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Neurofibromatosis in Infant/Neonate
See also in: External and Internal Eye
Other Resources UpToDate PubMed

Neurofibromatosis in Infant/Neonate

See also in: External and Internal Eye
Contributors: Craig N. Burkhart MD, Belinda Tan MD, PhD, Dean Morrell MD
Other Resources UpToDate PubMed


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, central nervous system (CNS), 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. 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
NF1 is often identified in childhood with the appearance of café au lait macules. It is more difficult to diagnose in infancy. One retrospective study found that approximately one-third of NF1 patients manifested just one of the above features by age 1, whereas 99% manifested 2 criteria by age 8.

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. In children, the most common NF1-associated malignancies are optic pathway gliomas (occurring in 10%-15% of all NF1 patients, usually by age 7) and other non-optic glioma CNS tumors. Later in adolescence, patients are at increased risk of developing malignant peripheral nerve sheath tumors. Other malignancies and tumors associated with NF1 include pheochromocytomas, meningiomas, sarcomas, gastrointestinal tumors of neuroendocrine origin (most commonly somatostatinoma, but gastrinomas, insulinomas, paragangliomas, and duodenal carcinoid tumors are also seen), and juvenile myelomonocytic leukemia (7-times increased risk compared to age-matched counterparts, and most commonly observed in NF1 patients who also have cutaneous juvenile xanthogranulomas). Children with NF1 have a 20-times greater risk, compared to the general population, of developing rhabdomyosarcomas, most commonly involving the bladder and prostate. In addition to tumors and skin findings, patients may also have learning disabilities (30%-50%), skeletal anomalies, vasculopathies (including heart disease), and endocrine 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.


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

19133005 – Neurofibromatosis syndrome

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Differential Diagnosis & Pitfalls

The differential diagnosis of NF1 includes the following.

Other forms of NF:
  • Mosaic NF1
  • Watson syndrome – A subset of NF associated with pulmonic stenosis.
  • Autosomal dominant café au lait macules – No other findings of NF1.
  • Autosomal dominant multiple café au lait macules alone (some allelic with NF1).
  • NF2 – 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
  • Legius syndrome – Lacks the neurofibromas and gliomas seen in NF1.
  • Russell-Silver syndrome
Many individuals with these disorders will have exhibited manifestations by adolescence / early adulthood.

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 NF are also common.

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Last Reviewed:04/30/2020
Last Updated:03/01/2022
Copyright © 2023 VisualDx®. All rights reserved.
Neurofibromatosis in Infant/Neonate
See also in: External and Internal Eye
A medical illustration showing key findings of Neurofibromatosis (Type 1) : Lisch nodules, Axillary freckles, Smooth papules
Clinical image of Neurofibromatosis - imageId=742400. Click to open in gallery.  caption: 'A close-up of pinkish and brownish papules and nodules (neurofibromas) and light brown patches (confetti and <span>café au lait </span> macules).'
A close-up of pinkish and brownish papules and nodules (neurofibromas) and light brown patches (confetti and café au lait macules).
Copyright © 2023 VisualDx®. All rights reserved.