Overview
Neurofibromatosis Type 1 (NF1)
1. Clinical Overview
Summary
Neurofibromatosis Type 1 (NF1), formerly known as Von Recklinghausen's disease, is the most common phakomatosis (neurocutaneous syndrome), affecting approx 1 in 3000 individuals. It is an Autosomal Dominant disorder caused by loss-of-function mutations in the NF1 gene on Chromosome 17q11.2, which encodes Neurofibromin (a tumour suppressor). This leads to failure of RAS downregulation and uncontrolled cell growth. The clinical phenotype is highly variable even within families (variable expressivity) but has almost 100% penetrance by adulthood. Diagnosis is clinical, based on the NIH Diagnostic Criteria (e.g., Café-au-lait macules, neurofibromas, axillary freckling, Lisch nodules). While life expectancy is only moderately reduced, patients face lifelong risks of malignant transformation (Malignant Peripheral Nerve Sheath Tumours - MPNST), vasculopathy, and learning difficulties. Management is multidisciplinary surveillance, with MEK inhibitors (Selumetinib) recently revolutionising treatment for inoperable plexiform neurofibromas. [1,2]
Key Facts
- Prevalence: 1 in 3000.
- Genetics: Autosomal Dominant (50% inherited, 50% de novo).
- Gene: NF1 (Chr 17). Product: Neurofibromin (RAS-GAP).
- Diagnostic Criteria: Need 2 of 7 NIH criteria.
- Malignancy Risk: Life-time risk of MPNST is 8-13%. Women <50y have increased Breast Cancer risk.
- Cognition: 50% have learning difficulties; ADHD is common.
- Blood Pressure: Always check BP (Renal Artery Stenosis or Phaeochromocytoma).
Clinical Pearls
"Crowe's Sign": Axillary or inguinal freckling is pathognomonic. It is the most specific sign in childhood.
"The Ugly Duckling Sign": If a patient has hundreds of soft, squishy neurofibromas, but ONE is hard, painful, and growing rapidly -> Think MPNST (Sarcoma). This is a red flag.
"Tibial Bowing": Anterolateral bowing of the tibia (and subsequent pseudoarthrosis) is a congenital manifestation of NF1. It presents in infancy.
"UBOs": Unidentified Bright Objects on T2 MRI. These are areas of vacuolisation/dysplasia seen in 70% of NF1 kids. They are benign and often disappear in adulthood. DO NOT mistake them for tumours.
2. Epidemiology
Incidence and Prevalence
- Incidence: 1 in 2500-3000 live births to 1 in 4000.
- Prevalence: One of the most common dominant genetic disorders.
- Penetrance: ~100% by age 5-10 years.
- Expressivity: Extremely variable. A parent may have only mild spots, while the child has severe plexiform tumours.
Demographics
- Sex: Equal M:F.
- Ethnicity: Pan-ethnic.
Genetic Origin
- Inherited: 50% have an affected parent.
- De Novo: 50% are new mutations (paternal age effect).
- Mosaicism (Segmental NF1): Somatic mutation occurs post-zygotically. Features restricted to one part of the body.
3. Pathophysiology
The Molecular Brake
- Normal: The NF1 Gene (Chr 17q11.2) produces Neurofibromin.
- Function: Neurofibromin acts as a RAS-GAP (GTPase Activating Protein). It accelerates the conversion of Active RAS-GTP to Inactive RAS-GDP.
- Analogy: Neurofibromin is the "brake pedal" on the RAS growth pathway.
- Pathology: Mutation causes Loss of Function of Neurofibromin.
- Consequence: RAS remains permanently in the GTP-bound (Active) state.
- Downstream:
- Activation of MAPK/MEK/ERK pathway.
- Activation of PI3K/AKT/mTOR pathway.
- Result: Uncontrolled cell proliferation and survival.
Tumourigenesis (The Second Hit)
- NF1 patients are born with one mutated copy in every cell (germline).
- Tumours (Neurofibromas) develop when the second copy (wild type) is lost somatically (Loss of Heterozygosity - LOH) in a Schwann cell precursor.
- Mast cells are also recruited to the tumour microenvironment (haploinsufficiency effect) and drive inflammation/growth.
4. Clinical Presentation (NIH Criteria)
Diagnosis requires 2 or more of the following:
1. Café-au-Lait Macules (CALMs)
- Description: Flat, coffee-coloured patches.
- Criteria:
- Pre-pubertal: >5mm (Need 6 or more).
- Post-pubertal: >15mm (Need 6 or more).
- Timeline: Often present at birth or appear in year 1.
- Nuance: Need to distinguish from McCune-Albright (Coast of Maine borders - jagged) vs NF1 (Coast of California - smooth).
2. Neurofibromas (2 types)
- Cutaneous:
- Soft, fleshy, pedunculated bumps. Move with the skin ("Button-hole" sign).
- Appear in puberty and pregnancy (hormonally driven). Increase with age.
- Number: From a few to thousands.
- Risk: Cosmetic burden, itching. benign.
- Plexiform:
- "Bag of worms" consistency. Infiltrate deep tissues/nerves.
- Congenital (present from birth).
- Risk: 10% transform to Malignant Peripheral Nerve Sheath Tumour (MPNST).
3. Axillary or Inguinal Freckling
- Crowe's Sign.
- Small <3mm freckles in skin folds.
- Not sun-exposed areas.
- Appears age 3-5.
4. Optic Pathway Glioma (OPG)
- Tumour: Low grade pilocytic astrocytoma of the optic nerve/chiasm.
- Prevalence: 15% of children <6 years.
- Symptoms: Often asymptomatic. Can cause visual loss, proptosis, precocious puberty (if chiasm involves hypothalamus).
- Screening: Annual ophthalmology until age 7.
5. Lisch Nodules
- Description: Iris hamartomas. Tan-coloured domes on slit-lamp exam.
- Prevalence: >90% of adults.
- Impact: Do not affect vision using. purely diagnostic.
6. Osseous Lesions
- Sphenoid Wing Dysplasia: Pulsatile exophthalmos.
- Tibial Pseudoarthrosis: Anterolateral bowing of tibia -> Fracture -> Non-union (False joint).
7. First Degree Relative
- Parent, Sibling, or Child with confirmed NF1.
(Note: New 2021 Criteria allow Genetic Testing as a standalone criterion replacing the need for a relative)
5. Other Manifestations (Non-Diagnostic)
Neurological
- Learning Disabilities: 50%. Specific deficits in visuospatial skills. Low IQ is rare.
- ADHD: 30-50%.
- Autism Spectrum: Increased prevalence.
- Headaches: Migraine burden is high.
- Epilepsy: 5-7%.
Cardiovascular
- Hypertension: Common. Causes:
- Essential (Vasculopathy).
- Renal Artery Stenosis (Fibromuscular dysplasia type).
- Phaeochromocytoma.
Skeletal
- Scoliosis: Dystrophic (sharp angle, severe) vs Non-dystrophic (like idiopathic).
- Short stature.
- Macrocphaly.
Oncological Risks
- MPNST: Lifetime risk 8-13%.
- Breast Cancer: Risk x4 in women <50. Start screening at 30?
- GIST: Gastrointestinal Stromal Tumours.
- JMML: Juvenile Myelomonocytic Leukaemia.
6. Investigations
Diagnosis
- Usually clinical.
- Genetic Testing:
- Sequence analysis (>95% sensitivity).
- Diagnosis in atypical cases (e.g. Legius Syndrome - SPRED1 mutation).
- Pre-implantation genetic diagnosis.
Surveillance Imaging
- MRI Brain/Orbits:
- Not routine for asymptomatic.
- Indicated if visual symptoms or precocious puberty.
- Shows "UBOs" (FASI - Focal Areas of Signal Intensity) in basal ganglia/cerebellum.
- Whole Body MRI:
- Used to quantify "Total Tumour Burden" (Plexiforms).
- PET CT:
- Vital for detecting malignant transformation in a plexiform neurofibroma (MPNST is highly metabolically active).
Laboratory
- Plasma Metanephrines: Screen for Phaeochromocytoma if hypertensive/symptomatic.
3. Deep Dive: The RAS-MAPK Pathway
"The Brake Pedal."
- Neurofibromin: The protein encoded by the NF1 gene acts as a GTPase Activating Protein (GAP).
- Function: It speeds up the conversion of Active RAS (GTP-bound) to Inactive RAS (GDP-bound). It turns RAS off.
- In NF1: The brake is broken. RAS remains constitutively active.
- Downstream: Active RAS stimulates the MAPK/MEK/ERK pathway -> Uncontrolled ell proliferation.
- Therapy: MEK Inhibitors (Selumetinib) block the downstream signal, shrinking plexiform neurofibromas.
4. Surgical Atlas: Plexiform Neurofibroma Resection
"The Bag of Worms."
- Challenge: Unlike cutaneous neurofibromas (which shell out easily), Plexiforms infiltrate the nerve fascicles and surrounding tissue. They are vascular and bleed heavily.
- Indication: Compressive symptoms (airway/spine), rapid growth (Malignant transformation?), or severe disfigurement.
- Technique:
- Debulking: Often total resection is impossible without sacrificing the nerve/limb.
- Intracapsular dissection: Trying to preserve functional fascicles.
- The Paradigm Shift: Medical therapy (Selumetinib) is now preferred over disfiguring surgery for inoperable tumors.
7. Management
(Renumbered) Management Algorithm
DIAGNOSIS CONFIRMED (NF1)
↓
┌──────────┼──────────────┐
ANNUAL SYMPTOMATIC TUMOUR
SURVEILLANCE MANAGEMENT THERAPY
↓ ↓ ↓
- BP Check - ADHD meds - Surgery
- Vision - Pain mgmt - Chemo (Vincristine)
- Scoliosis - Cosmetics - MEK Inhibitors
- Development (Selumetinib)
1. Surveillance Schedule
- 0-10 Years:
- Annual Paediatrician review.
- BP Check (Renal artery stenosis).
- Annual Vision Check (Optic glioma).
- Review development/schooling.
- Check spine (scoliosis) and legs (tibial bowing).
- Adults:
- BP Check.
- Neuro exam (cord compression).
- Malignancy awareness (MPNST symptoms).
2. Tumour Management
- Cutaneous Neurofibromas:
- Physical Removal: Excision, Laser, or Electrodessication. (High recurrence, risk of keloids).
- Plexiform Neurofibromas:
- Surgery: Often difficult due to vascularity and nerve entanglement. Debulking only.
- Medical: Selumetinib (MEK Inhibitor).
- Indication: Inoperable symptomatic plexiforms in children >3y.
- Efficacy: Shrinks tumour volume by >20% in 70% of patients.
- Side effects: Acneiform rash, cardiac Dysfunction. (The "Alexion" drug).
3. Optic Glioma
- Observation: Most remain stable and regress spontaneously.
- Chemotherapy: Vincristine/Carboplatin if visual acuity drops.
- Avoid Radiotherapy: Risk of secondary malignancy (Moyamoya or High Grade Glioma) is too high in NF1 brains.
4. Orthopaedic
- Scoliosis: Bracing or Spinal Fusion.
- Tibial Pseudoarthrosis: Bisphosphonates? BMP? Amputation often eventual outcome if union fails.
1. Surgical Atlas: Neurofibroma Management
"The Battle against the Bump."
- Cutaneous Neurofibromas:
- Indications: Cosmetic distress, itching, bleeding, catching on clothing.
- Techniques:
- KTP Laser: Good for hundreds of small macules (early stage).
- Electrodessication: Burning them off. Multple sessions. Local anaesthesia usually sufficient.
- Surgical Excision: For larger/deeper ones. Leaves a linear scar.
- Recurrence: High. New ones will grow elsewhere.
- Plexiform Neurofibromas:
- Challenge: They are not encapsulated. They infiltrate nerve fascicles and are extremely vascular.
- Debulking: complete resection is often impossible without sacrificing the parent nerve (and function). Surgeons aim to "debulk" to relieve pressure/cosmetic deformity.
- Bleeding Risk: High. Pre-operative embolisation may be needed.
2. Deep Dive: The RAS-MAPK Pathway
"The Signal that never stops."
- Normal Physiology:
- Growth Factor binds Receptor Tyrosine Kinase (RTK).
- RTK activates RAS (by adding GTP).
- RAS-GTP activates RAF -> MEK -> ERK.
- ERK enters nucleus -> Transcription of Cyclin D -> Cell Division (Go!).
- The Brake: Neurofibromin (NF1 Protein) swoops in and strips the GTP from RAS (Hydrolysis), turning it off (RAS-GDP).
- In NF1:
- The "Brake" (Neurofibromin) is missing.
- RAS stays active (GTP-bound) for too long.
- The downstream MEK/ERK pathway is hyperactive.
- Result: Uncontrolled proliferation.
- Therapeutic Target:
- We can't easily fix the broken brake (replace Neurofibromin).
- But we can block the downstream signal.
- MEK Inhibitors (Selumetinib/Trametinib) block the step between RAF and ERK. They effectively "cut the wire" of the stuck accelerator.
8. Complications
(Renumbered)
1. Malignant Peripheral Nerve Sheath Tumour (MPNST)
The most feared complication.
- Origin: Arises from a pre-existing Plexiform Neurofibroma (rarely de novo).
- Prevalence: 10% lifetime risk.
- Red Flags:
- Rapid growth.
- Change from soft to hard consistency.
- Pain (New, severe, nocturnal).
- Neurological deficit.
- Diagnosis: PET CT (Hot) -> Biopsy.
- Prognosis: Poor. Resistant to chemo/radio. Radical resection is only hope. 5-year survival ~40%.
2. Phaeochromocytoma
- Prevalence: 0.1-5% (Higher than general pop).
- Always screen if Hypertensive or before Elective Surgery.
3. Cerebrovascular (Moyamoya)
- Progressive stenosis of ICA termination. "Puff of smoke" collaterals.
- Risk of ischaemic stroke in children.
9. Prognosis
- Life Expectancy: Reduced by 10-15 years on average (Malignancy, Vasculopathy).
- Quality of Life: Heavily impacted by cosmetic burden (neurofibromas) and cognitive issues.
- Variable: Some live completely normal lives with just a few spots; others have severe deformity and cancer.
10. Evidence and Guidelines
Key Guidelines
- AAP (2019): Health Supervision for Children with Neurofibromatosis Type 1.
- ACMG (2013): Genetic testing and counselling.
- ERN GENTURIS: Tumour management guidelines.
Landmark Trials
- SPRINT Trial (NEJM 2020):
- Selumetinib in children with inoperable plexiform neurofibromas.
- Result: 66% had partial response (>20% shrinkage). Significant improvement in pain and function.
- Impact: FDA/EMA approval. First ever drug for NF1.
11. Patient and Layperson Explanation
What is NF1?
NF1 is a genetic condition that causes changes in the skin and nerves. It makes "coffee-coloured" birthmarks appear on the skin, and can cause small benign bumps (neurofibromas) to grow on nerves under the skin.
Is it cancer?
NF1 itself is not cancer. The lumps are almost always benign (safe). However, people with NF1 have a slightly higher chance of developing certain tumours, so we check you regularly to catch anything early.
Will my child have it?
If you have NF1, there is a 50% (1 in 2) chance of passing it to each child. However, the severity varies widely. Your child might have a very mild version even if you have a severe version (and vice versa).
Is there a cure?
There is no cure to fix the gene yet. But we have treatments for the symptoms. Lasers can remove the skin bumps. A new medicine (Selumetinib) can shrink the larger nerve lumps. Support is available for learning difficulties in school.
12. References
Primary Sources
- Legius E, et al. Revised diagnostic criteria for neurofibromatosis type 1 and Legius syndrome: an international consensus recommendation. Genet Med. 2021;23:1506-1513. PMID: 33976421.
- Gross AM, et al. Selumetinib in Children with Inoperable Plexiform Neurofibromas (SPRINT). N Engl J Med. 2020;382:1430-1442. PMID: 32187463.
- Ferner RE, Gutmann DH. Neurofibromatosis type 1 (NF1): diagnosis and management. Handb Clin Neurol. 2013;115:939-955.
13. Examination Focus
Common Exam Questions
1. Paediatrics:
- Q: A 5-year-old girl has 8 café-au-lait spots and axillary freckling. She is hypertensive. Diagnosis?
- A: NF1 with Renal Artery Stenosis (or Phaeochromocytoma).
2. Dermatology:
- Q: What is Crowe's Sign?
- A: Freckling in the axilla or inguinal region.
3. Oncology:
- Q: What is the risk of malignant transformation of a plexiform neurofibroma?
- A: Approx 10% lifetime risk (to MPNST).
4. Opthalmology:
- Q: What do Lisch nodules affect?
- A: The Iris. They do NOT affect vision.
Viva Points
- Legius Syndrome: Looks like mild NF1 (CALs + Freckling) but NO neurofibromas and NO Lisch nodules. Caused by SPRED1 mutation (also RAS pathway). Important differential diagnosis.
- Segmental NF1: If a parent has Segmental NF1 (mosaic), can they pass it on? Yes, if the mutation in is their germline (gonadal mosaicism), the child can get full blown generalised NF1.
14. Technical Appendix: Criteria Evolution
NIH (1988) vs International Consensus (2021)
- Why the change?
- To incorporate Genetic Testing.
- To differentiate from Legius Syndrome.
- Key Changes:
- Genetics: A pathogenic NF1 variant is now a standalone criterion (in 2021). You don't need a relative if you have the gene.
- Choroidal Anomalies: Added as an ophthalmic criterion (equivalent to Lisch nodules). Seen on OCT/NIR imaging.
- Legius Syndrome Exclusion: If a patient has CALMs + Freckling but NO other signs, and tests negative for NF1 but positive for SPRED1, they have Legius Syndrome.
Differential Diagnosis Table:
| Feature | NF1 | Legius Syndrome | McCune-Albright | Noonan Syndrome |
|---|---|---|---|---|
| Gene | NF1 | SPRED1 | GNAS | PTPN11 (RAS) |
| CaL Spots | Smooth (Coast of California) | Smooth | Jagged (Coast of Maine) | Present |
| Freckling | Yes | Yes | No | No |
| Neurofibromas | Yes | NO | No | No |
| Lisch Nodules | Yes | NO | No | No |
| Bone | Tibial bowing | No | Fibrous dysplasia | Sternum/Heart |
15. Rehabilitation: The Transition Clinic
"Falling off the cliff." Paediatric care is usually robust (multi-specialty input). Adult care is often fragmented.
- The Gap: Young adults (16-25) are at high risk of being lost to follow up.
- Psychosocial:
- Cosmetic burden of neurofibromas peaks in early adulthood.
- Relationship/Sexual anxiety.
- Career planning (impact of learning difficulties).
- Goals of Transition:
- Ensure BP monitoring continues (Stroke prevention).
- Self-examination education (How to spot an MPNST).
- Genetic Counselling (Reproductive choices).
16. Examination Focus (Expanded)
Advanced Viva Questions
1. Genetics:
- Q: What is the mechanism of inheritance of NF1?
- A: Autosomal Dominant with complete penetrance but variable expressivity. 50% are de novo mutations.
- Q: What is "Mosaic NF1"?
- A: Post-zygotic mutation. Features are segmental (e.g. only one arm affected).
2. Management:
- Q: A child with NF1 presents with headache and early morning vomiting. What do you suspect?
- A: Raised Intracranial Pressure. Causes: Hydrocephalus (Aqueductal stenosis is associated with NF1) or Brain Tumour (Glioma).
3. Pharmacology:
- Q: How does Selumetinib work?
- A: It is a MEK 1/2 Inhibitor. It inhibits the RAS-MAPK pathway downstream of the NF1 defect.
Medical Disclaimer: MedVellum content is for educational purposes and clinical reference. Clinical decisions should account for individual patient circumstances. Always consult appropriate specialists.