Neurofibromatosis type I

Neurofibromatosis type I (NF-1), or von Recklinghausen syndrome, is a complex multi-system neurocutaneous disorder caused by a subset of genetic mutations at the neurofibromin 1 (NF1) locus. Other conditions associated with mutation of the NF1 gene include Watson syndrome. NF1 is a gene on chromosome 17 that is responsible for production of a protein (neurofibromin) which is needed for normal function in many human cell types. NF-1 causes tumors along the nervous system that can grow anywhere on the body. NF-1 is one of the most common genetic disorders and is not limited to any person's race or sex. NF-1 is an autosomal dominant disorder, which means that mutation or deletion of one copy (or allele) of the NF-1 gene is sufficient for the development of NF-1, although presentation varies widely and is often different even between relatives affected by NF-1. Globally, NF-1 affects approximately 1 in 3,200 individuals. Common symptoms of NF-1 include brownish-red spots in the colored part of the eye called Lisch nodules, benign skin tumors called neurofibromas, and larger benign tumors of nerves called plexiform neurofibromas, scoliosis (curvature of the spine), learning disabilities, vision disorders, mental disabilities, multiple café au lait spots and epilepsy. While some people have major complications, others with the condition can lead productive and full lives. NF-1 is a developmental syndrome caused by germline mutations in neurofibromin, a gene that is involved in the RAS pathway (RASopathy). Due to its rarity, and to the fact that genetic diagnosis has been used only in recent years, in the past NF-1 was in some cases confused with Legius syndrome, another syndrome with vaguely similar symptoms, including cafe au lait spots. NF-1 is an age-specific disease; most signs of NF-1 are visible after birth (during infancy), but many symptoms of NF-1 occur as the person ages and has hormonal changes. NF-1 was formerly known as von Recklinghausen disease, after the researcher who first documented the disorder, Friedrich Daniel von Recklinghausen. The severity of NF-1 varies widely, and little is known about what causes a person to have more severe or less severe symptoms. Even within the same family (as there is a 50% chance that a parent will pass their condition to their offspring), levels of severity can vary enormously. 60% of people with NF-1 have mild cases, with few symptoms that have very little effect in their day-to-day lives. About 20% of people with NF-1 have what are considered moderate cases, with several symptoms that usually have a few cosmetic effects. The other 20% have severe cases, with several symptoms that affect the person's quality of life. Even in this last group, symptoms are rarely life-threatening.

Signs and symptoms

The following is a list of conditions and complications associated with NF-1, and, where available, age range of onset and progressive development, occurrence percentage of NF-1 population, method of earliest diagnosis, and treatments and related medical specialties. The progression of the condition is roughly as follows:

Congenital musculoskeletal disorders may or may not be present. Cutaneous conditions may be observed in early infancy. Small tumors may arise in the retina which can eventually lead to blindness. Also, Lisch nodules may grow on the iris, but these are harmless. Learning disabilities may arise in preschool children. Neurofibromas may occur and can sometimes cause many dependent neurological conditions and cutaneous and skeletal disfigurement. Depression and social anxiety may occur as a result of disabilities caused by the condition. Neurofibromas may, in 8-13% of cases, transition into cancer, which can be fatal.

Musculoskeletal disorder Musculoskeletal abnormalities affecting the skull include sphenoid bone dysplasia, congenital hydrocephalus and associated neurologic impairment. Disorders affecting the spine include:

In NF-1, there can be a generalized abnormality of the soft tissues in the fetus, which is referred to as mesodermal dysplasia, resulting in maldevelopment of skeletal structures. Meningoceles and formation of cystic diverticula of the dura of the spine, unrelated to Spina bifida 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. This may result in temporary or permanent loss of lower extremity sensorimotor function. Focal scoliosis and/or kyphosis are the most common skeletal manifestation of NF-1, occurring in 20% of affected patients. Approximately 25% of patients will require corrective surgery. Skeletal muscle weakness and motor control deficits Deficits in motor function in NF-1 have been long recognised and have been historically attributed to nerve dysfunction. In recent years however, studies suggest NF-1 is associated with a primary problem in muscle function (myopathy). Clinical findings in people with NF-1 include:

Reduced skeletal muscle size Reduced exercise capacity Muscle weakness (the most recent study reports between 30–50% reduced upper and lower limb muscle strength in NF-1 children compare with matched controls). Studies in genetically modified mice have thus far confirmed that the NF1 gene is vital for normal muscle development and metabolism. Knockout of the NF1 gene in muscle results in deregulated lipid metabolism and muscle weakness. NF-1 is a disease in the RASopathy family of diseases, which include Costello syndrome, Noonan syndrome, and cardiofaciocutaneous syndrome. The RASopathies also present with skeletal muscle weakness. It is likely that impaired muscle function in these disorders is linked to altered Ras/MAPK signalling, however, the precise molecular mechanisms remain unknown.

Facial bones and limbs

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