Orthopaedic Surgery - Neurofibromatosis

Basics

Neurofibromatosis is an inherited multisystem disorder that primarily affects tissues derived from the neural crest.

The skeletal and nervous systems account for many of its most important clinical manifestations.

The most common form is neurofibromatosis type 1 (NF1), which is the form discussed here.

NF1 has historically been called von Recklinghausen disease.

NF1 and NF2

NF1 should be distinguished from neurofibromatosis type 2, now more specifically associated with NF2-related schwannomatosis.

NF2 classically presents with:

Bilateral vestibular schwannomas, historically called bilateral acoustic neuromas.

The skeletal manifestations described here are primarily those of NF1.

Age at Presentation

NF1 is present genetically from birth, but many manifestations emerge gradually.

Some findings, such as:

Café-au-lait macules

may be visible during infancy.

Other features, including:

Neurofibromas, scoliosis, and other skeletal abnormalities

may not become apparent until later childhood or adolescence.

For this reason, the diagnosis may not be established immediately after birth.

Epidemiology

NF1 occurs in approximately:

1 in 3,000 newborns.

Males and females are affected with approximately equal frequency.

Risk Factors

The strongest risk factor is:

An affected parent or first-degree relative.

Advanced paternal age has historically been associated with an increased rate of new NF1 mutations.

Genetics

NF1 is inherited in an autosomal-dominant pattern.

Approximately half of affected individuals inherit the condition from an affected parent, while the remainder develop it from a de novo pathogenic variant.

Penetrance is nearly complete, although the severity and pattern of clinical manifestations vary widely.

Etiology

NF1 results from pathogenic variants in the NF1 gene, which encodes the protein neurofibromin.

Neurofibromin functions as an important regulator of cellular growth signaling.

Loss of normal neurofibromin activity contributes to:

Tumor formation, abnormal tissue growth, skeletal dysplasia, and other manifestations of NF1.

Associated Conditions

NF1 may affect multiple organ systems.

Important associated findings include:

Learning difficulties

Developmental delay

Attention or cognitive problems

Hypertension

Renal artery stenosis

Pheochromocytoma

Optic pathway glioma

Peripheral nerve tumors

Cognitive and Developmental Findings

A substantial proportion of children with NF1 have some degree of:

Learning disability, developmental delay, attention difficulty, or impaired school performance.

Severe intellectual disability is less common.

Hypertension

Hypertension may result from:

Renal artery stenosis

Pheochromocytoma

or ordinary essential hypertension.

Blood pressure should therefore be checked regularly.

Diagnosis

Diagnosis is based primarily on characteristic clinical findings.

Historically, the NIH criteria required two or more characteristic features.

Modern diagnostic criteria remain centered on similar manifestations, together with molecular testing when appropriate.

Café-au-Lait Macules

One classic diagnostic feature is:

Six or more café-au-lait macules.

Traditionally, size thresholds are:

At least 5 mm in prepubertal children

and

At least 15 mm after puberty.

These lesions are typically:

Flat, hyperpigmented, and well demarcated.

Axillary or Inguinal Freckling

Freckling in the:

Axillae or groin

is another characteristic finding.

It usually develops later than café-au-lait macules.

Neurofibromas

Diagnostic findings include:

Multiple cutaneous neurofibromas

or

A plexiform neurofibroma.

Cutaneous Neurofibromas

Cutaneous neurofibromas arise from peripheral nerves within or beneath the skin.

They usually cause few symptoms but may become numerous with age.

Plexiform Neurofibromas

Plexiform neurofibromas involve multiple branches of a nerve and may produce:

Pain

Neurologic deficit

Disfigurement

Functional impairment

They also carry a risk of malignant transformation.

Lisch Nodules

Lisch nodules are benign iris hamartomas.

Two or more Lisch nodules support the diagnosis.

They are best detected using a:

Slit-lamp ophthalmologic examination.

Optic Pathway Glioma

Optic pathway glioma is an important manifestation of NF1.

It may cause:

Visual impairment, proptosis, strabismus, or precocious puberty, depending on tumor location.

Skeletal Lesions

Characteristic osseous abnormalities include:

Dystrophic scoliosis

Vertebral scalloping

Rib penciling

Congenital tibial dysplasia and pseudarthrosis

Long-bone bowing

Other skeletal dysplasias may also occur.

Family History

A first-degree relative with confirmed NF1 strongly supports the diagnosis in an individual with compatible clinical findings.

Signs and Symptoms

Symptoms vary according to the involved organ system.

Plexiform Neurofibromas

These may cause:

Pain

Weakness

Sensory change

Compression of adjacent structures

Symptoms follow the distribution and location of the involved nerve.

Cutaneous Neurofibromas

These generally produce few neurologic symptoms but may cause:

Cosmetic concern, irritation, or local discomfort.

Physical Examination

A complete examination should include:

Skin inspection

Spinal assessment

Limb alignment

Neurologic evaluation

Blood pressure measurement

Developmental assessment

Skin Examination

Inspect the entire skin surface, including the:

Axillae and groin.

Look for:

Café-au-lait macules

Axillary or inguinal freckling

Cutaneous neurofibromas

Plexiform neurofibromas

Spine Examination

Assess the neck and entire spine for:

Scoliosis

Kyphosis

Asymmetry

Rapidly progressive deformity

NF-related spinal deformity can progress rapidly, especially when dystrophic features are present.

Limb Assessment

Measure:

Limb lengths

and assess for:

Bowing, angular deformity, pseudarthrosis, or asymmetric overgrowth.

A classic lower-extremity manifestation is anterolateral bowing of the tibia.

Ophthalmologic Examination

Children with suspected or confirmed NF1 should undergo appropriate ophthalmologic evaluation.

Assessment may include:

Visual acuity

Slit-lamp examination for Lisch nodules

Evaluation for optic pathway abnormalities

Laboratory Tests

Routine laboratory tests do not show a specific abnormality diagnostic of NF1.

Genetic testing can identify an NF1 pathogenic variant in many patients and is particularly useful when:

Clinical findings are incomplete, the diagnosis is uncertain, or genetic counseling is required.

Imaging

Plain Radiographs

Radiographs are useful for identifying many skeletal manifestations.

Spinal Findings

Radiographic abnormalities may include:

Posterior vertebral body scalloping

Rib penciling

Short, sharply angulated scoliosis

Severe vertebral rotation

Malformed or wedged vertebrae

Enlarged neural foramina

Dystrophic Scoliosis

Dystrophic scoliosis in NF1 is characteristically:

Short-segmented

Sharp

Highly rotated

and often associated with:

Kyphosis and penciled ribs.

It behaves more aggressively than ordinary idiopathic scoliosis.

Nondystrophic Scoliosis

Some patients initially have a longer, more typical scoliosis without obvious dystrophic features.

Because nondystrophic curves may later develop dystrophic changes, continued surveillance is important.

Dural Ectasia

NF1 may be associated with:

Dural ectasia, in which the dural sac becomes enlarged and may erode or remodel surrounding bone.

This can contribute to:

Vertebral scalloping, widening of neural foramina, and spinal instability.

Pseudomeningocele

Pseudomeningoceles may also develop and can alter the anatomy of the spinal canal and posterior elements.

MRI of the Spine

MRI should be obtained when significant spinal deformity is present, especially before surgery.

It helps assess:

Spinal cord position

Dural ectasia

Pseudomeningoceles

Neurofibromas

Intraspinal tumors

Neural compression

CT of the Spine

CT is useful for defining:

Pedicle morphology

Laminae

Vertebral dysplasia

Bone available for instrumentation

This information is particularly important when spinal fixation is planned.

Long-Bone Lesions

NF1 may produce a wide spectrum of long-bone abnormalities.

These range from:

Mild cortical scalloping

to

Marked dysplasia, bowing, fracture, and pseudarthrosis.

Some lesions can appear aggressive radiographically and mimic malignancy.

Tibial Dysplasia and Pseudarthrosis

A classic lesion is anterolateral bowing of the tibia, which may progress to fracture and pseudarthrosis.

Radiographic findings may include:

Cystic changes

Narrowing of the bone

Sclerosis

Tapering or pointed bone ends

Established nonunion

Some fractures occur very early in life.

Advanced MRI Techniques

Specialized MRI or metabolic imaging may be used when there is concern for:

Malignant transformation of a plexiform neurofibroma or other tumor complication.

Pathological Findings

NF1 affects tissues derived from the embryonic neural crest, helping explain its involvement of numerous organ systems.

Lisch Nodules

Lisch nodules are:

Hamartomatous deposits of the iris.

Pseudarthrosis

Bone at a pseudarthrosis site often shows:

Fibrosis, poor osteogenic activity, and limited osteoblast function.

This contributes to difficult fracture healing.

Neurofibromas

Cutaneous neurofibromas contain:

Schwann cells, fibroblasts, and connective-tissue elements.

Differential Diagnosis

Legius Syndrome

Legius syndrome can resemble NF1 because patients may develop:

Multiple café-au-lait macules and axillary freckling

but typically do not develop the neurofibromas, Lisch nodules, or characteristic tumors seen in NF1.

Proteus Syndrome

Proteus syndrome may resemble NF1 because of:

Segmental overgrowth, tumors, and skeletal abnormalities.

Its pattern of asymmetric overgrowth and other characteristic findings help distinguish it.

Congenital Tibial Pseudarthrosis

A child with apparently isolated congenital tibial dysplasia or pseudarthrosis should be followed carefully because other NF1 findings, especially café-au-lait macules, may become apparent later.

NF2-Related Schwannomatosis

NF2-related disease is distinct from NF1.

Its classic manifestation is:

Bilateral vestibular schwannomas, together with other nervous-system tumors.

Treatment

General Principles

NF1 requires lifelong multidisciplinary surveillance.

Patients should be followed by clinicians familiar with the disorder to detect:

Developmental problems

Growth abnormalities

Spinal deformity

Neurologic deterioration

Hypertension

Tumor complications

Activity

Activity should generally be encouraged and should not be restricted unnecessarily.

Restrictions are appropriate when a skeletal lesion creates a significant risk of:

Fracture or neurologic injury.

Tibial Bracing

Children with tibial dysplasia or pre-pseudarthrosis should generally receive protective bracing, especially during weight-bearing activity.

Protection may need to continue until:

Skeletal maturity.

Plexiform Neurofibroma Treatment

Management depends on:

Symptoms, location, growth, neurologic effects, and risk of malignant transformation.

Surgery may be difficult because plexiform lesions can be:

Diffuse and highly vascular.

Targeted Medical Therapy

Modern treatment for selected symptomatic, inoperable plexiform neurofibromas may include targeted inhibition of the RAS/MAPK pathway, such as MEK-inhibitor therapy.

This may reduce tumor volume and improve symptoms in selected patients.

Scoliosis Treatment

Nondystrophic Curves

Nondystrophic scoliosis may initially be treated similarly to idiopathic scoliosis, depending on:

Curve magnitude, progression, and skeletal maturity.

However, close follow-up is required because dystrophic features can develop.

Dystrophic Scoliosis

Dystrophic curves have a greater tendency to:

Progress rapidly, develop severe kyphosis, and fail nonoperative treatment.

Evidence of progression warrants early specialist evaluation.

Spinal Surgery

Surgery is frequently considered when there is:

Progressive dystrophic scoliosis

Severe kyphosis

Neurologic compromise

Marked deformity

Older treatment approaches frequently recommended combined anterior and posterior fusion for:

Focal kyphosis or curves greater than approximately 50–60° in skeletally immature patients.

Modern techniques may use posterior-only segmental instrumentation in selected cases, depending on anatomy and deformity severity.

Neurologic Risk During Correction

Severe dystrophic kyphosis may be associated with:

Malformed vertebrae, dural ectasia, and compromised spinal anatomy.

Aggressive correction can cause neurologic injury, so deformity correction must be planned carefully.

Tibial Pseudarthrosis

When tibial dysplasia is identified before fracture, prevention of fracture is a major priority.

If fracture and pseudarthrosis occur, treatment may include:

Intramedullary fixation

Bone grafting

Vascularized fibular grafting

Compression-distraction treatment using circular external fixation

Protection After Union

Even after apparent union, the affected tibia remains at risk for refracture.

Continued protection, often with bracing, may be required through the end of growth.

Limb-Length Discrepancy

Limb-length inequality should be monitored serially.

If discrepancy becomes significant, options may include:

Contralateral epiphysiodesis

or

Limb lengthening

depending on predicted discrepancy and remaining growth.

Follow-Up

Prognosis

Many patients with NF1 remain functionally independent.

Prognosis varies according to the severity of:

Neurologic disease

Skeletal deformity

Tumor burden

Malignant transformation

Life expectancy may be reduced in patients with severe complications.

Malignancy

NF1 is associated with an increased risk of several tumors.

One of the most important is:

Malignant peripheral nerve sheath tumor, which can arise from a preexisting plexiform neurofibroma.

Warning signs include:

Rapid tumor growth

New persistent pain

Hardening of a previously soft lesion

New neurologic deficit

These findings require prompt evaluation.

Central Nervous System Tumors

Patients also have an increased risk of:

Optic pathway glioma and other nervous-system tumors.

Severe Pseudarthrosis

Persistent tibial pseudarthrosis can be extremely difficult to treat.

In rare severe cases with repeated failed reconstruction and major functional impairment, amputation may become a salvage option.

Spinal Complications

Dystrophic scoliosis and kyphosis may cause:

Progressive deformity

Pain

Pulmonary compromise

Neurologic injury

Patient Monitoring

Children with NF1 require regular surveillance throughout growth.

Spine Monitoring

Physical examination for scoliosis should be performed at least:

Yearly during growth, with more frequent follow-up when deformity is present.

Limb-Length Monitoring

Children with limb-length inequality may require serial measurements or standing limb-length imaging.

Historically, annual scanograms have been used.

Blood Pressure

Blood pressure should be checked regularly because of the increased risk of:

Renal artery stenosis, pheochromocytoma, and other causes of hypertension.

Neurologic Monitoring During Surgery

Spinal cord monitoring should be used during major spinal reconstruction whenever feasible because patients with severe dystrophic deformity have increased neurologic risk.

Key Principle

NF1 is a multisystem genetic disorder with important orthopaedic manifestations, especially:

Dystrophic scoliosis, tibial dysplasia and pseudarthrosis, limb-length inequality, and tumor-related neurologic compromise.

Successful management depends on:

Early recognition, lifelong surveillance, protection of dysplastic bone, careful monitoring of spinal deformity, evaluation for malignant transformation, and multidisciplinary care.