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  • Updated 01.15.2024
  • Released 03.21.1995
  • Expires For CME 01.15.2027

Neurofibromatosis 1



Neurofibromatosis 1 is a common autosomal dominant neurocutaneous disorder displaying a typical pattern of dermatologic and systemic findings. In this article, the authors discuss diagnosis, clinical manifestations, treatment, and advancements in neurofibromatosis 1.

Key points

• Neurofibromatosis 1 is characterized by two of the following seven criteria in a patient who does not have a parent with neurofibromatosis 1: six café-au-lait spots, skinfold freckles; two neurofibromas or one plexiform neurofibroma; two Lisch nodules or two choroidal abnormalities; distinctive osseous lesion; optic pathway glioma; or a pathogenic neurofibromatosis 1 variant in the blood. A child of a parent with neurofibromatosis 1 need only have one criterion.

• Ninety-seven percent of patients with neurofibromatosis 1 meet diagnostic criteria by the age of 8 years, and approximately 100% meet diagnostic criteria by the age of 20 years.

• When the revised diagnostic criteria for neurofibromatosis type 1 are used, misdiagnosis is unlikely unless the diagnosis is made based only on pigmentary criteria. In patients presenting with isolated pigmentary criteria, only up to about 65% have neurofibromatosis 1.

• Individuals with multiple café-au-lait spots may warrant further investigations to rule out neurofibromatosis 1; familial café-au-lait spots; RASopathies, such as Legius or LEOPARD syndromes; McCune-Albright syndrome; constitutional mismatch repair syndrome; neurofibromatosis 2; or segmental neurofibromatosis 1.

• Legius syndrome is a neurofibromatosis 1–like syndrome caused by a germline mutation in the SPRED1 gene and is characterized by café-au-lait spots, axillary freckling, and macrocephaly; however, it lacks peripheral and nervous system tumors, typical osseous lesions, and Lisch nodules. About 50% of Legius syndrome patients fulfill the neurofibromatosis 1 diagnostic criteria based on their cutaneous findings.

NF1 is a tumor-suppressor gene. Thus, neurofibromatosis 1 is a tumor-predisposition syndrome, and patients with neurofibromatosis 1 have a propensity to develop both benign and malignant tumors through acquired inactivation of the functioning NF1 allele, with a cumulative risk of malignancy of 20% by the age of 50.

• Health supervision and management guidelines and recommendation for tumor surveillance for patients with neurofibromatosis 1 are available.

Historical note and terminology

Neurofibromatosis 1, previously known as von Recklinghausen disease, was first described in 1882 by the pathologist Frederick von Recklinghausen, who also identified the neural origin of neurofibromas. The other hallmark features of the disease were later described, including the café-au-lait spots by Marie Bernard in 1896, the Lisch nodules by the ophthalmologist Karl Lisch in 1937, and the skinfold freckling (or Crowe sign) by Dr. Frank Crowe in 1964 (07).

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. Increased clinical and laboratory research in the 1970s eventually lead to the localization of the NF1 gene locus on chromosome 17 in 1987. In 1988, the U.S. National Institutes of Health convened a consensus conference to establish diagnostic criteria for neurofibromatosis 1, and these criteria were used until the publication of the revised diagnostic criteria in 2021 (Table 1) (81; 63). The NF1 gene was discovered in 1990 (07).

Although both the central and peripheral forms of neurofibromatosis were recognized in the 19th century, for many years neurofibromatosis was discussed as a single entity. Not until 1980 was neurofibromatosis type 2, previously thought to be a central form of neurofibromatosis, recognized to be a distinct genetic disease (110). Today there are three major clinically and genetically distinct forms of neurofibromatosis: neurofibromatosis 1 (NF1) and NF2-related and schwannomatosis. Of these, neurofibromatosis 1 constitutes 90% of neurofibromatosis cases and is one of the most common autosomal dominant disorders in humans.

Table 1. Diagnosis Criteria for Neurofibromatosis 1 (At Least Two Criteria Are Required If No Parents Have Neurofibromatosis 1, Or One Criterion If A Parent Has Neurofibromatosis 1)*

(1) Six or more café-au-lait macules > 5 mm prior to puberty and > 15 mm postpubertal**

(2) Freckling in the axillary or inguinal regions**

(3) Two neurofibromas of any type or one plexiform neurofibroma

(4) Optic pathway glioma

(5) Two Lisch nodules (iris hamartomas) or two choroidal abnormalities

(6) A distinctive osseous lesion, such as sphenoid dysplasia, anterolateral bowing of the tibia, or pseudoarthrosis of a long bone

(7) A heterozygous pathogenic NF1 variant with an allele fraction of 50% in normal tissue, such as white blood cells

*According to National Institutes of Health in force since 1988 (81). The National Institutes of Health diagnostic criteria are highly specific and sensitive by the age of 8 years where 97% of patients meet diagnostic criteria, and 100% by age 21.

**At least one of the two pigmentary findings should be bilateral.

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