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
According to the latest AACR guidelines, the following screening tests are recommended for patients with neurofibromatosis type 1:
Optic glioma
- Ophthalmological examination: funduscopy, visual field, visual acuity from 6-8 months annually until the age of 8, then every 2 years until 18 years of age
- OCT (optical coherence tomography): if available during ophthalmological examination up to the age of 8 years
- If an ophthalmological examination is not feasible, unreliable, or inconsistent, an MRI should be performed in patients 2 years of age and older
- If visual impairment is suspected, cranial and orbital MRI should be performed. Ophthalmological follow-up should be performed within 3 months
- If a tumour is detected in patients with stable vision, close monitoring without therapeutic intervention is warranted
Plexiform neurofibromas
- A single whole-body MRI is performed during the transition period in late adolescence to detect asymptomatic tumours at risk for ANNUBP and MPNST and to determine tumour burden (close follow-up for >300 PN)
- A single whole-body MRI is performed prior to treatment with a MEK inhibitor (if a whole-body MRI is not availalble), a neck and pelvic MRI may be considered as an alternative
- A single preoperative MRI of the spine is performed as a baseline if surgical treatment of scoliosis is required
ANNUBP & MPNST
- Annual clinical examination: Rapidly growing tumours or changes in their nature? Pain? Functional limitations?
- Regional DWI (diffusion weighted imaging) MRI and F-FDG PET/MRI or F-FDG PET/CT for clinical signs/symptoms: neurological limitations, pain, rapid growth of PN in adolescents or young adults
Other brain tumours
No early detection is indicated. Diagnostic only in symptomatic patients.
Leukaemia
- Clinical examination, complete blood count including reticulocytes according to clinical indication
Pheochromocytoma
- Blood pressure measurement from birth or diagnosis yearly (DD renal artery stenosis in the absence of other symptoms of pheochromocytoma)
Rhabdomyosarcoma
No early detection is indicated. Diagnostic only in symptomatic patients.
Breast cancer
- Extended screening with mammography and, if necessary, breast MRI from age 30
GIST
No early detection is indicated. Diagnostic only in symptomatic patients.
