Neurofibromatosis in Infant/Neonate
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Synopsis
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
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 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 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 café au lait macules – No other findings of NF1.
- 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.
- 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
Conditions with pigmented macules:
- LEOPARD syndrome
- Neurocutaneous melanosis
- Peutz-Jeghers syndrome
- Piebaldism
Conditions causing subcutaneous tumors:
- Lipomatosis (see lipoma)
- Bannayan-Riley-Ruvalcaba syndrome
- Fibromatosis
- Multiple endocrine neoplasia type 1 (MEN1) and type 2B (MEN2B)
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Last Reviewed:05/01/2020
Last Updated:05/18/2021
Last Updated:05/18/2021
Neurofibromatosis in Infant/Neonate
See also in: External and Internal Eye