Neurofibromatosis type 1

Last revised by Dr Bahman Rasuli on 13 Sep 2021

Neurofibromatosis type 1 (NF1), also known as von Recklinghausen disease, is a multisystem neurocutaneous disorder, the most common phakomatosis, and a RASopathy. Additionally, it is also one of the most common inherited CNS disorders, autosomal dominant disorders, and inherited tumor syndromes. 

Individual systemic manifestations are discussed individually: 

The remainder of this article pertains to a general discussion of neurofibromatosis type 1. 

Neurofibromatosis affects 1:2500-3000 individuals 3. In half of the cases, the disease is inherited as an autosomal dominant condition. In the other half, the disease is due to a de novo mutation 6. There is a variable expression but 100% penetrance by 5 years of age 6.

As is the case with many phakomatoses, NF1 results in a variety of abnormalities of variable severity. To make the clinical diagnosis two or more of the following are required 2:

A mnemonic to help remember these features is CAFE SPOT.

In addition, ~45% (range 30-60%) of patients have learning disabilities, and approximately 1% have hypertension due to renal artery stenosis.

It is important to consider that NF1 has a much earlier age of onset than schwannomatosis and NF2, with approximately 50% of patients meeting the diagnostic criteria for NF1 by the age of 1 year and approximately 97% meeting the criteria by the age of 8 years 10

It should come as no surprise that a disease due to inactivation of a tumor suppressor gene (see below) is also associated with an increased incidence of numerous tumors 1-6:

The NF1 gene locus is on chromosome 17q11.2 and the gene product is neurofibromin, which acts as a tumor suppressor of the Ras/MAPK pathway; inactivation of the gene thus predisposes to tumor development 6,12,13. For this reason, the disorder is classified as a RASopathy 12.

The disease primarily is a hamartomatous disorder that involves the ectoderm and mesoderm. Usually, three types of neurofibromas occur in this disorder and are distinguished on the basis of their gross and microscopic appearances. 

  • localized neurofibroma (cutaneous neurofibroma): the most common type, is a focal lesion that typically is located in the dermis and subcutis
  • diffuse neurofibroma (subcutaneous neurofibroma): localized in the subcutis, usually in the head and neck region. 
  • plexiform neurofibroma: considered pathognomonic if present; they may be seen in virtually any location but usually occur in the neck, pelvis, and extremities 
  • FASI (focal areas of signal intensity): occur in deep white matter and basal ganglia or corpus callosum 5, areas of T2/FLAIR hyperintensity with no contrast enhancement
  • optic nerve glioma or optic pathway glioma (may manifest as enlarged optic foramen)
  • progressive sphenoid wing dysplasia
  • lambdoid suture defects
  • dural calcification at the vertex
  • moya-moya phenomenon (rare)
  • buphthalmos
  • cutaneous and subcutaneous neurofibromas: benign peripheral nerve sheath tumors

No single treatment exists, and a combination of supportive and surgical therapies are employed depending on the specific tumors and anomalies present. 

Although prognosis is very variable, overall life expectancy is approximately half that of non-affected individuals. Tumors or cardiovascular complications are the most common causes of mortality 8.

The first name of this condition was Von Recklinghausen disease because, in 1882, von Recklinghausen described cases of neurofibromatosis and recognized it as a nosological entity 14

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Cases and figures

  • Figure 1: Lisch nodules
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  • Case 1: plexiform neurofibroma
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  • Case 2: plexiform neurofibroma
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  • Case 3: neurofibromata
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  • Case 4: cutaneous neurofibromata
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  • Case 5: with optic nerve gliomas
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  • Case 6: with cord compression
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  • Case 7: hemifacial hypertrophy
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  • Case 8: ribbon-ribs deformity
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  • Case 9: neurofibromas in breast and axilla
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  • Case 10: sphenoid wing dysplasia
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  • Case 11: with ulnar pseudoarthrosis
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  • Case 12: plexiform neurofibroma of thigh
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  • Case 13: neurofibromas
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  • Case 14: neurofibromas dorsal nerve roots
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  • Case 15: intraspinal neurofibroma
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  • Case 16: plexiform neurofibroma of foot
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  • Case 17: plexiform neurofibroma femoral nerve
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  • Case 18
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  • Case 19
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  • Case 20: huge abdominal and retroperitoneal plexiform neurofibromatosis
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  • Case 21: cutaneous neurofibromata
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