Neurofibromatosis type I

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Neurofibromatosis type I (NF-1), formerly known as von Recklinghausen disease after the researcher who first documented the disorder, is a human genetic disorder. NF-1 is the most common inherited disorder caused by a single gene.

[edit] Simple Explanation

NF-1 is a tumor disorder that is caused by the malfunction of a gene on chromosome 17, that is responsible for control of cell division. It often comes with scoliosis (bone disease) and eye problems. Neurofibromatosis can be deadly. It has been shown to occasionally cause cancer. It is important to visit your doctor for a full diagnosis.

[edit] Genetics

NF-1 is inherited in an autosomal dominant fashion, although it can also arise due to spontaneous mutation.

NF-1 is caused by a mutation of a gene 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 intracellular signaling. The neurofibromin is a negative regulator of the Ras oncogene.

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^[1].

[edit] Neurofibromin

[edit] Discovery

In 1989, through linkage and cross over analyzes, neurofibromin was localized to chromosome 17^[2]. 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^[2]. It was this exchanging of genetic material that presumably caused a mutation in the neurofibromin gene thus leading to the NF1 phenotype.

[edit] Structure

The Neurofibromin gene was soon sequenced and found to be 350,000 base pairs in length^[3]. However, the protein is 2818 amino acids long leading to the concept of splice variants^[4]. For example, exon 9a, 23a and 48a are expressed in the neurons of the forebrain, muscle tissues and adult neurons respectively^[4].

Homology studies have shown that neurofibromin is 30% similar to proteins in the GTPase Activating Protein (GAP) Family^[3]. 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^[5].

Additionally, being such a large protein, more active domains of the protein have been identified. One such domain interacts with the protein adenylyl cyclase^[6], and a second with collapsin response mediator protein^[7]. 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^[8].

[edit] Clinical findings

[edit] Peripheral nervous system lesions

A neurofibroma is a mass lesion of the peripheral nervous system. Its cellular lineage is uncertain, and may derive from Schwann cells, other perineural cell lines, or fibroblasts. Neurofibromas may arise sporadically, or in association with NF-1. A neurofibroma may arise at any point along a peripheral nerve. A cutaneous neurofibroma manifests as single or multiple firm, rubbery bumps of varying sizes on a person's skin. A solitary neurofibroma may also occur in a deeper nerve trunk, and only be seen on cross-sectional imaging (e.g., computed tomography or magnetic resonance) as a fusiform enlargement of a nerve.

The hallmark lesion of NF-1 is the plexiform neurofibroma. These lesions are composed of sheets of neurofibromatous tissue that may infiltrate and encase major nerves, blood vessels, and other vital structures. These lesions are difficult and sometimes impossible to routinely resect without causing significant damage to surrounding nerves and tissue.

When a plexiform neurofibroma manifests on a leg or arm, it will cause extra blood circulation, and may thus accelerate the growth of the limb. This may cause considerable difference in length between left and right limbs. To equalize the difference during childhood, there is an orthopedic surgery called epiphysiodesis, where growth at the epiphyseal (growth) plate is halted. It can be performed on one side of the bone to help correct an angular deformity, or on both sides to stop growth of that bone completely. The surgery must also be carefully planned with regard to timing, as it is non-reversible. The goal is that the limbs are at near-equal length at end of growth.

This coronal contrast-enhanced fat-saturated T1-weighted image from an MRI of the pelvis shows the characteristic fasciculated appearance and infiltrative growth pattern of a plexiform neurofibroma.

Schwannomas are peripheral nerve-sheath tumor seen with increased frequency in NF-1. In practice, the major distinction between a schwannoma and a solitary neurofibroma is that a schwannoma can be resected while sparing the underlying nerve, whereas resection of a neurofibroma requires the sacrifice of the underlying nerve.

Malignant peripheral nerve-sheath tumors (MPNST), once called neurofibrosarcomas, can arise from degeneration of a plexiform neurofibroma; this is, however, a rare complication. A plexiform neurofibromas has a lifetime risk of 8-12% of transformation.

[edit] Dermatologic manifestations

In addition to the cutaneous neurofibroma, patients with NF-1 develop flat pigmented lesions of the skin called café au lait spots.[1].

NF-1 patients may also get freckles of the axillae (armpits). See Plexiform neurofibroma.

[edit] Central nervous system manifestations

The primary neurologic involvement is of the peripheral nervous system, as described above.

Intracranially, NF-1 patients have a predisposition to develop glial tumors of the central nervous system; primarily: optic gliomas and astrocytomas. Another CNS manifestation of NF-1 is the so-called "unidentified bright object" or UBO, which is a lesion which has increased signal on a T2 weighted sequence of a magnetic resonance imaging examination of the brain. These UBOs are typically found in the cerebellar peduncles, pons, midbrain, globus pallidus, thalamus, and optic radiations. Their exact identity remains a bit of a mystery since they disappear over time (usually, by age 16), and they are not typically biopsied or resected. They may represent a focally degenerative bit of myelin.

Within the CNS, this manifests as a weakness of the dura, which is the tough covering of the brain and spine. Weakness of the dura leads to focal enlargement (termed dural ectasia) due to chronic exposure to the pressures of CSF pulsation.

Radiographically, dural ectasia can lead to scalloping of the posterior vertebral bodies and to the formation of cystic diverticula of the dura of the spine (termed meningoceles).

[edit] Skeletal lesions

Bones, especially the ribs, can develop chronic erosions (pits) from the constant pressure of adjacent neurofibromas and schwannomas. Similarly, the neural foramen of the spine can be widened due to the presence of a nerve root neurofibroma or schwannoma.

In NF-1, these is also a generalized abnormality of the soft tissues, which is referred to as mesodermal dysplasia. This manifests as maldevelopment of skeletal structures, including

• Focal scoliosis and/or kyphosis, which is the most common skeletal manifestation of NF-1, occurring in 20% of affected patients. Approximately one quarter of patients will require corrective surgery.
• Bowing of a long bone with a tendency to fracture and not heal, yielding a pseudarthrosis. The most common bone to be affected is the tibia (causing congenital pseudarthrosis of the tibia or CPT). CPT occurs in 2-4% of individuals with NF-1.
• Malformation of the facial bones or of the eye sockets (lambdoid suture defects, sphenoid dysplasia)
• Unilateral overgrowth of a limb

[edit] Cognitive problems and learning disabilities in NF-1

The most common complication in patients with NF-1 is cognitive and learning disability. These cognitive problems have been shown to be present in approximately 80% of children with NF-1 and have significant effects on their schooling and everyday life.^[9] The most common cognitive problems are with perception, executive functioning and attention. ADHD has been shown to be present in approximately 38% of children with NF-1. Language, maths and motor deficits are also common. These cognitive problems have been shown to be stable into adulthood and do not get worse unlike some of the other physical symptoms of NF-1^[10].

[edit] Diagnosis

The National Institute 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.^[11]

• 6 or more café-au-lait macules over 5 mm in greatest diameter in pre-pubertal individuals and over 15 mm in greatest diameter in post-pubertal individuals
• 2 or more neurofibromas of any type or 1 plexiform neurofibroma
• Freckling in the axillary or inguinal regions
• Optic glioma
• 2 or more Lisch nodules (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

[edit] Prognosis

NF-1 is such a progressive and diverse condition that it makes it difficult to predict. The NF-1 gene manifest the disorder differently even amongst members of the same family. 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, but some of them are quite rare and they are listed in the following section.

[edit] Complications

• Chronic pain, numbness, Pritchetts face, and/or paralysis due to the peripheral nerve sheath tumors
• Blindness due to optic nerve gliomas
• Chronic hypertension from renal artery anomalies or pheochromocytoma, which patients with NF-1 are at increased risk of developing.
• Brain tumors
• Neurologic impairment due to severe spinal scoliosis and/or kyphosis, including but not limited to hydrocephalus
• Amputation due to a tibial pseudarthrosis
• Malignant degeneration of a plexiform neurofibroma into malignant peripheral nerve sheath tumor (MPNST), occurring in 8-12%
• Depression due to the shame of the disfigurement NF can cause to the body and face
• Social anxiety is also common among NF sufferers because of the reaction of others to the condition

[edit] Therapy

There is no cure for the disorder itself. Instead, people with neurofibromatosis are followed by a team of specialists to manage symptoms or complications. Surgery may be needed when the tumors compress organs or other structures. Less than 8-12% people with neurofibromatosis develop cancerous growths; in these cases, chemotherapy can be tried. There are several medical studies on NF-1. For more information, visit [2]. This is the official website of the National Institute of Health. Currently testing 3 drugs to stop the growth of NF-1, more info on one called R115777 here [3].

These drugs are, simplistically, utilize novel farnesyl transferase inhibitors to inhibit the Ras kinase in a post translational modification step before the kinase pathway becomes hyperactive. The R115777 drug successfully passed phase one clinical trials but was suspended (NCT00029354) in phase two^[12]. Another drug, lovastatin is currently in phase one of clinical trials (NCT00352599)^[13].

Early research has shown potential for using the c-kit tyrosine kinase blocking properties of Imatinib in treatment of plexiform neurofibromas in neurofibromatosis type I.^[14]

[edit] References

[edit] See also

• Cotran R, Kumar V, Robbins S (eds). Robbins Pathologic Basis of Disease, 5th ed. WB Saunders, 1994.