Neurofibromatosis Type 1 Clinical Presentation

Updated: Apr 12, 2022
  • Author: David T Hsieh, MD, FAAP; Chief Editor: George I Jallo, MD  more...
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In the absence of a parent with neurofibromatosis type 1 (NF1), the criteria for clinical diagnosis includes two or more of the following:

  • Six or more café-au-lait (CAL) macules greater than 5 mm in diameter in prepubertal children and greater than 15 mm postpubertal

  • Axillary or inguinal freckles (> 2 freckles) (if only CAL and freckling are present, one of these two cutaneous manifestations should be bilateral, and Legius syndrome should be considered, though the diagnosis is still likely NF1)

  • Two or more typical neurofibromas or one plexiform neurofibroma

  • Optic pathway glioma

  • Two or more iris hamartomas (Lisch nodules), often identified only through slit-lamp examination by an ophthalmologist; or two or more choroidal abnormalities (bright, patchy nodules imaged by optical adherence tomography/near infrared reflectance imaging)

  • Sphenoid dysplasia or typical long-bone abnormalities such as pseudarthrosis (exception is sphenoid dysplasia does not count as a separate criteria in the case of ipsilateral orbital plexiform neurofibroma)

  • Heterozygous pathogenic NF1 variant with a variant allele fraction of 50% in apparently normal tissue

In the presence of a parent with NF1, the criteria for clinical diagnosis include one of the above criteria.



The earliest clinical finding usually seen in children with neurofibromatosis type 1 (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. [16]

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.



Neurofibromatosis type 1 (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 needs be deleted or mutated to produce the condition.

The NF1 gene has been localized to the long arm of chromosome 17. Although more than 3,000 NF1 pathogenic variants have been identified, only four consistent genotype-phenotyp correlations have been reported, relevent to only 10–15% of NF1 patients. [18]

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. [19] 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.



Complications of neurofibromatosis type 1 (NF1) may include the following:

  • Locally invasive plexiform neurofibromas

  • Optic nerve gliomas, especially in children younger than 5 years

  • Dumbbell-shaped spinal cord neurofibromas or neurofibromas of the brachial or sacral plexus

  • Peripheral neuropathy

  • Scoliosis

  • Hypertension due to pheochromocytoma or renal vascular stenosis secondary to fibromuscular dysplasia

  • Bony modeling defects that may lead to pseudarthrosis, thoracic cage asymmetry, or pathologic fractures

  • Increased risk for brain tumors, leukemia, and other malignancies of neural crest origin (including neurofibrosarcomas and MPNSTs)

  • Learning disabilities, attention deficit disorder (ADD), attention deficit hyperactivity disorder (ADHD), or rarely, mental retardation