Review Article

Orthopaedic Manifestations of Neurobromatosis Type 1

Abstract
David S. Feldman, MD Charles Jordan, MD Lauren Fonseca, BA

From the Department of Orthopaedic Surgery, NYU Hospital for Joint Diseases, New York, NY. Dr. Feldman or an immediate family member serves as a board member, owner, officer, or committee member of Limb Lengthening Research Society; is a member of a speakers bureau or has made paid presentations on behalf of Stryker; serves as a paid consultant to or is an employee of Biomet; serves as an unpaid consultant to Orthopaediatrics; and has received research or institutional support from EBI, Smith & Nephew, and Stryker. Neither of the following authors nor any immediate family member has received anything of value from or owns stock in a commercial company or institution related directly or indirectly to the subject of this article: Dr. Jordan and Ms. Fonseca. J Am Acad Orthop Surg 2010;18: 346-357 Copyright 2010 by the American Academy of Orthopaedic Surgeons.

Neurobromatosis type 1 (NF-1) is an autosomal dominant disease that affects 1 in 3,000 persons worldwide. Caf-au-lait macules and peripheral nerve sheath tumors (ie, neurobromas) are the most commonly recognized manifestations of NF-1. However, NF-1 affects multiple organ systems, and a multidisciplinary approach to treatment is required. Management of the orthopaedic manifestations of NF-1 is often difficult. The most complex manifestations are scoliosis (dystrophic and nondystrophic), congenital pseudarthrosis of the tibia, and problems related to soft-tissue tumors. Metabolic bone disease is common; many patients are frankly osteopenic, which further complicates treatment. Dystrophic scoliosis, which may be caused by either bony dysplasia or intraspinal pathology, is characterized by early presentation and rapid progression. Pseudarthrosis is common even after instrumented fusion. Nondystrophic scoliosis tends to behave like adolescent idiopathic scoliosis, although it may present earlier and is associated with a higher rate of pseudarthrosis. Congenital pseudarthrosis of the tibia is a longbone dysplasia that afflicts patients with NF-1. Management of this osseous deformity is challenging. Failure to achieve union and refracture are common.

eurofibromatosis type 1 (NF-1), also known as von Recklinghausen disease, is an autosomal dominant genetic disorder that affects the cellular growth of neural tissues. With an incidence of approximately 1 in 3,000 persons worldwide and without prejudice to sex or race, NF-1 is one of the most common genetic disorders.1 The disease is characterized mainly by multiple cutaneous hyperpigmentations and neurofibromas. NF-1 also demonstrates a broad range of manifestations involving seemingly unrelated systems. German pathologist Frederick von Recklinghausen2 provided the first description of NF-1 in 1882. He hypothesized that the characteristic cutaneous tumors were derived from fi-

brous tissues surrounding the peripheral nerves. Other forms of NF have since been described. Neurofibromatosis type 2 (NF-2) is characterized primarily by bilateral vestibular schwannomas. It occurs far less frequently than NF-1 but is also of autosomal dominant inheritance. Segmental NF is the very rare mosaic form of NF-1. NF-2 and segmental NF are not known to exhibit orthopaedic manifestations.

Genetics
In 1989, the NF-1 gene (NF1) was identified and its locus found on chromosome 17q11.2. NF1 is very large; it spans 350 kilobases of DNA

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Table 1 Diagnostic Criteria for Neurobromatosis Type 1 The diagnostic criteria for NF-1 are met when two or more of the following are found: 6 caf-au-lait macules >5 mm in greatest diameter in prepubertal persons and >15 mm in greatest diameter in postpubertal persons 2 neurobromas of any type or one plexiform neurobroma Freckling in the axillary or inguinal region Optic glioma 2 Lisch nodules A distinctive osseous lesion, such as sphenoid dysplasia or thinning of long bone cortex, with or without pseudarthrosis A rst-degree relative (parent, sibling, or offspring) with NF-1 as diagnosed using the listed criteria
NF-1 = neurobromatosis type 1 Adapted with permission from Neurobromatosis: Conference statement. National Institutes of Health Consensus Development Conference. Arch Neurol 1988;45:575-578.

Figure 1

and is composed of 59 exons.3 NF1 was found to encode an approximately 280 kDa cytoplasmic protein termed neurofibromin.4,5 Although the allele is completely penetrant, spontaneous mutations account for approximately 50% of cases.6 Despite advances in the elucidation of a molecular basis for the disease, much phenotypic variability exists. Analysis of the NF1 sequence revealed a 360amino acid domain with similarities to guanosine triphosphataseactivating proteins (GAPs).7 This discovery was helpful in understanding the function of neurofibromin. GAPs are a well-known superfamily of genes that regulate the control of cell growth and division by acting as suppressors of RAS proto-oncogenes. In the case of neurofibromin, p21-RAS is the specific RAS proto-oncogene affected, which is known to promote cell growth, proliferation, and differentiation.7 Neurofibromin is ubiquitous in human tissue during development and is later found in high concentrations exclusively within the nervous system and related tissues.8 Neurofibromin has recently been found to be a key component in skeletal development and growth. Kolanczyk et al9 demonstrated in a mouse model that
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NF1 dysfunction is associated with abnormal limb and joint development, such as tibial bowing and stunted growth. Observed increases in osteoblastic proliferation and the inability of these osteoblasts to differentiate and mineralize tissues are thought to cause the porosity and decreased stiffness of affected cortical bone. Kolanczyk et al9 also argued that reduced growth is the result of defective chondrocyte proliferation and differentiation within growth plates.

Caf-au-lait lesion in a child with neurobromatosis type 1. (Courtesy of Lori A. Karol, MD, Texas Scottish Rite Hospital, Dallas, TX.)

accepted and applied, diagnosis may be delayed because of the variable age at which these features emerge. DeBella et al11 conducted a retrospective review of 1,893 patients with NF-1 diagnosed by age 20 years. Within this subject pool, 30% failed to meet the NIH diagnostic criteria by age 1 year, and 3% failed to meet the criteria by age 8 years.

Clinical Manifestations
Management of NF requires the aggressive treatment of its various manifestations. The patient with NF-1 will likely require a multidisciplinary approach to treatment. Approximately 70% of affected persons will have at least one surgical procedure or hospital admission for a problem related to NF.12

Diagnosis
Diagnosis can be made on careful examination of the patients presenting clinical manifestations. These signs may be dermatologic, ocular, cutaneous, endocrine, neurologic, cardiovascular, or orthopaedic, with variable severity in each category. The diagnostic criteria, defined by the National Institutes of Health (NIH) Consensus Development Program in 1987, consist of the most commonly presenting features of the disease10 (Table 1). Diagnosis of NF-1 requires the presence of at least two of the features listed. Although these criteria are widely

Dermal Features
Caf-au-lait macules are the most prevalent feature of NF-1 (Figure 1). Present in nearly all persons with NF-1, these macules are usually the first clinical feature to emerge within the first year of life. Ninety-nine percent of patients have six or more lesions >5 mm in diameter by age 1

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Figure 2

and usually develop in early childhood; however, they may occur as late as the third decade of life.13 These low-grade pilocytic astrocytomas of the optic nerve and/or optic chiasm may or may not be symptomatic. OPGs can cause proptosis, decreased visual acuity, nystagmus, and optic disk atrophy.

oping benign and malignant neoplasms, including melanoma, leukemia, rhabdomyosarcoma, pheochromocytoma, carcinoma, and pancreatic endocrine tumors.15,19 They are also at increased risk for developing brain tumors, specifically, tumors of astrocytic origin.

Clinical photograph demonstrating cutaneous neurobromas. (Reproduced with permission from McCann SA: Cutaneous manifestations of systemic disease: Leukemia/lymphoma, systemic malignancy, hypothyroidism, diabetes mellitus, and neurobromatosus. Dermatol Nurs 2006;18:476-478.)

year.11 These lesions appear flat along the skins surface as coffeecolored areas of hyperpigmentation. The lesions are oval or rounded in shape with well-defined borders, with an average size of 2 to 5 cm, although they may be 2 mm to >20 cm in size.11 Skin-fold freckling appears as small brown macules within regions that seldom freckle: the axillae, inguinal region, breast folds, neck, and upper eyelids. Such freckling typically emerges by age 7 years, making it the second dermatologic feature to develop. This occurs in approximately 90% of affected persons.11

Ocular/Orbital Features
Lisch nodules are hyperpigmented hamartomas of the iris consisting of spindle-shaped cells. These nodules are present in >70% of affected persons by age 10 years.11 Lisch nodules are easily observed on slit lamp examination. They do not cause visual impairment.

Neoplastic
Optic Pathway Glioma Optic pathway gliomas (OPGs) affect approximately 6.6% of patients

Neurobroma Neurofibromas are benign neoplasms of peripheral nerve sheath origin that are composed of Schwann cells, fibroblasts, perineural cells, and mast cells. These neoplasms may include associated axons. Characteristically benign, neurofibromas exhibit a variety of morphologies as well as unpredictable growth patterns.14 Neurofibromas are rarely present at birth and typically evolve in late childhood; >80% of patients develop neurofibromas by age 20 years.11 With time, neurofibromas may increase in size and magnitude. Periods of accelerated proliferation have been documented during puberty and pregnancy.14 Cutaneous neurofibromas can be seen on the surface of the skin as well-circumscribed, grayish tumors and may cause pruritus (Figure 2). Plexiform neurofibromas are diffuse and poorly defined and involve multiple nerve fascicles as well as surrounding tissues. Plexiform neurofibromas are composed primarily of the same cell types as cutaneous neurofibromas, but the plexiform type includes an extracellular matrix and vascular supply. Plexiform neurofibromas occur in as many as 40% of patients; this type has been indicated in association with complications such as hemorrhage, dysfunction, pain, disfigurement, and transformation into malignant peripheral nerve sheath tumors (MPNSTs).15-18 Malignancies Persons with NF-1 are at greater risk than the general population for devel-

Malignant Peripheral Nerve Sheath Tumor MPNSTs (ie, neurofibrosarcomas) are the most severe neoplastic complication of NF-1 because of their elusive nature, pattern of wide metastasis, and high rate of local recurrence.15,20 The presence of MPNSTs in patients with NF-1 imparts a poor prognosis, with 5-year survival rates of approximately 21%.21 For patients with NF-1, the lifetime risk of developing MPNSTs is 10% to 24%.15,21 MPNSTs usually originate within preexisting benign plexiform neurofibromas that undergo malignant transformation and that consist of high cellularity, tumor necrosis, dedifferentiation, and mitotic activity.15,20 Patients are at greatest risk of malignancies from plexiform neurofibromas approximately 10 to 20 years after the development of the original neurofibroma.22 This transformation is marked clinically by a sudden onset of pain and discomfort at the affected area, enlargement, and new neurologic deficits. The diagnosis of malignant transformation of a plexiform neurofibroma to an MPNST can be very difficult to make. MRI is likely the most useful imaging modality, although positron emission tomography scanning has been recently shown to be a useful diagnostic tool.23 Immunohistochemistry, particularly KI-67 and S-100 staining, is an important tool in differentiating plexiform neurofibromas from MPNSTs.24

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Table 2 Dystrophic Changes in Persons with Neurobromatosis Type 1 Vertebral scalloping (depth >3 mm in the thoracic spine or >4 mm in the lumbar spine). This is associated with either dural ectasia or neural tumor. Rib penciling (present when the width of the rib is smaller than that of the narrowest portion of the second rib) Transverse process spindling Vertebral wedging Paravertebral soft-tissue mass Short curve with severe apical rotation Intervertebral foraminal enlargement Widened interpediculate distances Dysplastic pedicles
Adapted with permission from Tsirikos AI, Saifuddin A, Noordeen MH: Spinal deformity in neurobromatosis type-1: Diagnosis and treatment. Eur Spine J 2005;14:427-439.

Figure 3

Neurologic and Cardiovascular Features

NF-1 is one of the most common genetic disorders known to cause learning disabilities in children, affecting as many as 75% of children with NF-1.25 Delayed gross motor development as well as speech and language deficits have also been noted. Psychiatric disorders affect 33% of persons with NF-1.25,26 Unidentified bright objects appear on MRI as areas of hyperintense signal on T2-weighted and other fluidsensitive sequences, most frequently in the cerebellum, brain stem, and basal ganglia. They affect up to 94% of children with NF-1, and they disappear through the third and fourth decades.27 These unidentified bright objects most likely have no clinical impact. Headaches are seen in 46% of patients with NF-1, deafness in 10%, seizures in 3% to 11%, and hydrocephalus in 4%.27 Persons with NF-1 are at increased risk for stroke, hypertension, congenital heart disease, and vasculopathy.28

Orthopaedic Manifestations
Spinal Deformity Spinal deformity has been reported in approximately 49% of patients
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with NF-1.16 Osteomalacia, intraspinal neurofibromas that erode and infiltrate bone, and endocrine disturbances are some of the entities that have been implicated in the development of spinal deformity.29 However, a definitive etiology remains elusive. Several dystrophic changes have been identified, including rib penciling, vertebral scalloping, dumbbell lesions, and dural ectasia (Table 2). Rib penciling, defined as a rib whose width is narrower than the narrowest portion of the second rib, is the most prevalent dystrophic osseous change30 (Figure 3). In addition to being a cause of deformity, penciled ribs are susceptible to dislocation and have been reported to enter the spinal canal and cause paralysis. Vertebral scalloping, or marginal erosion, can be appreciated radiographically when the depth of erosion measures >3 mm in the thoracic spine and >4 mm in the lumbar spine31 (Figure 4). Posterior scalloping is most common in NF-1; anterior and lateral scalloping occur far less frequently. Posterior vertebral scalloping is closely associated with the presence of intraspinal pathology, with 63% of scalloped vertebral sites closely located to either dural

AP radiograph demonstrating rib penciling (arrow) in a patient with neurobromatosis-1. (Courtesy of Lori A. Karol, MD, Texas Scottish Rite Hospital, Dallas, TX.)

ectasia or an intraspinal neurofibroma.31 Thus, the presence of scalloped vertebrae should signal the orthopaedic surgeon to approach the spine with increased clinical suspicion for potential pathologic processes. The dumbbell lesion is caused by the presence of neurofibromas within the canal. Its name derives from the dumbbell-like shape it assumes as it expands outward through the neural foramina. This is a commonly seen lesion in the dystrophic spine. Dural ectasia, another common phenomenon in the dystrophic spine, is described as a circumferential dilation of the thecal sac and is thought to erode surrounding osseous structures. Dural ectasia is thought to be a consequence of abnormally elevated pressure in the dural sac; however, it may be a primary erosion problem of bone. It is associated with posterior vertebral scalloping and thinning of the pedicles and lamina, and it can lead to meningocele formation31 (Figure 5). The thinning of surrounding osseous elements can result in significant instability and deformity, even leading to vertebral

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Figure 4

Figure 5

Coned-down lateral radiographs of the lumbar spine demonstrating posterior (A) and anterior (B) vertebral scalloping. (Reproduced with permission from Tsirikos AI, Saifuddin A, Noordeen MH: Spinal deformity in neurobromatosis type-1: Diagnosis and treatment. Eur Spine J 2005;14:427-439.) T2-weighted sagittal magnetic resonance image demonstrating dural ectasia with posterior vertebral scalloping. (Reproduced with permission from Tsirikos AI, Saifuddin A, Noordeen MH: Spinal deformity in neurobromatosis type-1: Diagnosis and treatment. Eur Spine J 2005;14:427-439.)

destabilization. Because of concomitant thecal sac expansion, however, neural elements are protected and generally remain intact, even in the presence of severe deformity. Less common dystrophic changes include spindling of the transverse process, vertebral wedging and rotation, foraminal enlargement, widened interpediculate distance, and dysplasia of the pedicles.30 Such intraspinal pathology is linked to dystrophic deformities and is even implicated as the possible cause. However, dystrophic changes can be seen without the presence of a pathologic lesion.

Scoliosis Persons with NF-1 may develop dystrophic and nondystrophic scoliosis. Dystrophic scoliosis is less common but more severe than nondystrophic scoliosis. Nondystrophic scoliosis typically progresses at the same rate as adolescent idiopathic scoliosis and has a similar clinical appearance. However, nondystrophic scoliosis in NF-1 has an earlier onset and poorer

prognosis posttreatment than does adolescent idiopathic scoliosis. Nondystrophic curves require careful observation because of the tendency for modulation, a process by which dystrophic characteristics develop over time. Some authors use this term to describe a change in the behavior of a curve from one that is characteristically nondystrophic and slowly progressing to one that over time becomes rapidly progressive with the appearance of dystrophic changes. Others think, however, that curves that appear to modulate are really those in which dystrophic changes had not yet become apparent, especially because in some curves, progression does not necessarily follow modulation.30 However, if such changes are noted to occur in a curve that had previously been believed to be nondystrophic, it is reasonable and acceptable to treat the deformity as a dystrophic curve. Durrani et al30 reported an overall modulation rate of 65% in nondystrophic curves. One major predictor

of modulation is the age at which scoliosis clinically presents. Modulation occurred in 81% of NF-1 patients presenting with scoliosis before age 7 years and in 25% of those who presented after age 7 years. Spinal deformities in patients with NF-1 should be followed closely for dystrophic changes and modulation because these affect treatment and prognosis. Persons with NF-1 require early scoliosis screening and regular follow-up. Following a diagnosis of scoliosis, all patients with NF-1 should be further evaluated with MRI and/or CT scanning to accurately assess the deformity and the presence of dystrophic changes. These studies may detect the presence of intraspinal and/or extraspinal neo-

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plasia. When a seemingly nondystrophic curve is noted to progress more rapidly than expected, repeat MRI and/or CT scanning is indicated to detect dystrophic change as well as intraspinal and paraspinal tumors, both of which may alter management overall and the surgical strategy in particular. Additionally, the presence of paraspinal tumors can limit surgical exposure or increase the risk of bleeding because of the increased vascularity of the tumor and surrounding tissues. As such, these should be ruled out before surgical intervention. The incidence of paraspinal tumors is reported to be as high as 40% in patients with NF-1 based on whole-spine MRI or CT scanning of the chest, abdomen, and pelvis.32 Nondystrophic scoliosis is managed based on the degree of curvature. Observation is sufficient for curves <20. Bracing is recommended once progression is documented or the curve measures 20 to 40 in the skeletally immature patient. Fusion is required for curves 40. Posterior instrumentation alone can be successful in treating less severe nondystrophic curves, but AP fusion is indicated for curves measuring 90.33,34 Dystrophic scoliosis is characterized by rapid progression, often despite treatment, leading to severe deformity. Dystrophic curves present as sharply angulated segments of four to six vertebrae and are accompanied by one or more of the osseous abnormalities outlined previously. These dystrophic changes tend to further complicate the deformity and the ensuing treatment. Dystrophic curves can be classified into two groups according to curve pattern. Type I curves consist of scoliosis in the coronal plane with a sagittal plane kyphosis measuring <50. The addition of a significant kyphotic deformity characterizes type II dystrophic curve. This kyphosis appears clinically as a severe, acute, sagittal plane anguJune 2010, Vol 18, No 6

lation and measures >50 radiographically.35,36 Curve progression can be predicted by the extent of dystrophic osseous deformities within the spine. Eightyfive percent of dystrophic curves progress when three or more heterogeneous dystrophic features are present.30 Durrani et al30 identified rib penciling as the only independent dystrophic deformity that is an indicator of curve progression; 87% of deformities involving three or more penciled ribs progressed. Kyphoscoliosis is usually associated with severe progression of dystrophic deformity as well, and it can be complicated by a draping of the spinal cord or compression that, left untreated, can lead to neurologic compromise and even paraplegia.35 The complex and severe nature of dystrophic curves and the risk of neurologic injury pose a major challenge to the orthopaedic surgeon. It is widely accepted that early and aggressive surgical intervention is necessary to prevent dystrophic curve progression.33-36 Bracing has not been shown to be effective in preventing progression. Curves of <20 may be observed with close follow-up, usually at 6-month intervals, to monitor progression. Once a dystrophic curve advances beyond 20 to 40, surgery is recommended.34 Some authors advocate the use of a combined anterior-posterior technique to achieve fusion in all but the most benign curves. The anteriorposterior approach is considered necessary for curves measuring >90 and in those that demonstrate rapidly progressing dystrophic changes and/or the development of acute kyphosis.33,35,36 The anterior-posterior approach facilitates greater spinal correction and may decrease the pseudarthrosis rate.33,36 Recent studies have suggested that type I dystrophic curves can be stabilized by posterior fusion alone with

segmental spinal instrumentation (Figure 6). One study in particular suggests that the posterior approach is successful in deformities of approximately 90 of scoliosis when fusion extends beyond the conventional fusion levels, abundant bone graft is used, and both the coronal and sagittal planes are corrected.33 Although posterior instrumentation alone is an accepted treatment for some dystrophic curves, it has been associated with high rates of pseudarthrosis, a complication that is less common with the combined anteriorposterior approach.34 In a retrospective study, Parisini et al35 assessed 56 NF-1related deformities and reported a failure rate of 47% in patients with type I curves treated with posterior fusion alone. Type II dystrophic curves require more aggressive surgical management because of the presence of severe sagittal deformity. These deformities have poor outcomes when treated with posterior spinal fusion alone. Thus, the more extensive anterior-posterior approach is indicated.33,35 When performing spinal fusion in the dystrophic spine, extra care must be taken in dissection and decortication because of the possible presence of laminar erosion and weakening. Kumar and Crawford37 advocate the use of the Bovie electrocautery device (Bovie Medical, St. Petersburg, FL) to avoid plunging through an eroded lamina, as could happen with elevators and other blunt instruments. Erosion and weakening of the bony posterior elements of affected segments destabilize the spine and contribute to instrumentation challenges. Hardware complications may arise with dislodgment of hooks used for proximal fixation. Such dislodgment occurs especially in the presence of osteoporosis and deformed posterior elements. Although the

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Figure 6

A, AP (left) and lateral (right) radiographs demonstrating a severe dystrophic curve in a 14-year-old boy. B, AP (left) and lateral (right) radiographs following posterior segmental instrumentation.

pedicles may be weak and thinned, pedicle screws are more likely to provide stable fixation and a reduced risk of hardware failure by providing better vertebral grip. Titanium instrumentation is preferred because intraspinal and paraspinal tumors are often present.38 This facilitates evaluation with postoperative MRI. Preoperative traction may be helpful in the management of severe curves. Winter et al39 advocated the use of preoperative traction to improve pulmonary function and some neurologic deficits in patients with a flexible kyphosis. Traction also was shown to reduce curve severity prior to fusion. More recently, the use of preoperative halo traction in dystrophic curves for 3 weeks has been used to achieve better correction and reduce the risk of intraoperative neu-

rologic complications.34 A preoperative CT scan can also be useful to determine whether the spinal anatomy allows for pedicle screw placement.

Abnormalities of the Cervical Spine Although abnormalities of the cervical spine are not frequently discussed in the literature, they are common in patients with NF-1. In their series of 56 patients with NF-1 and scoliosis, Yong-Hing et al40 found cervical spine involvement in 17 (30%), including cervical kyphosis, rotatory subluxation, and dysplastic changes.40 Cervical spine involvement was more frequent in patients with dysplastic curves. Kyphosis can be the result of instability between spinal segments or bony changes that cause loss of normal cervical alignment.

The deformity may cause a spondylolisthesis and be severe enough to cause a spondyloptosis.41 Patients with cervical spine abnormalities may present with neck pain or neurologic symptoms; however, many are asymptomatic. Thus, it is important to obtain screening radiographs in patients with NF-1 and scoliosis.42

Other Spinal Abnormalities Spondylolisthesis has been noted in association with NF-1, but it is unclear whether the incidence of this deformity is higher in patients with NF-1 than in the general population. Usually, if spondylolisthesis is found, it appears in conjunction with foraminal neurofibroma or dural ectasia. Spondylolisthesis in conjunction with dural ectasia presents a major

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challenge to the orthopaedic surgeon because the narrowed pedicles may preclude pedicle screw instrumentation. Toyoda et al43 reported a successful reduction with posterolateral fusion and posterior lumbar interbody fusion in a patient with NF-1 as well as severe spondylolisthesis and dural ectasia.

Congenital Pseudarthrosis of the Tibia and Other Bony Dysplasias Congenital pseudarthrosis of the tibia (CPT), also known as congenital tibial dysplasia, is relatively uncommon in the general population (1 in 250,000 births).44 However, CPT is found more commonly in the NF-1 population. Although only 5% of patients with NF-1 are diagnosed with CPT, 75% of all patients with CPT have NF-1.45,46 CPT in conjunction with NF-1 is described as anterolateral bowing of the tibia that typically presents within the first year of life and, occasionally, at birth.47 Most dysplastic tibial deformities in NF-1 involve cortical thickening with a narrowed medullary canal. This is contradictory to the NIH diagnostic criteria, which cite a thinning of long bone cortex as characteristic of long bone dysplasia.48 Anterolateral bowing may be coupled with spontaneous fracture followed by pseudarthrosis, a common complication of CPT in persons with NF-1. Highly cellular fibrovascular tissue surrounds the pseudarthrosis site. Histologic studies of the fibrous tissues have demonstrated an increase in spindle cells and a decrease in osteoclasts, implying dysfunction in the ability of the bone to remodel. Further investigation of the spindle cells revealed myofibroblastic differentiation and cartilage formation, which was suggestive of dysfunction in the differentiation of periosteum to myofibroblasts or chondrocytes. Such
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findings are consistent in patients with CPT, whether or not they have NF-1.48 In a rabbit model, Wright et al49 demonstrated that placement of a circumferentially constricting mesh constructed of knitted polypropylene monofilaments around the tibia leads to bony characteristics similar to those found in CPT. This finding led to the belief that the presence of fibrovascular tissue surrounding the dysplastic tibia causes the bony dysplasia. Several classification systems can be used to help determine management and outcome.50 No classification system uniformly aids in treatment. Outcome is related to the presence of a fracture, age at the time of fracture, and location of the fracture within the tibia. Perhaps the most relevant system of determining the optimal management of CPT is that suggested by Johnston.51 This system employs only two criteria the presence or absence of fracture and the age at which the initial fracture appears. Management of CPT is demanding. However, several methods are available for obtaining and maintaining union of the affected bone while minimizing angular deformity. Nonsurgical management of CPT consists of bracing with a kneeankle-foot orthosis or an ankle-foot orthosis. The child who is diagnosed with anterolateral bowing may be placed in an ankle-foot orthosis until weight bearing begins, at which time the switch should be made to a kneeankle-foot orthosis. Bracing can also be a useful adjunct postoperatively.51,52 Bracing is best used to prevent fracture in dysplastic bone. It can also be used in a fractured dysplastic tibia to delay surgical intervention. The brace may enable good ambulatory function even in the presence of a fracture. Casting and bracing of a fractured tibia rarely result in union in patients with CPT.

Union has been reported in 35% to 100% of cases following surgical management.52,53 The great variability in union rates is often the result of the difficulty in determining healing radiographically. Additionally, the refracture rate may be very high. Common surgical treatments include bone grafting with intramedullary fixation, external fixation, and freevascularized fibular grafting. With each method, the objective is to maximize union through resection of the pseudarthrosis site, including the hypertrophic tissue, periosteum, and possibly, bone. Stable fixation and correction of angular deformity are imperative to healing. Amputation may be the best solution when multiple attempts at surgical treatment have failed and the limb remains very short.51,54 Intramedullary fixation with iliac crest bone graft is recommended by some because it provides stable fixation and reduces the risk of refracture. Proponents argue that the relative ease of the procedure, as well as the minimally complicated postoperative course for the patient compared with alternative procedures, makes it a desirable first-line treatment. Several alternative nail designs have been used to manage CPT telescoping nails that lengthen with growth, fixed-length solid nails that are inserted through the calcaneus or proximal tibia, and nails that are inserted through the site of pseudarthrosis or fracture.51 Regardless of method, it has been shown that leaving the intramedullary device in place, even after fracture healing, helps prevent refracture55 (Figure 7). Circular wire fixation has been used in the therapeutic management of affected bone. Following resection of the pseudarthrosis site, a ring external fixator is placed straddling the site of nonunion to provide compression and stable fixation of bone.52 External fixation enables multidi-

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Figure 7

A, AP (left) and lateral (right) radiographs of the tibia in a 4-year-old girl with congenital tibial dysplasia who went on to develop pseudarthrosis. B, AP (left) and lateral (right) radiographs showing placement of a Williams intramedullary rod inserted through the calcaneus at age 5 years. C, AP (left) and lateral (right) radiographs of the same patient at age 14 years, demonstrating healed bone. The rod was left in the tibia to help prevent refracture.

mensional correction, making it possible to correct axial deviation and limb-length discrepancy while union is achieved.52 Paley et al56 obtained an initial union rate of 94% with external fixation. Free vascularized fibular grafting has varying rates of union, ranging as high as 95%.53 The fibula is harvested from the vascular pedicle of the contralateral leg and is fixed into the gap left behind from resection of the pseudarthrosis tissue. Risks include donor site morbidity, failure of graft incorporation, development of ankle valgus, and dorsiflexion weakness of the foot and ankle.52 Few options for further reconstruction are available if union is not achieved with this technique. Recently, the use of a fibular strut allograft was described for prophylaxis against the development of fracture and pseudarthrosis.57 In this series of 10 patients, the authors de-

scribe bypass grafting with a posteromedially placed allograft fibula, followed by bracing until skeletal maturity. The authors reported no cases of persistent pseudarthrosis at an average follow-up of 78 months. The use of osteoinductive agents, such as bone morphogenetic protein, is considered off-label in this setting. However, they may be a useful adjunct to the management of CPT.58 The most common complication associated with treatment of CPT is valgus deformity, which affected 57.8% of patients in one study.53 Other postoperative complications are malalignment (eg, anterior bowing), limb-length discrepancy, and refracture.56,59 Pseudarthrosis in conjunction with NF-1 has also been noted to occur with less frequency in other long bones, such as the humerus, radius, ulna, and clavicle.60 Pelvic dysplasias have been observed, as well (Figure 8).

Metabolic Bone Disorders NF-1 causes generalized metabolic bone disorders through the loss of neurofibromin function. Multiple studies have verified a general decrease in bone mass in the NF-1 population, including children, relative to average bone mass. The lowest levels of bone mineral density were found in the lumbar spine. In one study, the level of bone mineral density met the criteria for osteopenia in 48% of cases and for osteoporosis in 25%.61 Growth Patterns Overgrowth of some or all tissues in one region of the body is one of the most recognized traits of NF-1, which can lead to a characteristically distorted appearance. Such overgrowth has been described as unilateral segmental hypertrophy, or gigantism. Subperiosteal bone growth has also been noted in conjunction

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Figure 8

A, AP radiograph demonstrating pelvic dysplasia in a patient with neurobromatosis type 1. B, T1-weighted axial magnetic resonance image demonstrating the presence of a plexiform neurobroma along the sciatic nerve (arrow).

with NF-1 and results in irregular bone elongation.62 Equalization of limb length may achieve both cosmetic and functional improvement. Short stature is another trend, affecting 13% to 40% of patients.63 According to one report, children with NF-1 can be >2 SD shorter than the general population.63

egies to manage musculoskeletal disabilities can vastly improve the quality of life in persons with NF-1.
7.

sporadic neurofibromatosis type 1 (NF1) associated with dysmorphism and developmental delay. J Med Genet 1996; 33(2):148-152. Xu GF, OConnell P, Viskochil D, et al: The neurofibromatosis type 1 gene encodes a protein related to GAP. Cell 1990;62(3):599-608. Daston MM, Scrable H, Nordlund M, Sturbaum AK, Nissen LM, Ratner N: The protein product of the neurofibromatosis type 1 gene is expressed at highest abundance in neurons, Schwann cells, and oligodendrocytes. Neuron 1992;8(3): 415-428.

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Summary
NF-1 is a common genetic condition that is present in 1 in 3,000 persons worldwide. Much has been learned in recent years about the molecular basis for the disease. Studies currently under way are investigating the possibility of a molecular target on which to base treatment. For now, however, such a target remains elusive. The orthopaedic surgeon faces several common challenging disorders in patients with NF-1. Because NF- 1 affects multiple organ systems, patients are likely to benefit most from a multidisciplinary treatment strategy. Careful implementation of stratJune 2010, Vol 18, No 6

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