Cephalometry in adults and children with neurofibromatosis type 1: Implications for the pathogenesis of sphenoid wing dysplasia and the “NF1 facies”

https://doi.org/10.1016/j.ejmg.2015.09.001Get rights and content

Abstract

Background

Neurofibromatosis type 1 (NF1) is a common, autosomal dominant tumor-predisposition disorder that arises secondary to mutations in the tumor suppressor gene NF1. Cephalometry is an inexpensive, readily available and non-invasive technique that is under-utilized in studying the NF1 craniofacial phenotype. An analysis of NF1 cephalometry was first published by Heervä et al. in 2011. We expand here on that first investigation with a larger cohort of adult and pediatric patients affected with NF1 and sought objective insight into the NF1 facies, said to feature hypertelorism and a broad nasal base, from cephalometric analysis.

Methods

We obtained cephalograms from 101 patients with NF1 (78 adults and 23 children) from two NF1 protocols at the National Institutes of Health. Each subject had an age-, gender- and ethnicity-matched control. We used Dolphin software to make the cephalometric measurements. We assessed the normality of differences between paired samples using the Shapiro–Wilk test and evaluated the significance of mean differences using paired t-tests and adjusted for multiple testing. We explored the relationship between the cephalometric measurements and height, head circumference and interpupillary distance.

Results

In this dataset of American whites with NF1, we confirmed in a modestly larger sample many of the findings found by Heerva et al. in an NF1 Finnish cohort. We found a shorter maxilla, mandible, cranial base, (especially anteriorly, p = 0.0001) and diminished facial height in adults, but not children, with NF1. Only one adult exhibited hypertelorism.

Conclusions

The cephalometric differences in adults arise in part from cranial base shortening and thus result in a shorter face, mid-face hypoplasia, reduced facial projection, smaller jaw, and increased braincase globularity. In addition, we suggest that NF1 sphenoid bone shortening, a common event, is consistent with an intrinsic NF1 bone cell defect, which renders the bone more vulnerable to a random “second hit” in NF1, leading to sphenoid wing dysplasia, a rare event.

Section snippets

Background

Neurofibromatosis type 1 (NF1, also known as von Recklinghausen's disease) is a genetic disorder with an autosomal dominant pattern of inheritance involving the skin, skeletal, and neural tissues, and affects 1 in 3000 births with no gender or race predilection (Friedman et al., 1999). Individuals with NF1 are heterozygous (haploinsufficient) for a loss-of-function mutation in NF1, the gene that encodes the tumor suppressor neurofibromin, which negatively regulates the activity of the

Methods

Retrospective ascertainment of patients and phenotype data. A total of 80 adults were included in the study, but two adult patient-control pairs were excluded due to anomalously low measurements, yielding a total of 78 adult case-control pairs for our final analysis. These patients were diagnosed with NF1 per the NIH consensus criteria (National Institutes of Health Consensus Development Conference, 1988) and evaluated at the National Institutes of Health (NIH) in Bethesda, MD as part of the

Results

Patient demographics. Patient characteristics are summarized in Table 2. In the adult study, there were 33 males (42%) and 45 females (58%). In the pediatric study, there were 14 males (61%) and 9 females (39%). All subjects were white.

Cephalometric analyses in cases and controls. Analyses of difference in 16 cephalometric measurements between cases and controls are shown in Table 3 (adults) and in Table 4 (children); these analyses stratified by gender are shown in Supplemental Tables 1 and 2

Discussion

In our study of 101 persons with NF1 (78 adults and 23 children) with age-, ethnicity- and gender-matched controls, we found a shorter maxilla, mandible, cranial base, (especially anteriorly) and diminished facial height in adults, but not children, with NF1. The cranial base angle was significantly more oblique in adults with NF1. Some measures of facial height, mandible size and anterior cranial base correlated with height, less so with head circumference and not at all with interpupillary

Conclusions

In our study of 101 persons with NF1 (78 adults and 23 children) with age-, ethnicity- and gender-matched controls, we found a shorter maxilla, mandible, cranial base, (especially anteriorly) and diminished facial height in adults, but not children, with NF1. The cephalometric differences in adults arise in part from cranial base shortening and thus result in a shorter face, mid-face hypoplasia, reduced facial projection, smaller jaw, and increased braincase globularity. Hypertelorism was

Author contributions

WC, LF, NK, ER and DS analyzed data. PG, CB, AB, BW and DS evaluated patients. WC, LF, NK and DS wrote the paper. All authors reviewed the final draft of the manuscript.

Acknowledgments

This work was supported by the Division of Cancer Epidemiology and Genetics (DCEG) and the Center for Cancer Research of the National Cancer Institute's Intramural Research Program. We thank Janice Lee DDS, MD (NIDCR) for helpful discussions.

References (24)

  • J.M. Friedman

    Evaluation and Management

  • D.H. Gutmann

    Abnormalities of the Nervous System

  • Cited by (0)

    View full text