Neurofibromatose Typ 1

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.

Epidemiology

Neurofibromatosis affects 1:2500-3000 individuals . 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 . There is a variable expression but 100% penetrance by 5 years of age .

Clinical presentation

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 :

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 .

Neoplasms

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 :

Pathology

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 . For this reason, the disorder is classified as a RASopathy .

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 

Radiographic features

Breast
Central nervous system
  • FASI (focal areas of signal intensity): occur in deep white matter and basal ganglia or corpus callosum , 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
  • cutaneous and subcutaneous neurofibromas: benign peripheral nerve sheath tumors
Skeletal
Thoracic
Vascular

Treatment and prognosis

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 .

History and etymology

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 .

See also