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European Journal of Medical Genetics 50 (2007) 274e280 http://www.elsevier.com/locate/ejmg
Original article
Periapical cemental dysplasia is common in women with NF1 Vivian Visnapuu a,c,*, Sirkku Peltonen b, Tero Ellila¨ d, Eero Kerosuo e, Kalervo Va¨a¨na¨nen a, Risto-Pekka Happonen c,e, Juha Peltonen a,b a
Department of Anatomy, University of Turku, Kiinamyllynkatu 10, FIN 20520 Turku, Finland b Department of Dermatology, University of Turku, PO Box 52, FIN 20521 Turku, Finland c Department of Oral Diseases, Turku University Central Hospital, Lemminka¨isenkatu 2, FIN 20520 Turku, Finland d Medical Imaging Centre of Southwest Finland, PO Box 52, FI.20521 Turku, Finland e Institute of Dentistry, University of Turku, Lemminka¨isenkatu 2, FIN 20520 Turku, Finland Received 28 February 2007; accepted 7 April 2007 Available online 21 April 2007
Abstract Background: Neurofibromatosis type 1 (NF1) is a genetic disorder with skeletal involvement. Periapical cemental dysplasia is a rare finding in the normal population. Method: A total of 55 patients with NF1, 29 female and 26 male patients, were evaluated with orthopantomograms, supplemented with periapical radiographs if necessary. The vitality of the teeth was measured by two different testing methods. Results: A novel finding was the occurrence of cemental dysplasia affecting the periapical area of vital mandibular teeth in 8 adult women with NF1. Thus, cemental dysplasia was detected in 34.8% of the adult female NF1 patients, while cemental dysplasia was not present in men or children with NF1. Conclusion: Periradicular cemental dysplasia is indeed a new NF1 related bone lesion type. Our finding suggests that this is the first reported sexual dimorphism in the manifestations of NF1. Cemental dysplasia of NF1 patients should not be confused with periapical findings caused by endodontic pathoses. The former do not require active therapy whereas in the latter root canal treatment is necessary. Ó 2007 Elsevier Masson SAS. All rights reserved. Keywords: Cemental dysplasia; Craniofacial; Neurofibromatosis; Lower jaw; Dental
* Corresponding author. Department of Anatomy, University of Turku, Kiinamyllynkatu 10, FIN 20520 Turku, Finland. Tel.:þ358 2333 7203; fax: þ358 2333 7356. E-mail address:
[email protected] (V. Visnapuu). 1769-7212/$ - see front matter Ó 2007 Elsevier Masson SAS. All rights reserved. doi:10.1016/j.ejmg.2007.04.001
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1. Introduction Neurofibromatosis type 1 (NF1, von Recklinghausen’s disease) is a genetic syndrome affecting neural and skeletal tissues and skin [3]. The incidence of NF1 is w1:3000 and it is inherited as an autosomal dominant trait with variable phenotypic expression [13]. The diagnosis of NF1 is based on criteria outlined by the National Institute of Health (USA) Consensus Development Conference in 1987 [21]. Cutaneous neurofibromas and cafe´ au lait spots of the skin are the hallmarks of NF1. Cutaneous neurofibromas arise from small nerve tributaries. Neurofibromas may also grow along peripheral nerves, and occasionally manifest as plexiform neurofibromas. The latter may form large and disfiguring tumor masses in the craniofacial region, trunk, and extremities. Plexiform neurofibromas are associated with an increased risk of malignant transformation. In the central nervous system, the most common NF1-related tumors are pilocytic astrocytomas of the optic nerve [7]. Osseous dysplasias in neurofibromatosis include macrocephaly, sphenoid wing dysplasia, short stature, reduced bone mineral density, scoliosis, and congenital bowing and pseudarthrosis of the tibia [12,17]. These symptoms afflict up to 50% of NF1 patients and are sometimes debilitating. The protein encoded by the NF1 gene, neurofibromin, is a tumor suppressor protein that acts as Ras-GAP, thus inactivating Ras [1]. It has been shown that the NF1 gene is expressed at high level in the growth plate during endochondral ossification and in osteoclasts, osteoblasts and osteocytes. In addition, recent findings indicate that neurofibromin acts as a Ras-GAP also during ossification in NF1þ/þ and NF1þ/ mice [11]. To date, oral manifestations of NF1 have not been extensively studied, and only a few reports have been published [2,4,6,19]. Oral involvement is reported to occur in 3.4e92% of adult patients and in about 40% of children with NF1. Impacted, displaced, supernumerary or missing teeth, particularly in the mandible, and overgrowth of the alveolar ridge are recognized oral manifestations in NF1 [4,5,14,18]. The facial skeletal malformations are a result of both genetic and epigenetic factors, such as tumor growth [5]. Periapical cemental dysplasia belongs to the group of non-endodontic periapical pathoses [22]. Reports on frequency of periapical cemental dysplasia in the general Finnish or Scandinavian population have not been published, but according to our personal experience cemental dysplasia is rarely diagnosed. In Minnesota, USA, Stafne found 24 cases of periapical cemental dysplasia in 10,000 consecutive adults who were mainly Caucasian [20]. Out of a total of 32,625 patients seen by the Departments of Clinical Pathophysiology and Pathology at the Tokyo Dental College from 1966 to 2001, 22 cases of periapical cemental dysplasia were reviewed. Out of these cases, 5 were men and 17 were women [15]. A high prevalence of periapical cemental dysplasia (38/491 cases) has been reported among black women in South Carolina, USA [16]. It was not however mentioned in the previous studies whether any of these patients had NF1. The diagnosis of periapical cemental dysplasia is based on radiographic and clinical findings. Specifically, the radiographs show a radiolucent lesion with no or varying amount of hard tissue formation. The lamina dura around the apex is radiographically intact. The clinical examination reveals vitality in response to pulp tests [10]. Our aim was to characterize the NF1-related radiological findings of the jaws in detail. A total of 55 patients with NF1, 29 female and 26 male, were included in this study. An unexpected finding was the identification of cemental dysplasia affecting the periapical area of the mandibular teeth in 8 women, >20 years of age. These findings have an impact on the treatment of the patients, for example guiding to avoid unfounded endodontic treatment.
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2. Patients and methods A total of 55 Caucasian patients with NF1, 29 female patients aged 8e64 years and 26 male patients aged 9e73 years, were included in the present study (Table 1). The patients were recruited to the study from the patients attending the NF1 clinic at the Department of Dermatology, Turku University Central Hospital, as well as among members of the Finnish NF patient organization. This resulted in participation of patients from all parts of Finland. The study was approved by the Ethics Committee of the Southwest Finland Hospital District, Turku, Finland. All patients fulfilled the diagnostic criteria for NF1 [21]. The general clinical examination was performed by Dr Sirkku Peltonen and the craniofacial examination was carried out by Dr Vivian Visnapuu. There was no bias to recruit patients suffering from mandibular involvement or any particular dental problem. The craniofacial status was based on physical inspection and evaluation of orthopantomograms, supplemented with periapical radiographs when necessary. The diagnosis of periapical cemental dysplasia was based on consensus of four of the authors (V.V., T.E., E.K., R-P.H.) who performed the radiological evaluation. Additional documented material consisted of intraoral photographs. Vitality of the teeth was tested using a Vitality Scanner (model 2007, Analytic Technology, Orange, CA; US Patent 4,177,799) and Roeko EndoFrost device (Coltene/Whaledent, Langenau, Germany). 3. Results Radiological findings of 55 NF1 patients (Table 1) revealed information about the skeletal deformities of the mandible and maxilla, and malpositions of the teeth. Examination of 10 patients with plexiform neurofibromas revealed deformities of both jaws. More specifically, hypoplasia and/or hyperplasia of body and ramus and mandibular condyle and hypoplasia of tuberosity of maxilla were detected (Fig. 1). Furthermore, unerupted teeth were observed in the deformed side. However, five patients without plexiform neurofibromas had hypoplasia Table 1 Periapical cemental dysplasia in the jaws of patients with NF1 based on radiographic findings Age (years)
No. of patients
No. of patients with periapical involvement
Women with NF1 (N ¼ 29) 70
8 6 4 5 2 4 0
None 2 4 1 1 None
Men with NF1 (N ¼ 26) 70
9 2 4 3 6 1 1
None None None None None None None
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Fig. 1. Orthopantomogram showing hypoplasia of the right mandibular corpus and ramus in a 15-year-old NF1 boy with a plexiform neurofibroma of the trigeminal area.
of maxillary tuberosity and coronoid process of the mandibular ramus (Fig. 1). The present study revealed an enlarged mandibular foramen and inferior alveolar canal in 85% of all patients. Enlarged mandibular foramina were not associated with clinical evidence of neurofibromas. The study included 21 women over 20 years of age, one of them having a facial plexiform neurofibroma. Eight out of these 21 patients presented with cemental dysplasia affecting mandibular teeth (Fig. 2A). In one patient, all teeth except a missing d 44 were involved in the area 33e45 (Fig. 2B). A total of 24 teeth with periapical dysplasia were identified in the present study (Table 1). Out of these, 21 teeth were vital and without root canal filling, and 10 were intact. Of the cemental dysplasias detected, 20 were radiolucent (Fig. 2B), 2 radiodense (Fig. 2C), and 2 represented mixed lesions. Cemental dysplasia was not observed in male patients, nor was it seen in female patients under 20 years of age. The study included 6 women over 50 years of age. Four patients had their lower incisors and premolars in place, while 2 of the patients had had all or most of these teeth removed. Fourteen of the total 55 patients had undergone endodontic treatments of mandibular teeth. Interestingly, 4 of these patients were women. To conclude, 14.5% of all NF1 patients, and 34.8% of women aged 20e60 years, presented with cemental dysplasia. 4. Discussion The novel finding of the present study was the identification of periapical cemental dysplasia affecting the periapical area of mandibular teeth of women with NF1. All the lesions were identified exclusively in female patients over 20 years of age. Multiple lesions distributed evenly throughout the mandible were present in four out of eight patients with periapical cemental dysplasia. Mandibular canine was the most commonly involved tooth. The diagnosis of cemental dysplasia was based on radiographic findings and clinical examination of the teeth. Biopsy was not attempted since the teeth with dysplasia were vital and displayed no signs of caries. Instead, the patients will be in close follow-up in order to reveal the natural history of these lesions in NF1. Many radiolucent lesions of non-endodontic origin mimic endodontic pathoses such as inflammation, and vice versa. Teeth associated with radiolucent inflammatory periapical lesions
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Fig. 2. (A) Orthopantomogram, showing periradicular radiolucencies (arrows) around vital teeth number 38, 36, 34, 33, 44, 47, 48 and root filled 46, suggesting the diagnosis periapical cemental dysplasia in a 40-year-old woman NF1. (B) X-ray showing periradicular radiolucencies around vital teeth number 33, 32, 31, 41, 42, 43, 45, suggesting the diagnosis of periapical cemental dysplasia in a 25-year-old woman NF1. (C) Periapical X-ray showing periapical lesion with hard tissue formation D34 (arrow) in a 58-year-old woman NF1. Stroked arrow points to a normal healthy tooth.
have necrotic pulps, and therefore do not respond to vitality tests. In contrast, lesions of nonpulpal origin usually do not affect the blood or nerve supply to the adjacent tooth pulp, and therefore these teeth remain vital [22]. Pulp vitality tests and careful patient history are the most important aids in differentiating between endodontic and non-endodontic lesions. It would be logical to assume that the periapical lesions of these female patients are associated with disorders affecting bone metabolism, e.g. hyperparathyroidism [8]. However, routine laboratory tests evaluating bone metabolism, including evaluation of serum parathormone (data not shown), were within normal levels in these patients. Periradicular cemental dysplasias provide a pitfall for mistreatment if the diagnosis and treatment are based on radiographic findings only (Table 2). We cannot help noticing that some NF1 patients included in the present study had had endodontic treatments. It cannot be excluded that at least some of these NF1 patients may have had unnecessary root canal treatment. Thus, relevant vitality tests, radiographic examinations, clinical signs and symptoms and detailed patient history should be taken into consideration when making diagnosis and treatment decisions.
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Table 2 Periapical findings in the jaws of patients with NF1 based on radiographic findings Patient number Age (years) Tooth number 48 1. 2. 3. 4. 5. 6. 7. 8.
20 25 31 35 35 40 44 58
47
46 45
44
43
42
41
31
32
33
34
35
36
37 38
Liv Liv Lv Liv Lv Lv Liv
Lv
Lv Liv Lv Lv Lr
Liv
Liv
Liv
LDiv Liv
LDr Lv Dv Lr
Lv
Div
L, radiolucent lesion; D, radiodense lesion; LD, mixed radiolucent and radiodense lesion; i, intact tooth; v, vital tooth; r, tooth with root canal filling.
The present study revealed enlarged mandibular foramen and inferior alveolar canal in 85% of the patients. The mandibular foramen, which provides the entrance for inferior dental vessels and nerves into the mandibular canal, is usually apparent on lateral oblique and panoramic views of the jaws [23]. The preferential sites of neurofibromas in the mandible are the mandibular canal and/or foramen [14]. The presence of neurofibromas may explain the enlarged mandibular foramen and inferior alveolar canal at least in some of the cases even though we found no clinical evidence of neurofibromas in this anatomical location. Previous studies agree that enlargement of the mandibular foramen is a common finding in NF1. However, the association of enlarged mandibular foramen has been reported to be independent of tumor mass [14] or to be mainly associated with existence of plexiform neurofibroma in the same area [5]. Our study, which represents the highest number of patients to date, actually agrees with all these views showing that an enlarged mandibular foramen is very common (85%) and can be present without or in association with a plexiform tumor. The radiolucent findings of periradicular cemental dysplasia resemble osteofibrous dysplasia generally seen in the tibia or fibula during childhood. Cosegregation of osteofibrous dysplasia and NF1 has been reported [9]. In analogy to periradicular cemental dysplasia, the pathogenesis of osteofibrous dysplasia remains unknown. Periradicular cemental dysplasia among other endodontic pathoses is more common in women than in men. This may in part explain the gender-related difference observed in the present study. The role of NF1 syndrome as such, in the clear cut gender difference in the occurrence of periapical cemental dysplasia, remains open. In conclusion, we describe a new NF1 related bone lesion which represents the first sex specific finding associated with this syndrome. Cemental dysplasia of NF1 patients observed in the present study should not be confused with periapical findings caused by endodontic pathoses. The former do not require any active therapy besides the correct diagnosis, whereas the latter require root canal treatment.
Acknowledgments The authors thank Dr Vincent Riccardi for fruitful discussions on the topic and the manuscript. The research was financially supported by The Academy of Finland (J.P.) and Turku University Hospital EVO grants (J.P., R.-P.H.). The skillful technical assistance of Ms Kirsti Timonen, Ms Flora Notach and Ms Taru-Maija Peltonen is greatly acknowledged.
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