Neurofibromatosis Type 1 – Definition
Neurofibromatosis type 1 is a relatively common tumor predisposition syndrome clinically evident through café au lait spots, neurofibromas on and under the skin, and freckles in the armpits and 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.
Synonyms:
NF1, Recklinghausen’s disease
Gene:
NF1 tumor suppressor gene
Gene products:
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.
Pattern of inheritance:
Autosomal dominant (50%), de novo (50%; intron mutation, exon deletion, missense mutation, insertion, point mutation, stop mutations), rarely mosaic or segmentally limited postzygotic form of NF1
Prevalence:
1:3.000
Genotype-phenotype correlation:
Low, with very high expression variability
Penetrance:
Almost 100% in adulthood
Neurofibromatosis Type 1 – Diagnosis
Diagnostic Criteria
≥ 2 of the following criteria must be present: 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
- Legius syndrome
- Constitutive mismatch repair deficiency (CMMRD)
- Noonan syndrome with multiple lentigines
- Lynch syndrome
Clinical Presentation
In most cases, the diagnosis of “NF1” can be made clinically based on 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
Cancer Predisposition
- 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 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 of < 1%
- Endocrine tumors, pheochromocytomas, carcinoid tumors, or medullary thyroid carcinomas, risk of < 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 or mosaic mutations, sometimes not becoming symptomatic until school or early adulthood.
Special Features of Treatment
- 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 a last resort for reducing the size of inoperable plexiform NF (NUB, off-label use)
Diagnosis of Neurofibromatosis Type 1- What's Next?
Once diagnosed, it is recommended that a cancer predisposition specialist manage the patient. The following section explains whether cancer screening tests or other measures are necessary and how they should be performed. Some additional information, including links to support groups, is also included at the end of this page.
Diagnosis of Neurofibromatosis Type 1- What's Next?
Once diagnosed, it is recommended that a cancer predisposition specialist manage the patient. The following section explains whether cancer screening tests or other measures are necessary and how they should be performed. Some additional information, including links to support groups, is also included at the end of this page.
Recommendations for Early Detection for Children and Adults
Examination Recommendations of the AACR 2016
- Following diagnosis, molecular genetic testing to verify/confirm the diagnosis
- Annual clinical checkup (medical history and examination) focusing mainly 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
