Introduction
Background
Neurofibromatosis (NF) describes at least 2 distinct clinical entities with some overlapping features Neurofibromatosis-1 (NF-1) is by far more common. Neurofibromatosis is a multisystem genetic disorder commonly associated with skin, nervous system, and bone and joint manifestations. Neurofibromatosis-1 is the most common of the various conditions referred to as hamartomas.
Neurofibromatosis-1 differs from central neurofibromatosis, also known as neurofibromatosis-2 (NF-2). Patients with neurofibromatosis-2 have few dermatological findings, but they have a high incidence of meningiomas and acoustic neuromas. Patients with neurofibromatosis-1 have a better overall long-term prognosis than patients with neurofibromatosis-2. Visual loss secondary to optic nerve glioma is the most important ophthalmologic manifestation of neurofibromatosis-1.
The first description of this disease probably dates back to a 13th century illustration attributed to an Austrian scribe, Heinricus. The first medical descriptions of neurofibromatosis-1 are from the 1700s, when several medical authors described patients with clinical features of neurofibromatosis-1. It was not until 1882 that Frederich Daniel von Recklinghausen, a German professor of pathology, released a monograph, which reviewed previous literature and characterized the tumors of neurofibromatosis-1 as neurofibromas, consisting of an intense comingling of nerve cells and fibrous tissue.1
The popular early 20th century drama The Elephant Man was written by Sir Frederick Treves, a physician, about Joseph Merrick (often referred to erroneously as John Merrick) who lived in the late 1800s and had many skeletal deformities believed to be manifestations of neurofibromatosis. (Since that time, prevailing opinion has shifted, and it is now believed that Mr. Merrick was in fact afflicted with proteus syndrome.)
Pathophysiology
Neurofibromatosis-1 is a progressive genetic disease best known for its heterogeneity and variability. Neurofibromatosis-1 can manifest in many different ways in many different tissues within the same person and among family members. Neurofibromatosis is a disorder of the neuroectodermal system that results in benign hamartomatous tumors of any organ or system (most notably the skin, the eyes, and the nervous system) that increase in number and size throughout life. These tumors are of tissues derived from neural crest, particularly sensory nerves, Schwann cells, and melanocytes.
Frequency
United States
An estimated 0.05% of the population worldwide is affected by neurofibromatosis-1. Prevalence is estimated to be about 1 in 3000.
International
International incidence is similar to that in the United States.
Mortality/Morbidity
- Many people with mild neurofibromatosis lead healthy, productive lives with little disability.
- People affected by more severe variants of neurofibromatosis-1 may have a shorter life expectancy if the disease is associated with CNS tumors or other malignancies, mental retardation, or severe seizures.
- In 1944, Sorenson and coworkers conducted a study of 212 affected patients in Denmark and found that patients with neurofibromatosis, particularly the more severe forms requiring hospitalization, have a poorer survival rate. The group with severe neurofibromatosis also had 4 times the increased risk of development of CNS neoplasms during a 40-year follow-up period.2
Race
No predilection for race exists.
Sex
No predilection for sex exists.
Age
- Initial manifestations most often occur in childhood.
- Clinical signs may be apparent at birth; however, in some affected individuals, signs may not develop until adulthood.
- NF tends to be progressive throughout life, with the number and the size of associated tumors increasing.
Clinical
History
In 1987, the National Institute of Health (NIH) Consensus Development Conference on Neurofibromatosis reclassified neurofibromatosis into 2 distinct variants (neurofibromatosis-1 and neurofibromatosis-2) and established diagnostic criteria for the disease. According to the NIH Consensus Statement, diagnosis of neurofibromatosis-1 is established if 2 or more of the following characteristics are present:
- Six or more café au lait spots, 15 mm or larger, in an adult; 6 or more café au lait spots, 5 mm or larger, in a child (before puberty)
- Two or more neurofibromas of any type or 1 plexiform neurofibroma
- Freckling of the axillary or inguinal region, an optic pathway glioma, 2 or more Lisch nodules
Typical appearance of multiple Lisch nodules in a patient with neurofibromatosis-1.
- Characteristic osseous lesions, such as sphenoid dysplasia
- A first-degree relative with neurofibromatosis-1 (as defined by the above criteria)
The contemporaneous definition of neurofibromatosis-2 (NF-2) was divided into definite (confirmed), presumptive, and suggestive criteria:
- Definite neurofibromatosis-2: Bilateral vestibular schwannomas (VS), also known as acoustic neuroma
- Presumptive (probable) neurofibromatosis-2:
- Family history of neurofibromatosis-2 (first-degree family relative) PLUS
- Unilateral vestibular schwannomas (VS) or any 2 of the following:
- Meningioma
- Glioma
- Schwannoma
- Juvenile posterior subcapsular lens opacity
- Juvenile cortical cataract
- Suggestive (requiring evaluation) neurofibromatosis-2: Individuals with the following clinical features should be evaluated for neurofibromatosis-2:
- Unilateral vestibular schwannomas plus at least 2 of any of the following:
- Meningioma
- Glioma
- Schwannoma
- Juvenile posterior subcapsular lenticular opacities/juvenile cortical cataract
- Multiple meningiomas (2 or more) plus unilateral vestibular schwannoma or any 2 of the following:
- Glioma
- Schwannoma
- Juvenile posterior subcapsular lenticular opacities/juvenile cortical cataract
- Unilateral vestibular schwannomas plus at least 2 of any of the following:
Physical
Physical findings are discussed by organ system.
- Cutaneous involvement: The cutaneous manifestations of neurofibromatosis-1 are a prominent aspect of this disorder. They include hyperpigmentation, hypopigmentation, and cutaneous neurofibromas.
- Hyperpigmentation can occur in focal or diffuse forms.
- Focal hyperpigmentation: Café au lait spots are a distinct area of hyperpigmentation due to an increased number of melanocytes, as well as giant pigment granule (macromelanosome) production by melanocytes. Focal hyperpigmentation also includes axillary and inguinal freckling.
- Diffuse hyperpigmentation: Diffuse or generalized hyperpigmentation is not well characterized, but often it is noticed by an astute physician or family member.
- Hypopigmentation can occur in patients with neurofibromatosis-1.
- Hypomelanotic macules
- Punctate hypopigmented lesions
- Local areas of skin hypopigmentation
- Cutaneous neurofibromas
- Small, pink to skin-colored, dome-shaped papules
- May enlarge, becoming immense soft-tissue masses
- Can occur anywhere on the body
- Predilection for areolas in females
- Histologically indistinguishable from the solitary neurofibroma, they appear as well-circumscribed, nonencapsulated spindle-cell tumors of the dermis
- Hyperpigmentation can occur in focal or diffuse forms.
- CNS involvement: CNS involvement in neurofibromatosis-1 is multifaceted. Abnormalities of CNS development are common. Similarly, functional problems are often noted, and benign and malignant tumors of the CNS occur at a greatly increased incidence in neurofibromatosis-1.
- Abnormalities of CNS development
- Simple megalencephaly is common and generally harmless. Its main features are increased brain matter and skull circumference.
- Hydrocephalus may present at any age and is symptomatic (vomiting, irritability, lethargy, papilledema). If it is not due to a tumor, it is usually treated with a shunt.
- Vascular occlusions
- Dural ectasia
- Absence of the sphenoid wing
- Lambdoidal suture defect
- Functional problems include seizures (which affect as many as 5% of patients with neurofibromatosis-1), learning disabilities, and emotional/behavioral disturbances.
- Benign and malignant tumors of the CNS
- Nerve root and spinal cord neurofibromas can lead to deficits depending on location.
- Gliomas are more common in neurofibromatosis-2 but still are associated with neurofibromatosis-1. Incidence of optic nerve and optic chiasm gliomas has been estimated at 1% in neurofibromatosis-1 in a population-based series; however, incidence may be as high as 15% based on more recent data.3
- Meningiomas are more common in patients with neurofibromatosis-2 but can occur in patients with neurofibromatosis-1.
- Abnormalities of CNS development
- Skeletal involvement
- Progressive kyphoscoliosis may lead to paraparesis without intervention.
- Deformities of long bones include pseudoarthroses, hypertrophy/destruction associated with plexiform neurofibromas, and lytic metaphyseal and diaphyseal defects.
- Short stature is very common.
- Visceral involvement
- Neurofibromas of the GI tract
- Pheochromocytomas, which are 10 times more frequent in patients with neurofibromatosis (Approximately 5-10% of all pheochromocytomas are in patients with neurofibromatosis.)
- Reports of associations with other soft-tissue tumors
- Ophthalmic involvement
- Lisch nodules are the most common type of ocular involvement in neurofibromatosis-1. Lisch nodules are melanocytic hamartomas, usually clear yellow to brown in color, that appear as well-defined, dome-shaped elevations projecting from the surface of the iris. They may be seen without magnification, but a slit lamp examination may be necessary to differentiate them from nevi on the iris, which present as flat or minimally elevated, densely pigmented lesions with blurred margins. The nodules are not thought to cause any ophthalmologic complication.
- Lisch nodules are the most common clinical finding in adults older than 20 years with neurofibromatosis-1. Unlike café-au-lait spots, multiple nodules are specific for peripheral neurofibromatosis/neurofibromatosis-1. They are generally absent in central neurofibromatosis/neurofibromatosis-2.
- Specific for neurofibromatosis-1
- Smooth, usually bilateral, elevated nodules
- Lisch nodules usually arise in the first decade; virtually all patients with neurofibromatosis-1 have Lisch nodules by age 20 years.
- Benign hamartomas, histologically identical to iris nevi
- Plexiform neurofibromas of the eyelid
- Thickening of upper lid
- S-shaped deformity
- "Bag of worms" sensation
- Congenital glaucoma ipsilateral to plexiform neurofibromas has been described as a variation of anterior segment developmental disorders.
- Prominent corneal nerves
- Hamartomas of the choroid
- Usually in posterior pole
- Flat, ill-defined lesions
- Contain neuronal and melanocytic components
- Retinal tumors
- Astrocytic hamartomas (white tumors involving the optic nerve)
- Combined hamartomas of the retina and retinal pigment epithelium
- Retinal capillary hemangiomas
- Absence of the greater wing of the sphenoid bone may lead to pulsatile proptosis.
- Possible increase in the incidence of choroidal melanomas
- Optic nerve gliomas
- Fifteen to forty percent of children with neurofibromatosis-1 have optic nerve glioma or visual pathway gliomas involving the optic nerve, chiasm, or optic tract.4 Some of these lesions are asymptomatic. Bilateral optic nerve gliomas are almost pathognomonic for neurofibromatosis-1. Unilateral decreased acuity with relative afferent pupillary defect (+/-) and strabismus (+/-) may occur. Optic nerve glioma appears on CT scan or MRI as fusiform dilation of optic nerve. Optic nerve gliomas are locally invasive and slow growing with low malignant potential. Chiasmatic gliomas may invade hypothalamus and third ventricle, causing obstructive hydrocephalus.3 Ten to thirty-eight percent of pediatric patients with optic nerve glioma have neurofibromatosis-1.
- In most children with optic glioma, the presenting symptoms may be painless proptosis and decrease in visual acuity. Physical findings include visual loss, loss of color vision, an afferent pupillary defect, and optic nerve pallor or atrophy. A large lesion may compress the optic chiasm, causing nystagmus or other symptoms. Hypothalamic symptoms, such as changes in appetite or sleep, also may occur. Massive lesions may compress the third ventricle, resulting in obstructive hydrocephalus accompanied by headache, nausea, and vomiting.
Massive facial deformity in a young girl severely affected by neurofibromatosis-1.
Causes
- Approximately 50% of cases are transmitted genetically (autosomal dominant). The principal neurofibromatosis-1 genetic defect is located within the long arm of chromosome 17. The neurofibromatosis-1 phenotype has high penetrance but widely variable expression.
- Spontaneous mutations occur in 50% of cases. No specific causes for sporadic mutations have been identified.
More on Neurofibromatosis-1 |
 Overview: Neurofibromatosis-1 |
| Differential Diagnoses & Workup: Neurofibromatosis-1 |
| Treatment & Medication: Neurofibromatosis-1 |
| Follow-up: Neurofibromatosis-1 |
| Multimedia: Neurofibromatosis-1 |
| References |
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References
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Further Reading
Keywords
neurofibromatosis type 1, NF-1, NF, hamartoma, café au lait spots, von Recklinghausen's disease, von Recklinghausen disease, plexiform neurofibroma, axillary freckling, inguinal freckling, optic pathway glioma, Lisch nodules, osseous lesions, sphenoid dysplasia, neurofibromatosis-2, NF-2, meningioma, acoustic neuroma, hyperpigmentation, hypopigmentation, cutaneous neurofibromas, megalencephaly, hydrocephalus, vascular occlusion, dural ectasia, sphenoid wing absence, lambdoidal suture defect, seizures, learning disability, emotional disturbance, behavioral disturbance, glioma, kyphoscoliosis, paraparesis, pseudoarthroses, hypertrophy, metaphyseal defect, diaphyseal defect, short stature, pheochromocytomas, melanocytic hamartoma, retinal tumors, astrocytic hamartoma, combined hamartoma, retinal capillary hemangioma, pulsatile proptosis, choroidal melanoma, optic nerve glioma
