Neurofibromatosis type 1: NF1, a genetic disorder characterized by a number of remarkable skin findings including multiple cafe au lait (coffee with milk) spots, multiple benign tumors called neurofibromas on the skin, plexiform neurofibromas (thick and misshapen nerves due to the abnormal growth of cells and tissues that cover the nerve), and freckles in the armpit and groin. The cafe au lait spots increase in number and size with age. Ninety-seven percent of people with NF1 have 6 or more cafe au lait spots by age 20. The skin neurofibromas appear later, usually in the second decade of life. In NF1 there is an increased risk of scoliosis, optic gliomas (benign tumors on the optic nerve), epilepsy, and learning disability. The risk of malignant degeneration of neurofibromas is below 5 percent. NF1 is inherited in an autosomal dominant manner and is due to mutation of the NF1 gene (in chromosome band 17q11) that encodes a protein called neurofibromin. Half of cases are due to new mutations in the NF1 gene. Prenatal testing is available. Also called von Recklinghausen disease.
Symptoms may be limited to skin or eye markings or may include more serious complications. Which symptoms people with NF1 develop varies widely — even within families — but at least some symptoms are usually present by age 10 and may include: Skin and Eye Markings Café au lait ("coffee with milk") spots on the skin usually appear in the first few years of a person's life and increase in number and size over time. They can occur on most parts of the body other than the scalp, palms of the hands and soles of the feet. They often increase in number during puberty and may darken with exposure to sunlight. While helpful in diagnosing NF1, these spots don't cause health problems. Freckles may appear in places not typically exposed to the sun, such as the underarm (axillary freckling) or groin (inguinal freckling). Freckles may not develop until puberty. They are not a health problem, though they may sometimes itch. Lisch nodules — pigmented bumps on the eye's iris (also called iris hamartomas) — can help diagnose NF1 but don't affect vision. They often don't appear until later in childhood. Tumors Neurofibromas (sometimes called fibroneuromas) are slow-growing benign tumors that can develop along nerves almost anywhere in the body. They often appear as small, fleshy, pea-sized nodules within the skin, called dermal or cutaneous neurofibromas. People with NF1 may develop a few or many. People who do not have NF1 sometimes have neurofibromas, though usually no more than several. Plexiform neurofibromas are larger, more ropelike tumors that can wrap in and around nerves, blood vessels and other structures almost anywhere in the body. Neurofibromas can affect appearance, cause pain or affect function, depending on their location and size. Neurofibromas that affect large nerves or the spinal cord are the most likely to cause serious problems. Pheochromocytomas (tumors of the adrenal gland) also sometimes occur in people with NF1 and can cause high blood pressure (as can a neurofibroma that presses on the kidneys or renal artery). In rare instances, a neurofibroma (usually a plexiform neurofibroma) mutates into a malignant tumor (called a neurofibrosarcoma, malignant schwannoma, neurogenic sarcoma, or malignant peripheral nerve sheath tumor). Central Nervous System Effects Optic pathway gliomas (also called optic nerve gliomas or juvenile pilocytic astrocytomas) occur in about 30 percent of people with NF1. The optic pathway includes the optic nerve, which sends messages from the eye to the brain, and the optic chiasm, where the optic nerves from each eye cross before entering the two hemispheres of the brain. A glioma is a tumor that arises from glial cells (supporting cells of the nervous system). Optic pathway gliomas usually develop by age 10, but sometimes may not be detected until later. While many people with optic gliomas have no symptoms, signs might include:
- Impaired vision (which can lead to eventual blindness without treatment)
- Protrusion of the eyeball
- Early puberty (rare and due to the tumor pressing on the hypothalamus, the hormone center of the brain) "Unidentified bright objects" (UBOs) often show up on MRI brain scans of people with NF1.
Their significance is not understood. Weakness of the dura (covering of the brain and spinal cord) is associated with NF1 and can sometimes cause problems such as a meningocele (herniation of the spinal cord through the vertebrae) or hydrocephalus (excess fluid accumulation in the brain). Skeletal Abnormalities Abnormal development of the temple bone (sphenoid dyplasia) occurs in about 1 percent of people with NF1 and can lead to eye displacement or herniation of part of the brain. Thinning of the tibia in the shin or the radius in the arm is found at birth in about 1 percent of people with NF1. It can result in pseudarthrosis, meaning "false joint," because unhealed fractures resulting from bone loss can cause the bone to bow, bend and eventually break. It usually only occurs on one side of the body, and males are more likely than females to have the problem. About 20 percent to 30 percent of people with NF1 have scoliosis (abnormal curvature of the spine) or khyphosis (a hunched posture). Neurofibromas near bones can cause them to erode or to grow irregularly. Cognitive Problems Up to one half of children with NF1 may have learning disabilities involving reading, writing, and neuromotor skills that may be accompanied by attention deficit/hyperactivity disorder. Mental retardation occurs in fewer than 10 percent of people with NF1. Unlike other symptoms of NF1, cognitive problems are not progressive; they don't get worse with aging. Other Symptoms People with NF1 usually have a large head circumference relative to height and weight and are often shorter than average height. High blood pressure, seizures and hydrocephalus also occur more often in people with NF1 than in the general population.
The neurofibromin 1 gene
NF-1 is a microdeletion syndrome caused by a mutation of a gene located on chromosomal segment 17q11.2 on the long arm of chromosome 17 which encodes a protein known as neurofibromin (not to be confused with the disorder itself) which plays a role in cell signaling. The Neurofibromin 1 gene is a negative regulator of the Ras oncogene signal transduction pathway. It stimulates the GTPase activity of Ras. It shows greater affinity for RAS p21 protein activator 1, but lower specific activity. The mRNA for this gene is subject to RNA editing (CGA->UGA->Arg1306Term) resulting in premature translation termination. Alternatively spliced transcript variants encoding different isoforms have also been described for this gene.
In 1989, through linkage and cross over analyses, neurofibromin was localized to chromosome 17.[ It was localized to the long arm of chromosome 17 by chance when researchers discovered chromosome exchanges between chromosome 17 with chromosome 1 and 22. This exchange of genetic material presumably caused a mutation in the neurofibromin gene, leading to the NF1 phenotype. Two recurrent microdeletion types with microdeletion breakpoints located in paralogous regions flanking NF1 (proximal NF1-REP-a and distal NF1-REP-c for the 1.4 Mb type-1 microdeletion, and SUZ12 and SUZ12P for the 1.2 Mb type-2 microdeletion), are found in most cases.
Structure of the neurofinbromin gene
The Neurofibromin gene was soon sequenced and found to be 350,000 base pairs in length. However, the protein is 2818 amino acids long leading to the concept of splice variants. For example, exon 9a, 23a and 48a are expressed in the neurons of the forebrain, muscle tissues and adult neurons respectively.
Homology studies have shown that neurofibromin is 30% similar to proteins in the GTPase Activating Protein (GAP) Family. This homologous sequence is in the central portion of neurofibromin and being similar to the GAP family is recognized as a negative regulator of the Ras kinase.
Additionally, being such a large protein, more active domains of the protein have been identified. One such domain interacts with the protein adenylyl cyclase, and a second with collapsin response mediator protein.Together, likely with domains yet to be discovered, neurofibromin regulates many of the pathways responsible for overactive cell proliferation, learning impairments, skeletal defects and plays a role in neuronal development..
Inheritance and spontaneous mutation
The mutant gene is transmitted with an autosomal dominant pattern of inheritance, but up to 50% of NF-1 cases arise due to spontaneous mutation. The incidence of NF-1 is about 1 in 3500 live births.
Related medical conditions
Mutations in the NF1 gene have been linked to NF-1, Juvenile myelomonocytic leukemia and Watson syndrome. A condition with a separate gene mutation but similar Café au lait spots is Legius syndrome which has a mutation on the SPRED1 gene.
NF-1 cannot be prevented.
Prenatal testing may be used to identify the existence of NF-1 in the fetus. For embryos produced via in vitro fertilisation, it is possible via preimplantation genetic diagnosis to screen for NF-1.
Chorionic villus sampling or amniocentesis can be used to detect NF-1 in the Fetus.
The National Institutes of Health (NIH) has created specific criteria for the diagnosis of NF-1. Two of these seven "Cardinal Clinical Features" are required for positive diagnosis. There is practical flowchart to distinguish between NF1, NF2 and schwannomatosis .
Six or more café-au-lait spots over 5 mm in greatest diameter in pre-pubertal individuals and over 15 mm in greatest diameter in post-pubertal individuals. Note that multiple café-au-lait spots alone are not a definitive diagnosis of NF-1 as these spots can be caused by a number of other conditions.
Two or more neurofibromas of any type or 1 plexiform neurofibroma
Freckling in the axillary (Crowe sign) or inguinal regions
Two or more Lisch nodules (pigmented iris hamartomas)
A distinctive osseous lesion such as sphenoid dysplasia, or thinning of the long bone cortex with or without pseudarthrosis.
A first degree relative (parent, sibling, or offspring) with NF-1 by the above criteria.
NF-1 is a progressive and diverse condition, making the prognosis difficult to predict. The NF-1 gene mutations manifest the disorder differently even amongst people of the same family. This phenomenon is called variable expressivity. For example, some individuals have no symptoms, while others may have a manifestation that is rapidly more progressive and severe.
For many NF-1 patients, a primary concern is the disfigurement caused by cutaneous/dermal neurofibromas, pigmented lesions, and the occasional limb abnormalities. However, there are many more severe complications caused by NF-1, although most of them are quite rare. Many NF patients live perfectly normal and uninterrupted lives.
There is no cure for the disorder itself. Instead, people with neurofibromatosis are followed by a team of specialists to manage symptoms or complications.