eMedicine Specialties > Dermatology > Pediatric Diseases

Neurofibromatosis

Author: Jennifer R Kam, MD, Staff Physician, Southtowns Radiology Associates
Coauthor(s): Thomas N Helm, MD, Clinical Associate Professor, Departments of Dermatology and Pathology, State University of New York at Buffalo; Director, Buffalo Medical Group Dermatopathology Laboratory
Contributor Information and Disclosures

Updated: Oct 23, 2009

Introduction

Background

Neurofibromatosis is an autosomal dominant disorder that affects the bone, the nervous system, soft tissue, and the skin. At least 8 different clinical phenotypes of neurofibromatosis have been identified and are linked to at least 2 genetic disorders. Clinical manifestations increase over time. Neurologic problems and malignancy development may supervene.

Also see Neurofibromatosis, Type 1 and Neurofibromatosis, Type 2.

Pathophysiology

Neurofibromatosis is a neurocutaneous condition that can involve almost any organ system. Thus, the presenting signs and symptoms may vary widely. Two major subtypes exist: type 1 neurofibromatosis, which is the most common subtype and is referred to as peripheral neurofibromatosis, and type 2 neurofibromatosis, which is referred to as central neurofibromatosis. These descriptions are not especially accurate because type 1 neurofibromatosis often has central features. A third variant is known as segmental neurofibromatosis; this term is used to describe disease limited to a single body region. Segmental neurofibromatosis may be related to mosaicism or segmental hyperexpression of the condition. Loss of heterozygosity may create the clinical impression of segmental lesions.

Frequency

International

Worldwide, type 1 neurofibromatosis occurs in approximately 1 of 2,500-3,300 live births, regardless of race, sex, or ethnic background. The carrier incidence at birth is 0.0004, and the gene frequency is 0.0002. The incidence of type 2 neurofibromatosis is 1 case per 50,000-120,000 population.

Mortality/Morbidity

Neurofibromatosis can involve various body systems over time. Signs can range from benign cutaneous manifestations to profound disfigurement. The mortality rate is higher than that of the healthy population because of the increased potential for malignant transformation of diseased tissues and the development of neurofibrosarcoma. Patients with type 1 neurofibromatosis have an estimated 3-15% additional risk of malignant disease in their lifetime.

Race

All racial groups are affected equally by neurofibromatosis.

Sex

Women and men are affected equally by neurofibromatosis.

Clinical

History

• Although most individuals who develop neurofibromatosis are not born with café au lait macules, these skin lesions develop during the first 3 years of life, prompting parents to seek medical attention for their child.
• Neurofibromas form in late adolescence.
• Patients may report cutaneous discoloration or disfigurement or more serious physical symptoms (eg, pain caused by neurofibromas, pathologic fractures, hypertensive headaches due to pheochromocytoma).

Physical

• Neurofibromatosis is often diagnosed because of unusual pigmentary patterns. Café au lait spots are irregularly shaped, evenly pigmented, brown macules. Most individuals with neurofibromatosis have 6 or more spots that are 1.5 cm or greater in diameter. In young children, 5 or more café au lait macules greater than 0.5 cm in diameter are suggestive of neurofibromatosis and should be pursued. Less than 1% of healthy children have 3 or more such spots, although 1 or 2 café au lait macules are commonly encountered in healthy individuals without disease.
• Lisch nodules are hamartomas of the iris that appear dome shaped and are found superficially around the eyes on slit lamp examination. They are asymptomatic, but they help in confirming the diagnosis of neurofibromatosis.
• Axillary freckling (as well as freckling on the perineum), known as the Crowe sign, is a helpful diagnostic feature in neurofibromatosis. Both axillary freckling and inguinal freckling often develop during puberty. Areas of freckling and regions of hypertrichosis occasionally overlay plexiform neurofibromas.

• Bone involvement can include pseudoarthrosis of the tibia, bowing of the long bones, and orbital defects. Occasionally, pulsating exophthalmos can be encountered due to dysplasia of the sphenoid wings. Mild scoliosis may be encountered, and localized bony hypertrophy, especially on the face, may be identified. Whether these bony changes are caused by diffuse neurofibromas or other kinds of mesodermal defects is not entirely clear.
• Neurofibromas are the most common benign tumor of type 1 neurofibromatosis. These tumors are composed of Schwann cells, fibroblasts, mast cells, and vascular components. They can develop at any point along a nerve. Three subtypes of neurofibroma exist: cutaneous, subcutaneous, and plexiform. Both cutaneous lesions and subcutaneous lesions are circumscribed; neither is specific for type 1 neurofibromatosis. These nodules may be brown, pink, or skin colored. They may be soft or firm to the touch, and they may have the pathognomonic buttonhole invagination when pressed with a finger. Plexiform neurofibromas are noncircumscribed, thick, and irregular, and they can cause disfigurement by entwining important supportive structures. The plexiform subtype is specific for type 1 neurofibromatosis.
• Various neurologic abnormalities may occur. Acoustic nerve involvement and deafness may be seen, and gliomas of the optic nerve also occur. Various tumors, such as astrocytoma, meningioma, intramedullary glioma, and ependymoma, occur with greater frequency in these patients. Tumors may cause increased intracranial pressure, seizure, ataxia, or cranial nerve abnormalities. Schwannomas are uncommon in patients with type 1 neurofibromatosis, but they can present on spinal nerve sheaths. However, in type 2 neurofibromatosis, they are the most common tumor, involving cranial and peripheral nerves. The presence of a unilateral vestibular schwannoma (formerly known as an acoustic neuroma) should mandate inclusion of type 2 neurofibromatosis in the differential diagnosis.
• Many individuals with neurofibromatosis have below average intelligence. Of patients with type 1 neurofibromatosis, 25-40% may have learning disabilities, while 5-10% may have mental retardation. Types of learning disabilities may include neuromotor dysfunction and attention deficit hyperactivity disorder, as well as deficits in visuospatial processing.
• Endocrinologic problems associated with neurofibromatosis are common. Short stature and growth hormone deficiency are more common in these patients than in the general population, although the exact incidence is not known. Also, sexual precocity occurs in 3-5% of children who are affected, usually associated with an intracranial tumor. As mentioned, pheochromocytoma can occur.
• Diagnostic criteria for type 1 neurofibromatosis (The diagnostic criteria are met if 2 or more of the features listed are present.)^1,2,3
  • Six or more café au lait macules larger than 5 mm in greatest diameter in prepubertal individuals and those larger than 15 mm in greatest diameter in postpubertal individuals
  • Two or more neurofibromas of any type or 1 plexiform neurofibroma
  • Freckling in the axillary or inguinal regions
  • Optic glioma
  • Two or more Lisch nodules (iris hamartomas)
  • A distinctive osseous lesion, such as sphenoid dysplasia or thinning of the long bone cortex, with or without pseudoarthrosis
  • A first-degree relative with type 1 neurofibromatosis according to the above criteria
• Diagnosis criteria for type 2 neurofibromatosis (The criteria are met if condition 1 or 2 is present.)
  • Bilateral masses of the eighth cranial nerve seen with appropriate imaging techniques (eg, CT, MRI)
  • A first-degree relative with type 2 neurofibromatosis and either (a) a unilateral mass of the eighth cranial nerve or (b) 2 of the following: neurofibroma, meningioma, glioma, schwannoma, or juvenile posterior subcapsular opacity

Causes

• Neurofibromatosis is an autosomal dominant neurogenetic disorder. Increased concentrations of nerve growth stimulating activity have been linked with the development of neurofibromatosis. Type 1 neurofibromatosis is a disorder with variable phenotypic expression. Some patients may primarily have cutaneous expression, while others may have life-threatening or severely disfiguring complications. The variation of this disease is even demonstrated within families. The disease also tends to change and develop with time. Many different mutations in the neurofibromatosis gene have been described. The spontaneous mutation rate is 100 times greater than for many genes, and it is thought to contribute to approximately 30-50% of neurofibromatosis cases.
• NF-I is linked to a large gene on band 17q11.2.⁴ It encodes a protein termed neurofibromin, which has a guanosine triphosphatase (GTPase) region that binds to Ras and positively modulates conversion of guanosine triphosphate (GTP) to guanosine diphosphate (GDP). The protein has been shown to be essential for the negative regulation of Ras; this finding suggests that neurofibromin acts as a tumor suppressor. Several studies have confirmed this suggestion. The NF1 gene has at least 59 exons and encodes the 327-d protein known as neurofibromin. Truncations in neurofibromin led to the mutations responsible for type 1 neurofibromatosis in most cases.
• The gene for type 2 neurofibromatosis is on band 22q11.⁵ Less is known about the action of the protein encoded at this location; however, loss of heterozygosity at this region has been reported in cases of acoustic neuromas, neurofibromas, and meningiomas. Thus, the NF2 gene is speculated to also encode a tumor suppressor.

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