What are the signs, symptoms, and management options for a patient with Neurofibromatosis 1 (NF1)?

Neurofibromatosis Type 1: Clinical Presentation and Management

Adults with NF1 require lifelong multidisciplinary surveillance focused on early detection of malignant peripheral nerve sheath tumors (MPNST), breast cancer in women, pheochromocytoma, and cardiovascular complications, as these are the primary drivers of the 8-15 year reduction in life expectancy. 1, 2

Clinical Signs and Symptoms

Dermatologic Manifestations

• Café-au-lait macules (≥6 spots measuring ≥5mm prepubertal or ≥15mm postpubertal) are present in nearly all patients and serve as a diagnostic criterion 2, 3
• Cutaneous neurofibromas occur in >99% of adults with NF1, making this the most common tumor manifestation 1
• These lesions begin appearing at puberty, increase in number with age, and undergo rapid growth during puberty and pregnancy (60% of pregnant women develop new lesions) 1
• Skinfold freckling (axillary and inguinal) is characteristic 3
• Cutaneous neurofibromas cause significant morbidity through cosmetic burden, tenderness, bleeding, itching, and negative quality of life impacts 1

Tumor Manifestations

• Plexiform neurofibromas are highly vascular and can spontaneously bleed, sometimes life-threateningly 1
• MPNST risk increases dramatically with age: 8.5% by age 30,12.3% by age 50, and 15.8% by age 85 1, 2, 4
• High-grade MPNSTs are usually fatal with standardized mortality ratio >2,000 1
• Warning signs of malignant transformation: progressive severe pain, rapid tumor growth, new unexplained neurologic symptoms, changes in existing tumor volume 2, 4
• Optic pathway gliomas and glioblastoma can occur 3
• Gastrointestinal stromal tumors (GISTs) present around age 50 with a 200-fold increased risk 5

Cardiovascular Complications

• Hypertension is common and increases with age; causes include essential hypertension (most common), pheochromocytoma, and renal artery stenosis in young adults 1
• Pheochromocytoma symptoms: paroxysmal hypertension, headache, palpitations, diaphoresis 2
• NF1-associated vasculopathy affects small, medium, and large vessels (0.4-6.4% incidence overall; 2-5% cerebrovascular) 1
• Vascular abnormalities include arterial stenosis, moyamoya arteriopathy, aneurysms, arteriovenous malformations, and cardiac valve abnormalities 1
• Stroke risk (predominantly hemorrhagic) is increased, particularly in pregnant women 1
• Renal artery stenosis occurs in up to 1% of individuals 1

Musculoskeletal Manifestations

• Scoliosis (dystrophic and nondystrophic forms) with associated dural ectasia, vertebral degenerative changes, and spinal compression 1
• Dystrophic scoliosis presents in childhood with rapid progression; nondystrophic form can develop into adulthood with 50% showing curve progression 1
• Long bone dysplasia/pseudarthrosis, particularly congenital tibial pseudarthrosis 1, 6
• Sphenoid wing dysplasia 1
• Osteoporosis and decreased bone mineral density occur at earlier ages with 5.2-fold increased fracture risk in adults >41 years 1

Neuropsychiatric Manifestations

• Learning disabilities, attention deficits, and social/behavioral problems significantly impact quality of life 3, 7
• Depression, chronic pain, neuropathy, pruritus, and fingertip pain are common 2

Malignancy Risk

• Breast cancer occurs at significantly younger ages in women with NF1 7
• Other associated malignancies: malignant gliomas, rhabdomyosarcoma, thyroid cancer, malignant fibrous histiocytoma, somatostatinomas, and juvenile myelomonocytic leukemia 1

Management Approach

Essential Surveillance Strategy

All adults with NF1 should be evaluated by and have care coordinated through a specialized NF1 clinic, as this multidisciplinary approach significantly reduces morbidity and mortality. 1, 2, 4

Annual Screening Requirements

• Complete physical examination assessing for new or changing neurofibromas, particularly warning signs of MPNST 2, 4
• Blood pressure measurement to detect hypertension from any cause 4
• Scoliosis evaluation with Adam's forward bend test; refer to orthopedics if abnormal 1, 4
• Assessment for pheochromocytoma symptoms (diaphoresis, palpitations, paroxysmal hypertension) 2
• Screening for neuropathy, depression, chronic pain, and pruritus 2, 4

Breast Cancer Screening for Women

• Begin annual mammography at age 30 years (10 years earlier than general population) 2, 4
• Consider breast MRI with contrast between ages 30-50 years 2, 4

Imaging Surveillance

• Baseline MRI of known or suspected non-superficial plexiform neurofibromas to establish size and characteristics for future comparison 2, 4
• MRI is preferred over CT to avoid ionizing radiation exposure 2
• 18F-FDG PET/CT if malignant transformation suspected (sensitivity 0.89, specificity 0.95 for MPNST detection) 2
• For patients with GFR >30mL/min and suspected renal artery stenosis, contrast-enhanced MRA is highly sensitive and specific 1

Laboratory Testing

• Plasma free metanephrines if pheochromocytoma clinically suspected (most sensitive and specific single test) 2
• 24-hour urine catecholamines and metanephrines if plasma testing shows less than fourfold elevation 2
• Vitamin D supplementation to reach sufficient serum 25-hydroxyvitamin D concentrations, despite lack of published efficacy data for fracture prevention 1
• Consider DXA scanning and fracture risk assessment tools (entering NF1 as a risk factor) for osteoporosis evaluation 1

Tumor Management

• Surgical excision, laser removal, or electrodesiccation for symptomatic cutaneous neurofibromas 1
• For suspected MPNST, obtain minimum 6 core biopsies (4-8mm each) if safe and feasible 2
• Ensure evaluation by subspecialized pathologist for cytologic atypia, loss of neurofibromatous architecture, hypercellularity, mitotic count, and necrosis 2
• Plexiform neurofibroma surgery carries significant intraoperative transfusion risk due to high vascularity 1

Gastrointestinal Surveillance

• No routine GI imaging surveillance recommended for asymptomatic adults 5
• Follow general population colonoscopy screening guidelines 1, 5
• For suspected GIST, endoscopic ultrasound with fine needle aspiration or core needle biopsy is preferred 5
• Complete surgical resection with R0 margins is standard treatment for localized GISTs 5

Pregnancy Management

• Refer to high-risk obstetrician for all pregnant women with NF1 1, 4
• Educate about 50% offspring recurrence risk for each pregnancy 1, 2, 4
• Preanesthesia neuraxial imaging for spinal/paraspinal neurofibromas is probably not needed; consider spinal anesthesia if concerns exist 1
• Monitor for increased hypertension and cerebrovascular complications during pregnancy 1
• Expect increase in cutaneous neurofibroma size and number during pregnancy 1

Genetic Counseling

• Preimplantation genetic diagnosis (PGD) and prenatal diagnosis are available options 1, 2, 4
• Individuals with de novo mutations, somatic mosaicism, and large genomic rearrangements are less likely to have PGD available due to technical limitations 1

Osteoporosis Management

• Bisphosphonate therapy based on DXA values and clinical history using fracture risk assessment tools 1
• Note that in vitro studies suggest NF1 osteoclasts display reduced sensitivity to bisphosphonates, raising questions about optimal dosing 1

Critical Clinical Pitfalls

• Most common symptoms have common explanations: Most hypertension is essential (not pheochromocytoma), most back pain is not MPNST-related, most headaches are not tumor-associated 1
• However, maintain high index of suspicion for NF1-specific complications and educate patients about warning signs requiring urgent evaluation 1
• Avoid routine vascular screening in asymptomatic patients, as no data support this practice and NF1 vasculopathy is frequently asymptomatic 1
• Do not delay referral to specialized NF1 clinic, as coordinated multidisciplinary care is essential for optimal outcomes 1, 2, 4
• Remember pregnancy risks: Women require enhanced surveillance during pregnancy for hypertension, cerebrovascular complications, and neurofibroma growth 1