Neurofibromatosis

Contributed by: Eman Bahrani: Baylor College of Medicine, 1 Baylor Plaza, Houston, Tx 77030

Overview

Neurofibromatosis (NF) refers to autosomal dominant genetic disorders that lead to growth of tumors of the nervous system. There are two main types, NF1 and NF2, caused my mutations in distinct genes.

Genetics and Epidemiology

NF1, also known as von Recklinghausen�s disease, is caused by mutations of NF1, a gene on chromosome 17 which encodes the protein ��neurofibromin��. Inheritance is autosomal dominant, with 100% penetrance and variable expression. The disease affects 1 in 3,000 individuals.

NF2 is caused by a mutation of the NF2 gene on chromosome 22, which encodes the protein ��merlin��. Inheritance is also autosomal dominant. NF2 affects 1 in 40,000 individuals.

Pathogenesis

Neurofibromin is a GTPase activating Protein (GAP) that terminates RAS signaling. As RAS promotes cell growth, genetic lesions of neurofibromin, as seen in NF1, prevent inhibition of RAS and yield uncontrolled cell growth.

A fundamental feature of eukaryotic cells is that their proliferation is inhibited by contact with other cells, termed “contact growth inhibition”. Merlin is a signaling mediator that functions in this process; thus, mutations yield dysregulated cellular proliferation.

Clinical Manifestations

Typical pathological findings in NF1 include neurofibromas (peripheral nerve sheath tumors), gliomas of the optic nerve, pigmented nodules of the iris (Lisch nodules), and cutaneous hyperpigmented macules (cafe au lait spots). There is also a predilection for developing pheochromocytomas and scoliosis.
Additionally, neurofibromas in NF1 have a higher propensity for malignant degeneration to neurofibrosarcoma than those found in the general population.
Due to variable expression, the clinical course varies among affected individuals. Some have no symptoms with few cafe-au-lait macules, while others can develop disfiguring lesions, large plexiform neuromas, and eventual compression of nearby structures, including the spinal cord.

The most common pathological finding in NF2 is bilateral cranial nerve 8 schwannomas (acoustic or vestibular schwannomas) at the cerebellopontine angle. Patients can present as adolescents or adults with hearing loss, tinnitus, or balance problems.
Less common findings include multiple meningiomas, spinal cord ependymomas, neurofibromas, and cafe-au-lait macules.

Management

Management of NF1 and NF2 is beyond the scope of this work but largely revolves around treatment of symptomatic lesions, such as neuromas, pheochromocytomas, and schwannomas, often with a surgical approach.

Further Reading

Friedman JM. Review article: Neurofibromatosis 1: Clinical manifestations and diagnostic criteria. Journal of Child Neurology. 2002;17(8):548-554.
Sanna M, Di Lella F, Guida M, Merkus P. Auditory brainstem implants in NF2 patients: Results and review of the literature. Otology and Neurotology. 2012;33(2):154-164.

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