Neurofibromatosis Type 1: Genetics, Symptoms, and Treatment

Introduction to Neurofibromatosis Type 1

Neurofibromatosis Type 1 (NF-1) is an inheritable genetic condition in which benign neural tumors (neurofibromas) form on the dermis, at subcutaneous skin levels, in the brain, and on the spinal cord.¹ The condition has a high prevalence rate in terms of genetic transmission from parent to offspring. Generally, if one parent is a carrier, each offspring has greater than a 50% probability of developing the disease.² In addition to being inherited, NF-1 can appear in families with no prior genetic predisposition, the result of a spontaneous mutation in either gamete (sperm or egg).³ Specifically, this genetic anomaly is caused by the gene that regulates the expression of the protein neurofibromin.⁴ As with any genetic abnormality, the severity of the condition varies considerably across individuals.⁵ Common symptoms include large tumors under the skin, mild cognitive impairment, pigmented spots on the skin, and possible long-bone fractures — the last of which is more pronounced in young children.⁶

Neurofibromatosis is a disease that can affect individuals across a wide range of backgrounds. It is a disorder that can complicate pregnancy, adversely affect cardiovascular and respiratory function, and cause thoracic deformities. The purpose of this analysis is to discuss in detail the background of NF-1, from its genetic roots to its clinical manifestations. Additionally, this analysis focuses on the impact NF-1 has on various bodily systems, including the respiratory, cardiovascular, and thoracic systems. A review of the pharmacology currently utilized in treating this disorder is also evaluated on the basis of efficacy and impact. Finally, the analysis concludes with an overall assessment of the condition, a review of effective treatments, and an examination of the need for future research.

Genetics of NF-1 and the Protein Neurofibromin

The NF-1 gene has the dubious distinction of having the highest number of mutations and irregularities of any gene within the human genome.⁷ The NF-1 gene regulates the expression of the protein neurofibromin, which possesses certain tumor-suppression qualities.⁸ The incidence of NF-1 at birth is approximately 1 in 3,500, displaying 100% penetrance. Although penetrance is high, the phenotypic expression of NF-1 is quite variable.¹⁰

NF-1 mutations lie along the NF gene; however, there are eight distinct exons and introns in which mutations are expressed at significantly higher frequency.¹¹ In these eight regions of the NF-1 gene, upwards of 41% of all mutations are present. Recent studies have demonstrated that other areas may also harbor mutations. Accounting for the remaining mutations, 31% are frame-shift mutations, 9% are nonsense mutations, 8% are missense mutations, and 2% are due to amino acid deletions.¹²

Mutations within the NF-1 gene can ultimately lead to negative consequences in messenger RNA (mRNA) processing and in the production of neurofibromin. Because mRNA is directly responsible for the correct coding and expression of neurofibromin, any mutations will negatively impact protein expression. According to research,¹³ 31% of mutations can lead to recurring changes expressed through neurofibromin. There are over 1,000 variant mutations associated with the NF-1 gene and its production of neurofibromin. The two most common are mutation R304X, which causes a frame-shift and allows exon 7 to be skipped, and mutation Y2264X, which causes a nonsense mutation allowing exon 37 to be spliced from the genome.¹⁴ These mutations provide the nexus for the various symptoms associated with NF-1. Knowledge of the two most common mutations can drive researchers to examine these mutations, locate the chromosomal regions where they are most likely to be found, and develop treatments to suppress or reverse them.

Clinical Presentation and Pathology

The phenotypic presentations of NF-1 can be divided into two categories: tumor and non-tumor. The neurofibroma is the most prevalent tumor associated with neurofibromatosis. It is a mass consisting of Schwann cells, fibroblasts, perineurial cells, and mast cells arising from peripheral nerves or nerve roots, either growing focally or spreading along the length of the nerve.¹⁵ If the growth includes nerve branches, it is termed a plexiform neurofibroma. Dermal or cutaneous neurofibromas are skin tumor growths that commence prepubertally or during pregnancy and can be found either above or within the skin surface.¹⁶ The prevalence of dermal neurofibromas is approximately 95%, although the severity varies from patient to patient and cannot be predicted due to the variable genetic manifestation of the disease. Nodular neurofibromas originate in peripheral nerves but do not invade nearby tissue. Spinal neurofibromas, on the other hand, can cause spinal root compression and may also invade the spinal canal to compress the spinal cord.

Plexiform neurofibromas are the classic sign of neurofibromatosis. Found in approximately 30% of NF-1 patients, they cause nerve compression as well as attrition of surrounding structures such as bone. Although neurofibromas are typically benign, there is a 10% chance of conversion to malignant peripheral nerve sheath tumors (MPNSTs). Conversion to MPNSTs usually originates from deep rather than superficial plexiform neurofibromas. The prognosis of NF-1-derived MPNSTs is poor, with a five-year survival rate of approximately 21%. The best treatment of MPNSTs is surgery, while radiation and chemotherapy have unclear success rates.¹⁷

Transformation of neurofibromas can affect the central nervous system. The most common CNS manifestation is the optic glioma. Optic gliomas symptomatically present with visual field defects, vision loss, or neuroendocrine abnormalities. It is unusual for optic gliomas to progress past seven or eight years of age. NF-1 patients have an increased risk for malignant tumors such as leukemia (for example, acute myelomonocytic leukemia), as well as rhabdomyosarcoma and pheochromocytoma. Forty-six percent of patients develop Lisch nodules.

Non-tumor manifestations of neurofibromatosis include skin pigmentation abnormalities, learning disabilities, and skeletal and vascular dysplasias. Café-au-lait spots are hyperpigmented, flat, round areas of the skin that arise during infancy and increase throughout adulthood. Approximately 95% of NF-1 patients have café-au-lait spots as adults.¹⁸ Learning disabilities include difficulties with visuospatial construction, memory, and other cognitive skills. Vascular manifestations of the disease are rare, occurring in approximately 1–3% of cases. Possible manifestations include occlusions, stenosis, arteriovenous malformations, and fistulae.