Neurofibromatosis is a genetic disorder (neurocutaneous syndrome) with predominant neurological and skin manifestations. Neurofibromatosis is not a single medical disorder but refers to three distinct conditions involving the development of tumors that may affect the brain, spinal cord, and the nerves that send signals between the brain and spinal cord and all other parts of the body. The three conditions include:
Neurofibromatosis type 1 (NF1), historically called Von Recklinghausen disease
Neurofibromatosis type 2 (NF2)
Schwannomatosis (SWN)
NF1 accounts for 96% of all cases, NF2 for 3%, and schwannomatosis (SWN) for <1%. Neurofibromatosis occurs in both sexes and in all races and ethnic groups. NF1 is the most common, affecting 1 in 3000 newborns worldwide.
Types
Among the foregoing conditions, NF1 is the most common genetic disorder. This disease was first described in 1882 by a German pathologist, Frederich Von Recklinghausen, leading to the initial name of the condition, Von Recklinghausen disease. NF1 is inherited as an autosomal dominant disorder; however, up to 50% of cases occur sporadically due to spontaneous mutation. Although many affected patients present in childhood with classic clinical findings, up to 10% of patients present later in life with atypical manifestations. Patients with NF1 are at increased risk for central nervous system (CNS) manifestations including structural, functional and neoplastic disease. Clinically, NF1 presents with the occurrence of Café-au-lait spots, Lisch nodules, axillary freckling and multiple neurofibromas. Other complications include learning disabilities, mental retardation, optic gliomas, certain bone abnormalities, CNS tumors, and an increased risk for certain malignancies. Neurofibromatosis type 2 is a less common condition, seen in approximately 1 in 50,000 individuals and is characterized more often by central nervous system tumors such as meningiomas and gliomas. Schwannomatosis (SWN) is the rarest form of neurofibromatosis (NF), and it causes intense pain. 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, a disorder characterized by multiple non-cancerous (benign) tumors called schwannomas, which are a type of tumor that grows on nerves. Schwannomas develop when Schwann cells, which are specialized cells that normally form an insulating layer around the nerve, grow uncontrollably to form a tumor. Although NF1 is inherited as an autosomal dominant disorder with nearly 50% of the cases of NF being inherited, the other 50% of cases can occur sporadically due to spontaneous mutation of the gene.
Global scenario
Neurofibromatosis type 1 (NF1) affects 1 in 3000 newborns worldwide. NF1 afflicts about 1 in every 3,500 people, or roughly 100,000 people in the United States. The incidence rates of different types of neurofibromatosis is highly variable. NF1 occurs in approximately one out of every 3,500 births, NF2 occurs in approximately one out of every 40,000 births and Schwannomatosis occurs an estimated one out of every 40,000 births. Tumors in these disorders are overwhelmingly benign and they may be/become malignant in 3 to 5% of all cases. The lifetime risk of cancer developing in a person with NF1 is estimated to be about 7%.
In India, while neurofibromatosis type 1 (NF1) is seen in 1 in 2,500 to 4,000 persons, neurofibromatosis type 2 (NF2) is seen in 1 in 25,000 persons.
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 general 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
Neurofibromatosis is a multisystem genetic disorder with manifestations involving various parts of the body and associated complications, there has been little improvement in the quality of life and survival rate of the patients. Although 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.
Quality of life
Health-related quality of life is a complex multidimensional construct that depends on biological and psychological variables, symptoms, functional status, general health perceptions, and the influences of personal/individual, environmental as well as nonmedical factors. The various manifestations of neurofibromatosis cause considerable morbidity through physical and psychosocial burden and are often cosmetically disfiguring and physically distressing, which leads to a significant lowering of quality of life through feelings of embarrassment and low self-esteem. Hence, centers of excellence that are able to provide these patients with multidisciplinary clinics to address their complex needs in a longitudinal fashion will be key to improving the management of this growing population of patients with neurofibromatosis.
