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NEUROFIBROMATOSIS (VON RECKLINGHAUSEN DISEASE)

Introduction

Neurofibromatosis type 1 (NF1) is also known as von Recklinghausen’s disease because it was first described by him in 1882. NF1 is a rare, autosomal-dominant disorder associated primarily with changes in skin color and benign tumors of the peripheral nerve sheath (ie, neurofibromas). However, patients with NF1 have increased risk of developing many different types of tumor, including cancerous tumors.

The three major types of neurofibroma are cutaneous, spinal, and plexiform. The cutaneous types are nodule-like surface tumors, also called dermal (cutaneous) neurofibromas. They are uncommon in young children and tend to develop with age. While cutaneous tumors do not undergo malignant transformation, cosmetic problems are often significant. The spinal types are larger tumors with few symptoms. Care may be required for back pain, numbness in an arm or leg, and minor weakness. The plexiform types are extensive tumors that grow from any nerve in the body and may change into malignant peripheral nerve sheath tumors (MPNST). Plexiform tumors are present in 20–40% of patients with NF1, and MPNST—the most common cancerous growth—occurs in 10%. In children with NF1, the most common tumors are optic glioma and brain tumors.

NF1 affects multiple organ systems, and orthopedic manifestations in particular, can be debilitating and difficult to manage. The severity and specific characteristics of the condition vary greatly among patients (even within a family), and the prognosis varies accordingly. Generally, patients live relatively long and healthy lives, but median life expectancy is 8 years shorter than it is in the general population. Management requires multidisciplinary intervention.

Pathology

NF1 is a tumor-suppressor gene on chromosome 17 (17q11.2) that codes for the ubiquitously expressed neurofibromin protein. Normally, this protein negatively regulates the Ras signaling pathway. The inactivation of the NF1 gene leads to skeletal pathology through Ras-dependent mitogen-activated protein kinase (MAPK) activity, which affects the distribution of osteoclasts and osteoblasts. It is hypothesized that defects in endochondral ossification and bone dynamics may be involved.

Incidence and Related Conditions

  • Incidence of NF1 is <0.1%; prevalence is ~1 in 2500–3500 live births; NF1 is more prevalent than NF2 or segmental NF
  • Incidence of NF1 is higher in families that carry the autosomal dominant NF1 gene
  • ~50% of NF1 cases are inherited; the remainder have spontaneous mutations
  • Penetrance approaches 100% by age 20 years
  • The lifetime risk of a MPNST is 8–13%
  • Related conditions include NF2, segmental NF, schwannomatosis, familial café-au-lait spots, and NF1-like syndrome, a disorder involving mutation of the SPRED1 gene that presents with multiple café-au-lait macules, axillary freckling, and macrocephaly

Differential Diagnosis

  • Other forms of neurofibromatosis
    • Mosaic/segmental NF1
    • NF2
    • Schwannomatosis
    • Watson syndrome
  • Other conditions with café au lait spots
    • DNA repair syndromes
    • McCune-Albright syndrome
  • Conditions with pigmented macules
    • LEOPARD syndrome
    • Neurocutaneous melanosis
    • Peutz–Jeghers syndrome
    • Piebaldism
  • Overgrowth syndromes
    • Klippel–Trenaunay–Weber syndrome
  • Proteus syndrome conditions with tumors
    • Bannayan-Riley-Ruvalcaba
    • Fibromatosis
    • Lipomatosis
    • Multiple endocrine neoplasia type 2B
ICD-10 Codes

  • NEUROFIBROMATOSIS (VON RECKLINGHAUSEN'S)

    Diagnostic Guide Name

    NEUROFIBROMATOSIS (VON RECKLINGHAUSEN'S)

    ICD 10 Diagnosis, Single Code, Left Code, Right Code and Bilateral Code

    DIAGNOSISSINGLE CODE ONLYLEFTRIGHTBILATERAL (If Available)
    NEUROFIBROMATOSIS (VON RECKLINGHAUSEN'S)Q85.01   

    ICD-10 Reference

    Reproduced from the International statistical classification of diseases and related health problems, 10th revision, Fifth edition, 2016. Geneva, World Health Organization, 2016 https://apps.who.int/iris/handle/10665/246208

Clinical Presentation Photos and Related Diagrams
Neurofibromatosis (NF1, von Recklinghausen Disease)
  • Cutaneous neurofibroma (arrow) associated with neurofibromatosis (NF1, von Recklinghausen disease)
    Cutaneous neurofibroma (arrow) associated with neurofibromatosis (NF1, von Recklinghausen disease)
Symptoms
Behavioral problems in children (high frequency)
Café-au-lait spots (regular or irregular borders)
Deformed (bowed) lower legs and forearms
Early/late onset of puberty (<1% of cases)
Fracture, spontaneous or after minor injury, that heals slowly
Freckling of the armpit and groin
High blood pressure
Learning disability (IQ in the low-to-average range) and/or Mental retardation (<1% of cases)
Seizures
Typical History

Patients will typically present to an orthopedist with congenital tibial dysplasia, spinal deformity such as scoliosis, or a disorder of excessive bone and soft tissue growth. Scoliosis is the most common of these osseous symptoms in NF1, affecting ~10–30% of patients. Pediatric patients may present with anterolateral bowing of the tibia, which may have resulted in a fracture that will not heal without intervention (pseudoarthrosis). Many NF1 features develop with age; therefore, when there is no family history, several years may pass before the diagnosis is made.

Positive Tests, Exams or Signs
Treatment Options
Treatment Goals
  • Establish an accurate diagnosis
  • Treat accordingly to eliminate symptoms and maintain hand function
Conservative
  • Currently, there are no medical therapies that target the underlying inactive NF1 gene, and there is no way to prevent tumor growth.
Operative
  • Because there are no medical therapies that target the underlying inactive NF1 gene, and there is no way to prevent tumor growth. A multidisciplinary treatment approach is required.
  • Anterolateral tibial bowing
    • Nonoperative: bracing with total contact orthosis
    • Operative: bone grafting is indicated for bowing with pseudoarthrosis/fracture, and amputation is indicated for multiple, failed surgeries. Other options include external fixation and use of an intramedullary rod.
  • Pigmentary disturbances: patients are advised to wear sunscreen
  • Scoliosis
    • Nonoperative: nondystrophic scoliosis in children with NF1 can be treated with bracing
    • Operative: dystrophic scoliosis in children (aged <7 y) can be treated with surgical spinal decompression involving anterior and posterior spinal fusion (ASF, PSF) with instrumentation
  • Tumor management
    • Disfiguring or irritating neurofibromas located on or just below the skin can be surgically removed; referral to a plastic surgeon is advisable for tumors on the face and neck
    • MPNSTs are completely excised when possible; chemotherapy and/or radiation may also be necessary
    • Optic gliomas associated with NF1 typically do not cause symptoms; however, if vision is threatened, they may be treated with surgery or chemotherapy
  • Patient education is critical due to the multifactorial nature of the disease. The patient should remain alert for any unusual symptoms and bring them to the attention of the NF1 treatment team.
CPT Codes for Treatment Options

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Common Procedure Name
Excision benign nerve tumor
CPT Description
Excision of neurofibroma or neurolemmoma; cutaneous nerve
CPT Code References

The American Medical Association (AMA) and Hand Surgery Resource, LLC have entered into a royalty free agreement which allows Hand Surgery Resource to provide our users with 75 commonly used hand surgery related CPT Codes for educational promises. For procedures associated with this Diagnostic Guide the CPT Codes are provided above. Reference materials for these codes is provided below. If the CPT Codes for the for the procedures associated with this Diagnostic Guide are not listed, then Hand Surgery Resource recommends using the references below to identify the proper CPT Codes.

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CPT 2021 Professional Edition: Spiralbound

Complications
  • Intraoperative hemorrhage of neurofibroma tissue that is difficult to control
  • When PSF is used alone to treat scoliosis, pseudoarthrosis rates increase
  • Tumor excision: fever, pain, skin graft necrosis, amputation
  • Neurological deficit
  • Surgery for anterolateral tibial bowing: results extremely variable (eg, new fractures can still occur, deterioration of mobility and articular function, malalignment, failure to prevent ankle valgus, residual limb-length discrepancy)
Outcomes
  • Aesthetic and functional results are extremely variable; conventional surgery often produces acceptable outcomes
  • Long-term follow-up studies are needed to determine check durability of union and bone healing
    • Some studies report union rate of 80% with intramedullary rod
    • Pseudoarthrosis can still occur in ~10% of patients who receive ASF and PSF
Key Educational Points
  • NF1 affects multiple organ systems and requires a multidisciplinary team approach for management and treatment.
  • Some NF1 symptoms may not present until later in life; therefore, the NIH diagnostic criteria are not sensitive in young children.
  • Currently, there are no approved treatments that target the inactive NF1 gene and no way to prevent tumor growth.
  • Genetic testing is available for patients who do not fulfill diagnostic criteria or for prenatal testing in families with a history of NF1.
  • Absence of orbital wall
  • Bone growth disorders and reduced bone density
  • Cerebrovascular occlusion (<1% of cases)
  • Neurofibromas (almost all patients have benign form)
  • Lisch nodules
  • Neurofibromas (almost all patients have benign form)
  • Lisch nodules
  • There is a epidemiologic association between neourfibromatous (NF1) and glomus tumors of the hand and digit. 7
References

New Articles

  1. The Children’s Tumor Foundation. Diagnosis of NF1. 2016. Accessed September 28, 2016 at http://www.ctf.org/Learn-About-NF/Diagnosis-of-NF1.html.
  2. İncecik F, Hergüner MÖ, Balli T, Altunbaşak S. Pseudoarthrosis of the hand in neurofibromatosis type 1: a case report. Turk J Pediatr 2013;55(3):335-6. PMID: 24217084
  3. National Institutes of Health. Genetic and Rare Diseases Information Center. Neurofibromatosis type 1. 2015–2016. Accessed September 28, 2016 at https://rarediseases.info.nih.gov/diseases/7866/neurofibromatosis-type-1
  4. Zhou J, Li M, Luo C, et al. Giant neurofibroma in the right lower limb of a 26-year-old woman: report of a case. Int Surg 2012;97(1):71-7. PMID: 23102003
  5. Washington University Neurofibromatosis Center. Nerve tumors. 2016. Accessed September 28, 2016 at https://nfcenter.wustl.edu/what-is-nf/neurofibromatosis-type-1/nerve-tumors/.
  6. Widemann BC, Dombi E, Gillespie A, et al. Phase 2 randomized, flexible crossover, double-blinded, placebo-controlled trial of the farnesyltransferase inhibitor tipifarnib in children and young adults with neurofibromatosis type 1 and progressive plexiform neurofibromas. Neuro Oncol 2014;16(5):707–18. PMCID: PMC3984559
  7. Harrison B, Moore AM, Calfee R, Sammer DM. The association between glomus tumors and neurofibromatosis.  J Hand Surg AM 2013; 38A: 1571-1574.

Reviews

  1. Boyd KP, Korf BR, Theos A. Neurofibromatosis type 1. J Am Acad Dermatol 2009;61(1):1-16. PMID: 19539839
  2. Ferner RE, Huson SM, Thomas N, et al. Guidelines for the diagnosis and management of individuals with neurofibromatosis 1. J Med Genet 2007;44:81–8. PMID: 17105749
  3. Shah H, Rousset M, Canavese F. Congenital pseudarthrosis of the tibia: Management and complications. Indian J Orthop 2012;46(6)616-26. PMCID: PMC3543877

Classics

  1. Riccardi V. Von Recklinghausen neurofibromatosis. N Engl J Med 1981;305(27):1617-27. PMID: 6796886
  2. Kuorilehto T, Pöyhönen M, Bloigu R, et al. Decreased bone mineral density and content in neurofibromatosis type 1: lowest local values are located in the load-carrying parts of the body. Osteoporos Int 2005;16(8):928-36. PMID: 15551055
  3. National Institutes of Health (NIH). Neurofibromatosis: NIH Consensus Development Conference Statement. 1987. Accessed September 26, 2016 at https://consensus.nih.gov/1987/1987Neurofibramatosis064html.htm
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