Neurofibromatosis type 1

Wendy Sherman MD (Dr. Sherman of Feinberg School of Medicine at Northwestern University in Chicago, Illinois, has no relevant financial relationships to disclose.)
Jeffrey J Raizer MD (Dr. Raizer, Medical Director of Neuro-Oncology at Feinberg School of Medicine at Northwestern University, received honorariums from Agenus, BMS, Genentech, Novartis, and Stemline for service on advisory boards; honorariums from Genetech and Merck for speaking engagements; and stock options from Aurasense for service on their advisory board.)
Edward J Dropcho MD, editor. (Dr. Dropcho of Indiana University Medical Center has no relevant financial relationships to disclose.)
Originally released March 21, 1995; last updated August 4, 2014; expires August 4, 2017
Notice: This article has expired and is therefore not available for CME credit.

This article includes discussion of neurofibromatosis type 1, NF1, peripheral neurofibromatosis, and Von Recklinghausen neurofibromatosis. The foregoing terms may include synonyms, similar disorders, variations in usage, and abbreviations.


Neurofibromatosis 1 is an autosomal dominant neurocutaneous disorder displaying a stereotyped pattern of dermatologic and systemic findings. It was first described in 1882 by von Recklinghausen in Germany and later differentiated from neurofibromatosis type 2. In the past decade, with advancements in molecular genetics studies, research has led to further understanding of the genotype and consequence phenotype of neurofibromatosis type 1. In this article, the authors address the recent advancements in neurofibromatosis type 1 studies.

Key points


• Neurofibromatosis type 1 is an autosomal dominant genetic disorder characterized by the prominent cutaneous manifestations of café au lait spots, skin-fold freckles and neurofibromas, hamartomatous nodules of the iris, dysplasia of bones, and a tendency to develop certain types of tumors, especially of the peripheral and central nervous system.


• The gene locus for neurofibromatosis type 1 is found on chromosome 17, which is thought to lead to loss of transcription of neurofibromin, resulting in the disease manifestations of neurofibromatosis type 1.


• There is currently no specific preventative treatment for any of the disease features of neurofibromatosis type 1; though the consequences of some disease complications may be prevented, or at least minimized, by timely interventions.


• Legius syndrome is a neurofibromatosis type 1-like syndrome characterized by café au lait macules, axillary freckling, and macrocephaly but is not associated with peripheral and nervous system tumors, as in neurofibromatosis type 1.

Historical note and terminology

Neurofibromatosis is a term applied to a spectrum of disorders with some overlapping clinical features. The 2 best of these that are best characterized are neurofibromatosis type 1, formerly known as von Recklinghausen disease or peripheral neurofibromatosis, and neurofibromatosis type 2, also known as bilateral acoustic or central neurofibromatosis, each with distinctive clinical features and genetic origins on different chromosomes (Korf 1990).

Neurofibromatosis type 1, the more common of the 2, constitutes 90% of all types of the neurofibromatoses and is one of the most common autosomal dominant disorders in humans, with an estimated incidence of approximately 1 in 3000 live births (Huson et al 1989). It has diverse manifestations in tissues that are primarily, although not exclusively, of neural crest origin, including some of its hallmark features of skin neurofibromas, café au lait spots, and Lisch nodules (Huson 1994a). It is also associated with a tendency to develop certain types of central and peripheral nervous system tumors (Huson 1994a).

Early portrayals of possible neurofibromatosis type 1 date as far back as the second century; a Hellenistic era Greek statue that may represent the first known medical depiction of neurofibromatosis type 1 has been identified (Zanca and Zanca 1980; Ragge and Munier 1994). The earliest convincing medical descriptions of what we now know to be neurofibromatosis type 1 occurred in the 18th century (Akenside 1785; Ludwig and von Tilesius 1793). However, Friedrich von Recklinghausen put the disorder in the medical lexicon with his correct identification in 1882 of the neural origin of its most common lesion, the neurofibroma (von Recklinghausen 1882). Following this important work, the disorder became known as von Recklinghausen disease. The significance of the café au lait spots as part of the disease was noted by Marie Bernard in 1896 (Huson 1994a). The familial occurrence of neurofibromatosis type 1 was recognized in 1847 by Virchow; the autosomal dominant inheritance pattern was suspected in 1918 by Preiser and Davenport (Huson 1994a). The mode of inheritance, high penetrance rate, and high frequency of new mutations, along with the broad spectrum of complications, were recognized by the 1950s (Huson 1994a).

The description and story of Joseph Merrick, the "elephant man," chronicled by the physician Sir Frederick Treves and later dramatized on stage and in film, served to stimulate interest in neurofibromatosis type 1. Ironically, this patient probably did not have neurofibromatosis type 1, but suffered from the Proteus syndrome. Nevertheless, his story did bring neurofibromatosis type 1 to public attention (Huson 1994a).

Increased clinical and laboratory research began in the 1970s, eventually leading to the localization of the neurofibromatosis type 1 gene on chromosome 17 as well as cloning of the gene (Barker et al 1987; Viskochil et al 1990; Wallace et al 1990). More recently, advancements in genetics and chromosomal mapping have led to greater understanding of the abnormal gene product in neurofibromatosis as well as the pathogenesis of the displayed phenotype.

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