Knowledge without truth: Screening for complications of neurofibromatosis type 1 in childhood

The modern era in the care of individuals with neurofibromatosis type 1 (NF1) began in 1981 with the publication of Riccardi’s treatise on the clinical manifestations of NF1 based on his experience caring for over 250 families withNF1 as part of the Baylor Neurofibromatosis Program [Riccardi, 1981]. Over the ensuing 22 years, the NF1 gene and its product, neurofibromin, have been identified, direct gene testing for NF1 has become available, and insights into its molecular biology have led to the first treatment trials of plexiform neurofibromas [Packer and Rosser, 2002]. In addition, numerous multidisciplinary clinics for the care of individuals with NF1 have arisen in academicmedical centers, andmultiple lay organizations around the world, including the National Neurofibromatosis Foundation and Neurofibromatosis, Inc. in the U.S., continue to provide venues for support, fundraising, and advocacy. Despite these remarkable successes, the bulk of the day-to-day care of individuals with NF1 relies on appropriate, ongoing counseling, and the early detection of complications. In this issue of the Journal, Blazo et al. [2003] report their experience of systematic neuroimaging screening of all children diagnosed with NF1 over a 5-year period at an NF multidisciplinary clinic. Their screening protocol mandates both MRI scans and complete ophthalmologic exams yearly between 1 and 3 years of age, the peak period for the development of optic pathway tumors (OPT), and at the time of diagnosis for children seen between 3 and 6 years for the first time. The authors compare the group of children with OPT discovered by screening to those referred during the same period with already discovered OPT; although the latter group is older, the small number of patients including those lost to follow-up make meaningful comparisons impossible. Moreover, one of the three ‘‘screened’’ patients who required chemotherapy was not treated until he had definite ophthalmologic signs, which would have been identified by a visual screening protocol. It would appear that the ‘‘unscreened’’ group had a much higher rate of visual loss. However, closer inspection shows that four of the five patients in this group had orbital tumors (not present in the screened group) that had led to proptosis and visual impairment; these tumors have markedly different biologic properties than their often quiescent chiasmal counterparts, generally leading to permanent visual loss [Listernick et al., 1994]. Even annual MRI scans may fail to detect these tumors in a timely fashion, as their growth rates can be very rapid [Listernick et al., 1992]. Finally, Blazo suggests that at least one advantage of screening neuroimaging lies in its ability to detect radiologic progression prior to ophthalmologic progression; they had two such patients. The significance of this knowledge is uncertain; tumor growth without a change in the visual exam should not necessarily result in the initiation of therapy. If all childrenwithNF1underwent screening neuroimaging, OPT would be found in 15%. However, only half of these patients will ever develop symptoms, giving an overall incidence for symptomatic OPT of 7%. The period of greatest risk for thedevelopment of symptomaticOPT is during thefirst 6 years of life, the median age of detection in one study being 4.2 years [Listernick et al., 1989, 1994]. Approximately 30% of children with symptomatic OPT will present with the rapid onset of proptosis, with moderate to severe visual loss in the affected eye. The remainder of the children will be discovered either as a result of abnormal ophthalmologic exams, as part of their annual NF evaluation, or signs of precocious puberty [Listernick et al., 1994; Habiby et al., 1995]. Most importantly, only a small percentage of the symptomatic tumors demonstrate clinically significant growth or progression of visual disturbances following presentation, necessitating treatment. As a result of these data, the National Neurofibromatosis Foundation Optic Pathway Task Force has recommended against routine neuroimaging of all childrenwithNF1; rather, yearly eye examinations by either pediatric ophthalmologists or ophthalmologists knowledgeable of the ocular manifestations of NF1 were advocated for all young children with NF1 [Listernick et al., 1997]. While often quite successful, the routine use of screening tests to identify both diseases and their complications may be problematic. Applying the principles of mass screening, in order for a screening test to be successful, treatment for the disease, once identified, must exist, there must be an advantage to early treatment, the cost of screening must not be prohibitive, and no harm should come to the patient as a result of the screening process [Khoury et al., 2003]. Unfortunately, experience suggests that the screening process is not always benign. False positive testing may lead to heightened parental anxiety and improper maternal-child bonding, as has been reported in cystic fibrosis [al-Jader et al., 1990]. Alternatively, uncertainty regarding the efficacy of the offered interventions for individuals positive for BRCA1 or BRCA2 can be just as psychologically damaging [Burke et al., 2001]. *Correspondence to: Robert Listernick, M.D., Division of General Academic Pediatrics, The Children’s Memorial Hospital, Box 16, 2300 Children’s Plaza, Chicago, IL 60614. E-mail: boblist@northwestern.edu