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
