A lateral cephalometry study of patients with neurofibromatosis type 1

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Abstract

Purpose

Neurofibromatosis type 1 (NF1) is an autosomal dominant transmitted tumour suppressor syndrome and also a bone disease. Osseous dysplasia affecting the craniofacial region is characteristic of NF1. The aim of this study was to analyse the lateral cephalograms of NF1 patients in comparison to individuals who were not affected by this condition in order to describe the skeletal phenotype of NF1 in more detail.

Materials and methods

The study comprises the lateral cephalograms of 172 patients with established NF1 diagnoses (female = 85, male = 87). NF1 patients were distinguished by radiological and/or histological findings of the facial region suggestive of plexiform neurofibroma (PNF) or disseminated cutaneous NF (DNF). The analysed radiographs of a collection of 29 healthy volunteers with ideal occlusion served as controls. The focus of this analysis was cephalometrically defined angles.

Results

Cephalometric analyses of patients with DNF did not differ from those of controls for the vast majority of parameters. However, the measurement results of patients with PNF differed significantly from those of healthy volunteers and patients with DNF. The number of trigeminal nerve branches affected in PNF patients had an effect on the measurement results.

Conclusion

Lateral cephalograms revealed no significant alteration of the facial skeleton in NF1 patients as compared to controls. Indeed, the stigma of a so-called ‘NF1 facies’ cannot be derived from the cephalometric findings presented. Notably, a wide range of deviating readings were recorded for individuals with facial PNF. Clinicians who treat patients with NF1 should be aware of deviations from cephalometric standards on lateral cephalograms in NF1 patients, especially when craniofacial surgical procedures are planned. Some of these findings, particularly asymmetries of the facial skeleton, could be indicators of an associated PNF.

Introduction

Neurofibromatosis type 1 (NF1) is a relatively common human autosomal dominant inherited disease affecting a multitude of organs and systems (Riccardi, 1992). About 1:2500 children living at birth are affected by this condition (Lammert et al., 2005a, Ferner et al., 2007). Predecessors with established NF1 diagnosis are known in about every second affected individual (Riccardi, 1992). Diagnosis is made in most cases with the aid of repeatedly revised clinical diagnostic criteria proposed by the US National Institutes of Health (National Institutes of Health, 1987, National Institutes of Health, 1988, Gutmann et al., 1997, Ferner and Gutmann, 2013). The identification of a relevant gene coding for a protein that was later denominated neurofibromin represented a great step forward in our understanding of the pathogenesis of NF1 (Daston and Ratner, 1992). Mutations of this gene located on chromosome 17q11.2 are causal for NF1 (Viskochil et al., 1990, Seizinger et al., 1987). The most recognized findings in NF1 is neurofibroma, i.e. benign nerve sheath tumours most likely originating from Schwann cells or their precursors (von Recklinghausen, 1882, Verocay, 1910). However, it was early after establishing neurofibromatosis as a morphologically defined entity that skeletal lesions were identified as a distinct facet of what is now called the NF1 phenotype (Adrian, 1901). The disease is now accepted a genetic skeletal disorder (Lammert et al., 2005b, Stevenson et al., 2007; Elefteriou et al., 2009, Seitz et al., 2010, Adrian, 1901). In several locations – including the craniofacial bones – a close association of plexiform neurofibroma (PNF) and osseous dysplasia was noted (Friedrich et al., 1994, Friedrich et al., 2003 & 2013), but this association may not necessarily be provided in every case (Binet et al., 1969, Friedrich, 2011). In the facial region, various locations of PNF show the underlying pattern of a more or less close topographical association with the terminal branches of the trigeminal nerve (Riccardi, 1992). These tumours can cause extensive facial soft tissue damage leading to severe disfigurement and are almost always confined to one side of the face (Friedrich, 2010). In the facial region, the PNF may also cause severe osseous alterations (Heine, 1927, D'Ambrosio et al., 1988). In contrast to these well-known local facial affections characteristic for a morphologically defined tumour type in NF1, some authors have suggested a distinctive facial appearance of NF1-affected individuals which is not caused by tumour growth (Grabb et al., 1980, Kaplan and Rosenblatt, 1985, Lin et al., 1989, Norman, 1972). Cephalometric analyses of NF1 patients led to the conclusion that sagittal projections of mandible, maxilla and cranial base are reduced compared to those in matched controls. Thus, these distinct skeletal findings may have a reproducible effect on the physiognomy of the individual NF1 patient. Indeed, it was concluded from these findings that skeletal variations of the viscerocranium may contribute to form the NF1-phenotype (Heervä et al., 2011). However, these differences proved to be significant only in adults. Furthermore, the study group included only a small number of patients affected with trigeminal PNF. Recently, these metric sagittal findings on cephalograms of NF1 patients were confirmed in another study (Cung et al., 2015). On the other hand, Riccardi has recalled the distinctive facial appearance of NF1 patients as caused by pigmentation disorders, macrocephaly, and neurofibroma. He emphasizes that NF1 patients appear to share facial characteristics of their family members (Riccardi, 1992, Riccardi, 1999). In another report, Friedman and Riccardi (1999) stressed their assessment that not a single set of facial characteristics defines patients with NF1 as a group. Taking into consideration the importance of cephalometric findings for the evaluation of facial proportions, the relationship of certain skull parts is of particular importance. This topographical relationship can be measured in angles (Hasund, 1974). Determining these relationships could provide more insights into the skeletal basis of NF1 affected individuals and contribute to clarify contradictory assumptions for a characteristic facial expression that could stigmatize. Furthermore, a cephalometric analysis of NF1 patients should be a prerequisite for planning craniofacial surgical procedures in these individuals (Heiland et al., 2004). Therefore, this study intended to describe the cephalometrically defined relationship of the jaws to the skull base with special reference to the impact of PNF on the observations.

Section snippets

Materials and methods

Standardized lateral cephalograms used for cephalometric analysis were investigated for 172 white patients with NF1 (male: 87 (50.58%), female: 85 (49.42%)). These patients were radiologically investigated for skeletal anomalies in the department of oral and craniomaxillofacial surgery, Eppendorf University Hospital, University of Hamburg, between 1980 and 2010. The age of patients at the time of radiography ranged from 4 to 78 years (mean for males, 27.6 years) and from 7 to 62 years (mean for

Mandibular angle

The comparison of the mandibular angle (MA angle) between the control group and the entire group of NF1 patients revealed highly significant differences of this item (analysis of co-variance [ANCOVA]: p = 0.003) that were not dependent on age or gender. However, for this first general comparison, the tumour-affected side of patients was selected in the patient subgroup with facial PNF. A double contour of a line or angle which forced the consideration of two measurements of a measured value was

Discussion

This study describes relevant relationships of the skull base and the contours of the viscerocranium as seen on lateral cephalograms in patients affected by a hereditary condition, NF1, with particular attention to the impact of benign peripheral nerve sheath tumours on the selected parameters. The work focused on the calculation of angles between the skull base, maxilla and mandible (Segner and Hasund, 1991). The comparison of the measured values of NF1 patients with those of subjects with

Conclusion

This analysis adds some craniofacial skeletal findings to current cephalometric analyses of patients with NF1 that delineate the impact of a characteristic nerve sheath tumour on the outline of bones and their relationships to one another. These findings could have some significance for the estimation of the facial appearance of affected individuals, e.g. in clinical genetics, and in the planning of craniofacial skeletal surgery in these patients.

Conflict of interest

The authors declare no conflict of interest.

Acknowledgement

The authors appreciate the cooperation with Andrea Rusche, Computerforum, Elmshorn, Germany, who programmed the software allowing the cephalometric analysis with Dental Vision®. This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

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