The Genetic Aspects of Neurofibromatosisa
Neurofibromatosis (NF) is one of the most common, potentially serious, autosomal dominant conditions in man.Crowe estimated the prevalence to be one in 2500 to 3300 and from this figure calculated a mutation rate of 1 X per gamete per generation, long considered the highest in humans.'The phenotypic manifestations consist of cutaneous pigmentary changes and multiple benign neurofibromas; affected individuals are at risk for a diverse array of osseous, central nervous system, and neoplastic complications.There is marked variability in clinical involvement, making N F a prototypic condition for the study of the biologic mechanisms of variable expressivity in autosomal dominant disorders?Because of the diversity of clinical manifestations, presentation can range from the child with a multiple congenital anomaly /dysplasia syndrome to the adult with a solid tumor malignancy.Various authors have labeled NF as a phacomatosis, a hamartomatous disorder, a neurocutaneous condition, and most recently a neuro~ristopathy.~Despite the recent increased interest in this genetic disorder, many unanswered questions about the clinical and biologic aspects of NF remain obvious and emphasize the need for this symposium.Several comprehensive population studies in various parts of the world have established the mode of transmission of NF as autosomal dominant with high pene-In particular, Riccardi's investigation in Houston consists of an ongoing longitudinal study of over 200 affected persons and continues to expand the growing knowledge base on the genetic aspects and natural history.On first glance, the number of series and their wide geographical distribution might suggest that further research into the classical genetics of NF is unnecessary.However, several basic genetic issues are still unresolved and the interpretation of the genetic data is often conflicting.These issues are of more than theoretical significance as the available genetic information is important for clinicians involved in the delivery of clinical genetic services.The purpose of this paper is to review and document the unresolved issues regarding the hereditary aspects of the condition.We will summarize and reinterpret the recent available data on the genetics of NF.The presentation will overview the following 'This work