Neurofibromatosis Type 1

Updated: Oct 27, 2017
  • Author: David T Hsieh, MD, FAAP; Chief Editor: Amy Kao, MD  more...
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Overview

Practice Essentials

Neurofibromatosis type 1 (NF1) is a multisystem genetic disorder that is characterized by cutaneous findings, most notably café-au-lait spots and axillary freckling (see the images below), by skeletal dysplasias, and by the growth of both benign and malignant nervous system tumors, most notably benign neurofibromas.

Café-au-lait spots in a 4-year-old boy. Café-au-lait spots in a 4-year-old boy.
Axillary freckles. Axillary freckles.

Signs and symptoms

Signs and symptoms of NF1 can vary widely from patient to patient. 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.

Axillary or inguinal freckles are rarely present at birth, but appear during childhood through adolescence. Subcutaneous or cutaneous neurofibromas are seen rarely in young children but appear over time in older children, adolescents, and adults.

Other signs and symptoms may include the following:

  • High blood pressure (potentially from renal artery stenosis or pheochromocytoma)
  • Bone abnormalities
  • Optic nerve tumors
  • Lisch nodules
  • Learning disabilities; Attention deficit hyperactivity disorder; Autism spectrum disorder
  • Larger than average head size
  • Short stature

See Clinical Presentation for more detail.

Diagnosis

Clinical diagnosis requires the presence of at least 2 of 7 criteria to confirm the presence of NF1. Many of these signs do not appear until later childhood or adolescence; thus, confirming the diagnosis often is delayed despite a suspicion of NF1. The 7 clinical criteria used to diagnose NF1 are as follows, in the absence of alternative diagnoses:

  • Six or more café-au-lait spots or hyperpigmented macules =5 mm in diameter in prepubertal children and 15 mm postpubertal
  • Axillary or inguinal freckles (>2 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

See Workup for more detail.

Management

Medical care

There is no cure for neurofibromatosis. Patients should be routinely monitored for complications. Annual examinations should include the following:

  • Assessment of skin to look for new neurofibromas or progression of existing lesions
  • Check of blood pressure
  • Evaluation of growth and development
  • A complete eye exam
  • Evaluation of skeletal changes and abnormalities
  • Assessment of learning development

Chemotherapy, radiation therapy, or both may be used to treat cancerous tumors, but with the avoidance of radiation therapy when possible, due to the incurred increased risk of secondary malignancies.

Surgical care

Surgery can be used to remove tumors that cause pain or a loss of function. Neurofibromas that press on vital structures, obstruct vision, or grow rapidly deserve immediate attention.

Orthopedic intervention is indicated for rapidly progressive scoliosis and for some severe bony defects.

See Treatment and Medication for more detail.

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Background

Neurofibromatosis type 1 (NF1) 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 lower incidence of central nervous system (CNS) tumors than NF2. However, complications of NF1 can include visual loss secondary to optic nerve gliomas, spinal cord tumors, scoliosis, vascular lesions, and long-bone abnormalities.

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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.

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Frequency

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.

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Mortality/Morbidity

Life expectancy in NF1 is approximately 8 years less than the general population. [1]

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, particularly gliomas, 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. [2]

Plexiform neurofibromas, generally larger, more diffuse, and locally invasive are seen in more than one fourth of patients with NF1 [3] and can present difficult management decisions. The management of close surveillance 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 most common. [4] 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. MPNSTs in patients with NF1 carry a poorer prognosis than in patients without this condition; tumor volume is an independent prognostic indicator. [5]

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 (GIST), often multiple with a predilection for the proximal small bowel, may be seen in patients with NF1. Therefore, there should be a high index of suspicion for a GIST in a patient who presents with GI bleeding or intestinal obstruction. [6] Gene mutations typically seen in sporadic GISTs leading to malignant transformation are rarely identified in the GISTs removed from patients with NF1. [7] Instead, activation of the Ras-MAPK pathway and loss of heterozygosity of specific chromosomal regions may underlie the development of GISTs in patients with NF1. [8]

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. Furthermore, a recent population based study reported a prevalence of autism spectrum disorder in 30%. [9]

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. [10] 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. [11]

Emerging evidence shows that vitamin D deficiency combined with a higher than normal bone turnover contributes to decreased bone mineral density (BMD) in patients with NF1. [12] One study looking at adults with NF1 (mean age, early 40s), showed that 50% had osteopenia and 19% had frank osteoporosis. Males were more likely than females to have reduced BMD; 56% of patients had a low 25-hydroxy-vitamin D while 34% had elevated parathyroid hormone. [13] Judicious vitamin D supplementation may prove beneficial for patients with NF1 who have vitamin D deficiency or evidence of osteopenia.

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 (< 5%) 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. Rarely, coronary artery aneurysms are identified in symptomatic or even asymptomatic individuals with NF1. [14]

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-, sex-, and age-related demographics

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

Males and females are affected equally with this autosomal dominant condition. However, one study showed that female patients with NF1-associated optic glioma were twice as likely to undergo brain magnetic resonance imaging for visual symptoms and three times more likely to require treatment for visual decline than their male counterparts. [15]

Scoliosis may be especially severe in young girls compared to their male counterparts.

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.

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