Neurofibromatosis (NF) type 1 (von Recklinghausen Disease) is caused by a mutation in the NF1 tumor suppressor gene situated on chromosome 17 and is inherited in an autosomal dominant manner. NF1 exhibits 100% penetrance, ensuring that individuals possessing the genotype will invariably display phenotypic manifestations. Mutations in the gene encoding neurofibromin, a GTPase which suppresses the Ras pathway under normal conditions, results in an unchecked cell cycle when mutated.
Clinically, NF1 present with several distinctive features. Cafe-au-lait spots, which are hyperpigmented macules, are typically noticed in infancy. As they age, axillary and inguinal freckling become evident. Later in childhood, Lisch nodules, or tan hamartomas in the iris, may be observed. Neurofibromas—benign tumors of peripheral nerve sheaths primarily localized on the trunk and neck— emerge from Schwann cells and most frequently arise in adulthood. Other manifestations of NF1 include optic gliomas, CNS tumors such as meningiomas, adrenal medullary pheochromocytomas, and bone anomalies such as congenital pseudarthrosis and scoliosis.
Neurofibromatosis (NF) type 2 results from a mutation in the NF2 gene found on chromosome 22, which encodes the tumor suppressor protein merlin. A defining feature of NF2 is the presence of bilateral vestibular schwannomas, or acoustic neuromas, which stain positive for S100. Originating from the vestibular branch of CN VIII, these benign tumors can instigate a myriad of symptoms such as vertigo & nystagmus, sensorineural hearing loss, and tinnitus. These tumors can also impinge CN V, resulting in the loss of facial sensation masseter weakness, and CN VII, which can lead to facial muscle weakness and loss of taste to the anterior tongue. Vestibular schwannomas are tumors of neoplastic Schwann cells, displaying alternating areas of hypercellularity and hypocellularity on histology.
Alongside primary tumors, patients with NF2 can also develop multiple meningiomas, cataracts, and various spinal tumors such as spinal schwannomas, meningiomas, and ependymomas, which may cause motor dysfunction.
NF1, also known as ‘von Recklinghausen disease,’ is the most common form of NF and is caused by a mutation in the NF1 tumor suppressor gene on chromosome 17. It is an autosomal dominant disease that presents with café-au-lait spots, freckling in skin folds, Lisch nodules, and neurofibromas, mainly in adulthood. On the other hand, NF2 is caused by a mutation in the NF2 gene on chromosome 22 and primarily presents with bilateral vestibular schwannomas, which can lead to symptoms like vertigo, nystagmus, sensorineural hearing loss, and tinnitus.
NF1 can present with a variety of manifestations, most commonly including café-au-lait spots, freckling in skin folds, Lisch nodules, and neurofibromas. Additionally, it can present with optic gliomas, other CNS tumors (such as meningiomas, astrocytomas, and other gliomas), pheochromocytomas in the adrenal medulla, and bony abnormalities (such as long bone dysplasia and fractures, and scoliosis). It can also lead to the formation of pseudarthrosis due to incorrectly healed fractures.
NF2 primarily presents with bilateral vestibular schwannomas (also known as acoustic neuromas) which can result in a range of symptoms such as vertigo and nystagmus, sensorineural hearing loss, and tinnitus due to impingement of different cranial nerves. Additionally, NF2 can lead to the development of multiple meningiomas, cataracts as well as spinal tumors which might result in motor dysfunction.
Neurofibromatosis is caused by mutations in specific genes. NF1 is caused by a mutation in the NF1 gene on chromosome 17, and this gene mutation is inherited in an autosomal dominant fashion. This means that a person only needs one copy of the faulty gene from either parent to develop the condition. The NF1 gene mutation has 100% penetrance, meaning every individual with the mutation will exhibit some symptoms of the disease. NF2 is caused by a mutation in the NF2 gene on chromosome 22 and follows a similar autosomal dominant inheritance pattern.
The NF1 gene encodes a protein called neurofibromin, which is a GTPase that normally inhibits the Ras signalling pathway involved in cell cycle regulation. In cases of NF1, the mutated neurofibromin fails to inhibit the Ras signalling pathway, leading to an uninhibited cell cycle activation. This contributes to the formation of neurofibromas, benign peripheral nerve sheath tumors composed of Schwann cells.