Neurofibromatosis type I

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.

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

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.

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 orthopedical 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.

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.

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.^*.

NF-1 patients may also get freckles of their axillae (armpits).

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.

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).

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 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

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 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 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

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

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