neurofibromatosis

Orthopaedic Manifestations ofNeurofibromatosis Type 1

Abstract

Neurofibromatosis type 1 (NF-1) is an autosomal dominant diseasethat affects 1 in 3,000 persons worldwide. Café-au-lait macules andperipheral nerve sheath tumors (ie, neurofibromas) are the mostcommonly recognized manifestations of NF-1. However, NF-1affects multiple organ systems, and a multidisciplinary approach totreatment is required. Management of the orthopaedic manifesta-tions of NF-1 is often difficult. The most complex manifestations arescoliosis (dystrophic and nondystrophic), congenital pseudarthrosisof the tibia, and problems related to soft-tissue tumors. Metabolicbone disease is common; many patients are frankly osteopenic,which further complicates treatment. Dystrophic scoliosis, whichmay be caused by either bony dysplasia or intraspinal pathology, ischaracterized by early presentation and rapid progression. Pseud-arthrosis is common even after instrumented fusion. Nondystrophicscoliosis tends to behave like adolescent idiopathic scoliosis, al-though it may present earlier and is associated with a higher rateof pseudarthrosis. Congenital pseudarthrosis of the tibia is a long-bone dysplasia that afflicts patients with NF-1. Management of thisosseous deformity is challenging. Failure to achieve union and re-fracture are common.

Neurofibromatosis type 1 (NF-1),also known as von Reckling-

hausen disease, is an autosomal dom-inant genetic disorder that affects thecellular growth of neural tissues. Withan incidence of approximately 1 in3,000 persons worldwide and withoutprejudice to sex or race, NF-1 is one ofthe most common genetic disorders.1

The disease is characterized mainlyby multiple cutaneous hyperpigmen-tations and neurofibromas. NF-1also demonstrates a broad range ofmanifestations involving seeminglyunrelated systems.

German pathologist Frederick vonRecklinghausen2 provided the firstdescription of NF-1 in 1882. He hy-pothesized that the characteristic cu-taneous tumors were derived from fi-

brous tissues surrounding theperipheral nerves. Other forms of NFhave since been described. Neurofi-bromatosis type 2 (NF-2) is charac-terized primarily by bilateral vestibu-lar schwannomas. It occurs far lessfrequently than NF-1 but is also ofautosomal dominant inheritance.Segmental NF is the very rare mosaicform of NF-1. NF-2 and segmentalNF are not known to exhibit ortho-paedic manifestations.

Genetics

In 1989, the NF-1 gene (NF1) wasidentified and its locus found onchromosome 17q11.2. NF1 is verylarge; it spans 350 kilobases of DNA

David S. Feldman, MD

Charles Jordan, MD

Lauren Fonseca, BA

From the Department ofOrthopaedic Surgery, NYU Hospitalfor Joint Diseases, New York, NY.

Dr. Feldman or an immediate familymember serves as a board member,owner, officer, or committee memberof Limb Lengthening ResearchSociety; is a member of a speakers’bureau or has made paidpresentations on behalf of Stryker;serves as a paid consultant to or isan employee of Biomet; serves asan unpaid consultant toOrthopaediatrics; and has receivedresearch or institutional support fromEBI, Smith & Nephew, and Stryker.Neither of the following authors norany immediate family member hasreceived anything of value from orowns stock in a commercialcompany or institution relateddirectly or indirectly to the subject ofthis article: Dr. Jordan andMs. Fonseca.

J Am Acad Orthop Surg 2010;18:346-357

Copyright 2010 by the AmericanAcademy of Orthopaedic Surgeons.

Review Article

346 Journal of the American Academy of Orthopaedic Surgeons

and is composed of 59 exons.3 NF1was found to encode an approxi-mately 280 kDa cytoplasmic proteintermed neurofibromin.4,5 Althoughthe allele is completely penetrant,spontaneous mutations account forapproximately 50% of cases.6 De-spite advances in the elucidation of amolecular basis for the disease, muchphenotypic variability exists.

Analysis of the NF1 sequence re-vealed a 360–amino acid domain withsimilarities to guanosine triphos-phatase–activating proteins (GAPs).7

This discovery was helpful in under-standing the function of neurofibro-min. GAPs are a well-known super-family of genes that regulate thecontrol of cell growth and divisionby acting as suppressors of RASproto-oncogenes. In the case of neu-rofibromin, p21-RAS is the specificRAS proto-oncogene affected, whichis known to promote cell growth,proliferation, and differentiation.7

Neurofibromin is ubiquitous in hu-man tissue during development andis later found in high concentrationsexclusively within the nervous sys-tem and related tissues.8 Neurofibro-min has recently been found to be akey component in skeletal develop-ment and growth. Kolanczyk et al9

demonstrated in a mouse model that

NF1 dysfunction is associated withabnormal limb and joint develop-ment, such as tibial bowing andstunted growth. Observed increasesin osteoblastic proliferation and theinability of these osteoblasts to dif-ferentiate and mineralize tissues arethought to cause the porosity and de-creased stiffness of affected corticalbone. Kolanczyk et al9 also arguedthat reduced growth is the result ofdefective chondrocyte proliferationand differentiation within growthplates.

Diagnosis

Diagnosis can be made on careful ex-amination of the patient’s presentingclinical manifestations. These signsmay be dermatologic, ocular, cutane-ous, endocrine, neurologic, cardio-vascular, or orthopaedic, with vari-able severity in each category. Thediagnostic criteria, defined by theNational Institutes of Health (NIH)Consensus Development Program in1987, consist of the most commonlypresenting features of the disease10

(Table 1). Diagnosis of NF-1 requiresthe presence of at least two of thefeatures listed.

Although these criteria are widely

accepted and applied, diagnosis maybe delayed because of the variableage at which these features emerge.DeBella et al11 conducted a retro-spective review of 1,893 patientswith NF-1 diagnosed by age 20years. Within this subject pool, 30%failed to meet the NIH diagnosticcriteria by age 1 year, and 3% failedto meet the criteria by age 8 years.

Clinical Manifestations

Management of NF requires the aggres-sive treatment of its various manifesta-tions. The patient with NF-1 will likelyrequire a multidisciplinary approach totreatment. Approximately 70% of af-fected persons will have at least one sur-gical procedure or hospital admissionfor a problem related to NF.12

Dermal FeaturesCafé-au-lait macules are the mostprevalent feature of NF-1 (Figure 1).Present in nearly all persons withNF-1, these macules are usually thefirst clinical feature to emerge withinthe first year of life. Ninety-nine per-cent of patients have six or more le-sions >5 mm in diameter by age 1

Table 1

Diagnostic Criteria for Neurofibromatosis Type 1

The diagnostic criteria for NF-1 are met when two or more of the following are found:≥6 café-au-lait macules >5 mm in greatest diameter in prepubertal persons and

>15 mm in greatest diameter in postpubertal persons≥2 neurofibromas of any type or one plexiform neurofibromaFreckling in the axillary or inguinal regionOptic glioma≥2 Lisch nodulesA distinctive osseous lesion, such as sphenoid dysplasia or thinning of long bone

cortex, with or without pseudarthrosisA first-degree relative (parent, sibling, or offspring) with NF-1 as diagnosed using the

listed criteria

NF-1 = neurofibromatosis type 1Adapted with permission from Neurofibromatosis: Conference statement. National Institutesof Health Consensus Development Conference. Arch Neurol 1988;45:575-578. Café-au-lait lesion in a child with

neurofibromatosis type 1. (Courtesyof Lori A. Karol, MD, Texas ScottishRite Hospital, Dallas, TX.)

Figure 1

David S. Feldman, MD, et al

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year.11 These lesions appear flatalong the skin’s surface as coffee-colored areas of hyperpigmentation.The lesions are oval or rounded inshape with well-defined borders,with an average size of 2 to 5 cm, al-though they may be 2 mm to >20 cmin size.11

Skin-fold freckling appears assmall brown macules within regionsthat seldom freckle: the axillae, in-guinal region, breast folds, neck, andupper eyelids. Such freckling typi-cally emerges by age 7 years, makingit the second dermatologic feature todevelop. This occurs in approxi-mately 90% of affected persons.11

Ocular/Orbital FeaturesLisch nodules are hyperpigmentedhamartomas of the iris consisting ofspindle-shaped cells. These nodulesare present in >70% of affected per-sons by age 10 years.11 Lisch nodulesare easily observed on slit lamp ex-amination. They do not cause visualimpairment.

Neoplastic

Optic Pathway GliomaOptic pathway gliomas (OPGs) af-fect approximately 6.6% of patients

and usually develop in early child-hood; however, they may occur aslate as the third decade of life.13

These low-grade pilocytic astrocyto-mas of the optic nerve and/or opticchiasm may or may not be sympto-matic. OPGs can cause proptosis, de-creased visual acuity, nystagmus, andoptic disk atrophy.

NeurofibromaNeurofibromas are benign neoplasmsof peripheral nerve sheath origin thatare composed of Schwann cells, fibro-blasts, perineural cells, and mast cells.These neoplasms may include associ-ated axons. Characteristically benign,neurofibromas exhibit a variety of mor-phologies as well as unpredictablegrowth patterns.14

Neurofibromas are rarely presentat birth and typically evolve in latechildhood; >80% of patients developneurofibromas by age 20 years.11

With time, neurofibromas may in-crease in size and magnitude. Periodsof accelerated proliferation havebeen documented during pubertyand pregnancy.14 Cutaneous neurofi-bromas can be seen on the surface ofthe skin as well-circumscribed, gray-ish tumors and may cause pruritus(Figure 2).

Plexiform neurofibromas are diffuseand poorly defined and involve multi-ple nerve fascicles as well as surround-ing tissues. Plexiform neurofibromas arecomposed primarily of the same celltypes as cutaneous neurofibromas, butthe plexiform type includes an extracel-lular matrix and vascular supply. Plex-iform neurofibromas occur in as manyas 40% of patients; this type has beenindicated in association with compli-cations such as hemorrhage, dysfunc-tion, pain, disfigurement, and transfor-mation into malignant peripheral nervesheath tumors (MPNSTs).15-18

MalignanciesPersons with NF-1 are at greater riskthan the general population for devel-

oping benign and malignant neoplasms,including melanoma, leukemia, rhab-domyosarcoma, pheochromocytoma,carcinoma, and pancreatic endocrinetumors.15,19 They are also at in-creased risk for developing brain tu-mors, specifically, tumors of astro-cytic origin.

Malignant Peripheral NerveSheath TumorMPNSTs (ie, neurofibrosarcomas)are the most severe neoplastic com-plication of NF-1 because of theirelusive nature, pattern of wide me-tastasis, and high rate of local recur-rence.15,20 The presence of MPNSTsin patients with NF-1 imparts a poorprognosis, with 5-year survival ratesof approximately 21%.21 For pa-tients with NF-1, the lifetime risk ofdeveloping MPNSTs is 10% to24%.15,21

MPNSTs usually originate withinpreexisting benign plexiform neu-rofibromas that undergo malignanttransformation and that consist ofhigh cellularity, tumor necrosis, dedif-ferentiation, and mitotic activity.15,20

Patients are at greatest risk of malig-nancies from plexiform neurofibro-mas approximately 10 to 20 yearsafter the development of the originalneurofibroma.22 This transformationis marked clinically by a sudden on-set of pain and discomfort at the af-fected area, enlargement, and newneurologic deficits. The diagnosis ofmalignant transformation of a plexi-form neurofibroma to an MPNSTcan be very difficult to make. MRI islikely the most useful imaging mo-dality, although positron emissiontomography scanning has been re-cently shown to be a useful diagnos-tic tool.23 Immunohistochemistry,particularly KI-67 and S-100 stain-ing, is an important tool in differ-entiating plexiform neurofibromasfrom MPNSTs.24

Clinical photograph demonstratingcutaneous neurofibromas. (Repro-duced with permission fromMcCann SA: Cutaneousmanifestations of systemic disease:Leukemia/lymphoma, systemicmalignancy, hypothyroidism,diabetes mellitus, andneurofibromatosus. Dermatol Nurs2006;18:476-478.)

Figure 2

Orthopaedic Manifestations of Neurofibromatosis Type 1


Neurologic andCardiovascular FeaturesNF-1 is one of the most common ge-netic disorders known to cause learn-ing disabilities in children, affectingas many as 75% of children withNF-1.25 Delayed gross motor devel-opment as well as speech and lan-guage deficits have also been noted.Psychiatric disorders affect 33% ofpersons with NF-1.25,26

Unidentified bright objects appearon MRI as areas of hyperintense sig-nal on T2-weighted and other fluid-sensitive sequences, most frequentlyin the cerebellum, brain stem, andbasal ganglia. They affect up to 94%of children with NF-1, and they dis-appear through the third and fourthdecades.27 These unidentified brightobjects most likely have no clinicalimpact. Headaches are seen in ≤46%of patients with NF-1, deafness in10%, seizures in 3% to 11%, andhydrocephalus in 4%.27

Persons with NF-1 are at increasedrisk for stroke, hypertension, congen-ital heart disease, and vasculopathy.28

Orthopaedic Manifestations

Spinal DeformitySpinal deformity has been reportedin approximately 49% of patients

with NF-1.16 Osteomalacia, intraspi-nal neurofibromas that erode and in-filtrate bone, and endocrine distur-bances are some of the entities thathave been implicated in the develop-ment of spinal deformity.29 However,a definitive etiology remains elusive.

Several dystrophic changes havebeen identified, including rib pencil-ing, vertebral scalloping, dumbbelllesions, and dural ectasia (Table 2).Rib penciling, defined as a rib whosewidth is narrower than the narrow-est portion of the second rib, is themost prevalent dystrophic osseouschange30 (Figure 3). In addition tobeing a cause of deformity, penciledribs are susceptible to dislocationand have been reported to enter thespinal canal and cause paralysis.

Vertebral scalloping, or marginalerosion, can be appreciated radio-graphically when the depth of ero-sion measures >3 mm in the thoracicspine and >4 mm in the lumbarspine31 (Figure 4). Posterior scallop-ing is most common in NF-1; ante-rior and lateral scalloping occur farless frequently. Posterior vertebralscalloping is closely associated withthe presence of intraspinal pathol-ogy, with 63% of scalloped vertebralsites closely located to either dural

ectasia or an intraspinal neurofibro-ma.31 Thus, the presence of scallopedvertebrae should signal the ortho-paedic surgeon to approach the spinewith increased clinical suspicion forpotential pathologic processes.

The dumbbell lesion is caused bythe presence of neurofibromas withinthe canal. Its name derives from thedumbbell-like shape it assumes as itexpands outward through the neuralforamina. This is a commonly seenlesion in the dystrophic spine.

Dural ectasia, another commonphenomenon in the dystrophic spine,is described as a circumferential dila-tion of the thecal sac and is thoughtto erode surrounding osseous struc-tures. Dural ectasia is thought to bea consequence of abnormally ele-vated pressure in the dural sac; how-ever, it may be a primary erosionproblem of bone. It is associatedwith posterior vertebral scallopingand thinning of the pedicles and lam-ina, and it can lead to meningoceleformation31 (Figure 5). The thinningof surrounding osseous elements canresult in significant instability anddeformity, even leading to vertebral

Table 2

Dystrophic Changes in Persons with Neurofibromatosis Type 1

Vertebral scalloping (depth >3 mm in the thoracic spine or >4 mm in the lumbarspine). 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 narrowestportion of the second rib)

Transverse process spindlingVertebral wedgingParavertebral soft-tissue massShort curve with severe apical rotationIntervertebral foraminal enlargementWidened interpediculate distancesDysplastic pedicles

Adapted with permission from Tsirikos AI, Saifuddin A, Noordeen MH: Spinal deformity inneurofibromatosis type-1: Diagnosis and treatment. Eur Spine J 2005;14:427-439.

AP radiograph demonstrating ribpenciling (arrow) in a patient withneurofibromatosis-1. (Courtesy ofLori A. Karol, MD, Texas ScottishRite Hospital, Dallas, TX.)

Figure 3


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destabilization. Because of concomi-tant thecal sac expansion, however,neural elements are protected andgenerally remain intact, even in thepresence of severe deformity.

Less common dystrophic changesinclude spindling of the transverseprocess, vertebral wedging and rota-tion, foraminal enlargement, wid-ened interpediculate distance, anddysplasia of the pedicles.30 Such in-traspinal pathology is linked to dys-trophic deformities and is even impli-cated as the possible cause. However,dystrophic changes can be seen with-out the presence of a pathologic le-sion.

ScoliosisPersons with NF-1 may develop dys-trophic and nondystrophic scoliosis.Dystrophic scoliosis is less commonbut more severe than nondystrophicscoliosis. Nondystrophic scoliosistypically progresses at the same rateas adolescent idiopathic scoliosis andhas a similar clinical appearance.However, nondystrophic scoliosis inNF-1 has an earlier onset and poorer

prognosis posttreatment than doesadolescent idiopathic scoliosis. Non-dystrophic curves require careful ob-servation because of the tendency formodulation, a process by which dys-trophic characteristics develop overtime. Some authors use this term todescribe a change in the behavior ofa curve from one that is characteris-tically nondystrophic and slowlyprogressing to one that over time be-comes rapidly progressive with theappearance of dystrophic changes.Others think, however, that curvesthat appear to modulate are reallythose in which dystrophic changeshad not yet become apparent, espe-cially because in some curves, pro-gression does not necessarily followmodulation.30 However, if suchchanges are noted to occur in a curvethat had previously been believed tobe nondystrophic, it is reasonableand acceptable to treat the deformityas a dystrophic curve.

Durrani et al30 reported an overallmodulation rate of 65% in nondys-trophic curves. One major predictor

of modulation is the age at whichscoliosis clinically presents. Modula-tion occurred in 81% of NF-1 pa-tients presenting with scoliosis be-fore age 7 years and in 25% of thosewho presented after age 7 years. Spi-nal deformities in patients with NF-1should be followed closely for dys-trophic changes and modulation be-cause these affect treatment andprognosis.

Persons with NF-1 require early scoli-osis screening and regular follow-up.Following a diagnosis of scoliosis, allpatients with NF-1 should be furtherevaluated with MRI and/or CT scan-ning to accurately assess the deformityand the presence of dystrophic changes.These studies may detect the presenceof intraspinal and/or extraspinal neo-

T2-weighted sagittal magneticresonance image demonstratingdural ectasia with posteriorvertebral scalloping. (Reproducedwith permission from Tsirikos AI,Saifuddin A, Noordeen MH: Spinaldeformity in neurofibromatosistype-1: Diagnosis and treatment.Eur Spine J 2005;14:427-439.)

Figure 5

Coned-down lateral radiographs of the lumbar spine demonstrating posterior(A) and anterior (B) vertebral scalloping. (Reproduced with permission fromTsirikos AI, Saifuddin A, Noordeen MH: Spinal deformity in neurofibromatosistype-1: Diagnosis and treatment. Eur Spine J 2005;14:427-439.)

Figure 4



plasia. When a seemingly nondystro-phic curve is noted to progress morerapidly than expected, repeat MRIand/or CT scanning is indicated to de-tect dystrophic change as well as in-traspinal and paraspinal tumors, bothof which may alter management over-all and the surgical strategy in partic-ular. Additionally, the presence ofparaspinal tumors can limit surgical ex-posure or increase the risk of bleedingbecause of the increased vascularity ofthe tumor and surrounding tissues. Assuch, these should be ruled out beforesurgical intervention. The incidence ofparaspinal tumors is reported to be ashigh as 40% in patients with NF-1based on whole-spine MRI or CT scan-ning of the chest, abdomen, and pel-vis.32

Nondystrophic scoliosis is managedbased on the degree of curvature. Ob-servation is sufficient for curves <20°.Bracing is recommended once progres-sion is documented or the curve mea-sures 20° to 40° in the skeletally imma-ture patient. Fusion is required forcurves ≥40°. Posterior instrumentationalone can be successful in treating lesssevere nondystrophic curves, but AP fu-sion is indicated for curves measuring≥90°.33,34

Dystrophic scoliosis is character-ized by rapid progression, often de-spite treatment, leading to severe de-formity. Dystrophic curves present assharply angulated segments of fourto six vertebrae and are accompaniedby one or more of the osseous abnor-malities outlined previously. Thesedystrophic changes tend to furthercomplicate the deformity and the en-suing treatment.

Dystrophic curves can be classifiedinto two groups according to curve pat-tern. Type I curves consist of scoliosisin the coronal plane with a sagittalplane kyphosis measuring <50°. Theaddition of a significant kyphotic defor-mity characterizes type II dystrophiccurve. This kyphosis appears clinicallyas a severe, acute, sagittal plane angu-

lation and measures >50° radio-graphically.35,36

Curve progression can be predictedby the extent of dystrophic osseousdeformities within the spine. Eighty-five percent of dystrophic curvesprogress when three or more hetero-geneous dystrophic features arepresent.30 Durrani et al30 identifiedrib penciling as the only independentdystrophic deformity that is an indi-cator of curve progression; 87% ofdeformities involving three or morepenciled ribs progressed. Kyphoscoli-osis is usually associated with severeprogression of dystrophic deformityas well, and it can be complicated bya draping of the spinal cord or com-pression that, left untreated, can leadto neurologic compromise and evenparaplegia.35

The complex and severe nature ofdystrophic curves and the risk ofneurologic injury pose a major chal-lenge to the orthopaedic surgeon. Itis widely accepted that early and ag-gressive surgical intervention is nec-essary to prevent dystrophic curveprogression.33-36 Bracing has not beenshown to be effective in preventingprogression. Curves of <20° may beobserved with close follow-up, usu-ally at 6-month intervals, to monitorprogression. Once a dystrophic curveadvances beyond 20° to 40°, surgeryis recommended.34

Some authors advocate the use ofa combined anterior-posterior tech-nique to achieve fusion in all but themost benign curves. The anterior-posterior approach is considerednecessary for curves measuring >90°and in those that demonstrate rap-idly progressing dystrophic changesand/or the development of acute ky-phosis.33,35,36 The anterior-posteriorapproach facilitates greater spinalcorrection and may decrease thepseudarthrosis rate.33,36

Recent studies have suggested thattype I dystrophic curves can be stabi-lized by posterior fusion alone with

segmental spinal instrumentation(Figure 6). One study in particularsuggests that the posterior approachis successful in deformities of ap-proximately 90° of scoliosis whenfusion extends beyond the conven-tional fusion levels, abundant bonegraft is used, and both the coronaland sagittal planes are corrected.33

Although posterior instrumentationalone is an accepted treatment forsome dystrophic curves, it has beenassociated with high rates of pseud-arthrosis, a complication that is lesscommon with the combined anterior-posterior approach.34 In a retrospec-tive study, Parisini et al35 assessed 56NF-1–related deformities and re-ported a failure rate of 47% in pa-tients with type I curves treated withposterior fusion alone.

Type II dystrophic curves requiremore aggressive surgical manage-ment because of the presence of se-vere sagittal deformity. These defor-mities have poor outcomes whentreated with posterior spinal fusionalone. Thus, the more extensiveanterior-posterior approach is indi-cated.33,35

When performing spinal fusion inthe dystrophic spine, extra care mustbe taken in dissection and decortica-tion because of the possible presenceof laminar erosion and weakening.Kumar and Crawford37 advocate theuse of the Bovie electrocautery device(Bovie Medical, St. Petersburg, FL)to avoid “plunging” through aneroded lamina, as could happen withelevators and other blunt instru-ments.

Erosion and weakening of thebony posterior elements of affectedsegments destabilize the spine andcontribute to instrumentation chal-lenges. Hardware complications mayarise with dislodgment of hooks usedfor proximal fixation. Such dislodg-ment occurs especially in the pres-ence of osteoporosis and deformedposterior elements. Although the


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pedicles may be weak and thinned,pedicle screws are more likely to pro-vide stable fixation and a reducedrisk of hardware failure by providingbetter vertebral grip. Titanium in-strumentation is preferred becauseintraspinal and paraspinal tumorsare often present.38 This facilitatesevaluation with postoperative MRI.

Preoperative traction may be help-ful in the management of severecurves. Winter et al39 advocated theuse of preoperative traction to im-prove pulmonary function and someneurologic deficits in patients with aflexible kyphosis. Traction also wasshown to reduce curve severity priorto fusion. More recently, the use ofpreoperative halo traction in dystro-phic curves for ≥3 weeks has beenused to achieve better correction andreduce the risk of intraoperative neu-

rologic complications.34 A preopera-tive CT scan can also be useful to de-termine whether the spinal anatomyallows for pedicle screw placement.

Abnormalities of theCervical SpineAlthough abnormalities of the cervi-cal spine are not frequently discussedin the literature, they are common inpatients with NF-1. In their series of56 patients with NF-1 and scoliosis,Yong-Hing et al40 found cervicalspine involvement in 17 (30%), in-cluding cervical kyphosis, rotatorysubluxation, and dysplastic chang-es.40 Cervical spine involvement wasmore frequent in patients with dys-plastic curves. Kyphosis can be theresult of instability between spinalsegments or bony changes that causeloss of normal cervical alignment.

The deformity may cause a spondy-lolisthesis and be severe enough tocause a spondyloptosis.41 Patientswith cervical spine abnormalitiesmay present with neck pain or neu-rologic symptoms; however, manyare asymptomatic. Thus, it is im-portant to obtain screening radio-graphs in patients with NF-1 andscoliosis.42

Other Spinal AbnormalitiesSpondylolisthesis has been noted inassociation with NF-1, but it is un-clear whether the incidence of thisdeformity is higher in patients withNF-1 than in the general population.Usually, if spondylolisthesis is found,it appears in conjunction with fo-raminal neurofibroma or dural ecta-sia. Spondylolisthesis in conjunctionwith dural ectasia presents a major

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.

Figure 6



challenge to the orthopaedic surgeonbecause the narrowed pedicles maypreclude pedicle screw instrumenta-tion. Toyoda et al43 reported a suc-cessful reduction with posterolateralfusion and posterior lumbar inter-body fusion in a patient with NF-1as well as severe spondylolisthesisand dural ectasia.

Congenital Pseudarthrosisof the Tibia and OtherBony DysplasiasCongenital pseudarthrosis of thetibia (CPT), also known as congeni-tal tibial dysplasia, is relatively un-common in the general population (1in 250,000 births).44 However, CPTis found more commonly in the NF-1population. Although only 5% ofpatients with NF-1 are diagnosedwith CPT, 75% of all patients withCPT have NF-1.45,46

CPT in conjunction with NF-1 isdescribed as anterolateral bowing ofthe tibia that typically presentswithin the first year of life and, occa-sionally, at birth.47 Most dysplastictibial deformities in NF-1 involvecortical thickening with a narrowedmedullary canal. This is contradic-tory to the NIH diagnostic criteria,which cite a “thinning of long bonecortex” as characteristic of longbone dysplasia.48 Anterolateral bow-ing may be coupled with spontane-ous fracture followed by pseudar-throsis, a common complication ofCPT in persons with NF-1.

Highly cellular fibrovascular tissuesurrounds the pseudarthrosis site.Histologic studies of the fibrous tis-sues have demonstrated an increasein spindle cells and a decrease in os-teoclasts, implying dysfunction in theability of the bone to remodel. Fur-ther investigation of the spindle cellsrevealed myofibroblastic differentia-tion and cartilage formation, whichwas suggestive of dysfunction in thedifferentiation of periosteum to myo-fibroblasts or chondrocytes. Such

findings are consistent in patientswith CPT, whether or not they haveNF-1.48 In a rabbit model, Wright etal49 demonstrated that placement ofa circumferentially constricting meshconstructed of knitted polypropylenemonofilaments around the tibialeads to bony characteristics similarto those found in CPT. This findingled to the belief that the presence offibrovascular tissue surrounding thedysplastic tibia causes the bony dys-plasia.

Several classification systems canbe used to help determine manage-ment and outcome.50 No classifica-tion system uniformly aids in treat-ment. Outcome is related to thepresence of a fracture, age at thetime of fracture, and location of thefracture within the tibia. Perhaps themost relevant system of determiningthe optimal management of CPT isthat suggested by Johnston.51 Thissystem employs only two criteria—the presence or absence of fractureand the age at which the initial frac-ture appears.

Management of CPT is demand-ing. However, several methods areavailable for obtaining and main-taining union of the affected bonewhile minimizing angular deformity.Nonsurgical management of CPTconsists of bracing with a knee-ankle-foot orthosis or an ankle-footorthosis. The child who is diagnosedwith anterolateral bowing may beplaced in an ankle-foot orthosis untilweight bearing begins, at which timethe switch should be made to a knee-ankle-foot orthosis. Bracing can alsobe a useful adjunct postoperative-ly.51,52 Bracing is best used to preventfracture in dysplastic bone. It canalso be used in a fractured dysplastictibia to delay surgical intervention.The brace may enable good ambula-tory function even in the presence ofa fracture. Casting and bracing of afractured tibia rarely result in unionin patients with CPT.

Union has been reported in 35% to100% of cases following surgicalmanagement.52,53 The great variabil-ity in union rates is often the resultof the difficulty in determining heal-ing radiographically. Additionally,the refracture rate may be very high.Common surgical treatments includebone grafting with intramedullaryfixation, external fixation, and free-vascularized fibular grafting. Witheach method, the objective is to max-imize union through resection of thepseudarthrosis site, including the hy-pertrophic tissue, periosteum, andpossibly, bone. Stable fixation andcorrection of angular deformity areimperative to healing. Amputationmay be the best solution when multi-ple attempts at surgical treatmenthave failed and the limb remainsvery short.51,54

Intramedullary fixation with iliaccrest bone graft is recommended bysome because it provides stable fixa-tion and reduces the risk of refrac-ture. Proponents argue that the rela-tive ease of the procedure, as well asthe minimally complicated postoper-ative course for the patient comparedwith alternative procedures, makes ita desirable first-line treatment.

Several alternative nail designshave been used to manage CPT—telescoping nails that lengthen withgrowth, fixed-length solid nails thatare inserted through the calcaneus orproximal tibia, and nails that are in-serted through the site of pseudar-throsis or fracture.51 Regardless ofmethod, it has been shown that leav-ing the intramedullary device inplace, even after fracture healing,helps prevent refracture55 (Figure 7).

Circular wire fixation has beenused in the therapeutic managementof affected bone. Following resectionof the pseudarthrosis site, a ring ex-ternal fixator is placed straddling thesite of nonunion to provide compres-sion and stable fixation of bone.52

External fixation enables multidi-


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mensional correction, making it pos-sible to correct axial deviation andlimb-length discrepancy while unionis achieved.52 Paley et al56 obtainedan initial union rate of 94% with ex-ternal fixation.

Free vascularized fibular graftinghas varying rates of union, rangingas high as 95%.53 The fibula is har-vested from the vascular pedicle ofthe contralateral leg and is fixed intothe gap left behind from resection ofthe pseudarthrosis tissue. Risks in-clude donor site morbidity, failure ofgraft incorporation, development ofankle valgus, and dorsiflexion weak-ness of the foot and ankle.52 Few op-tions for further reconstruction areavailable if union is not achievedwith this technique.

Recently, the use of a fibular strutallograft was described for prophy-laxis against the development offracture and pseudarthrosis.57 In thisseries of 10 patients, the authors de-

scribe bypass grafting with a postero-medially placed allograft fibula, fol-lowed by bracing until skeletalmaturity. The authors reported nocases of persistent pseudarthrosis atan 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 ad-junct to the management of CPT.58

The most common complication as-sociated with treatment of CPT is val-gus deformity, which affected 57.8%of patients in one study.53 Otherpostoperative complications are mal-alignment (eg, anterior bowing),limb-length discrepancy, and refrac-ture.56,59

Pseudarthrosis in conjunction withNF-1 has also been noted to occur withless frequency in other long bones, suchas the humerus, radius, ulna, andclavicle.60 Pelvic dysplasias have beenobserved, as well (Figure 8).

Metabolic Bone DisordersNF-1 causes generalized metabolicbone disorders through the loss ofneurofibromin function. Multiplestudies have verified a general de-crease in bone mass in the NF-1 pop-ulation, including children, relativeto average bone mass. The lowestlevels of bone mineral density werefound in the lumbar spine. In onestudy, the level of bone mineral den-sity met the criteria for osteopenia in48% of cases and for osteoporosis in25%.61

Growth PatternsOvergrowth of some or all tissues inone region of the body is one of themost recognized traits of NF-1,which can lead to a characteristicallydistorted appearance. Such over-growth has been described as unilat-eral segmental hypertrophy, or gi-gantism. Subperiosteal bone growthhas also been noted in conjunction

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

Figure 7



with NF-1 and results in irregularbone elongation.62 Equalization oflimb length may achieve both cos-metic and functional improvement.Short stature is another trend, affect-ing 13% to 40% of patients.63 Ac-cording to one report, children withNF-1 can be >2 SD shorter than thegeneral population.63

Summary

NF-1 is a common genetic conditionthat is present in 1 in 3,000 personsworldwide. Much has been learnedin recent years about the molecularbasis for the disease. Studies cur-rently under way are investigatingthe possibility of a molecular targeton which to base treatment. Fornow, however, such a target remainselusive.

The orthopaedic surgeon faces sev-eral common challenging disordersin patients with NF-1. Because NF- 1affects multiple organ systems, pa-tients are likely to benefit most froma multidisciplinary treatment strat-egy. Careful implementation of strat-

egies to manage musculoskeletal dis-abilities can vastly improve thequality of life in persons with NF-1.

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

Figure 8


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