eMedicine Specialties > Neurology > Pediatric Neurology

Neurofibromatosis, Type 1

Author: Beth A Pletcher, MD, Associate Professor, Co-Director of The Neurofibromatosis Center of New Jersey, Department of Pediatrics, University of Medicine and Dentistry of New Jersey
Contributor Information and Disclosures

Updated: Dec 10, 2008

Introduction

Background

Neurofibromatosis (NF) is a multisystem genetic disorder that commonly is associated with cutaneous, neurologic, and orthopedic manifestations. It is the most frequent of the so-called hamartoses.

NF type 1 (NF1) is differentiated from central NF or NF type 2 in which patients demonstrate a relative paucity of cutaneous findings but have a high incidence of meningiomas and acoustic neuromas (which are frequently bilateral). NF1 has a better prognosis with a lower incidence of CNS tumors than NF2. However, morbidity and mortality rates in NF1 are not negligible. Some of the more severe complications are visual loss secondary to optic nerve gliomas, spinal cord tumors, scoliosis, vascular lesions, and long-bone abnormalities, which sometimes necessitate amputation.

Pathophysiology

The manifestations of NF1 result from a mutation in or deletion of the NF1 gene. The gene product neurofibromin serves as a tumor suppressor; decreased production of this protein results in the myriad of clinical features.

Frequency

International

The estimated incidence of NF1 is 1 in 3000, but the actual frequency may be higher because of less than complete ascertainment of mildly affected individuals. Approximately half of affected individuals represent first cases in the family as a result of a new genetic event or mutation.

Mortality/Morbidity

• Lifetime risks for both benign and malignant tumors are increased in NF1-affected individuals.
• Cutaneous or subcutaneous neurofibromas, optic nerve gliomas, dumbbell-shaped spinal cord tumors, and brain tumors represent some of the well-recognized nerve-related neoplasms.
  • Adolescence for both genders may precipitate the development of subcutaneous and cutaneous neurofibromas. Increase in the size of existing neurofibromas and the appearance of new neurofibromas during pregnancy is a frequent observation in women with NF1.¹
  • Plexiform neurofibromas, generally larger, more diffuse, and locally invasive are seen in more than one fourth of patients with NF1² and can present a surgical or medical management conundrum. The wisdom of watchful waiting versus intervention is often debated, with the recognition that complete resection of a plexiform neurofibroma without residual functional deficits is rarely possible. On the other hand, debulking or partial resection of plexiform neurofibromas may be undertaken for cosmetic purposes or if progressive functional consequences are anticipated.
  • Gliomas in patients with NF1 tend to be lower grade and have a more favorable prognosis than in patients without NF1, with pilocytic astrocytomas and low-grade astrocytomas (subtype intermediate) being quite common.³   However, diffusely infiltrating astrocytomas are also seen in a subset of patients and need to be managed accordingly.
• Malignant peripheral nerve sheath tumors (MPNSTs) and neurosarcomas are not uncommon in adolescents and adults with NF1, with an approximate lifetime risk of 10%. These malignancies frequently arise from large plexiform neurofibromas or extensive peripheral nerve lesions.
• More than 1% of patients with NF1 develop an indolent symmetric sensory axonal neuropathy. However, some cases of polyneuropathy occur in association with diffuse nerve root lesions or MPNSTs.
• Gastrointestinal stromal tumors, often multiple with a predilection for the proximal small bowel, may be seen in patients with NF1.
• Learning disabilities with or without attention deficit hyperactivity disorder (ADHD) are seen in approximately 40% of NF1-affected individuals. A much smaller percentage experience more significant cognitive difficulties such as mild or moderate mental retardation.
• Scoliosis in NF1 is often mild, but a subset of children younger than 10 years develop a more rapidly progressive form of scoliosis that requires aggressive intervention.
• Bony abnormalities may be clinically silent, with radiographic evidence of long bone intramedullary fibrosis, cortical thinning, or vertebral dural ectasias often found incidentally.
  • Sphenoid bone dysplasia and long-bone bowing or pseudarthrosis are common features of NF1.
  • In the past, congenital tibial pseudarthrosis led to below-the-knee amputation; however, recent advances in orthopedic management with limb-sparing procedures have decreased the need for such drastic procedures.
• Osteoporosis with statistically significant decreases in bone mineral density can be identified in individuals with NF1, perhaps even as early as childhood.⁴ Whereas a number of metabolic pathways impacting bone metabolism have been implicated in the pathogenesis of bone abnormalities in people with NF, studies in children and teens with NF have provided evidence for increased rates of bone resorption as a likely cause for osteopenia.⁵
• Hypertension in NF1 can be seen at any age, with many adults with NF1 manifesting the usual essential form of hypertension. However, any person with NF1 and high blood pressure must be evaluated carefully for 2 alternative causes of hypertension (see Prognosis).
  • Pheochromocytomas are not rare in NF1 and can cause severe, fluctuating hypertension.
  • Vascular stenosis (ie, renal artery stenosis secondary to fibromuscular dysplasia) also may result in hypertension that may not respond well to standard pharmacologic management.
• Other vascular lesions, especially in the central nervous system, such as vascular ectasias, stenoses, moyamoya disease, and aneurysms, occur more frequently in patients with NF1.
• Short stature is common in NF1; affected individuals are often shorter than their unaffected siblings.
• Macrocephaly is common in NF1 and should not cause undo alarm if present in affected infants or young children, unless serial head circumference measurements confirm the rapid crossing of percentiles.
• Chiari type 1 malformations are seen with increased frequency in the NF1 population.
• Puberty usually occurs at a normal age, but precocious puberty with growth acceleration may occur in a small number of individuals. When precocious puberty is present, the patient must be evaluated for a chiasmal lesion causing disruption of the hypothalamic-pituitary axis.

Race

All races and ethnic backgrounds are affected equally. However, recent evidence indicates that the risk for optic nerve glioma is lower in African Americans than in Caucasians and Hispanics.

Sex

• Males and females are affected equally with this autosomal dominant condition.
• Scoliosis may be especially severe in young girls compared to their male counterparts.

Age

Although the genetic change causing NF1 is present at conception, clinical manifestations may appear slowly over many years.

• Diagnosis often is made earlier in children born to an NF1-affected parent; the clinical criteria for diagnosis are fulfilled more easily, and the clinician may be more attuned to this possible diagnostic concern.
• If an at-risk individual reaches the age of 10 years without meeting the diagnostic criteria for NF1, he or she is unlikely to be affected.

Clinical

History

• Clinical diagnosis requires the presence of at least 2 of 7 criteria to confirm the presence of neurofibromatosis, type 1. Many of these signs do not appear until later childhood or adolescence, and thus confirming the diagnosis often is delayed despite a suspicion of NF1. The 7 clinical criteria used to diagnose NF1 are as follows:
  • Six or more café-au-lait spots or hyperpigmented macules greater than or equal to 5 mm in diameter in children younger than 10 years and to 15 mm in adults
  • Axillary or inguinal freckles
  • Two or more typical neurofibromas or one plexiform neurofibroma
  • Optic nerve glioma
  • Two or more iris hamartomas (Lisch nodules), often identified only through slit-lamp examination by an ophthalmologist
  • Sphenoid dysplasia or typical long-bone abnormalities such as pseudarthrosis
  • First-degree relative (eg, mother, father, sister, brother) with NF1

Physical

• The earliest clinical finding usually seen in children with NF1 is multiple café-au-lait spots.
  • These may be present at birth or may appear over time, frequently increasing in size and number throughout childhood (see Image 1).
  • In adults, café-au-lait spots tend to fade and may be less obvious on clinical examination.
• Axillary or inguinal freckles are rarely present at birth, but appear during childhood through adolescence (see Images 2-3).
• Subcutaneous or cutaneous neurofibromas are seen rarely in young children but appear over time in older children, adolescents, and adults (see Image 4).
  • Deep lesions may be detected only through palpation, whereas cutaneous lesions may appear initially as small papules on the trunk, extremities, scalp, or face.
  • Puberty or pregnancy may be associated with an increased number of neurofibromas as well as more rapid growth of preexisting lesions.
• Plexiform neurofibromas are more diffuse growths that can be locally invasive and quite deep; they may be associated with bony erosion and pain (see Image 5).
  • Plexiform neurofibromas also may be accompanied by overlying hyperpigmentation or hypertrichosis.
  • Rarely, rapid growth of a neurofibroma may occur and can be suggestive of malignant transformation.
• Optic nerve tumors, which may be clinically silent, occur primarily in children younger than 5 years.
  • Asymmetric, noncorrectable visual loss is the most common presenting symptom, but subtle peripheral field defects, color discrimination difficulties, optic nerve pallor, or proptosis may occur without visual acuity problems.
  • Some older children and adolescents may present with worsening vision secondary to a slow-growing optic nerve glioma (ONG) and, therefore, monitoring for visual difficulties should continue throughout childhood and adulthood. Adults may have a visually insignificant optic nerve glioma detected incidentally on a head imaging study.
• Although Lisch nodules occasionally can be seen with a direct or indirect ophthalmoscope, especially in individuals with light-colored irides, they are usually not readily visible without using a slit lamp (see Image 6).
• Choroidal abnormalities with a patchy appearance may also be noted on funduscopic examination using infrared monochromatic light. Retinal corkscrew vascular changes have also been described in some patients with NF1.
• Sphenoid bone dysplasia is usually asymptomatic, but occasionally can be associated with herniation through the bony defect. In the occasional patient with a plexiform neurofibroma of the eyelid, ipsilateral sphenoid dysplasia is frequently present.
• Congenital pseudarthrosis may be evident at birth, with bowing of the tibia being the most typical presentation (see Image 7).
  • Thinning and angulation of long bones can occur throughout early childhood and adolescence, with prominence of the anterior tibia and progressive deformity.
  • Less commonly, bowing of the forearm can occur.
• Scoliosis with or without kyphosis may become evident in childhood or adolescence.
  • When found in a child younger than 10 years, it is associated with a much poorer prognosis and is likely to progress rapidly.
  • Scoliosis detected during adolescence still should be monitored clinically, but is much less likely to require orthopedic intervention.
• Blood pressure should be checked during every clinical visit because of the distinct possibility of alternative causes of hypertension in NF1.
• Head circumference should be monitored throughout the first 3 years of life, as with any child. Relative macrocephaly should not cause alarm, unless serial measurements suggest rapid growth with crossing of 2 or more percentile lines.

Causes

• NF1 is an autosomal dominant condition caused by decreased production of the protein neurofibromin, which has a putative tumor suppressor function. Only one NF1 gene need be deleted or mutated to produce the condition.
• The NF1 gene has been localized to the long arm of chromosome 17; more than 250 mutations leading to protein truncation having been identified in affected individuals. A more severe phenotype has been observed in a subset of patients with a complete gene deletion.
• The precise role of neurofibromin is not fully understood, but the multitude of clinical effects suggests that this gene product has diverse functions in various tissues.

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