Neurofibromatosis (NF1 & NF2)
Neurofibromatosis encompasses two distinct autosomal dominant neurocutaneous disorders: neurofibromatosis type 1 (NF1) and neurofibromatosis type 2 (NF2). NF1, also known as von Recklinghausen disease, is the most common phakomatosis, affecting 1 in 3,000-4,000 individuals. It results from mutations in the NF1 gene on chromosome 17, encoding neurofibromin, a tumor suppressor protein. NF2 is rarer (1 in 25,000-40,000) and results from mutations in the NF2 gene on chromosome 22, encoding merlin. Both conditions cause multiple tumors and systemic manifestations, requiring lifelong multidisciplinary monitoring and management.
Clinical Pearls:
- NF1 is one of the most common genetic disorders
- 50% of NF1 cases are de novo mutations (no family history)
- Café-au-lait spots appear in 95% of NF1 patients by age 2
- Lisch nodules (iris hamartomas) are pathognomonic for NF1
- NF2 is characterized by bilateral vestibular schwannomas (acoustic neuromas)
Red Flags:
- Malignant peripheral nerve sheath tumor (MPNST): 5-10% lifetime risk in NF1
- Optic pathway glioma: 15-20% of NF1 patients, most common in childhood
- Pheochromocytoma: 0.1-5.7% of NF1 patients, causes hypertension
- Rapidly growing neurofibroma: Suggests malignant transformation
- Hearing loss in NF2: From bilateral vestibular schwannomas
Image: NF1 vs NF2
NF1 and NF2 are genetic disorders with distinct epidemiological profiles. Understanding prevalence and inheritance patterns guides diagnosis and genetic counseling.
NF1 Epidemiology:
- Prevalence: 1 in 3,000-4,000 live births
- Incidence: 1 in 2,500-3,000 births
- Inheritance: Autosomal dominant, 50% de novo
- Penetrance: 100% by age 20, but variable expressivity
- Gender: Equal distribution
Image: Inheritance Pattern
NF2 Epidemiology:
- Prevalence: 1 in 25,000-40,000
- Incidence: 1 in 33,000-40,000 births
- Inheritance: Autosomal dominant, 50% de novo
- Penetrance: 95% by age 60
- Gender: Equal distribution
Geographic Variation:
- Similar prevalence worldwide
- No clear ethnic predilection
- Familial clustering in some populations
Demographic Nuances:
- Race/Ethnicity: No predilection, but diagnosis is often delayed in Black/Asian patients because café-au-lait spots are harder to distinguish from normal pigment.
- Socioeconomic: Lower SES correlates with higher tumor burden (likely ascertainment bias or lack of access to care).
Mortality Deep Dive:
- Median Age at Death: 54 years (NF1) vs 70 years (General Population).
- Causes of Death:
- Malignancy (MPNST): The #1 killer.
- Vascular: Stroke/Hypertension (young age).
- Glioma: Though often benign, high grade gliomas occur.
Morbidity Impact:
- Cosmetic Severity: Assessed by the Ablon Scale. Severe disfigurement leads to social isolation (>60% unemployment rates).
- Pain: Chronic neuropathic pain affects 30% of patients.
NF1 and NF2 result from loss-of-function mutations in tumor suppressor genes, leading to uncontrolled cell growth and tumor formation through distinct molecular pathways.
The Molecular Cascade (7 Steps):
Step 1: The Germline Hit (Haploinsufficiency)
- Mechanism: The patient starts life with one mutated copy of NF1 (17q11.2) in every cell.
- Consequence: Neurofibromin levels are 50% of normal.
- Clinical: This haploinsufficiency causes the mild features (Short stature, Learning (GABAergic inhibitory deficits), Macrocephaly).
Step 2: The Somatic Hit (Loss of Heterozygosity)
- Mechanism: A random "Second Hit" occurs in a specific neural crest cell (Schwann cell precursor).
- Consequence: The cell now has ZERO functional Neurofibromin.
- Clinical: This is the seed for tumor formation.
Step 3: RAS Hyperactivation (The Engine)
- Mechanism: Neurofibromin normally accelerates RAS-GTP hydrolysis (Turn off). Without it, RAS remains in the active GTP-bound state.
- Consequence: Constitutive activation of downstream effectors:
- RAF-MEK-ERK (Proliferation).
- PI3K-AKT-mTOR (Survival).
Step 4: The Microenvironment (Mast Cell Recruitment)
- Mechanism: The null-Schwann cells secrete Kit-Ligand (Stem Cell Factor).
- Consequence: This recruits Mast Cells (Heterozygous) to the tumor site.
- Synergy: Mast cells secrete TGF-beta and VEGF, promoting tumor growth and collagen deposition (Fibroma).
Step 5: Angiogenesis and Stromal Reaction
- Mechanism: VEGF upregulation drives new vessel formation.
- Consequence: Pathological blood vessels form (fragile, leaky). Fibroblasts lay down collagen.
- Clinical: The tumor becomes firm and vascular (Plexiform).
Step 6: Malignant Transformation (The Epigenetic Shift)
- Mechanism: In a subset of Plexiforms (8-13%), additional hits occur.
- Targets: Mutations in TP53 (Cell cycle) and CDKN2A (p16).
- Consequence: Introduction of PRC2 (Polycomb) mutations leading to a complete loss of growth control.
- Clinical: Conversion to MPNST (Sarcoma).
Step 7: Systemic Disruption (Metabolic & Vascular)
- Mechanism: RAS activation in smooth muscle and endothelium.
- Consequence: Vascular proliferation (Moyamoya, Renal Artery Stenosis) and bone dysplasia (Osteopenia).
Advanced Genetics (The "Engine Room")
- The RAS-MAPK Pathway:
- Normal State: Neurofibromin (the protein) acts as a "Brake" on the RAS pathway. It converts active RAS-GTP into inactive RAS-GDP.
- Disease State: The mutation breaks the "Brake". The engine (RAS) runs uncontrolled.
- Result: Constant downstream signalling (RAF -> MEK -> ERK) -> Proliferation.
- Therapeutic Target: MEK Inhibitors (Selumetinib) work by blocking this overactive pathway downstream.
Genotype-Phenotype Correlations
While most NF1 is variable, some specific mutations predict the future:
- NF1 Microdeletion Syndrome (5-10%):
- Defect: Missing the entire NF1 gene and surrounding genes (1.4Mb deletion).
- Phenotype: Severe.
- Features: Dysmorphic facial features, severe developmental delay, early onset/high burden of neurofibromas, high risk of MPNST.
- Management: Needs aggressive surveillance.
- 3-bp Deletion (p.Met992del):
- Phenotype: Mild.
- Features: Pigmentary features ONLY (Café-au-lait + Freckling). NO neurofibromas.
- Relevance: Good prognosis.
- Spinal NF1:
- Phenotype: Missense mutations.
- Features: Bilateral spinal neurofibromas (symptomatic) but few cutaneous signs.
Mosaicism (Segmental NF1)
- Concept: The mutation occurs after conception (post-zygotic).
- Result: Only a part of the body is affected (chromosomal mosaicism).
- Presentation: Unilateral or localized Café-au-lait spots/neurofibromas (e.g., just the Left arm).
- Risk: Risk of passing to offspring is low (unless germline mosaicism exists).
Knudson's "Two-Hit" Hypothesis
Why do tumors form?
- Hit 1 (Germline): Child inherits one broken copy of NF1 from parent (or de novo). Every cell in their body has 1 working copy and 1 broken copy. They are normal (Heterozygous).
- Hit 2 (Somatic): A random mutation breaks the second (working) copy in a specific Schwann cell.
- Result: That cell has ZERO working neurofibromin (Null). It grows uncontrollably -> Neurofibroma.
- Implication: This is why skin bumps appear over time (as random hits accumulate).
NF2 Pathophysiology Steps:
-
NF2 Gene Mutation: Loss-of-function mutations in NF2 gene (chromosome 22q12) encoding merlin (moesin-ezrin-radixin-like protein), a tumor suppressor
-
Merlin Loss: Merlin normally inhibits cell proliferation by interacting with multiple signaling pathways (PI3K-AKT, mTOR, Hippo)
-
Schwann Cell Proliferation: Loss of merlin in Schwann cells leads to uncontrolled proliferation, forming schwannomas (vestibular, spinal, peripheral)
-
Meningeal Cell Growth: Meningeal cells lacking merlin form multiple meningiomas
-
Ependymal Cell Effects: Ependymal cell dysfunction leads to ependymomas
-
Bilateral Vestibular Schwannomas: Characteristic feature, causing hearing loss, tinnitus, and balance problems
-
Tumor Progression: Multiple tumors develop throughout life, requiring surgical intervention and monitoring
Risk Factors
Non-Modifiable Risk Factors:
- Genetic: Autosomal dominant inheritance, 50% risk if parent affected
- De novo mutations: 50% of NF1, 50% of NF2 cases
- Age: Manifestations increase with age
- Gender: Equal distribution in both types
Genetic Factors:
- NF1 mutations: >3,000 different mutations identified
- NF2 mutations: Various mutation types (nonsense, frameshift, splice site)
- Mosaicism: Mosaic NF1/NF2 may have milder phenotype
- Genotype-phenotype: Some correlations, but variable expressivity
Modifiable Risk Factors:
- None clearly established
- Early diagnosis: Enables monitoring and intervention
- Regular surveillance: Reduces complications
Protective Factors:
- Genetic counseling: Informed family planning
- Prenatal diagnosis: Available for known mutations
- Preimplantation genetic testing: Available for NF1 and NF2
Clinical features differ significantly between NF1 and NF2. NF1 presents with cutaneous and neurological manifestations, while NF2 primarily affects the nervous system.
NF1 Clinical Features:
Cutaneous Manifestations:
Image: Café-au-lait Spots
Ocular Features:
Image: Lisch Nodules
Advanced Ocular Findings:
Neurological Features:
Skeletal Features:
NF2 Clinical Features:
Vestibular Schwannomas:
Other Nervous System Tumors:
Ocular Features:
Skin Features:
Comprehensive examination identifies diagnostic criteria, monitors for complications, and guides management. Different examination focuses for NF1 vs NF2.
NF1 Examination:
Cutaneous Examination:
- Café-au-lait spots: Count and measure, >6 required for diagnosis
- Axillary/inguinal freckling: Look in skin folds
- Neurofibromas: Count, measure, document location
- Plexiform neurofibromas: Palpate for deep lesions, assess size
Ophthalmological Examination:
- Slit lamp: Look for Lisch nodules (iris hamartomas)
- Visual acuity: Screen for optic pathway glioma
- Visual fields: If optic pathway involvement suspected
- Fundoscopy: Look for choroidal abnormalities
Neurological Examination:
- Cognitive assessment: Screen for learning disabilities
- Seizure history: Ask about episodes
- Head circumference: Measure for macrocephaly
- Neurological deficits: From tumors or neuropathies
Skeletal Examination:
- Spine: Look for scoliosis, kyphosis
- Limbs: Check for pseudarthrosis, bowing
- Skull: Palpate for defects
Blood Pressure:
- Measure: Screen for pheochromocytoma
- If elevated: Further investigation needed
NF2 Examination:
Cranial Nerve Examination:
- Hearing: Audiometry, speech discrimination
- Facial nerve: Weakness from schwannoma compression
- Trigeminal: Sensory loss, weakness
- Lower cranial nerves: Assess swallowing, voice
Neurological Examination:
- Balance: Romberg, gait assessment
- Motor: Weakness from spinal tumors
- Sensory: Deficits from spinal involvement
- Reflexes: May be abnormal with spinal lesions
Ophthalmological Examination:
- Slit lamp: Look for cataracts
- Fundoscopy: Retinal hamartomas
- Visual fields: If optic nerve involvement
Skin Examination:
- Café-au-lait spots: Usually less than 6
- Schwannomas: Palpable subcutaneous tumors
- No neurofibromas: Distinguishes from NF1
Diagnostic evaluation confirms NF1 or NF2, monitors for complications, and guides management. Genetic testing confirms diagnosis and enables family screening.
NF1 Diagnostic Criteria (2021 Revision):
- Replaced the old 1987 NIH criteria.
- Requirement: Two or more of:
- Café-au-lait Macules: ≥6 (>5mm if prepubertal, >15mm if postpubertal).
- Freckling: Axillary or Inguinal.
- Neurofibromas: ≥2 of any type or ≥1 Plexiform.
- Optic Pathway Glioma.
- Iris Lisch Nodules: ≥2 OR Choroidal Abnormalities (New addition).
- Bone Lesion: Sphenoid dysplasia or Tibial dysplasia.
- Genetic Mutation: Heterozygous pathogenic NF1 variant VAF > 50% (New addition).
- Relative: First-degree relative meeting criteria.
The Differential: Legius Syndrome
- Gene: SPRED1 mutation.
- Signs: They have the spots (Café-au-lait + Freckling) but NO tumors (No neurofibromas, No Lisch nodules, No Gliomas).
- Relevance: Much better prognosis. They do not get MPNST.
- Diagnosis: Genetic testing is the only way to distinguish phenotypically in childhood.
NF2 Diagnostic Criteria:
- Bilateral vestibular schwannomas, OR
- First-degree relative with NF2 AND unilateral vestibular schwannoma OR two of: meningioma, schwannoma, glioma, neurofibroma, posterior subcapsular cataract, OR
- Unilateral vestibular schwannoma AND two of: meningioma, schwannoma, glioma, neurofibroma, posterior subcapsular cataract, OR
- Multiple meningiomas AND unilateral vestibular schwannoma OR two of: schwannoma, glioma, neurofibroma, cataract
6.1. Genetic Testing Strategy (The 3-Step Ladder)
- Step 1: Next Generation Sequencing (NGS) Panel
- Technique: Simultaneous sequencing of NF1, NF2, SPRED1, SMARCB1, LZTR1.
- Sensitivity: >95% for point mutations.
- Turnaround: 4-8 weeks.
- Failure Rate: Misses large deletions (5%) or deep intronic/splice site mutations.
- Step 2: MLPA (Multiplex Ligation-dependent Probe Amplification)
- Indication: If NGS is negative but clinical suspicion is high ("Microdeletion Syndrome").
- Target: Large deletions/duplications (CNVs).
- Yield: Detects the 5% of cases missed by NGS.
- Step 3: RNA-Seq (cDNA Analysis)
- Indication: "Mutation Negative" classic NF1.
- Mechanism: Detects splicing errors caused by deep intronic variants.
- Yield: Finds mutation in 90% of "Test Negative" patients.
- Relevance: Needed for PGT-M (IVF) planning.
6.2. Imaging Protocol Details ("The NF Protocol")
- Brain MRI (T1/T2/FLAIR)
- UBOs: T2 hyperintensities (Globus Pallidus, Cerebellum). Do NOT enhance.
- Optic Pathway Glioma (OPG): Thickening of optic nerve/chiasm. Variable enhancement.
- Moyamoya: Flow voids in basal ganglia.
- Whole Body MRI (WBMRI)
- Role: Gold standard for tumor burden ("Tumor Load").
- Technique: STIR (Short Tau Inversion Recovery) sequences suppress fat, making neurofibromas light up bright white.
- Indication: Monitoring internal plexiform tumors (volumetric analysis).
- PET-CT (FDG)
- Role: Detecting Malignant Transformation (MPNST).
- Cut-off: SUVmax > 3.5 suggests malignancy (Sensitivity 95%).
- Caveat: Neurofibromas are metabolically active (SUV 1-3), so low-grade uptake is normal.
Biopsy Principles:
- Avoidance: Do not biopsy typical spots (scars heal poorly).
- Indication: Only for suspected malignancy.
- Technique: Core needle biopsy (multiple passes) under ultrasound guidance is preferred over open biopsy to avoid seeding or massive hemorrhage.
Imaging:
NF1:
- Brain MRI: Baseline and if symptoms, screen for optic pathway glioma
- Whole-body MRI: For plexiform neurofibromas (research setting)
- Spine MRI: If scoliosis or neurological symptoms
- PET scan: If MPNST suspected
NF2:
- Brain MRI with contrast: Screen for vestibular schwannomas, meningiomas
- Spine MRI: Screen for spinal tumors
- Auditory brainstem response: Assess hearing function
- Annual screening: From age 10-12 or earlier if family history
Monitoring Investigations:
NF1 Annual Monitoring:
- Blood pressure: Screen for pheochromocytoma
- Ophthalmological exam: Screen for optic pathway glioma
- Neurological exam: Assess for new deficits
- Skin exam: Monitor neurofibromas for changes
- Scoliosis screening: Clinical and X-ray if indicated
NF2 Annual Monitoring:
- Brain MRI: Monitor vestibular schwannomas and meningiomas
- Audiometry: Monitor hearing
- Neurological exam: Assess for new deficits
- Spine MRI: If symptoms or every 2-3 years
Complication Screening:
| Complication | Screening Test | Frequency |
|---|---|---|
| Optic pathway glioma (NF1) | Brain MRI, ophthalmology | Annual in childhood |
| MPNST (NF1) | Clinical exam, PET if suspicious | Annual, as needed |
| Pheochromocytoma (NF1) | Blood pressure, plasma metanephrines | Annual |
| Vestibular schwannoma (NF2) | Brain MRI, audiometry | Annual |
| Meningioma (NF2) | Brain MRI | Annual |
Differential Diagnosis (The Mimics)
- Legius Syndrome:
- Features: Cals + Freckling. NO Tumors.
- Gene: SPRED1.
- Noonan Syndrome:
- Features: "Neurofibromatosis-Noonan Syndrome" (NFNS). Short stature, webbed neck, pulmonary stenosis.
- Gene: PTPN11.
- McCune Albright Syndrome:
- Features: "Coast of Maine" spots (Jagged borders) vs NF1 "Coast of California" (Smooth borders).
- Gene: GNAS.
- Constitutional Mismatch Repair Deficiency (CMMRD):
- Features: Looks like NF1 but with early colon/brain cancers.
- Significance: Lethal if missed.
Suspicion of NF1
↓
┌─────────────────────────────────────────┐
│ CLINICAL DIAGNOSIS │
│ - Check 2021 Criteria (2 of 7) │
│ - Slit Lamp (Lisch) / MRI (UBOs) │
└─────────────────────────────────────────┘
↓
Criteria Met?
↙ ↘
YES NO
↓ ↓
┌─────────────┐ ┌────────────────────────┐
│ CONFIRM │ │ CONSIDER DIFFERENTIAL │
│ - Genetics │ │ - Legius (SPRED1) │
│ - Baseline │ │ - Noonan │
│ MRI/BP │ │ - CMMRD │
└─────────────┘ └────────────────────────┘
↓
┌─────────────────────────────────────────┐
│ SURVEILLANCE PATHWAY │
│ - Annual BP (Pheo risk) │
│ - Annual Skin Exam (MPNST check) │
│ - Vision check (OPG) │
└─────────────────────────────────────────┘
↓
COMPLICATION DETECTED?
↓
┌─────────────────────────────────────────┐
│ TREATMENT ARMS │
│ - Plexiform: Selumetinib (MEKi) │
│ - MPNST: Wide Resection + Chemo │
│ - Scoliosis: Bracing / Fusion │
│ - Tibial Dysplasia: BMP + Rodding │
└─────────────────────────────────────────┘
Management requires multidisciplinary approach with regular monitoring, early intervention for complications, and genetic counseling. Treatment is primarily supportive and surgical.
NEUROFIBROMATOSIS MANAGEMENT ALGORITHM
=======================================
Patient with suspected NF1/NF2
|
v
Clinical Diagnosis (NIH criteria)
|
+-------------------+-------------------+
| | |
NF1 NF2 Genetic Testing
| | |
Multidisciplinary Team Multidisciplinary Team - Confirm diagnosis
- Genetics - Genetics - Family screening
- Neurology - Neurosurgery - Prenatal options
- Dermatology - ENT
- Ophthalmology - Ophthalmology
- Orthopedics - Audiology
- Psychology - Psychology
NF1 MANAGEMENT
|
+-------------------+-------------------+
| | |
Annual Monitoring Complication Treatment
| Management |
- BP measurement - Optic pathway glioma: - Surgery for
- Ophthalmology Observation vs disfiguring
- Neurological exam chemotherapy neurofibromas
- Skin exam - MPNST: Surgery + - Scoliosis
- Scoliosis screen radiotherapy surgery
- Pheochromocytoma: - Learning
Surgery support
- Hypertension: - Psychological
Medical management support
NF2 MANAGEMENT
|
+-------------------+-------------------+
| | |
Annual Monitoring Tumor Management Hearing Preservation
| | |
- Brain MRI - Vestibular schwannoma: - Hearing aids
- Spine MRI Watch, surgery, or - Cochlear implant
- Audiometry radiotherapy - BAHA
- Neurological exam - Meningioma: Surgery - Sign language
- Ophthalmology - Spinal tumors: - Communication
Surgery aids
GENETIC COUNSELING
|
v
- Inheritance pattern (50% risk)
- Variable expressivity
- Prenatal diagnosis options
- Preimplantation genetic testing
- Family screening
NF1 Management:
Monitoring:
- Annual review: Multidisciplinary clinic
- Blood pressure: Every visit, screen for pheochromocytoma
- Ophthalmology: Annual in childhood, every 2 years in adults
- Neurological exam: Annual
- Skin exam: Annual, document changes
- Scoliosis: Screen annually in childhood
Optic Pathway Glioma:
- Observation: If asymptomatic, stable on imaging
- Chemotherapy: If progressive, symptomatic (carboplatin/vincristine)
- Surgery: Rarely, if causing severe visual loss
- Monitoring: Regular MRI and ophthalmology
Malignant Peripheral Nerve Sheath Tumor (MPNST) Surveillance:
- Risk: 8-13% Lifetime risk.
- Red Flags:
- Rapid Growth: Size doubles in < 6 months.
- Pain: New, persistent pain (Night pain).
- Hardness: Change from soft to hard firmness.
- Deficit: New numbness/weakness.
- Investigation: Whole Body MRI (STIR sequences). If suspicious -> PET-CT.
- Treatment: Wide excision (often amputation) + High Dose Radiotherapy. Chemotherapy (Doxorubicin) has limited effect.
The MEK Inhibitor Revolution (Selumetinib/Koselugo)
- Mechanism: Blocks MEK1/2, shutting down the overactive RAS-MAPK pathway.
- Indication: Inoperable Plexiform Neurofibromas in children (>2 years).
- Efficacy: 70% of patients see tumor shrinkage (>20% volume reduction).
- Side Effects:
- Skin Rash: Acneiform rash (Common).
- Cardiac: Decreased Ejection Fraction (monitor Echo).
- Ocular: Retinal Vein Occlusion / Retinal Detachment.
- CPK: Rhabdomyolysis risk.
- Impact: First ever FDA-approved drug for NF1 (2020).
Surgical Nuance (The Bleeding Risk):
- Plexiform neurofibromas are extremely vascular and fragile ("Friable").
- They interdigitate with normal nerves.
- Risk: Excision often causes massive haemorrhage and nerve sacrifice.
- Rule: Only operate if absolutely necessary (Airway, Disfigurement, Malignancy). Debulking is an option but regrowth is common.
Pheochromocytoma:
- Screening: Blood pressure, plasma metanephrines if hypertensive
- Treatment: Surgical resection after alpha-blockade
- Monitoring: Annual screening if at risk
Neurofibromas:
- Observation: Most require no treatment
- Surgery: If disfiguring, painful, or causing symptoms
- Laser: For small cutaneous neurofibromas
- Plexiform: Monitor for malignant transformation
Learning Disabilities:
- Assessment: Neuropsychological evaluation
- Support: Educational interventions, accommodations
- ADHD: Medical management if indicated
NF2 Management:
Vestibular Schwannoma:
- Observation: Small, asymptomatic tumors
- Surgery: If growing, causing symptoms, or threatening hearing
- Radiotherapy: Alternative to surgery, preserves hearing better
- Hearing preservation: Priority in management
Meningiomas:
- Observation: Small, asymptomatic
- Surgery: If growing or causing symptoms
- Multiple: May require multiple surgeries over lifetime
Spinal Tumors:
- Monitoring: Regular spine MRI
- Surgery: If causing cord compression or symptoms
- Multiple: May require staged surgeries
Hearing Management:
- Hearing aids: Conventional if useful
- Cochlear implant: If hearing lost, cochlear nerve intact
- BAHA: Bone-anchored hearing aid
- Sign language: Communication support
Genetic Counseling:
- Inheritance: 50% risk to offspring
- Prenatal diagnosis: Available if mutation known
- Preimplantation: Available for both NF1 and NF2
- Family screening: Screen at-risk relatives
Both NF1 and NF2 cause significant complications requiring vigilant monitoring and management. Early detection improves outcomes.
NF1 Complications:
Malignancies:
- MPNST: 5-10% lifetime risk, poor prognosis
- Optic pathway glioma: 15-20%, most benign but can cause visual loss
- Other CNS tumors: Gliomas, astrocytomas
- Pheochromocytoma: 0.1-5.7%, causes hypertension
Neurological:
- Learning disabilities: 30-60% of patients
- ADHD: 30-50% prevalence
- Seizures: 4-7% of patients
- Peripheral neuropathy: From neurofibromas
Skeletal:
-
Scoliosis: 10-26%, may require surgery
-
Tibial pseudarthrosis: 2-5%, difficult to treat
-
Sphenoid wing dysplasia: Rare but characteristic
-
Short stature: Common
-
Short stature: Common. (GH deficiency vs Skeletal dysplasia).
Vascular Manifestations (The Silent Killer):
- Hypertension: Very common. Causes:
- Essential: Most common.
- Renal Artery Stenosis: Fibromuscular dysplasia (FMD) of the renal artery. Screen with Renal MRA.
- Pheochromocytoma: Rare but lethal. Screen with Plasma Metanephrines.
- Aortic Coarctation: Rare.
- Moyamoya Syndrome:
- Pathology: Progressive stenosis of the distal ICA (Circle of Willis).
- Result: Brain forms tiny collaterals ("Puff of Smoke" on Angio).
- Risk: High stroke risk in children.
- Treatment: Revascularisation surgery (EDAMS/Pial synangiosis).
- Cerebrovascular Aneurysms: Increased risk. Screen if symptomatic.
Obstetric Considerations (High Risk Pregnancy):
- Hormonal Sensitivity: Neurofibromas have progesterone receptors.
- Result: 80% of women see rapid tumor growth (size and number) during pregnancy.
- Risk: Plexiform tumors can become massive and obstruct the airway or birth canal.
- Hypertension:
- Preeclampsia: Risk is higher in NF1.
- Pheochromocytoma: MUST be ruled out before delivery (Catastrophic hypertensive crisis during labour).
- Neuraxial Anaesthesia:
- Contraindication: Spinal tumors (check MRI Spine before epidural).
- Scoliosis: May make epidural placement impossible.
The Neurocognitive Phenotype (Hidden Disability):
- General Intelligence: Mean IQ is shifted left (Low Average, ~85-90), but Intellectual Disability (IQ < 70) is rare (8%).
- Visuospatial Deficit: "Can't read a map", "Clumsy child". Poor handwriting.
- ADHD: 50% prevalence. Respond well to Methylphenidate (Ritalin).
- Autism Spectrum Disorder (ASD):
- Overlap: 30-40% of NF1 children have ASD traits.
- Social: Difficulty interpreting social cues, poor eye contact.
- UBO Correlation: The presence of MRI UBOs correlates with cognitive impairment.
Advanced Orthopaedics (The Dystrophic Bone):
- Tibial Dysplasia:
- The "Pencil Point": The tibia tapers to a sharp point at the fracture site.
- Biology: The periosteum is infiltrated by neurofibroma tissue, preventing callus formation.
- Failure: Plating fails. Rodding fails.
- Salvage: Vascularized Fibular Graft or Amputation (Symes).
- Dystrophic Scoliosis:
- Feature: "Scalloping" of the vertebral bodies (dural ectasia).
- Rib Pencilling: Ribs become thin (twisted ribbon sign).
- Surgery: High rate of pseudoarthrosis (hardware failure/pull-out). Needs anterior+posterior fusion.
NF2 Complications:
Hearing Loss:
- Bilateral: Progressive, from vestibular schwannomas
- Complete deafness: Common in advanced disease
- Impact: Significant on quality of life and communication
Neurological:
- Cranial nerve deficits: From schwannomas and meningiomas
- Spinal cord compression: From spinal tumors
- Hydrocephalus: From tumors blocking CSF flow
- Seizures: From brain tumors
Visual:
- Cataracts: Juvenile posterior subcapsular
- Visual loss: From optic nerve tumors or meningiomas
Functional:
- Balance problems: From vestibular dysfunction
- Facial weakness: From facial nerve schwannomas
- Swallowing difficulties: From lower cranial nerve involvement
Prognosis varies significantly between NF1 and NF2, and depends on complications. Early diagnosis and management improve outcomes.
NF1 Prognosis:
- Life expectancy: Reduced by 8-15 years
- Mortality: Primarily from malignancies (MPNST)
- Quality of life: Variable, depends on complications
- Most patients: Live relatively normal lives with monitoring
NF2 Prognosis:
- Life expectancy: Reduced, median survival 15-20 years from diagnosis
- Mortality: From complications of tumors
- Quality of life: Significantly impacted by hearing loss and neurological deficits
- Functional outcomes: Depend on tumor burden and management
Factors Affecting Prognosis:
- Early diagnosis: Enables monitoring and intervention
- Regular surveillance: Detects complications early
- Access to care: Multidisciplinary management improves outcomes
- Genetic counseling: Informed family planning
- Complication burden: More complications worsen prognosis
Long-term Outcomes:
- NF1: Most patients manage well with support
- NF2: Progressive disability from tumors
- Both: Require lifelong monitoring and management
Major Guidelines:
- NIH Consensus Development Conference (1987): Diagnostic criteria for NF1
- International Consensus (2011): NF2 diagnostic criteria and management
- American Academy of Pediatrics (2019): Health supervision for NF1
- European NF Guidelines (2012): Management recommendations
Landmark Clinical Trials:
-
Selumetinib Trial (2020): MEK inhibitor for plexiform neurofibromas
- Significant tumor volume reduction
- First FDA-approved medical therapy for NF1
- Well-tolerated, improves quality of life
- PMID: 32053505
-
Optic Pathway Glioma Studies: Chemotherapy for OPG
- Carboplatin/vincristine effective
- Preserves vision in most patients
- Better outcomes than observation alone
- PMID: 21803784
-
MPNST Treatment Studies: Multimodal therapy
- Wide surgical excision essential
- Adjuvant radiotherapy improves local control
- Chemotherapy for advanced disease
- PMID: 31209658
-
Vestibular Schwannoma Management: Hearing preservation
- Radiotherapy preserves hearing better than surgery
- Early intervention improves outcomes
- Monitoring vs intervention strategies
- PMID: Various
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Genetic Testing Studies: Diagnostic utility
- High detection rates with modern techniques
- Enables family screening and prenatal diagnosis
- Improves diagnostic certainty
- PMID: Various
Meta-Analyses:
- NF1 complications: Systematic review of prevalence (Uusitalo, 2016)
- NF2 management: Review of treatment strategies (Evans, 2009)
- Genetic testing: Utility in diagnosis and management (Yap, 2019)
Systematic Reviews:
- NF1 management: Comprehensive review (Ferner, 2007)
- NF2 tumors: Management strategies (Evans, 2005)
- Quality of life: Impact of NF1 and NF2 (Vranceanu, 2013)
Additional Trial Data:
- RAPID Trial (MEK Inhibitor for Cutaneous NF):
- Drug: Selumetinib Gel (Topical).
- Result: Disappointing. Poor penetration into the dermis.
- mTOR Inhibitor Trials (Sirolimus/Everolimus):
- Rationale: mTOR is downstream of RAS.
- Result: Failed to shrink Plexiform Neurofibromas (Phase II).
- Niche: Some benefit in prolonging time to progression in OPG (chemo-sparing), but inferior to MEK inhibitors.
- Cablo-1 Trial (Cabozantinib):
- Target: Tyrosine Kinase (c-Met, VEGFR2).
- Population: Adult Plexiform Neurofibroma.
- Result: 42% Partial Response rate. Useful alternative for adults (Selumetinib is only approved for children in many regions).
"What is neurofibromatosis?" Neurofibromatosis is a genetic condition that causes tumors to grow on nerves throughout your body. There are two types: NF1 (more common) and NF2 (rarer). NF1 causes skin changes like café-au-lait spots and bumps called neurofibromas, while NF2 mainly causes tumors in the brain and spine, especially affecting hearing. Both conditions run in families, but about half of cases happen by chance with no family history.
"How did I get it?" Neurofibromatosis is inherited from a parent in about 50% of cases - if a parent has it, each child has a 50% chance of inheriting it. In the other 50% of cases, it happens by chance due to a new genetic change (mutation) that wasn't inherited. It's not caused by anything you did or didn't do.
"What symptoms will I have?" Symptoms vary a lot between people, even in the same family. NF1 typically causes:
- Light brown skin spots (café-au-lait spots)
- Small bumps on the skin (neurofibromas)
- Learning difficulties in some people
- Sometimes tumors in the eyes or brain
NF2 typically causes:
- Hearing loss (often in both ears)
- Balance problems
- Tumors in the brain and spine
"How is it diagnosed?" Your doctor will examine you and look for specific features. For NF1, you need at least 2 of: 6 or more café-au-lait spots, neurofibromas, freckling in armpits/groin, eye findings, bone changes, or a family history. For NF2, it's usually diagnosed by finding bilateral hearing nerve tumors. Genetic testing can confirm the diagnosis.
"Is there a cure?" There's no cure, but there are treatments to manage symptoms and complications. Most people with NF1 live relatively normal lives with regular check-ups. Treatment focuses on:
- Monitoring for problems
- Removing tumors if they cause issues
- Managing learning difficulties
- Treating complications as they arise
"Will I need surgery?" Maybe, but not everyone does. Surgery might be needed if:
- Tumors are growing and causing problems
- Tumors are disfiguring or painful
- There are complications like spinal cord compression
- Hearing needs to be preserved in NF2
"What about my children?" If you have neurofibromatosis, each of your children has a 50% chance of inheriting it. Genetic counseling can help you understand the risks and options, including:
- Testing during pregnancy (if you want)
- Testing embryos before implantation (IVF)
- Early screening of children if they inherit it
"How often do I need check-ups?" You'll need regular monitoring, usually:
- Once a year for a full check-up
- More often if there are specific concerns
- Specialized scans (like MRI) as needed
- Eye exams, especially in childhood for NF1
"What should I watch for?" Call your doctor if you notice:
- A bump that's growing quickly or becoming painful
- New weakness or numbness
- Vision changes
- High blood pressure
- Hearing loss (especially in NF2)
- Any new or worsening symptoms
"Will I pass this to my children?"
- Yes, there is a 50% chance for each pregnancy.
- Option 1: Preimplantation Genetic Testing (PGT-M) - IVF to select unaffected embryos.
- Option 2: Prenatal Testing (CVS/Amnio) - Test the baby at 11-15 weeks.
- Option 3: No testing - Scan the baby after birth.
"What about cosmetic surgery?"
- Removing neurofibromas is possible but they can grow back.
- Insurance: In many countries, removing them is considered "Medical" if they cause pain or catch on clothing, but "Cosmetic" if purely for looks.
- Laser: CO2 laser can treat hundreds of small bumps at once ("Laser ablation").
"What happens when I turn 18? (Transition of Care)"
- The Gap: Many patients get lost between Paediatrics and Adult care.
- Adult Issues: Focus shifts from "Learning difficulties" to "Malignancy surveillance" and "Reproduction".
- Plan: You need a named "Adult Lead" (usually a Geneticist or Neurologist) before you leave the children's hospital.
"Can I drive?"
- Generally yes.
- Exceptions: If you have seizures (Brain tumor) or severe vision loss (Optic glioma). You must notify the DVLA/DMV if these complications develop.
"Can I live a normal life?" Yes, many people do. While neurofibromatosis can cause challenges, most people with NF1 manage well with support and monitoring. NF2 can be more challenging due to hearing loss, but with good management and support, people can lead fulfilling lives. Early diagnosis and regular care make a big difference.
Historical Context (The Elephant Man)
- Joseph Merrick (1862-1890): Famous "Elephant Man".
- Misdiagnosis: Long thought to have severe NF1.
- Correction: Modern testing (1986) suggests he actually had Proteus Syndrome (AKT1 mutation).
- Difference: Proteus causes disproportionate, asymmetric overgrowth (Mosaic), whereas NF1 is progressive and generalized.
- Relevance: Highlights the difficulty of diagnosing mosaic overgrowth syndromes.
The SPRINT Trial (Phase II) - NEJM 2020
- Question: Does Selumetinib shrink inoperable plexiform neurofibromas?
- Population: Children with NF1 + Symptomatic Inoperable PN.
- Result:
- 66% had Partial Response (>20% volume reduction).
- Pain scores improved significanty.
- Quality of Life scores improved.
- FDA Approval: Based on this trial, Selumetinib became the first approved drug.
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Friedrich von Recklinghausen (1882): Über die multiplen Fibrome der Haut und ihre Beziehung zu den multiplen Neuromen. (First description).
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Gross AM, et al. Selumetinib in Children with Inoperable Plexiform Neurofibromas. N Engl J Med. 2020;382:1430-1442. (SPRINT). [PMID: 32053505]
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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: 33966033]
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Tora MS, Xenos D, Texakalidis P, et al. Treatment of neurofibromatosis 1-associated malignant peripheral nerve sheath tumors: a systematic review. Neurosurg Rev. 2020;43(2):513-523. PMID: 31209658
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Uusitalo E, Leppävirta J, Koffert A, et al. Incidence and mortality of neurofibromatosis: a total population study in Finland. J Invest Dermatol. 2015;135(3):904-906. PMID: 25268585
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Evans DG, Baser ME, O'Reilly B, et al. Management of the patient and family with neurofibromatosis 2: a consensus conference statement. Br J Neurosurg. 2005;19(1):5-12. PMID: 16147579
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Acar S, Nieblas-Bedolla E, Armstrong AE, et al. A Systematic Review of Recent and Ongoing Clinical Trials in Patients With the Neurofibromatoses. Pediatr Neurol. 2022;134:10-23. PMID: 35759947
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Santoro C, Servedio M, Diana MC, et al. Real-world experience with selumetinib in children with neurofibromatosis type 1: a multicentric retrospective study. J Neurooncol. 2025;165(3):445-453. PMID: 40802118
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Hu X, Wu Z, Wang J, et al. Phase 1 Study of Luvometinib Use in Pediatric Patients with Neurofibromatosis Type 1-Related Unresectable Plexiform Neurofibromas. Target Oncol. 2025;20(6):893-902. PMID: 41139346
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Cassiman C, Legius E, Spileers W, et al. Ophthalmological assessment of children with neurofibromatosis type 1. Eur J Pediatr. 2013;172(10):1327-1333. PMID: 23708214
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Avery RA, Katowitz JA, Fisher MJ, et al. Orbital/Periorbital Plexiform Neurofibromas in Children with Neurofibromatosis Type 1: Multidisciplinary Recommendations for Care. Ophthalmology. 2017;124(1):123-132. PMID: 27817916
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Dalla Via P, Opocher E, Pinello ML, et al. Visual outcome of a cohort of children with neurofibromatosis type 1 and optic pathway glioma followed by a pediatric neuro-oncology program. Neuro Oncol. 2007;9(4):430-437. PMID: 17704361
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National Institutes of Health Consensus Development Conference. Neurofibromatosis. Conference statement. Arch Neurol. 1988;45(5):575-578. PMID: 3128965
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Baser ME, Friedman JM, Wallace AJ, Ramsden RT, Joe H, Evans DG. Evaluation of clinical diagnostic criteria for neurofibromatosis 2. Neurology. 2002;59(11):1759-1765. PMID: 12473761
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Yap YS, McPherson JR, Ong CK, et al. The NF1 gene revisited - from bench to bedside. Oncotarget. 2014;5(15):5873-5892. PMID: 25115390
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Vranceanu AM, Merker VL, Park E, Plotkin SR. Quality of life among adult patients with neurofibromatosis 1, neurofibromatosis 2, and schwannomatosis: a systematic review of the literature. J Neurooncol. 2013;114(3):257-262. PMID: 23836361
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Ibrahim IA, Abdelkader RE, Nada AH, et al. Effect of Everolimus on Prognosis of Neurofibromatosis Type 1 Lesions: A Systematic Review and Meta Analysis. Clin Ther. 2024;46(11):e312-e325. PMID: 39244488
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Elzaafarany O, Elhomosany S, Rincones A, et al. Optic Pathway Glioma: Current Treatment Approaches and Ongoing Clinical Trials. Brain Sci. 2025;15(8):1123. PMID: 40867225
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Vernimmen V, De Rycke M, Moutou C, et al. Preimplantation genetic testing for neurofibromatosis type 1: molecular genetic aspects and impact on reproductive counseling. Hum Reprod. 2025;40(12):2856-2865. PMID: 41289058
Q1: What is the genetic mechanism of NF1? A: It is a loss-of-function mutation in the NF1 tumor suppressor gene on chromosome 17q11.2. The gene encodes Neurofibromin, a GAP (GTPase Activating Protein) that downregulates the RAS-MAPK pathway. Without it, RAS is constitutively active, leading to cell proliferation.
Q2: Explain the "Two-Hit Hypothesis" in NF1. A: Knudson's hypothesis states that individuals inherit one mutated copy (germline) and are heterozygous in all cells. Tumors form when the widespread second copy (wild type) is mutated (somatic hit) in a specific cell (e.g., Schwann cell), rendering it null for neurofibromin.
Q3: Features distinguishing NF1 from NF2? A:
- NF1: Ch17. Neurofibromin. Lisch Nodules. Neurofibromas. Optic Gliomas.
- NF2: Ch22. Merlin. Cataracts. Schwannomas (Bilateral VS). Meningiomas.
Q4: What are Lisch Nodules and do they affect vision? A: They are iris hamartomas (melanocytic). They appear dome-shaped and yellow-brown on slit lamp. They do NOT affect vision but are highly specific for diagnosis (>90% of adults).
Q5: What is the risk of malignancy in NF1? A:
- MPNST: 8-13% lifetime risk. Arise from pre-existing plexiform neurofibromas.
- Gliomas: 15-20% risk of Optic Pathway Glioma.
- Pheochromocytoma: <1% general, but 5% in hypertensives.
- Breast Cancer: Risk is increased ($RR \approx 3.5$) in women <50.
- GIST: Increased risk of Gastrointestinal Stromal Tumors.
Q6: How do you manage a Plexiform Neurofibroma? A:
- Observation: If asymptomatic.
- Medical: MEK Inhibitor (Selumetinib) for inoperable symptomatic tumors (SPRINT trial).
- Surgical: Debulking is difficult due to vascularity and nerve infiltration. Total resection often sacrifices the nerve.
Q7: Signs of malignant transformation in a neurofibroma? A: "Rapid growth, Pain (especially night pain), Change in consistency (harder), New neurological deficit".
Q8: Explain the Tibial Pseudarthrosis pathology. A: Anterolateral bowing of the tibia presents at birth. The periosteum is abnormal (hamartomatous). If fracture occurs, union is blocked by this tissue. Treatment involves resection of the pseudarthrosis, BMPs, and rodding (Williams rod) or vascularized fibular graft.
Q9: What is the "Buttonhole Sign"? A: When palpating a cutaneous neurofibroma, it is soft and can be pushed down into the dermis (invaginated) like a button through a buttonhole. This confirms it is discrete and cutaneous, not subcutaneous/plexiform.
Q10: Why do NF1 patients get hypertension? A:
- Essential (most common).
- Renal Artery Stenosis (fibromuscular dysplasia).
- Pheochromocytoma (catecholamine excess).
- Aortic Coarctation (rare).
Q11: Can a woman with NF1 have a normal pregnancy? A: Yes, but it is high risk. Tumors grow rapidly. Hypertension is a risk. Epidurals may be difficult (scoliosis/spinal tumors). There is a 50% risk of transmission to the fetus.
Q12: What is "Segmental NF1"? A: It is Mosaicism. A post-zygotic mutation leads to features (spots/bumps) confined to one region of the body. Risk of transmission is low unless gonadal mosaicism is present.
Q13: List the criteria for NF2. A: Bilateral Vestibular Schwannomas is the hallmark. Alternatively, a first-degree relative plus unilateral VS or multiple other tumors (Meningioma, Schwannoma, Glioma, Cataract).
Q14: What is the "Cataract" of NF2? A: Juvenile Posterior Subcapsular Cataract (or cortical opacity). Often the first sign in children.
Q15: What is Neurofibromatosis-Noonan Syndrome? A: A phenotype with features of both (Spots + Webbed neck/Pulmonic stenosis). Usually due to a specific NF1 mutation, sometimes PTPN11.
Technical Appendix: Surgical Excision of Cutaneous Neurofibroma
- Indication: Pain, disfigurement, bleeding.
- Anaesthesia: Local (Lidocaine with Adrenaline).
- Incision: Elliptical excision around the lesion (include overlaying skin).
- Dissection: The tumor separates easily from the subcutaneous fat.
- Haemostasis: Bipolar diathermy (can be vascular).
- Closure: Deep dermal (3-0 Monocryl) and Subcuticular (4-0 Monocryl).
Technical Appendix: Management of Plexiform Neurofibroma (Debulking)
- Setting: General Anaesthesia. Cross-match blood (high bleeding risk).
- Exposure: Wide exposure of the involved region.
- Dissection:
- Identify the normal nerve entering and exiting the mass (if possible).
- Use a nerve stimulator to identify functional fascicles.
- The tumor infiltrates the nerve; a plane is often absent.
- Resection:
- Perform an intra-capsular debulking if the nerve must be saved.
- Perform en-bloc resection if the nerve is non-functional or sacrificed (requires graft).
- Haemostasis: Critical. Use Harmonic scalpel, Ligasure, or multiple transfixion sutures.
- Closure: Drains are mandatory (large dead space).
Case 1: The Child with Spots
Presentation: A 5-year-old girl is brought in by her mother who noticed "dirty marks" on her back. Examination reveals 8 café-au-lait macules (>5mm) and freckling in the axilla. She is otherwise well and meeting milestones. Discussion:
- Does she meet criteria? Yes (CALs + Freckling = 2 criteria).
- Next Step: Ophthalmology referral (exclude Lisch/OPG). Genetic testing (confirm NF1 vs Legius).
- Counseling: Reassure parents that severe complications (MPNST/Tibial dysplasia) are rare. Most children lead normal lives.
Case 2: The Teenager with Back Pain
Presentation: A 14-year-old boy with known NF1 presents with worsening back pain and "uneven shoulders". He has noticed his right leg feels shorter. Discussion:
- Diagnosis: Dystrophic Scoliosis. The "short leg" may be due to pelvic obliquity or a tibial pseudarthrosis (though usually presents earlier).
- Red Flag: Rapid progression is typical in dystrophic curves.
- Action: Whole Spine MRI (screen for dural ectasia and spinal tumors). Orthopaedic referral for likely fusion.
Case 3: The Rapidly Growing Lump
Presentation: A 32-year-old man with NF1 complains of a lump in his thigh that has been there for years (Plexiform) but has suddenly doubled in size over 3 months and is now painful at night. Discussion:
- Diagnosis: Suspect MPNST until proven otherwise.
- Red Flags: Rapid growth, Night pain, Hard consistency.
- Action: Urgent PET-CT and Biopsy. Do NOT simply excise (high risk of seeding).
- Prognosis: If MPNST, 5-year survival is <50%.
Case 4: The Pregnant Woman
Presentation: A 28-year-old woman with NF1 is 12 weeks pregnant. She is worried about her baby and her own health. Discussion:
- Risks to Mom: Hypertension (Rule out Pheochromocytoma NOW). Tumor growth (Progesterone effect).
- Risks to Baby: 50% chance of inheritance.
- Action: Genetic counseling. Monitoring BP. Anesthesiology review (Spine MRI if considering epidural).