Von Recklinghausen disease, also called neurofibromatosis-1 (NF-1) is a genetic condition which manifests with neural hamartomas in various locations. It is autosomal dominant in inheritance, and the changes affect the bones, skin, and nervous system. It is the most widespread hamartomatous disorder associated with tumor growth.

The diagnosis of NF-1 is based on unmistakable clinical signs in the brain function. For instance, over half of the patients with Von Recklinghausen disease will show abnormal findings on imaging of the brain, the orbit, or both. The lesions may consist of hamartomas or of neoplasms, such as gliomas of the optic nerve and of the parenchyma of the brain. Bilateral optic gliomas are specific for this condition.

NIH criteria

The National Institutes of Health appointed a committee to evolve diagnostic criteria for NF-1, of which two or more must be present for the condition to be established. The following are the criteria set by the institute.

• Café-au-lait macules: These are light brown patches with a sharp border. They should be six or more in number, more than 5 mm wide and 1.5 cm wide in children before and after puberty, respectively. These are the first to appear,and are seen in all patients, increasing in number and growing larger in the first decade of life.
• Neurofibromas: Patients should present with two or more lesions of any type or a single plexiform neurofibroma. Typical neurofibromas are soft and dome-shaped tumors where a few only being stalked. In most cases, they occur over the trunk and limbs, rarely extending beyond a few centimeters. The plexiform neurofibroma is a more spread-out tumor extending along the nerve and may trap the fifth cranial nerve and the cervical nerves. Usually described as feeling like a “bag of worms”, they are noticed during the first two years after birth.
• Freckles: Multiple freckles in the axillary region called Crow’s sign is a characteristic feature seen later on in café-au-lait spots but may also occur in the groin. Seven out of ten patients get freckles associated with the disease.  
• Iris hamartomas (Lisch nodules): These are two or more dome-shaped lesions seen on slit lamp microscopy in more than 90% of patients, rarely causing symptoms.
• A single pathognomonic bone lesion such as dysplasia of the sphenoid or thinned-out cortex of the long bones, with or without pseudoarthrosis
• Bilateral optic glioma
• Family history in a first-degree relative with two or more of the criteria above

The diagnosis is typically made only in midlife because of the benign nature of the swellings and few related complications. The nature of the presenting symptoms is partly dependent upon the mutation present rather than expression of the normal gene.

Other features

Other lesions which may occur in NF-1 include the following:

• Oral papillomatous neurofibromas over the hard palate or tongue in up to a tenth of affected individuals
• Skeletal deformities such as the pathognomonic sphenoid wing dysplasia or kyphoscoliosis (2%) sometimes causing breathing trouble and pseudoarthrosis of the tibia or radius
• Malignancies such as gliomas of the optic nerve, astrocytomas, and schwannomas may occur and may be responsible for convulsions. Meanwhile, non-neurological cancers include rhabdomyosarcoma, Wilms tumor, and retinoblastoma.

Surveillance

Some patients may show café-au-lait macules and freckling or neurofibromas over only one segment of the body. These patients would probably have mosaic or segmental NF-1. In about half of NF-1 cases, there is no positive family history, and as such, children must be followed up under the presumption that they have the condition. Lisch nodules may help establish the diagnosis in children with only six café-au-lait macules and no other lesions. Molecular genetic testing may also help in ambiguous cases and is advisable before offering genetic counseling. In other situations, genetic testing is not required as a routine measure; neither is biopsy of a cutaneous neurofibroma unless it is responsible for some symptoms.

MRI scanning in children between the ages of 8 and 16 years reveals hyperintense multifocal signals on T2-weighted imaging due to changes in the myelin or of the structure of the brainstem, cerebellum, basal ganglia, optic nerve, and dentate nucleus. There is a slight association between NF-1 and these cognitive abnormalities. An investigation is required as a routine test, but the detection of these lesions will confirm a diagnosis of NF-1.

Visual evaluation should be done in young children who may not realize that their vision is impaired. Diligent monitoring is also pertinent to assist the child with difficulties in cognitive development. Any symptomatic patient, for instance, with a rapid enlargement of the head since the last visit, or any abnormality in development, should be immediately screened for malignant transformation or other complications. Adults may be scheduled for yearly follow up. Genetic counseling and psychological care are essential, especially since many patients start to develop neurofibromas only towards the end of the adolescent period.