical resection is often impossible (20). Clinically they can have varied presentation, but when more superficial can feel like a “bag of worms” on palpation (31). Diagnostic evaluation for plexiform neurofibromas includes annual physical and neurological exam with regional MRI with contrast if suspected. Repeat MRI is recommended to reevaluate progression if malignant transformation is suspected due to worsening symptoms. Treatment options include surgical resection and recently approved MEK inhibitors such as Selumetinib (27).

Importantly, malignant peripheral nerve sheath tumors (MPNST) can arise from plexiform neurofibromas. These tumors are aggressive, metastasize early, and are often fatal. Early detection is key to improve survival, and surgical resection with clear margins is the mainstay of treatment. If there is clinical suspicion of malignant transformation due to rapid growth, functional impairment, or progressive persistent pain, regional contrast MRI is recommended. PET can also be used to confirm malignancy and guide biopsy (27, 33).

There is also an increased risk of breast cancer in those with NF1. Of note, breast cancer in NF1 has an increased 5-year mortality. Risk is greatest in those under 40, with earliest cases presenting around 30 years of age, falling to population risk at approximately 70 (36). The National comprehensive cancer network guidelines recommend an annual mammogram starting at age 30 and consider MRI with and without contrast from ages 30-50 for screening in patients with NF1. However, given the paucity of evidence on different screening modalities for breast cancer in the NF1 population, individual shared decision making is important (33). Bilateral mastectomy should be considered after diagnosis of breast cancer (27).

Individuals with NF1 are also at increased risk for pheochromocytomas, with incidence estimated at 0.1-5.7% (39). One study found a median age of 43, with 20% being multifocal and 12% malignant (4). Although screening of asymptomatic patients is not recommended, pheochromocytoma should be considered in the setting of hypertension, especially when it is resistant to treatment (27, 33). The preferred screening test is plasma free metanephrines, followed by 24-hour urine metanephrine and catecholamines if there is less than a four-fold elevation (33).

Other cancers that have been associated with NF1 include juvenile myelomonocytic leukemia, rhabdomyosarcoma, gastrointestinal stromal tumors, and thyroid cancers (36). In young adults, there is also a 10 to 50-fold increased risk for malignant gliomas (15), and thus adults with NF1 and signs of increased intracranial pressure, new onset seizures, or focal deficits should be promptly evaluated with neuroimaging (6).

Individuals with NF1 are often found to have hypertension (13), most commonly essential hypertension. Other causes of hypertension include pheochromocytoma, as discussed above, as well as renal artery stenosis (13). In patients under 30 with hypertension, or those who are pregnant or have abdominal bruits, renal artery stenosis should be evaluated preferably using MRA. CTA or spiral CT can be used in patients with renal impairment. Concomitant screening for pheochromocytoma is also recommended (33). Common vasculopathies other than renal artery stenosis include cerebrovascular vasculopathy and vasculopathy of the aorta (13). Screening for hypertension includes regular blood pressure measurements, starting in childhood (27).

Bony lesions and skeletal abnormalities are also extremely common in NF1, and sphenoid wing dysplasia, anterolateral bowing of the tibia, and pseudarthrosis of long bones are part of the diagnostic criteria (24). Aside from these characteristic osseous lesions, there is increased incidence of osteoporosis occurring at an earlier age than the general population (22), as well as scoliosis with onset during both childhood and adulthood (35). Clinical monitoring for scoliosis includes forward bend test, plain radiographs, and referral to orthopedics for consideration of bracing and surgery in case of concerning clinical findings. Screening for osteoporosis includes DEXA scan and vitamin D levels. Vitamin D and calcium supplementation are recommended. Treatment of osteoporosis does not differ from its treatment in the general population (33, 27).

Finally, it is important to recognize the prevalence of neurological and cognitive disorders in NF1 patients. One study of insurance claim data found that common neurological disorders include headaches, as in the case presented above, as well as epilepsy and neuropathic pain (28,33). These conditions are not treated differently than in non-NF1 populations. Two rarer neurologic complications are glomus tumors and neurofibromatosis 1 neuropathy. NF1 neuropathy is non-progressive polyneuropathy in adults (12). Glomus tumors are benign tumors typically found in the fingers and toes. These tumors can cause tenderness, paroxysmal pain, and cold sensitivity (34). Chronic pain not attributable to any anatomic lesion is also likely very common. Because of the higher incidence of neuropathy and chronic pain, NF1 patients should be screened for pain, and asked in particular about pain in the fingertips and toes. Pain not attributable to a compressive tumor or other anatomic lesion may be treated medically and with physical therapy depending on its likely etiology (33).

Cognitive and behavioral difficulties are also highly prevalent among those with NF1. One study, prevalence of cognitive impairment was as high as 80% of children, with prevalence of ADHD in up to 38% (18). Although cognitive impairment in adults with NF1 is well documented, persistence of ADHD into adulthood is understudied (33). Studies have also demonstrated an increased prevalence of psychiatric disorders, in particular depression (7). It is recommended to screen adults with NF1 for depression (33). ADHD is not managed differently than in the general population.

One important recent development in the management of patients with NF1 is the approval of MEK inhibitors such as Selumetinib for inoperable plexiform neurofibromas. A range of potential chemotherapeutics has been studied for inoperable plexiform neurofibromas in the past. Some agents such as Tibifarnib and Pirfenidone showed no objective response (41,42), while others such as sirolimus, pegylated interferon-alpha 2b, and imatinib had only modest results (19, 32, 40). Initial phase I and II data for Selumetinib were very promising, with phase II data demonstrating confirmed regression of plexiform neurofibromas by >20% in 68% of patients, with 56% of participants demonstrating durable response (10, 14). Secondary outcomes included clinical features such as improvement in pain, daily function, strength, range of motion, and general quality of life. 68% of participants met criteria for at least one secondary outcome (14). In addition, subsequent studies indicate that treatment with MEK inhibitors may improve working memory and executive function in those with NF1, though further study is needed (38).

Support

There are several organizations that offer support to patients with NF1. The Children's Tumor Foundation, or CTF, is a national organization that helps fund research, provides information to patients, and hosts a yearly conference on NF1, NF2, and Schwannomatosis. NF Network has several divisions across the country and hosts NF Walks, lobbying efforts, and other events as well as offering support to patients. The local division is “NF Midwest”.

CONCLUSION

Neurofibromatosis type 1 is a multisystem genetic disease resulting from dysregulation of the cell cycle and subsequent increased tumorigenesis. Though typically diagnosed in childhood, it causes a wide variety of complications in adult patients. Clinicians caring for patients with NF1 should be versed in its various manifestations as well as NF1 specific guidelines for screening and treatment. Due to its systemic nature, care for patients with NF1 involves multidisciplinary follow-up for both screening and treatment.

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