Neurofibromatosis type I (NF-1), also known as von Recklinghausen syndrome, comprises, along with neurofibromatosis type II (a.k.a. MISME syndrome), tuberous sclerosis, Sturge-Weber, and Von Hippel-Lindau disease, the phakomatoses or neurocutaneous syndromes, all of which have both neurologic and dermatologic lesions. This grouping is an artifact of an earlier time in medicine, before the distinct genetic basis of each of these diseases was understood. The International Statistical Classification of Diseases and Related Health Problems (commonly known by the abbreviation ICD) is a detailed description of known diseases and injuries. ... The following codes are used with International Statistical Classification of Diseases and Related Health Problems. ... The International Statistical Classification of Diseases and Related Health Problems (commonly known by the abbreviation ICD) is a detailed description of known diseases and injuries. ... The following is a list of codes for International Statistical Classification of Diseases and Related Health Problems. ... In 1882 Frederich Daniel von Recklinghausen released a monograph which reviewed previous literature and characterized the tumors of Neurofibromatosis 1 or NF-1 as neurofibromas, consisting of an intense commingling of nerve cells and fibrous tissue ... Neurofibromatosis Type II (or MISME Syndrome, for Multiple Inherited Schwannomas, Meningiomas, and Ependymomas) is an inherited disease. ... Tuberous sclerosis, (meaning hard potatoes), is a rare genetic disorder primarily characterized by a triad of seizures, mental retardation, and skin lesions (called adenoma sebaceum). ... This article needs to be cleaned up to conform to a higher standard of quality. ... Von Hippel-Lindau disease (VHL) is a rare inherited genetic condition involving the abnormal growth of tumors in parts of the body which are particularly rich in blood supply. ... Phakomatoses (or neurocutaneous syndromes) are diseases that are caused by neurological disorders, and primarily result in lesions on the skin and the retina. ... Phakomatoses (or neurocutaneous syndromes) are diseases that are caused by neurological disorders, and primarily result in lesions on the skin and the retina. ...

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 (aka NF1, not to be confused with the disease itself) which plays a role in intracellular signaling. The neurofibromin is a negative regulator of the Ras oncogene. Image File history File links Autosomal_Dominant_Pedigree_Chart. ... Image File history File links Autosomal_Dominant_Pedigree_Chart. ... An autosomal dominant gene is one that occurs on an autosomal (non-sex determining) chromosome. ... Chromosome 17 is one of the 23 pairs of chromosomes in humans. ... Neurofibromin can refer to one of two different proteins: Neurofibromin 1 Neurofibromin 2 Category: ... In molecular biology, Ras is the name of a protein, the gene that encodes it, and the family and superfamily of proteins to which it belongs. ...

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 3000 live births.

Clinical findings

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 a solitary or as multiple firm, rubbery bumps of varying sized 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. Neurofibromas are moderately firm, benign, encapsulated, slow-growing tumors of the nervous system arising from the supporting cells (Schwann cells) of peripheral nerves. ... Schwann cells are a variety of neuroglia that wrap around axons in the peripheral nervous system, forming the myelin sheath. ... A fibroblast is a cell that makes the structural fibers and ground substance of connective tissue. ... CT apparatus in a hospital Computed tomography (CT), originally known as computed axial tomography (CAT or CT scan) and body section roentgenography, is a medical imaging method employing tomography where digital geometry processing is used to generate a three-dimensional image of the internals of an object from a large... This article or section does not cite its references or sources. ...

The hallmark lesion of NF-1 is the plexiform neurofibroma. These lesions are composed of sheets of neurofibromatous tissue which may infiltrate and encase major nerves, blood vessels, and other vital structures. Because of this, these lesions are impossible to routinely resect.

If a plexiform fibroma 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 equalise the difference during childhood, there is an orthopedic surgery called "epiphysiodesis", in which the epiphyseal (growth) plate is removed. It can be removed in one of the bone's end to slow down the growth, or in both ends to stop growth of that bone completely. The surgery must also be carefully planned with regard to timing, as it is non-reversible, so 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, while resection of a neurofibroma requires the sacrifice of the underlying nerve. This coronal contrast-enhanced fat-saturated T1 weighted image from an MRI of the pelvis shows the characteristic fascuculated appearance and infiltrative growth pattern of a plexiform neurofibroma. ... This coronal contrast-enhanced fat-saturated T1 weighted image from an MRI of the pelvis shows the characteristic fascuculated appearance and infiltrative growth pattern of a plexiform neurofibroma. ... Schwannomas, also referred to as Neurilomas, are slow-growing central nervous system tumours arising from the supporting cells of peripheral nerves, which include cranial and spinal nerve roots). ...

Malignant peripheral nerve-sheath tumors, or neurofibrosarcomas, can arise from degeneration of a plexiform neurofibroma; this is, fortunately, a rare complication.

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]. Café au lait spots or cafe-au-lait spots (CAL) are pigmented birthmarks. ...

NF-1 patients may also get freckles of the axillae (armpits). [Predisposition]] to freckles is genetic and is related to the presence of the MC1R gene variant. ...

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 NF1 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. This article or section does not cite its references or sources. ... In neuroscience, myelin is an electrically insulating phospholipid layer that surrounds the axons of many neurons. ...

 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 ectasa) 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). 

Dura may refer to: Dura (linguistics), a critically endangered language of Nepal Dura mater, the outer membrane of the meninges which envelop the brain and spinal cord This is a disambiguation page, a list of pages that otherwise might share the same title. ... CSF may refer to: California Scholarship Federation California State University, Fullerton, a university in Southern California Cerebrospinal fluid CONMEBOL or CSF (Confederación Sudamericana de Fútbol) City Service Firm, a football hooligan gang attaching themselves to Bristol City football club Classical swine fever Collège de la Sainte Famille... Diverticula are outpouchings of the intestinal wall. ... Spina bifida is a Latin term which means split spine and describes birth defects caused by an incomplete closure of one or more vertebral arches of the spine, resulting in malformations of the spinal cord. ...

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. The vertebral column seen from the side Different regions (curvatures) of the vertebral column The vertebral column (backbone or spine) is a column of vertebrae situated in the dorsal aspect of the abdomen. ...

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 The mesoderm is one of the three germ layers in the early developing embryo, the other two layers being the ectoderm and the endoderm. ... Dysplasia (latin for bad form) is an abnormality in the appearance of cells indicative of an early step towards transformation into a neoplasia. ...

• 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 pseudoarthrosis. 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

Kyphosis in the sense of a deformity is the pathologic curving of the spine, where parts of the spinal column lose some or all of their lordotic profile. ... Pseudarthrosis is the movement of a bone at the location of a fracture resulting from inadequate healing of the fracture. ...

Cognitive problems and learning disabilities in NF1

The most common complication in patients with NF1 is cognitive and learning disability. These cognitive problems have been shown to be present in approximately 80% of children with NF1 and have significant effects on their schooling and everyday life (Hyman et al., 2005). 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 NF1. 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 NF1 (Hyman et al., 2003).

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 (from: Huson SM, Hughes RAC. The Neurofibromatoses. London, UK: Chapman and Hall; 1994;1.3.2:9):

• 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 harmartomas)
• 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 NF1 by the above criteria

Lisch nodules are iris hamartomas seen in neurofibromatosis. ...

Prognosis

There is wide variability in how different individuals with the NF-1 gene manifest the disease. Some individuals may have no symptoms, while others may have rapidly progressive disease.

The primary problem of NF-1 is the disfigurement due to the cutaneous neurofibromas, pigmented lesions, and occasional limb abnormalities.

Several more severe complications of NF-1 are enumerated in the following section.

Complications

• Chronic pain, numbness, and/or paralysis due to the peripheral nerve sheath tumors
• Blindness due to malignant optic nerve gliomas
• Brain tumors
• Neurologic impairment due to severe spinal scoliosis and/or kyphosis
• Amputation due to a tibial pseudarthrosis
• Malignant degeneration of a plexiform neurofibroma into a neurofibrosarcoma, occurring in 10-12%

Therapy

Therapy for a patient with neurofibromatosis type I is aimed at palliating symptoms and improving quality of life. Treatment modalities offered may include:

• Radiation therapy
• Chemotherapy
• Surgical resection or decompression of an enlarging lesion

References

1. Cotran R, Kumar V, Robbins S (eds). Robbins Pathologic Basis of Disease, 5th ed. WB Saunders, 1994.
2. Smirniotopoulos J, The Phakomatoses. In Radiologic Pathology, 2nd ed (the syllabus of the Armed Forces Institute of Pathology Radiographic-Pathlogic correlation course) 2003-2004.
3. Hyman, SL. et al.(2005). The Nature and Frequency of Cognitive Deficits in Children with Neurofibromatosis Type 1. Neurology, 65, 1037-1044.
4. Hyman, S.L. et al. (2003). Natural History of Neuropsychological Ability and T2-Hyperintensities in Patients with Neurofibromatosis Type 1. Neurology, 60(7), 1139-1145.