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Neurofibromatosis in Adult
See also in: External and Internal Eye
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Neurofibromatosis in Adult

See also in: External and Internal Eye
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Contributors: Noah Craft MD, PhD, Lindy P. Fox MD, Belinda Tan MD, PhD, Lowell A. Goldsmith MD, MPH
Other Resources UpToDate PubMed

Synopsis

Neurofibromatosis type 1 (von Recklinghausen disease or NF1) is a multisystem genetic disorder with hallmark cutaneous findings, including café au lait macules, neurofibromas, and axillary freckling. NF1 may affect the skin, nervous system, eyes, bone, and soft tissue. It is the most common autosomal dominant genetic disorder, affecting approximately 1 in 3000 individuals and occurring as either an inherited defect or, frequently, as a spontaneous (ie, de novo) mutation.

NF1 occurs equally in all ethnicities and among both sexes and is often identified in childhood with the appearance of café au lait macules. The genetic defect is in a tumor suppressor gene on chromosome 17, which codes for neurofibromin, a RAS GTPase activating protein. Patients are at increased risk of developing benign and malignant neoplasms. Benign neoplasms include neurofibromas – complex tumors of admixed Schwann cells, fibroblasts, myelinated and unmyelinated nerve axons, endothelial cells, and mast cells – that occur in 1 of 4 forms: cutaneous, subcutaneous, nodular, and deep. Plexiform neurofibromas (present in 25% of patients) are a variant of neurofibroma that are typically deeper, more anatomically complex, and more likely to be symptomatic. Deep plexiform neurofibromas may degenerate into malignant peripheral nerve sheath tumors. Other malignancies and tumors associated with neurofibromatosis include gliomas (especially optic pathway gliomas in 10%-15% of patients), pheochromocytomas, meningiomas, sarcomas, gastrointestinal tumors of neuroendocrine origin such as duodenal carcinoid tumors, and juvenile myelomonocytic leukemia. In addition to tumors and skin findings, patients may also have learning disabilities (30%-50%), skeletal anomalies, vasculopathies, and endocrinologic abnormalities.

The diagnosis of NF1 is made on clinical grounds, based on 2 or more of the following features:
  • Six or more café au lait macules greater than 5 mm in prepubertal individuals and greater than 15 mm in diameter in postpubertal patients
  • Two or more Lisch nodules (iris hamartomas) in older patients
  • Sphenoid dysplasia or thinning of a long bone's cortex, with or without pseudoarthrosis
  • Two or more neurofibromas of any type or a single plexiform neurofibroma
  • Freckling in the axillary or inguinal region
  • Optic glioma (in early childhood)
  • First-degree relative with NF1 (although new mutations are frequent)
Patients with neurofibromatosis type 2 (NF2) present primarily with acoustic neuromas (schwannomas of the eighth cranial nerve), which are frequently bilateral. Hearing loss may also be present. NF2, which is 10 times less common than NF1, is associated with mutation of a different tumor suppressor gene that is located on chromosome 22 and codes for a protein called merlin. Patients have fewer café au lait macules than those with NF1, and they do not form Lisch nodules in the iris.

Many individuals with NF lead long and healthy lives. Overall life expectancy may be decreased by as much as 15 years secondary to complications, however.

For more information on Neurofibromatosis Type 1, see OMIM.

For more information on Neurofibromatosis Type 2, see OMIM.

Codes

ICD10CM:
Q85.01 – Neurofibromatosis, type 1
Q85.02 – Neurofibromatosis, type 2

SNOMEDCT:
19133005 – Neurofibromatosis syndrome

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Differential Diagnosis & Pitfalls

The differential diagnosis of NF1 includes the following.

Other forms of neurofibromatosis:
  • Segmental / mosaic NF1
  • Watson syndrome (a subset of neurofibromatosis associated with pulmonic stenosis)
  • Autosomal dominant multiple café au lait macules alone (some allelic with NF1)
  • Neurofibromatosis type 2
  • Schwannomatosis (disorder associated with mutation in the gene INI1)
Other conditions with café au lait macules:
  • McCune-Albright syndrome – Premature puberty, bony abnormalities, and a few large café au lait macules with an irregular outline. In NF1, the outline of the café au lait macule is smooth.
  • Genetic disorders of DNA repair or chromosomal instability
  • Homozygosity for one of the genes causing hereditary nonpolyposis
  • Cancer of the colon
  • Noonan syndrome
Conditions with pigmented macules confused with NF1:
Localized overgrowth syndromes:
Conditions causing tumors confused with those seen in NF1:
Note: 1 or 2 café au lait macules may commonly be seen in patients unaffected by NF1.

Isolated neurofibromas without neurofibromatosis are also common.

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Therapy

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References

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Last Updated: 10/31/2018
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Neurofibromatosis in Adult
See also in: External and Internal Eye
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Neurofibromatosis (Type 1 General Manifestations) : Lisch nodules, Axillary freckles, Smooth papules
Clinical image of Neurofibromatosis
A close-up of pinkish and brownish papules and nodules (neurofibromas) and light brown patches (confetti and café au lait macules).
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