Neurofibromatosis (NF) is a genetic multisystem disorder characterized by the development of tumors in the central or peripheral nervous system including the brain, spinal cord, organs, skin and bones with predominant neurological and skin manifestations. There are three types of NF: NF1 accounting for 96% of all cases, NF2 in 3%, and schwannomatosis (SWN) in <1%.  Neurofibromatosis occurs in both sexes and in all races and ethnic groups. NF1 being the most common, affecting 1 in 3000 newborns worldwide. The gene for NF1 is located on chromosome 17. The NF1 gene makes a protein called neurofibromin, which regulates cell division in the nervous system and functions as a kind of molecular brake to keep cells from growing out of control. The gene for NF2 is located on chromosome 22. The NF2 gene product is a tumor-suppressor protein, called merlin or schwannomin. Merlin leads to schwannomatosis, the disorder characterized by multiple non-cancerous (benign) tumors called schwannomas, which are a type of tumor that grows on nerves.

A genetic multisystem disorder with predominant neurological and skin manifestations.

Clinical features

The signs and symptoms of neurofibromatosis may appear during the course of progression of the disease from early infancy to childhood, puberty as well as in adulthood. As NF is a genetic hereditary disorder which may be familial or sporadic, most of the pathognomonic features appear in childhood. Approximately half of the cases can occur sporadically without a known family history. The clinical manifestations of NF1 includes:

• Six or more café au lait spots that are 1.5 cms or larger in people who have had puberty, or 0.5 cms or larger in people who haven’t

• Two or more neurofibromas (tumors that develop from the cells and tissues that cover nerves) of any type, or one or more plexiform neurofibroma (a nerve that has become thick and misshapen due to the abnormal growth of cells and tissues that cover the nerve)

• Freckling in the armpit or groin

• Optic glioma (tumor of the optic pathway)

• Two or more Lisch nodules in the iris

• A distinctive bony lesion, dysplasia of the sphenoid bone, or dysplasia or thinning of long bone cortex

• A first-degree relative with NF1

Similarly, for NF2 the characteristic features are:

• Bilateral (on both sides) vestibular schwannomas, also known as acoustic neuromas. These are benign tumors that develop from the balance and hearing nerves supplying the inner ear.

OR

• Family history of NF2 (first-degree family relative) plus unilateral (on one side) or bilateral vestibular schwannomas, or any two of the following health conditions:

• Multiple meningiomas (tumors that occur in the meninges, the membranes that cover and protect the brain and spinal cord)

• Glioma (cancer of the brain that begins in glial cells, which are those that surround and support nerve cells)

• Any neurofibromas

• Schwannoma

• Juvenile cataracts

• Gradual hearing loss

• Ringing in the ears

• Balance problems

• Headaches

The features suggestive of Schwannomatosis are:

• An individual is in adulthood and have no evidence of vestibular tumors on an MRI scan, no known NF2 gene mutation, and two or more schwannomas within or between skin layers, one being confirmed by a biopsy.

• One schwannoma confirmed by biopsy and a first-degree relative who also meets the criteria.

• A type called segmental schwannomatosis, is present where the tumors are limited to one area of the body, such as the arm, leg, or spine.

Diagnosis

​The diagnosis of neurofibromatosis is challenging as it involves multiple system involvement of clinical manifestations, the genetic predisposition and familial autosomal dominant inheritance pattern. Neurofibromatosis may be diagnosed by conducting various clinical systemic examinations along with diagnostic tests, imaging modalities and invasive surgical techniques. These include physical examination, medical history, family history, plain radiographs, computerized tomography (CT) scans, magnetic resonance imaging (MRI), and biopsy if required for neurofibromas. Various tests are done for specific symptoms such as, visual assessment for visual problems, tests for hearing deficits, neurocognitive deficits, and learning disabilities. Although recent advances in genetic testing may permit the laboratory diagnosis in as many as 95%, for the majority of patients, the diagnosis is made on the basis of clinical manifestations.

Management

There is no cure for both NF1 and NF2, the complexity of the disease process and the wide spectrum of clinical complications emphasizes the importance of multidisciplinary teams to provide a holistic approach of patient management. An ideal model of care for NF patients is to be managed in multispecialty clinics with specialists and experts with interests in NF consisting of surgeons, oncologists, neurologists, dermatologists, geneticists, genetics counselors, ophthalmologists, psychologists and others as and when the particular symptoms appear during the progression of the disease. At present, management paradigms are focused on early detection of treatable complications through routine surveillance and symptomatic treatment.  However, Neurofibromatosis is a multisystem genetic disorder with manifestations involving various parts of the body, hence it is an underrecognized and understudied disorder as a result of which there has been little improvement in the quality of life and survival rate of the patients.