What is Neurofibromatosis (NF)?
Neurofibromatosis (NF) is one of the most common genetic conditions and can affect anyone, regardless of family history, race, gender, or ethnic background.
NF1 affects approximately one out of every 3,000 individuals. NF2 affects one out of every 25,000 individuals. A third classification, Schwannomatosis, is a rare form of NF that has only recently been recognized and appears to affect around 1:40,000 individuals. It is less well understood than NF1 and NF2, and features may vary greatly between patients.
Both NF1 and NF2 are characterized by the growth of benign tumors called neurofibromas.
These tumors can grow anywhere in the body where there are nerve cells.
This includes nerves just under the surface of the skin, as well as nerves deeper within the body, spinal cord, and/or brain.
In NF1, neurofibromas most commonly grow on the skin or on the nerve to the eye. A tumor which grows on the nerve to the eye is called an optic glioma and, if it grows large enough, can cause problems with vision, including blindness.
In NF2, neurofibromas most commonly grow within the spinal cord or brain. Specifically, the tumors are found on the nerves to the ear, called acoustic neuromas, or the nerves for balance, called vestibular schwannomas. Acoustic neuromas, if large enough, can lead to deafness.
How is the diagnosis of Neurofibromatosis made?
Features of NF1
To be given the diagnosis of NF1, an individual must have at least two of the following features. Some people with NF1 have only two, while others can have many of these features:
- Six or more café-au-lait spots over 5 mm in prepubertal patients and over 15 mm after puberty.
- Two or more neurofibromas of any type or one plexiform neurofibroma.
- Freckling in axillary or inguinal regions.
- Optic pathway tumor
- Two or more Lisch nodules
- A distinctive osseous lesion such as sphenoid wing dysplasia or thinning of the cortex of the long bones.
- A first-degree relative with NF1 by the above criteria.
- Also, 50% of patients with NF1 have learning disabilities, making early diagnosis of the disease and intervention even more crucial.
It is proposed that UBOs
"Unidentified Bright Objects" be a diagnostic criterion for NF1
since 43 %-93% of NF children will exhibit areas of increased T2-weighted
signal intensity on MRI
The Diagnostic Evaluation and Multidisciplinary Management of Neurofibromatosis 1 and Neurofibromatosis 2 (Journal of the American Medical Association, July 2, 1997 278:51-57)
Features of NF2
Individuals with NF2 have fewer outside signs of the condition than individual with NF1. This form of the disease affects 1 in 35,000 people and has two separate paths to diagnosis:
- Bilateral vestibular schwannomas that are visualized on magnetic resonance imaging.
- Family history of NF2 in a parent, sibling, or child, plus unilateral vestibular schwannomas before age 30, or any two of the following: meningioma, glioma, schwannoma, or juvenile posterior subcapsular lenticular opacities (juvenile cortical cataract).
Patients with NF2 often have hearing loss and cataract formation. These can develop during childhood, but are most common during the teenage years or in the early twenties.
Possible NF1 Manifestations At Different Life Stages
- Café-au-lait spots. Can occur at any time from birth to age 2.
- Plexiform neurofibromas. In the first year of life, these may present as a subtle soft-tissue enlargement or a large patch of cutaneous hyperpigmentation.
- Tibial dysplasia with anterolateral bowing of the lower leg. Should be referred to an orthopedic surgeon who is familiar with NF1.
- Skinfold freckling. May appear between ages 3 and 5.
- Optic pathway gliomas. Peak incidence is between ages 4 and 6. Annual vision screening, part of standard NF1 surveillance, should detect these lesions and make visual loss rare.
- Two or more Lisch nodules. Occurs in half of patients by age 5.
- Learning disabilities. This common feature of NF1 requires early intervention.
- Attention-deficit disorder. Stimulant medication may be beneficial.
- High blood pressure. Usually associated with renal artery stenosis, but in rare cases may result from pheochromocytomas.
- Plexiform neurofibromas. Tend to be difficult to remove, and may regrow. Surgical treatment and follow-up requires a multidisciplinary team that includes surgeons, radiologists, and oncologists.
- Migraine headaches. May be accompanied by nausea and abdominal pain. Exclude other underlying causes. Standard migraine prophylaxis often helps.
- Dermal neurofibromas. Tend to appear first in late childhood.
- Scoliosis. Can occur in late childhood or adolescence. Spinal fusion may be necessary.
- Dermal neurofibromas. It is impossible to predict the location of lesions or the number that will develop. Some may be surgically removable.
- Hypertension. In adults, this is usually essential hypertension. Persistent hypertension or signs of pheochromocytoma merit further evaluation.
- Malignant peripheral nerve sheath tumors. These can arise from preexisting plexiform neurofibromas. Rapid growth or de novo pain should prompt immediate evaluation. NF1 patients have a 5% lifetime risk of this malignancy.
How does a person get NF?
NF is caused by a change in our genetic material. NF1 is caused by a change in a gene carried on chromosome 17. NF2 is caused by a change in a gene carried on chromosome 22.
The change in the genetic material that causes NF1 and NF2 can be inherited from a parent, referred to as autosomal dominant inheritance, or it can occur spontaneously at conception. The NF gene is always present at birth, though symptoms may not appear until later in life.
Autosomal Dominant Inheritance
If either parent has NF, there is a 50% chance with each pregnancy that the gene causing NF will be passed on to the child. There is no way to predict whether a child who inherits the gene will be affected more severely, the same, or less than the parent. If one parent has an autosomal dominant condition such as NF, there is a 50% chance that it will be passed to each child.
In approximately 50% of cases, NF occurs in an individual who has no family history of the disorder. Anyone can be born with NF. This happens when there is a spontaneous change in the genetic material carried by either the sperm or the egg when pregnancy begins. There is nothing a parent can do or not do to cause this change. Once a person has the changed gene that causes NF, he or she will have NF and therefore have a 50% chance of passing the gene on to his or her children.
Neurofibromatosis type 1 and type 2 both occur in mosaic forms. Mosaicism results from somatic mutations. Early somatic mutations cause generalized disease, clinically indistinguishable from nonmosaic forms. Later somatic mutation gives rise to localized disease often described as segmental. In individuals with mosaic or localized manifestations of neurofibromatosis type 1 (segmental neurofibromatosis type 1), disease features are limited to the affected area, which varies from a narrow strip to one quadrant and occasionally to one half of the body. Distribution is usually unilateral but can be bilateral, either in a symmetric or asymmetrical arrangement. Patients with localized neurofibromatosis type 2 have disease-related tumors localized to one part of the nervous system; for example a unilateral vestibular schwannoma with ipsilateral meningiomas or multiple schwannomas in one part of the peripheral nervous system. The recognition of mosaic phenotypes is important. Individuals with the mosaic form, even with a generalized phenotype, are less likely to have severe disease. They also have lower offspring recurrence risk than individuals with the nonmosaic form. The mosaic forms of neurofibromatosis provide a good example of the effects of somatic mutation. It is increasingly recognized that mild and unusual forms of many dominantly inherited disorders are caused by the same mechanism.