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J Oral Maxillofac Surg70:1351-1357, 2012

Radiographic Findings in the Jaws ofPatients With Neurofibromatosis 1

Vivian Visnapuu, DDS, PhD,* Sirkku Peltonen, MD, PhD,†

Tapio Tammisalo, DDS, PhD,‡ Juha Peltonen, MD, PhD,§ and

Risto-Pekka Happonen, DDS, PhD�

Purpose: Neurofibromatosis 1 (NF1) is a neurocutaneous-skeletal disorder with variable phenotypicexpression and an incidence of 1:3,000 worldwide. The objective was to characterize the NF1-relatedradiologic alterations found in the jaws of these patients.

Patients and Methods: In total, 102 patients with NF1 were included in the present study. Six patientshad a plexiform neurofibroma in the craniofacial region.

Results: Radiologic abnormalities in the jaws were found in 29 of 102 patients with NF1, including 6patients with plexiform neurofibroma in the head and neck region. The most common radiologic findingwas enlargement of the mandibular canal. The most prominent skeletal deformities and alterations ofvarying severity were detected in the jaws of 6 patients with plexiform neurofibroma. In these patients,the skeletal deformities were seen on the side affected by the tumor and possibly caused by the tumor.In 1 patient, however, the skeletal changes were on the opposite side.

Conclusions: Radiologic abnormalities were found in 29 of 102 patients. The most significant findingswere profound deformities of the mandible and maxilla in all 6 patients with plexiform neurofibroma, butnot in the other patients. The facial bone deformities found in young patients did not progress markedlyat older ages with cessation of the patients’ growth.© 2012 American Association of Oral and Maxillofacial Surgeons

J Oral Maxillofac Surg 70:1351-1357, 2012

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eurofibromatosis 1 (NF1) is a neurocutaneous-skel-tal disorder with variable phenotypic expression andn incidence of 1:3,000 worldwide.1,2 The diagnosisf NF1 is based on criteria outlined by the Nationalnstitutes of Health (United States) Consensus Devel-pment Conference in 1987.3 Osseous dysplasias inF1 may include decreased bone mineral density,

coliosis, and congenital pseudoarthrosis. NF1-relatedraniofacial findings include macrocephaly and sphe-oid wing dysplasia. The facial skeletal malformations

*Senior Lecturer, Department of Cell Biology and Anatomy, Uni-

versity of Turku, Turku, Finland.

†Senior Lecturer, Department of Dermatology, University of

Turku and Turku University Hospital, Turku, Finland.

‡Senior Consultant, Medical Imaging Center Tomodent, Turku,

Finland.

§Professor and Head, Department of Cell Biology and Anatomy,

Institute of Biomedicine, University of Turku, Turku, Finland.

�Professor and Head, Department of Oral and Maxillofacial Sur-

gery, University of Turku, Turku, Finland; Department of Oral

Diseases, Turku University Hospital, Turku, Finland.

Address correspondence and reprint requests to Dr Visnapuu:

Department of Cell Biology and Anatomy, University of Turku,

Kiinamyllynkatu 10, FIN 20520 Turku, Finland; e-mail: vivvis@utu.fi

© 2012 American Association of Oral and Maxillofacial Surgeons

278-2391/12/7006-0$36.00/0

oi:10.1016/j.joms.2011.06.204

1351

re a result of genetic and epigenetic factors, such asumor growth.1 The protein encoded by the NF1

gene, neurofibromin, is a tumor suppressor proteinthat acts as a Ras-GTPase activating protein (GA), thusinactivating Ras.4 It has been shown that the NF1gene is expressed at a high level in the growth plateduring endochondral ossification and in osteoclasts,osteoblasts, and osteocytes. In addition, recent find-ings have indicated that neurofibromin acts as a Ras-GAP during ossification in Nf1�/� and Nf1�/� mice.5

Previous studies have shown that NF1 involves theoral and facial structures in 3.4% to 92% of adultpatients and in approximately 40% of children withNF1.6 Impacted, displaced, supernumerary, or miss-ng teeth, particularly in the mandible, widening ofhe alveolar canal, and overgrowth of the alveolaridge are recognized oral manifestations of NF1.6 Fur-hermore, a specific lytic bone lesion of the jaws,eriapical cemental dysplasia, has been found to beommon in women with NF1.7 The objective in the

present work was to characterize the NF1-relatedradiologic alterations found in the jaws of 102 pa-tients, which is the largest collection of material stud-ied to date.

Patients and Methods

One hundred two patients with NF1 (55 female

patients 3 to 64 years old and 47 male patients 8 to 73

W

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1352 CRANIOFACIAL RADIOGRAPHIC FINDINGS IN NF1

years old) were included in the present study. Sixpatients had plexiform neurofibroma of the craniofa-cial region. The patients were recruited into the studyfrom patients attending the NF1 clinic at the Depart-ment of Dermatology, Turku University Central Hos-pital and from members of a Finnish organization ofpatients with NF. This resulted in participation ofpatients from all parts of Finland. The study wasapproved by the ethics committee of the SouthwestFinland Hospital District, Turku, Finland. The studywas carried out with the written consent of the pa-tients or their parents.

All patients fulfilled the diagnostic criteria for NF1.3

The craniofacial status of patients was evaluated at theDepartment of Oral Diseases, Turku University Hos-pital from 2005 through 2009. Evaluation includedphysical examination and analysis of cephalogramsand panoramic images supplemented with tomo-grams and periapical radiographs as necessary. Nofurther radiologic examinations using computed to-mography were performed to avoid unnecessary ra-diation and because no surgical intervention wasplanned for any patient at the time the study wasconducted.

Results

Radiologic abnormalities were found in 29 of 102patients with NF1, including 6 patients with plexi-form neurofibroma in the head and neck area. Themost common radiologic finding was enlargement ofthe mandibular canal (Table 1). In patients withoutplexiform neurofibroma, bilateral widening of themandibular canal was seen in 11 of 96 patients andunilateral widening in 10 of 96 patients. In patientswith plexiform neurofibroma, widening of the man-dibular canal was seen on the side affected by thetumor. Other skeletal deformities and alterations ofvarying severity were detected in the jaws of 6 pa-tients with plexiform neurofibroma. The radiologicfindings of patients with facial plexiform neurofi-

Table 1. RESULTS OF RADIOLOGIC EVALUATION OF TH

Patients n

M

Bil

With plexiform neurofibroma (n � 6)Male, 10–42 yrs old 5Female, 64 yrs old 1ithout plexiform neurofibroma (n � 96)Male, 8–73 yrs old 42Female, 7–76 yrs old 54

Visnapuu et al. Craniofacial Radiographic Findings in NF1. J Or

broma are described below.

PATIENT 1

The patient was a 10-year-old boy with sporadicNF1 diagnosed within the first year of life. Physicalexamination disclosed a plexiform neurofibroma ofthe left side of the face causing facial soft tissuedeformity. A mild malocclusion was observed in anotherwise complete mixed dentition. Intraoral exam-ination showed soft tissue hyperplasia on the lingualside of the lower anterior teeth. The radiologic exam-ination showed an oval 10- � 20-mm bone defect inthe lower border of the posterior part of the leftmandibular ramus (Fig 1).

PATIENT 2

The patient was studied at 11 and 14 years of age.His NF1 was diagnosed 3 months after birth. Thepatient’s father has NF1. Interestingly, the most prom-inent osseous changes were found on the side oppo-site to the plexiform tumor. At 11 years of age, thepatient had a plexiform neurofibroma involving theleft eyelid and left maxillary region (not shown). Clin-ically, the right first upper molar in the late mixeddentition was unerupted, whereas the left first molarwas erupted (Fig 2A). Papillary soft tissue hyperplasiawas seen on the mobile gingiva of the left maxilla.Radiographs showed that the right mandibular ramuswas taller compared with the opposite side (Fig 2A).The posterior part of the right mandibular body wasmore prominent than on the left side. In addition, thebone structure had a milk-glass appearance resem-bling the radiologic features of fibrotic dysplasia. Fur-thermore, the borders of the right mandibular canalwere largely undetectable and the cortical bone in theinferior border of the mandible was almost lacking.No radiographically pathologic changes were seen onthe left side of the mandible.

Examination 2 years, 6 months later at 14 years ofage showed that the right mandibular body was stillsomewhat more prominent than on the left side (Fig2B). However, the bony structure on the right sidehad become almost normal and the border of the

S OF 102 PATIENTS WITH NEUROFIBROMATOSIS 1

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Unilateral Mandible Maxilla Mandible and Maxilla

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VISNAPUU ET AL 1353

side. In the late mixed dentition, the right first andsecond upper molars remained unerupted and erup-tion of the canine was delayed, whereas the corre-sponding teeth on the left side had erupted normally.

PATIENT 3

The patient was a 14-year-old boy with sporadicNF1 diagnosed during the fourth year of life. Thephysical examination showed a plexiform neurofi-broma causing distortion of the right side of the facein the eyelid and cheekbone regions. The patient hadserious malocclusion involving the right and left sidesof both jaws and the mandibular anterior area. Onepremolar had been extracted from the right side ofeach jaw. Inspection showed hyperplastic rugose for-mation in the maxilla and several sublingual lobularsoft tissue nodules on the floor of the mouth. Thelingual gingival tissue was abnormally thick in themandibular anterior region.

Radiologic examination showed that the mandibu-lar ramus, the posterior part of the body of the man-dible, and the mandibular angle were poorly devel-oped vertically on the right side, which was affectedby the tumor. The neck of the right temporomandib-ular joint was abnormally long and narrow. In theright ramus, there was an oval 20- � 30-mm bonydefect. The second molars on the right side of theboth jaws were unerupted, whereas those on the leftside were completely erupted.

All these findings were present on the panoramicimage taken at 10 years of age. No major changes hadoccurred in the jaw abnormalities during these years

FIGURE 1. Patient 1, a 10 year-old boy with plexiform neurofibrohe lower border of the posterior part of the left mandibular ramusn the left than on the right side.

isnapuu et al. Craniofacial Radiographic Findings in NF1. J Or

when the growth of the patient is considered.

PATIENT 4

The patient was a 38-year-old man with sporadicNF1 diagnosed before 3 years, 6 months of age. Thepatient had a plexiform neurofibroma of the leftside of the face involving the eyelid and maxillaryregion. The left side of the maxilla was underdevel-oped, resulting in severe malocclusion on the leftside. The neck of the left condyle was exceptionallylong and deformed (Fig 3A). As a result, the leftramus was taller compared with the opposite side.The heights of the left body of the mandible and theposterior part of the maxilla were decreased. Therewas an oval 30- � 30-mm bone defect in the leftamus. The anterior part of the mandibular canalas markedly widened on the left side. The second

nd third mandibular molars and the maxillaryhird molar on the left side were completely uneru-ted.Radiographs taken at 10 and 33 years of age were

lso available for evaluation. No significant progressf the abnormalities had occurred in the previous 5ears. The oval bone defect in the left ramus andidening of the left mandibular canal were detectable

t 10 years of age (Fig 3B). These changes had pro-ressed during the subsequent years with the growthf the mandible.

PATIENT 5

The patient was a 42-year-old man with sporadicNF1. He had a large congenital plexiform neurofi-broma covering the entire right side of the face (the

the right side of the face. An oval bone defect (10 � 20 mm) inseen (large arrow). The width of the mandibular ramus is smaller

illofac Surg 2012.

ma oncan be

right eye was not visible at birth). He had a severe

xillofac

1354 CRANIOFACIAL RADIOGRAPHIC FINDINGS IN NF1

malocclusion, and numerous soft tissue hyperplasialesions were seen within the mouth, especially on theright side. The radiologic examination showed that

FIGURE 2. Patient 2, a boy with plexiform neurofibroma on the left sideis smaller than that on the right side. The bone structure on the right side ha(asterisk). The course of the mandibular canal is poorly detectable and theB, Two years, 6 months later at age 14 years, the left body of the mandibside has become almost comparable to that on the left side, but the corti

Visnapuu et al. Craniofacial Radiographic Findings in NF1. J Oral Ma

the ramus, the posterior part of the body of the

mandible, and a substantial part of the maxilla weremissing on the affected right side. The anterior part ofthe maxilla was underdeveloped. The maxilla was

ce. A, At 11 years old, the posterior part of the left body of the mandible-glass appearance resembling the radiologic features of fibrotic dysplasiabone is lacking on the lower border of the right mandibular body (arrow).l somewhat smaller than on the right side. The bony structure on the righte is still lacking on the lower border of the mandibular body (arrow).

Surg 2012.

of the fas a milkcorticalle is stilcal bon

retrusive and the mandible was protrusive in relation

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VISNAPUU ET AL 1355

to the base of the skull. The patient had undergonedozens of surgeries of the maxillofacial region, eg, theright side of the mandible was partly reconstructed

FIGURE 3. Patient 4, a 38-year-old man with a plexiform tumor oeformed (large arrow). A large oval bone defect (30 � 30 mm)orpus is underdeveloped and the mandibular canal is markedly w

mandibular condyle (large arrow), the oval bone defect in the leftwere detectable at 10 years of age. There was no difference in theof development.

Visnapuu et al. Craniofacial Radiographic Findings in NF1. J Or

with a bone graft.

PATIENT 6The patient was a 64-year-old woman with sporadic

NF1 diagnosed during childhood. The patient had a

eft side. A, The neck of the left condyle is exceptionally long andly visible in the left ramus (asterisk). The left posterior mandibularcompared with the right side (small arrow). B, Lengthening of the

asterisk), and widening of the left mandibular canal (small arrow)the mandibular corpus between the left and right sides in this stage

illofac Surg 2012.

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1356 CRANIOFACIAL RADIOGRAPHIC FINDINGS IN NF1

involving the eyelid and cheekbone regions. Numer-ous teeth had been extracted in previous years and amild malocclusion was seen. Intraoral examinationshowed soft tissue hyperplasia on the palate, sublin-gually on the floor of the mouth, and on the lingualside of the mandibular anterior teeth. Radiologically,the posterior part of the body of left mandibularcorpus was significantly lower and the ramus wasshorter than on the right side. The neck of the leftcondyle was very long and thin. There was a largeoval 13- � 25-mm bony defect in the posterior part ofthe left body of the mandible. The anterior part of theleft mandibular canal was wide and the margins werepartly irregular. A sclerotic bone lesion resemblingperiapical cemental dysplasia was detected adjacentto the left mandibular second molar.

Discussion

Twenty-nine (13 female and 16 male) of 102 pa-tients with NF1 had radiologic alterations in theirjaws. In general, the alterations were more pro-nounced in patients with plexiform neurofibromathan in those without. Prominent deformities weredetected in the mandible and maxilla of all 6 patientswith plexiform neurofibroma. An extensive influenceof the neurofibroma tumor on bone tissue was foundin patient 5 whose large plexiform neurofibroma hadmarkedly affected the development of facial bones.The tumor of this patient, whose right eye was miss-ing at birth, fits well in the category of the cranio-orbital subtype of NF.8,9 Involvement of the eyelid

as found also in 4 other patients. However, becauseo computed tomograms were available, it was notossible to determine precisely the effect of the tu-ors on the sphenoid and other bones bordering the

rbital region and the base of skull in these patients.Jaw deformities included under- and/or overgrowth

f the mandibular body, ramus, and condyle and hy-oplasia of the maxillary tuberosity. Some alterationsere apparently caused by tumor invasion and localestruction by a plexiform neurofibroma originatingrom the trigeminal nerve, whereas other findingsay represent primary developmental osseous altera-

ions. It is interesting to note that the facial deformi-ies found in young patients did not progress mark-dly at older ages with the cessation of growth inhese patients, indicating a decrease of the growthotential of the plexiform neurofibroma.Various bony defects of the jaws were detected in

ll 6 patients with plexiform neurofibroma. Thesenvolved both the mandible and maxilla in 4, the

andible in 2, and the maxilla in 1 patient. Theandibular angle was poorly developed vertically and

he mandibular condyle was abnormal in size and

hape in 3 patients. The affected side of the mandib- i

lar corpus was underdeveloped compared with thepposite side in 5 patients. Furthermore, in 1 patientpatient 2), the bony structure on the affected sideesembled that of fibrous dysplasia and the corticalone in the inferior border of the mandible was al-ost lacking. The bony structure of that patient be-

ame apparently normal after 2 years, 6 months withhe growth of the patient, but the cortical bone re-ained abnormal.An oval bone defect was seen in 3 patients with

lexiform neurofibroma in the area of the foramenandibular, indicating overgrowth of the mandibularerve. In 1 patient, the corresponding defect wasetected in the posterior aspect of the ascendingamus of the mandible. None of these lesions requiredny intervention. In a previous report, multiple peri-pical cemental dysplasias were found in the mandi-les of female patients with NF1.10 More patientsith these lesions were not found in this sample.Other radiologic findings detected included en-

argement of the mandibular canal in 26 patients,ilaterally in 11 and unilaterally in 15, including 5atients with plexiform neurofibroma in the head andeck area. The mandibular canal was undetectable in

patients. In patients without plexiform neurofi-roma, bilateral widening of the mandibular canalas seen in 11 and unilateral widening was seen in 10f 96 patients. In patients with plexiform neurofi-roma, widening of the mandibular canal was seennly on the side affected by the tumor in 5 of 6atients. The enlargement varied from slight widen-

ng of the canal to 2-fold in diameter. Also, an irregularorder of the mandibular canal was frequently seen assign of involvement of the nerve. It is logical to

ssume that enlargement of the mandibular canal cane caused by the overgrowth of the mandibularerve, although no direct evidence on the nervetructure is available.

Deviations in dentition and occlusion were seen inll 6 patients with plexiform neurofibroma. Four ofhese can be classified as severe malocclusion. Such aalocclusion can develop as the result of the dis-

orted growth and abnormal eruption of teeth. Ge-etic factors and local tumor growth can be involved

n this deviated development. No major malocclusionas detected in patients without plexiform neurofi-roma. Engagement of an orthodontic specialist forhe treatment of patients with NF1 at an early phase isf utmost importance for the comprehensive care ofhese patients. Expert knowledge in orthodontics andrthognathic surgery can be used to guide the facialrowth and alignments of dentition to prevent andecrease the need for extensive orthodontic and sur-ical interventions.The radiologic features described in this article are

n accord with previous reports on the jaw manifes-

VISNAPUU ET AL 1357

tations of NF1.11,12 Common findings such as enlarge-ment of the mandibular canal and other bone defectsassociated with the canal are easy to detect on routinepanoramic radiologic images. It is important that oraland maxillofacial surgeons and dentists recognizethese abnormalities in order to refer the patient forfurther medical examinations.

Acknowledgments

This research was supported by the Academy of Finland (J.P.)and Turku University Hospital EVO grants (J.P., R.-P.H., S.P.). Theauthors are thankful for the active participation of the patients inthe study. The technical assistance of Kirsti Timonen, Flora Notach,and Taru-Maija Peltonen is greatly acknowledged.

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2. Lammert M, Friedman JM, Kluwe L, et al: Prevalence of neuro-

fibromatosis 1 in German children at elementary school enroll-ment. Arch Dermatol 141:71, 2005

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5. Crawford AH, Schorry EK: Neurofibromatosis in children: Therole of the orthopaedist. J Am Acad Orthop Surg 7:217, 1999

6. Kuorilehto T, Nissinen M, Koivunen J, et al: NF1 tumor sup-pressor protein and mRNA in skeletal tissues of developing andadult normal mouse and NF1-deficient embryos. J Bone MinerRes 19:983, 2004

7. Friedrich RE, Giese M, Schmelzle R, et al: Jaw malformationsplus displacement and numerical aberrations of teeth in neu-rofibromatosis type 1: A descriptive analysis of 48 patientsbased on panoramic radiographs and oral findings. J Cranio-maxillofac Surg 31:1, 2003

8. Erb MH, Uzcategui N, See RF, et al: Orbitotemporal neurofibro-matosis: Classification and treatment. Orbit 26:223, 2007

9. Poole MD: Experiences in the surgical treatment of cranio-orbital neurofibromatosis. Br J Plast Surg 42:155, 1989

10. Visnapuu V, Peltonen S, Ellilä T, et al: Periapical cementaldysplasia is common in women with NF1. Eur J Med Genet50:274, 2007

11. D’Ambrosio JA, Langlais RP, Young RS: Jaw and skull changesin neurofibromatosis. Oral Surg Oral Med Oral Pathol OralRadiol Endod 66:391, 1988

12. Lee L, Yan YH, Pharoah MJ: Radiographic features of themandible in neurofibromatosis: A report of 10 cases and review

of the literature. Oral Surg Oral Med Oral Pathol Oral RadiolEndod 81:361, 1996