Neurofibromatosis

Neurofibromatosis Type 1 (NF1) is a common genetic disorder.

• Genetics: Autosomal dominant. NF1 gene on chromosome 17 (encodes neurofibromin, a tumor suppressor).
• Incidence: 1 in 3,000.
• 50% new mutations: Often no family history.
• Key Features: Cafe-au-lait spots, neurofibromas, Lisch nodules.
• Malignancy Risk: 8-13% lifetime risk of malignant peripheral nerve sheath tumor (MPNST).

NF1 Gene Function

• Neurofibromin is a tumor suppressor (Ras-GAP).
• Loss leads to uncontrolled cell proliferation (neurofibromas).
• Affects Schwann cells, melanocytes, bone.

Why Scoliosis in NF1?

• Dystrophic features suggest mesodermal dysplasia.
• Vertebral scalloping from dural ectasia and abnormal bone.
• Non-dystrophic curves likely from neurofibromas affecting paraspinal muscles.

Why Tibial Pseudarthrosis?

• Local mesodermal defect in tibial periosteum/bone.
• Reduced blood supply and poor bone healing.
• Anterolateral bowing progresses to fracture and non-union.

NIH Diagnostic Criteria (≥2):

1. ≥6 cafe-au-lait spots (≥5mm prepubertal, ≥15mm postpubertal).
2. ≥2 neurofibromas or 1 plexiform neurofibroma.
3. Freckling in axillary or inguinal region.
4. Optic glioma.
5. ≥2 Lisch nodules.
6. Bony lesion (sphenoid dysplasia, tibial dysplasia).
7. First-degree relative with NF1.

Physical Exam:

1. Skin: Cafe-au-lait spots, neurofibromas, freckling.
2. Spine: Scoliosis assessment.
3. Lower Limbs: Tibial bowing.
4. Eyes: Slit lamp for Lisch nodules.

Genetic Testing:

• NF1 mutation testing (available but not always needed for clinical diagnosis).

Imaging:

• Spine X-ray: Scoliosis, vertebral changes.
• MRI Spine: Pre-op for scoliosis (dural ectasia, intraspinal neurofibromas).
• Lower Limb X-ray: Tibial bowing.
• MRI Brain: Optic pathway glioma screening.

Ophthalmology:

• Slit lamp for Lisch nodules.

• Scoliosis: Bracing post-op, close follow-up for pseudarthrosis.
• Tibial Surgery: Protected weight-bearing, external fixator care.
• All Patients: Long-term surveillance for malignancy.

• Dystrophic Scoliosis: Challenging. High failure rate even with combined fusion.
• Tibial Pseudarthrosis: Healing is difficult. Multiple surgeries often needed.
• Life Expectancy: Reduced due to malignant transformation (MPNST), other complications.

Global epidemiology

• NF1 affects roughly 1 in 2,500-3,000 births worldwide with no major ethnic or geographic variation — it is one of the most common single-gene disorders.
• About half of cases are de novo mutations, so a negative family history is common.
• Scoliosis is the commonest skeletal manifestation (around 10-30%); congenital pseudarthrosis of the tibia is rare but disproportionately associated with NF1 (NF1 implicated in roughly half of all cases, Hefti EPOS series).

Side-by-side guidance

Registry and surveillance notes

• There is no single global NF1 implant registry, but national NF registries (e.g. UK regional registers used by Evans et al) provide the population-level MPNST and cancer-risk data.
• Spinal deformity and limb-reconstruction outcomes are tracked through specialist paediatric spine and pseudarthrosis databases rather than arthroplasty registries.

High- vs limited-resource practice variation

• Well-resourced settings: genetic confirmation, MRI surveillance, MEK inhibitors (e.g. selumetinib) for symptomatic inoperable plexiform neurofibromas, and microvascular fibular transfer for tibial pseudarthrosis.
• Limited-resource settings: diagnosis remains clinical (NIH criteria), surveillance is examination-based, and tibial reconstruction relies more on Ilizarov/autograft techniques; refractory cases more often proceed to amputation and prosthetic fitting.
• Universal principles: multidisciplinary care (genetics, neurology, orthopaedics, ophthalmology, dermatology, oncology) and a low threshold for sarcoma-MDT referral when a lesion enlarges or becomes painful.

• Timing of dystrophic curve surgery: Most agree dystrophic curves need early instrumented fusion, but the threshold (Cobb angle, age, degree of modulation) and whether to perform combined anterior-posterior versus posterior-only with modern pedicle-screw constructs remain debated.
• Combined vs posterior-only fusion: Historically combined fusion was standard for high pseudarthrosis rates; modern segmental instrumentation has led some centres to favour posterior-only, though dural ectasia, thin dystrophic pedicles and bone quality still drive failures.
• Best biology for tibial pseudarthrosis: No technique reliably prevents refracture. Vascularized fibula, Ilizarov, intramedullary rodding, autograft and BMP are all used, often in combination; the optimal sequence is unsettled and recurrence to skeletal maturity is the rule rather than the exception.
• Role of BMP: Bone morphogenetic protein is used off-label as an adjunct in congenital pseudarthrosis, but evidence is low-level and theoretical oncological concerns in a tumour-predisposition syndrome are unresolved.
• MEK inhibitors and bone: Selumetinib transformed management of inoperable plexiform neurofibromas; whether MEK-pathway modulation can aid bone healing in pseudarthrosis is an active research question.
• Surveillance intensity for MPNST: Whole-body MRI and FDG-PET can detect malignant transformation early, but cost, radiation and false positives mean there is no universal consensus on routine imaging surveillance versus symptom-triggered investigation.

Cafe-au-lait Spots and Related Conditions:

Key Distinguishing Points:

• NF1 vs NF2: NF1 has CAL spots and peripheral neurofibromas; NF2 has acoustic neuromas
• NF1 vs McCune-Albright: NF1 has smooth-bordered CAL spots; McCune-Albright has "coast of Maine" irregular borders
• NF1 vs Legius: Very similar but Legius lacks neurofibromas (SPRED1 mutation)