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Neurofibromatosis in the Lower Extremity: A Case Report by Lauren Coe, DPM1 and Georgeanne Botek, DPM2

The Northern Ohio Foot and Ankle Journal 4(19): 1-3

Abstract: Neurofibromatosis type 1 (NF1) is the most common single gene disorder to the affect the human nervous system (5). Throughout the entire human genome, the NF1 gene is known to have the highest rate of spontaneous mutations (7). In 50% of cases, NF1 is inherited but even in familial cases NF1 has extreme clinical variability (1, 3). Many people with NF1 only have mild manifestations, such as pigmentary lesions, Lisch nodules, or learning disabilities but the frequency or seriousness increases with age.

Key words: Neurofibromatosis, neurofibromin, neurofibroma, café-au-lait macules and Lisch nodules

Accepted: January, 2018 Published: February, 2018

This is an Open Access article distributed under the terms of the Creative Commons Attribution License. It permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. ©The Northern Ohio Foot and Ankle Foundation Journal. (www.nofafoundation.org) 2014. All rights reserved.

Neurofibromatosis is an autosomal dominant

multisystem disorder that affects 1 in 3500 people (7). The National Institute of Health (NIH) recognizes two forms of neurofibromatosis: type 1 and type 2 (4). NF1, or von Recklinghausen disease, is the most common form of neurofibromatosis (1). NF1 is due to heterozygous mutations in the NF1 gene, which is located on chromosome 17q11.2 (3, 1). Normally the NF1 gene encodes for the protein neurofibromin, which functions as a tumor suppressor. When mutations occur at the NF1 gene, neurofibromin production is decreased or lost, leading to uncontrolled cell proliferation (1,7). Upwards of one thousand different mutations of the NF1 gene have been identified, leading to extreme clinical variability (2, 3). Variability can be seen between unrelated individuals, related individuals and throughout an

individual’s life time (2). Manifestations of NF1 have varying times of

Address correspondence to: LMCoe@mercy.com. 1Podiatric Medicine and Surgical Resident, Mercy Regional Medical Center. 2Podiatric Medicine and Surgical Physician, Cleveland Clinic.

appearance, with worsening and increasing frequency with age (3).

In 1987, the NIH created the seven cardinal diagnostic criteria for NF1 (7). The NIH diagnostic criteria for NF1 is met when an individual has two or more of the following features:

• Six or more café-au-lait macules over 5 mm in greatest diameter in pre-pubertal individuals and over 15 mm in greatest diameter in post-pubertal individuals.

• Two or more neurofibromas of any type or one plexiform neurofibroma.

• Freckling in the axillary or inguinal region. • Optic glioma.

The Northern Ohio Foot & Ankle Foundation Journal, 2018

Volume 4, No. 19, January 2018 The Northern Ohio Foot & Ankle Foundation Journal• Two or more Lisch nodules (iris hamartomas). • A distinctive osseous lesion such as sphenoid

dysplasia or thinning of long bone cortex with or without pseudoarthrosis.

• A first-degree relative (parent, sibling, or offspring) with NF-1 by the above criteria (4).

Dermatologically, café-au-lait macules (CALMs) are usually the first indicator of NF1 and occur 99% of the time within the first year of life. CALMs continue to arise throughout childhood but often fade in adulthood. CALMs are flat ovoid lesions that are uniform in color with well-defined borders. CALMs are not seen on the palms or soles but can occur anywhere else on the body. While CALMs are the most commonly seen cardinal diagnostic sign, skinfold freckling is the most specific cardinal diagnostic sign. When present, skinfold freckling is most commonly seen in the axillae and/or groin. Skinfold freckling usually occurs between the ages of 3 and 5 and is present in 90% of affected adults. The hallmark sign of NF1 are neurofibromas. Neurofibromas don’t usually form till puberty and can continue to increase in size and/or frequency throughout adulthood. Neurofibromas are soft, raised and benign tumors that arise from a nerve. Pathologically, neurofibromas are comprised of schwann cells, fibroblasts, mast cells and perineural cells. Due to their size and number, neurofibromas end up being the main source of morbidity in patients with NF1. Unlike neurofibromas, plexiform neurofibromas are congenital. Plexiform neurofibromas grow along the length of a nerve, are diffuse and have the potential to become disfiguring. 8-12% of pre-existing plexiform neurofibromas develop into malignant peripheral nerve sheath tumors, which are the most frequent malignant neoplasm in individuals with NF1 (2, 7). Non-cutaneous manifestations of NF1 can be seen in orthopedics, ophthalmology and neurology. The most common orthopedic finding in patients with NF1 is scoliosis, which occurs in about 10% of affected individuals. Dysplasia of a long bone is another common manifestation, with the tibia being most commonly affected. In regard to ophthalmology, Lisch nodules are hyperpigmented lesions on the iris. These nodules are benign, have no effect on vision and are present in 95% of affected individuals. On the other hand, optic gliomas are tumors of the optic nerve. They are slow-growing tumors that typically presents around the age of 3 due to decreased visual acuity. Neurologically, learning disabilities are present in at least 50% of individuals with NF1 (7).

Methods

A search of the literature was conducted regarding NF1 until January 2018. References from the appropriate articles were also reviewed to find all reports and outcomes of neurofibromatosis type 1 in the literature.

Case Report

A 34-year-old female presented for a painful mass on the dorsum of her left foot. The mass had been present for twenty years, with increasing size over time. Admits to mild discomfort when wearing shoes. She has attempted modifying her shoe gear with little relief. She denied any sharp sensations, shooting pains, burning, tingling or numbness in her feet. Patient’s past medical history is positive for NF1, neurofibromas, optic glioma and spina bifida. She was diagnosed with an optic glioma at the age of four due to visual impairments. In 2014, she had a neurofibroma removed from her vagus nerve, in her neck, due to difficulties swallowing. Her family history is positive for NF1 in her father and sister.

"

Figure 1. Soft tissue mass noted the dorsal aspect of the patient’s midfoot

On physical exam, a soft lobular mass was palpated over the dorsum of the patient’s midfoot. No neuritic symptoms could be elicited upon percussion of the dorsal cutaneous nerves. Café-au-lait spots and axillary freckling were present upon dermatological examination. Upon radiographic examination, an increase in soft tissue density was noted to be overlying the midfoot. No bony erosions, breaks in the cortices or osseous tumors were noted. Upon advanced imaging, a hypointense mass was noted on T1 and STIR imaging. The mass measured 4.1 cm x

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Volume 4, No. 19, January 2018 Coe, Botek4.2 cm x 1.2 cm and was noted to be overlying the tarsal bones.

"Figure 2. Localized soft tissue swelling overlying the tarsal bones.

" Figure 3. On sagittal STIR image, a hypointense lesion can be seen overlying the midfoot.

Intraoperatively, the mass was noted to be pink and have an irregular shape that was non-encapsulated. The mass was soft, fleshy and rubbery in consistency. The mass appeared to be stemming from the intermediate dorsal cutaneous nerve and surrounding soft tissues. The mass was dissected out bluntly, proximally, while preserving the intermediate dorsal cutaneous nerve. To remove the mass in toto, the second and third common dorsal digital nerves had to be compromised because the mass was too entwined, encapsulated and invasive to preserve the distal branches. The mass measured 4.0 cm x 3.2 cm x 1.1. The intermediate dorsal cutaneous nerve was buried into the inferior extensor retinaculum.

! ! Figure 4 &5. Diffuse-type neurofibromatosis measuring 4.0 cm x 3.2 cm x 1.1 cm

Discussion NF1 is a progressive and unpredictable disorder associated with a variety of complications and manifestations (6). NF1 can nearly affect every organ system in the human body but it primarily affects cell growth of neural tissue (1, 4, 7). The most frequent clinical manifestations of NF1 are alterations in skin pigmentation, Lisch nodules, and neurofibromas which are all derivatives of neural crest cells (3, 7). In general, most patients are mildly affected by NF1 and live healthy and productive lives (5). The average life-span of individuals with NF1 is reduced but the cause of death is similar to the general population (6). References

1. Korf, B. Neurofibromatosis type 1 (NF1): Pathogenesis, clinical features and diagnosis. Uptodate. 2018:1-9

2. Fr iedman JM. Neurof ibromatosis 1 . GeneReviews. 2018:1-47.

3. Jett K, Friedman, J. Clinical and genetic aspects of neurofibromatosis 1. Genetics in Medicine. 2010;12(1):1-11

4. Neurofibromatosis. NIH Consens Statement Online. 1987;6(12):1-19.

5. North, K. Neurofibromatosis Type 1. Semin. Med. Genet. 2010;97:119-127.

6. F r i e d m a n J M . E p i d e m i o l o g y o f Neurofibromatosis Type 1. Semin. Med. Genet. 1999;89:1-6.

7. B o y d K P, K o r f B R , T h e o s A . Neurofibromatosis type 1. J Am Acad Dermatol. 2009;61(1):1-16.

The Northern Ohio Foot & Ankle Foundation Journal, 2018