Neurofibromatosis Type 1 Clinical Presentation

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

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 prepubertal children and 15 mm postpubertal
  • Axillary or inguinal freckles (>2) [16]
  • 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
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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 the image below).

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

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 the images below).

Axillary freckles. Axillary freckles.
Inguinal freckles. Inguinal freckles.

Subcutaneous or cutaneous neurofibromas are seen rarely in young children but appear over time in older children, adolescents, and adults (See the image below).

Multiple neurofibromas in a 28-year-old man. Multiple neurofibromas in a 28-year-old man.

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 the image below).

Plexiform neurofibroma of the right thigh. Plexiform neurofibroma of the right thigh.

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 pathway tumors, typically histologically low-grade pilocytic astrocytomas, occur in 15-20%. They may be clinically silent, but can be symptomatic in 30-50%, primarily in children younger than 6 years. [17] Gender may be a major prognostic factor, as females have been reported to have a three-fold risk to require treatment for visual decline than males. [15]

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.

Posterior optic pathway tumors with hypothalamic encroachment may present as precocious puberty.

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 the image below).

Lisch nodules. Lisch nodules.

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 the image below).

Radial and ulnar bowing and obliteration of the in Radial and ulnar bowing and obliteration of the intramedullary spaces.

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.

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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 have 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.

Mutations in another gene (SPRED1) have been identified in a subset of patients described to have an NF-like syndrome, also known as Legius syndrome. [18] Individuals with a SPRED1 mutation may be incorrectly diagnosed with NF1 based on the presence of multiple café-au-lait spots and axillary or inguinal freckles, but these patients do not go on to develop the neurofibromas or Lisch nodules that are found in most adults with true NF1.

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