50 Years Ago in The Journal of Pediatrics:

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Chao DH. J Pediatr 1959;54:189-99

Fifty years ago in The Journal, Chao reviewed the neurocutaneous disorder neurofibromatosis type 1 (NF1) and highlighted common features through a small case series. Decades since, we have witnessed the establishment of clinical diagnostic criteria and discovery of the causative gene. However, little has changed regarding management and prognosis of this disorder.

As Chao described, NF1 is a slowly progressive, multisystem disorder with variable presentation. NIH diagnostic criteria in 1987 required 2 or more of the following: 6 or more café-au-lait spots; 2 or more neurofibromas or 1 plexiform neurofibroma; skinfold freckling; optic glioma; 2 or more Lisch nodules (iris hamartomas); characteristic skeletal dysplasia; or first-degree relative with NF1. Additional complications include cognitive impairment, vasculopathy, and increased risk of malignancy, specifically malignant peripheral nerve sheath tumor, pilocytic astrocytoma, leukemia, and rhabdomyosarcoma.

Early confirmation as a familial disorder resulted from discovery of the massive 350-kb NF1 gene in 1990. Such a large gene allows many unclustered mutations, over 800 reported to date, and leads to a germline mutation rate for NF1 10-fold higher than that observed in most other comparable inherited diseases. Indeed, de novo mutations account for half of individuals affected by this autosomal dominant disease. Allelic heterogeneity and additional modifying genes likely contribute further to variable expression in NF1. Although tumors have 2 mutated copies, 1 inherited and 1 acquired, of the NF1 tumor suppressor gene, pathogenesis of nontumor manifestations is largely unknown.

Despite these advances, management of NF1 has not changed much since 1959. We continue to spot the diagnosis based on the 1987 clinical criteria. Genetic testing is not used routinely, and its sensitivity in research labs approaches only 80%.¹ Management consists primarily of genetic counseling, surveillance for disease progression, and treatment of symptomatic or malignant complications. Complete surgical resection, although sometimes not possible, remains the primary treatment goal for both benign and malignant tumors. Over the next 50 years, we hope that increased knowledge about the pathogenesis of NF1 will finally translate to simpler diagnosis, effective treatments, and improved prognosis for individuals with NF1.

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1. Griffiths S, Thompson EP, Frayling I, Upadhyaya M. Molecular diagnosis of neurofibromatosis type 1: 2 years experience. Familial Cancer. 2007;6:21–34
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