Von Recklinghausen disease, which is also referred to as neurofibromatosis-1 (NF-1), is a genetic condition that manifests with neural hamartomas in various locations. NF-1 is autosomal dominant in inheritance and can induce physical changes that affect the bones, skin, and nervous system. Moreover, NF-1 is the most widespread hamartomatous disorder associated with tumor growth.
The diagnosis of NF-1 is based on unmistakable clinical signs in 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 often unique to this condition.
A Curse From The Most High: Incurable Disorder Type 1 Neurofibromatosis
NIH criteria
The diagnosis of NF-1 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 the expression of the normal gene.
The National Institutes of Health (NIH) appointed a committee to evolve the diagnostic criteria for NF-1, of which two or more must be present for the condition to be established. These criteria determined by the NIH include café-au-lait macules, neurofibromas, freckles, iris hamartomas, and several other symptoms.
Café-au-lait macules
These are light brown patches with a sharp border. In patients with NF-1, these macules should be six or more in number, more than 5 millimeters (mm) and 1.5 centimeters (cm) wide in children before and after puberty, respectively.
These are the first symptoms to appear in NF-1 and are seen in all patients, increasing in number and growing larger in the first decade of life.
Neurofibromas
NF-1 patients typically 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,” these tumors are often detected 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 NF-1 patients get freckles associated with the disease.
Iris hamartomas (Lisch nodules)
Iris hamartomas are two or more dome-shaped lesions seen on slit-lamp microscopy in more than 90% of patients, rarely causing symptoms.
Other symptoms
Additional symptoms of NF-1 can include a single pathognomonic bone lesion, such as dysplasia of the sphenoid or thinned-out cortex of the long bones, with or without pseudoarthrosis. A positive family history of the disease in a first-degree relative with two or more of the aforementioned criteria above.
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, 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. Furthermore, a biopsy of a cutaneous neurofibroma is also not warranted unless it is responsible for some symptoms.
Magnetic resonance imaging (MRI) scans in NF-1 children between the ages of 8 and 16 years reveal 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 rapid enlargement of the head since their last visit, or any abnormality in development, should be immediately screened for malignant transformation or other complications.
Adults with NF-1 may be scheduled for yearly follow-up appointments. Genetic counseling and psychological care are essential, especially since many patients start to develop neurofibromas only towards the end of the adolescent period.
References
- Diagnosis: Von Recklinghausen disease (NF1). (2012). Medical Journal, Armed Forces India, 68(3), 310–311. http://doi.org/10.1016/j.mjafi.2012.06.001.
- Ghalayani, P., Saberi, Z., & Sardari, F. (2012). Neurofibromatosis type I (von Recklinghausen’s disease): A family case report and literature review. Dental Research Journal, 9(4), 483–488.
- Friedman, J.M. (1998).Neurofibromatosis 1. In Adam et al. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2018. Retrieved from https://www.ncbi.nlm.nih.gov/books/NBK1109/.
- https://www.nih.gov/
Further Reading