Neurofibromatosis type 1 is a relatively common tumor predisposition syndrome that is clinically evident through café au lait spots, neurofibromas on and under the skin, and freckles in the armpits and the groin area. In addition, NF1 is characterized by iris hamartomas, characteristic bone changes, scoliosis, macrocephaly, dwarfism, and learning disabilities. Occasionally, tumors may also develop in the vicinity of cranial nerves or the spinal cord and, in principle, around every peripheral nerve. NF1 is normally diagnosed during childhood.

Key Data

< swipe to see entire table >
Synonyms NF1, Recklinghausen’s disease
Gene NF1 tumor suppressor gene
Gene product Neurofibromin
Function The regulation of cell growth and cell differentiation in nerve cells and myelin sheaths. Tumors develop due to the down-regulation of the RAS signal transduction cascade.
Heredity Autosomal dominant (50%), de novo (50% ; intron mutation, exon deletion, missense mutation, insertion, point mutation, stop mutations), rarely mosaicism or a segmentally limited postzygotic form of NF1
Prevalence 1:3.000
Genotype-phenotype correlation Low, with very high expression variability
Penetrance Nearly 100% in adulthood
< swipe to see entire table >


Diagnostic Criteria

≥ 2 of the following criteria must be present; please note: age-dependent development!

  • ≥ 6 café au lait spots, with the largest > 5 mm in diameter before puberty and > 15 mm in diameter after puberty

  • ≥ 2 neurofibromas of every type or a plexiform neurofibroma

  • Freckling (in the armpits and/or groin area)

  • Optic glioma

  • ≥ 2 Lisch nodules (hamartomas of the iris)

  • Characteristic bone changes (sphenoidal wing dysplasia, tibial pseudarthrosis)

  • NF1 in first-grade relatives (parents, siblings, children)

Differential Diagnoses

Clinical Presentation

In the vast majority of cases, the diagnosis of “NF1” can be made clinically on the basis of the classic diagnostic criteria. Other common but not pathognomonic findings include the following:

  • Macrocephaly

  • Dwarfism

  • Scoliosis

  • Non-ossifying fibromas

  • Osteoporosis

  • Vertebral scalloping (dural ectasia)

  • Rib penciling (thoracic X-ray)

  • Hypertension

  • Vasculopathy

  • Aqueduct stenosis

  • Learning difficulties, cognitive deficits

  • NF1-associated bright spots in a T2-weighted cranial MRI

Predisposition to Cancer

  • Malignant peripheral nerve sheath tumors (MPNST) usually develop from plexiform or deeper lying neurofibromas; the lifetime risk is between 8% and 12%.

  • The progression of the optic glioma (pilocytic astrocytoma) peaks between the age of 0 and 6. The lifetime risk is around 15%.

  • High-grade CNS tumors (brain stem gliomas) < 1%, often associated with optic gliomas

  • Juvenile myelomonocytic leukemia (JMML, 1:300)

  • Embryonal rhabdomyosarcoma (ERMS), with the age of onset between 0 and 5 years and a risk < 1%

  • Endocrine tumors, pheochromocytomas, carcinoid tumors, or medullary thyroid carcinomas, risk < 1%

  • Glomus tumors, small, painful nodules in the fingertips

  • Gastrointestinal stromal tumors (GIST), risk 2%

  • Mammary carcinoma, risk increased by 4-5 times with a moderate (20%) lifetime risk

With familial NF1, an early clinical diagnosis is often possible (during infancy / early childhood). Discreet progressions are also found with de novo mutations or mosaic mutations, sometimes not becoming symptomatic until school age or early adulthood.

Therapeutic Considerations

  • Symptom/complication-oriented

  • Consider chemotherapy for symptomatic optic gliomas (loss of vision, protrusio bulbi; radiation is not recommended.

  • MEK1/2 inhibitors (selumetinib, cobimetinib, trametinib) as the last resort for reducing the size of inoperable plexiform NF (NUB, off-label use)

Surveillance Recommendations

Surveillance Recommendations

Examination Recommendations from AACR 2016

  • Following diagnosis, molecular genetic testing to verify/confirm the diagnosis

  • Annual clinical checkup (medical history and examination) with the main focus on skin changes and neurological status, blood pressure measurement (to rule out renal artery stenosis and pheochromocytoma), and a development assessment of size, weight, and the pubertal stage.

  • Every 6-12 months, supplementary ophthalmological examinations until the age of 8 (vision, visual fields, pupillary reflexes, fundus) and then once or twice a year until the age of 20

  • One-time (baseline) examination to check for color vision and visual fields as soon as the child’s development allows

  • If available, OCT (optical coherence tomography) at every ophthalmological examination

  • A checkup is recommended after 2 weeks when there is a loss of vision during screening to rule out other causes (refractive error, cataract); an MRI is justified if findings are confirmed.

  • Annual clinical screening for MPNST (please note: rapidly growing and/or painful, non-dermal neurofibromas leading to neurological deficits and the loss of function and/or exhibiting changes in quality)

  • During the transition to young adulthood – between the ages of 16 and 20 – it is worth considering a whole-body MRI, as it is well known that the development of MPNST is associated with a high risk of internal tumors.

  • Patient education concerning the fact that the risk of developing breast cancer is 4-5 times as high; offer of breast cancer screening for women 30-50 years of age

  • During adulthood, annual clinical checkups with blood pressure measurement and access to all special outpatient clinics if corresponding clinical symptoms are present

  • No routine MRI with mild clinical symptoms

Additional Information