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Neurofibromatosis in Adult
See also in: External and Internal Eye
Other Resources UpToDate PubMed

Neurofibromatosis in Adult

See also in: External and Internal Eye
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 (also known as 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 a spontaneous (ie, de novo) mutation in up to 50% of cases. 

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.

The diagnosis of NF1 is made on clinical grounds, based on 2 or more of the following features if not better explained by an alternate diagnosis:
  • Six or more café au lait macules greater than 5 mm in diameter in prepubertal patients and greater than 15 mm in diameter in postpubertal patients
  • Two or more Lisch nodules (iris hamartomas)
  • An osseous lesion such as sphenoid dysplasia or thinning of a long bone's cortex, with or without pseudoarthrosis
  • At least 2 neurofibromas of any type or a single plexiform neurofibroma
  • Freckling in the axillary or inguinal region
  • Optic glioma (in early childhood)
  • A first-degree relative with NF1
Patients with NF1 are at increased risk of developing both benign and malignant neoplasms. Neurofibromas are seen in up to 60% of adult patients. 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 NF1 include gliomas (especially optic pathway gliomas, occurring 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 (including heart disease), and endocrinologic abnormalities.

Neurofibromatosis type 2 (also known as bilateral acoustic neurofibromatosis, central neurofibromatosis, or NF2) is an inherited, autosomal dominant genetic disorder that affects approximately 1 in 33 000 individuals. Patients with NF2 present primarily with vestibular schwannomas (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 NF1, see OMIM.

For more information on NF2, 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 – Skin schwannomas may be an early but rare sign of NF2.
  • Schwannomatosis – A 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 – Constitutional mismatch repair-deficiency syndrome is an inherited autosomal recessive condition that can present with axillary freckling and café au lait macules but is associated with early onset hematologic malignancies.
  • Hereditary nonpolyposis colorectal cancer (HNPCC)
  • Noonan syndrome
Conditions with pigmented macules:
Localized overgrowth syndromes:
Conditions causing subcutaneous tumors:
Note: Café au lait macules are common in the general population; up to 57.1% of patients with one or two café au lait macules did not have NF1 by clinical examination or genetic testing in one study. Isolated neurofibromas without neurofibromatosis are also common.

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Last Updated:07/25/2021
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Neurofibromatosis in Adult
See also in: External and Internal Eye
Neurofibromatosis (Type 1) : 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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