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. Jump to: navigation, search The following codes are used with International Statistical Classification of Diseases and Related Health Problems. ... The following is a list of codes for International Statistical Classification of Diseases and Related Health Problems. ... Jump to: navigation, search Neurofibromatosis Type II is an inherited disease. ... Tuberous sclerosis, (meaning hard potatoes), also known as Bourneville disease, is a rare genetic disorder primarily characterized by a triad of seizures, mental retardation, and skin lesions (called adenoma sebaceum). ... 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. ...

Genetics

NF-1 is caused by a mutation of a gene on the long arm of chromosome 17 which encodes a protein known as neurofibromin which plays a role in intracellular signaling. 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 2,500 live births.

Clinical findings

Peripheral nervous system lesions

Fat saturated contrast-enhanced T1 weighted axial images of the neck from a MRI of a young child with Neurofibromatosis type I shows a weakly enhancing tumor mass infiltrating through the tissue planes of the neck and upper mediastinum. This appearance is characteristic of that of a plexiform neurofibroma, and pathognomonic for the diagnosis of Neurofibromatosis type I.

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. Fat saturated contrast-enhanced T1 weighted axial images of the neck from a MRI of a young child with Neurofibromatosis type I shows a weakly enhancing tumor mass infiltrating through the tissue planes of the neck and upper mediastinum. ... Fat saturated contrast-enhanced T1 weighted axial images of the neck from a MRI of a young child with Neurofibromatosis type I shows a weakly enhancing tumor mass infiltrating through the tissue planes of the neck and upper mediastinum. ... 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. ... Jump to: navigation, search CT apparatus in a hospital Computed tomography (CT), originally known as computed axial tomography (CAT) and body section roentgenography, is a medical imaging method employing tomography where digital processing is used to generate a three-dimensional image of the internals of an object from a large... Jump to: navigation, search Magnetic resonance imaging (MRI) - also called tomography (MRT) - is a method of creating images of the inside of opaque organs in living organisms as well as detecting the amount of bound water in geological structures. ...

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.

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 cafe-au-lait spots[1]. Cafe-au-lait spots are pigmented birthmarks. ...

NF-1 patients also get freckles of their axillae (armpits). Predisposition to freckles is genetic and is related to the presence of red hair. ...

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. Jump to: navigation, search Magnetic resonance imaging (MRI) - also called tomography (MRT) - is a method of creating images of the inside of opaque organs in living organisms as well as detecting the amount of bound water in geological structures. ... In neuroscience, myelin is an electrically insulating fatty layer that surrounds the axons of many neurons, especially those in the peripheral nervous system. ...

There is a generalized soft tissue abnormality in NF-1. 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). The meninges (singular meninx) are the system of membranes that contain the brain. ... CSF is an abbreviation of: Classical swine fever (also called hog cholera) Cerebrospinal fluid Complement set filtering Critical Success Factor This is a disambiguation page — a navigational aid which lists other pages that might otherwise share the same title. ... Diverticula are outpouchings of the intestinal wall. ...

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. Spine is a word with several meanings. ...

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

• Focal scoliosis and/or khyphosis, which is the most common skeletal manifestation of NF-1, occurring in 10% of affected patients
• Malformation of the facial bones or of the eye sockets (lambdoid suture defects, sphenoid dysplasia)
• Unilateral overgrowth of a limb
• Bowing of a long bone with a tendency to fracture and not heal, yielding a pseudoarthrosis

This film of the forearm of a patient with NF-1 shows a bowing of the ulna and a lytic lesion in the radius with a pathologic fracture. Hypertrophic changes on either side of the fracture denote the formation of a pseudoarthrosis.

This film of the forearm shows a bowing of the ulna and a lytic lesion in the radius with a pathologic fracture. ...

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 prepubertal individuals and over 15 mm in greatest diameter in postpubertal 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

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 optic nerve gliomas
• Brain tumors
• Neurologic impairment due to severe spinal scoliosis and/or khyphosis
• 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.