Neurofibromatosis

Overview

Neurofibromatosis (NF) is a group of genetic disorders that primarily affect the growth and development of nerve cell tissue. These conditions cause tumors called neurofibromas to grow on nerves throughout the body, and can also affect skin pigmentation and bone development. The disorder is caused by mutations in specific genes that normally function as tumor suppressors, regulating cell growth and division.

There are three main types of neurofibromatosis: NF1 (neurofibromatosis type 1), NF2 (neurofibromatosis type 2), and schwannomatosis. NF1, also known as von Recklinghausen disease, is the most common form, accounting for about 90% of all cases. It typically presents with café-au-lait spots (light brown skin patches), neurofibromas, and various other complications. NF2 is characterized primarily by the development of schwannomas, particularly bilateral acoustic neuromas that can cause hearing loss. Schwannomatosis, the rarest form, involves the development of schwannomas throughout the body but typically spares the eighth cranial nerve.

Neurofibromatosis is inherited in an autosomal dominant pattern, meaning only one copy of the altered gene is needed to cause the disorder. However, approximately 50% of cases result from new mutations with no family history. The severity and specific manifestations can vary greatly, even within the same family. While the tumors are usually benign, they can cause significant complications depending on their size and location, potentially affecting vision, hearing, learning, cardiovascular function, and overall quality of life.

Management of neurofibromatosis requires a multidisciplinary approach with regular monitoring and surveillance for complications. While there is no cure, various treatments can help manage symptoms and complications. Recent advances in understanding the molecular basis of these disorders have led to the development of targeted therapies, offering new hope for patients. With proper medical care and monitoring, many people with neurofibromatosis can lead relatively normal lives, though some may face significant challenges requiring ongoing medical support.

Symptoms

The symptoms of neurofibromatosis vary significantly depending on the type and individual presentation. Symptoms can appear at birth, develop during childhood, or emerge later in life as the condition progresses.

Primary Symptoms

Neurofibromatosis Type 1 (NF1) Symptoms

Skin Manifestations

• Café-au-lait spots (light brown patches) - present in over 95% of patients
• Neurofibromas (soft, flesh-colored tumors on or under skin)
• Freckling in unusual areas (armpits, groin)
• Plexiform neurofibromas (larger, more complex tumors)

Eye Problems

• Lisch nodules (harmless brown spots on the iris)
• Optic pathway gliomas (tumors of the optic nerve)
• Vision problems or blindness
• Glaucoma

Bone and Skeletal Issues

• Scoliosis (curvature of the spine)
• Bone deformities (bowing of legs)
• Short stature
• Macrocephaly (enlarged head)
• Osteoporosis or osteopenia

Learning and Cognitive Issues

• Learning disabilities (present in 50-70% of children)
• Attention deficit hyperactivity disorder (ADHD)
• Speech delays
• Fine and gross motor skill problems
• Social and emotional difficulties

Neurofibromatosis Type 2 (NF2) Symptoms

Hearing and Balance Problems

• Progressive hearing loss (often the first symptom)
• Tinnitus (ringing in the ears)
• Balance problems and dizziness
• Facial numbness or weakness

Neurological Symptoms

• Bilateral acoustic neuromas (schwannomas of the 8th cranial nerve)
• Meningiomas (brain and spinal cord tumors)
• Spinal cord tumors
• Peripheral neuropathy

Eye Problems

• Cataracts (often juvenile-onset)
• Retinal abnormalities
• Visual field defects
• Epiretinal membranes

Schwannomatosis Symptoms

• Multiple schwannomas throughout the body
• Chronic pain (often the primary symptom)
• Numbness and weakness
• Headaches
• Typically spares hearing (unlike NF2)

Complications and Advanced Symptoms

Cardiovascular Issues

• High blood pressure
• Heart defects
• Vascular abnormalities
• Renal artery stenosis

Malignant Transformation

• Malignant peripheral nerve sheath tumors (MPNSTs)
• Brain tumors (gliomas)
• Pheochromocytomas
• Gastrointestinal stromal tumors (GISTs)

Endocrine Problems

• Precocious or delayed puberty
• Growth hormone abnormalities
• Thyroid problems
• Adrenal gland tumors

Causes

Neurofibromatosis is caused by mutations in specific genes that normally function as tumor suppressors. These genetic alterations disrupt normal cell growth and division, leading to the characteristic features of the condition.

Genetic Basis

NF1 Gene Mutation

Neurofibromatosis type 1 is caused by mutations in the NF1 gene:

• Location: Chromosome 17q11.2
• Function: Produces neurofibromin protein
• Role: Tumor suppressor that regulates cell growth
• Mechanism: Loss of neurofibromin leads to uncontrolled cell proliferation
• Size: One of the largest known genes (350,000 base pairs)

NF2 Gene Mutation

Neurofibromatosis type 2 results from mutations in the NF2 gene:

• Location: Chromosome 22q12.2
• Function: Produces merlin (schwannomin) protein
• Role: Cytoskeletal protein that regulates cell shape and movement
• Mechanism: Loss of merlin affects cell adhesion and signaling
• Target cells: Primarily affects Schwann cells and meninges

Schwannomatosis Genes

Multiple genes can cause schwannomatosis:

• SMARCB1: Most common cause (chromosome 22q11.23)
• LZTR1: Second most common cause (chromosome 22q11.21)
• Other genes: Additional genes being identified
• Unknown causes: Some cases have no identified mutation

Inheritance Patterns

Autosomal Dominant Inheritance

• Pattern: Only one mutated copy needed to cause disease
• Risk: 50% chance of passing to each child
• Penetrance: Nearly 100% for NF1, variable for NF2
• Expressivity: Highly variable even within families

New Mutations (Sporadic Cases)

• Frequency: About 50% of NF1 cases, 50% of NF2 cases
• Cause: New mutations occurring during gamete formation
• Risk factors: Advanced paternal age may increase risk
• Family history: No previous family history of the condition

Molecular Mechanisms

Tumor Suppressor Function

Normal gene products prevent tumor formation:

• Neurofibromin: Regulates RAS protein activity
• Cell cycle control: Prevents excessive cell division
• Growth signaling: Modulates growth factor responses
• Apoptosis: Promotes programmed cell death when appropriate

Two-Hit Hypothesis

Tumor development requires loss of both gene copies:

• First hit: Inherited or early acquired mutation
• Second hit: Somatic mutation in specific cells
• Result: Complete loss of tumor suppressor function
• Timing: Explains age-related tumor development

Environmental Factors

While neurofibromatosis is primarily genetic, some factors may influence expression:

• Hormonal changes: Puberty and pregnancy may worsen symptoms
• Radiation exposure: May increase tumor risk
• Trauma: May trigger neurofibroma growth
• Other genetic factors: Modifier genes may influence severity

Somatic Mosaicism

Some individuals have a mixture of normal and mutated cells:

• Mechanism: Mutation occurs after conception
• Presentation: May have milder or localized symptoms
• Diagnosis: Can be challenging to diagnose
• Inheritance risk: Lower but present risk to offspring

Risk Factors

Since neurofibromatosis is primarily a genetic condition, the main risk factors are related to inheritance and family history. However, several factors can influence the development and severity of symptoms.

Genetic Risk Factors

Family History

• Parent with NF: 50% chance of inheriting the condition
• Affected sibling: Small increased risk due to parental mosaicism
• Extended family history: May indicate familial pattern
• Consanguinity: Marriage between relatives may increase risk of rare forms

Parental Factors

• Advanced paternal age: Slightly increased risk of new mutations
• Parental mosaicism: Parent may have mild or unrecognized disease
• Germline mosaicism: Mutations present only in reproductive cells

Demographic Risk Factors

• No ethnic predilection: Affects all racial and ethnic groups equally
• Gender: Equal distribution between males and females
• Geographic distribution: Found worldwide with similar prevalence
• Socioeconomic status: No association with socioeconomic factors

Modifying Factors

Hormonal Influences

• Puberty: May trigger rapid growth of neurofibromas
• Pregnancy: Can cause existing tumors to grow larger
• Menopause: May stabilize or reduce tumor growth
• Hormone therapy: May influence tumor development

Environmental Factors

• Radiation exposure: May increase risk of malignant transformation
• Trauma: Physical injury may stimulate neurofibroma growth
• Surgery: Incomplete tumor removal may lead to regrowth
• Infections: No known infectious triggers

Factors Affecting Severity

Type of Mutation

• Complete gene deletion: Often associated with more severe symptoms
• Point mutations: Variable severity depending on location
• Truncating mutations: Generally more severe than missense mutations
• Mosaicism: Usually results in milder symptoms

Modifier Genes

• Genetic background: Other genes may influence symptom severity
• Epigenetic factors: Gene expression modifications
• Copy number variations: Large chromosomal changes
• Single nucleotide polymorphisms: Common genetic variants

Age-Related Risk Factors

Prenatal Period

• Advanced maternal age: Slight increase in chromosomal abnormalities
• Prenatal exposures: No known teratogenic effects
• Intrauterine growth: May be affected in severe cases

Childhood and Adolescence

• Growth spurts: May accelerate tumor development
• Learning challenges: More apparent during school years
• Social factors: Visible symptoms may affect psychological development

Adulthood

• Reproductive planning: Genetic counseling considerations
• Malignant transformation: Increased risk with age
• Cumulative effects: Progressive nature of some complications

Protective Factors

While there are no known protective factors that prevent neurofibromatosis, some factors may help minimize complications:

• Early diagnosis and monitoring: Allows prompt treatment of complications
• Regular medical care: Prevents or minimizes secondary problems
• Genetic counseling: Informed reproductive decisions
• Avoiding unnecessary radiation: Reduces malignancy risk
• Healthy lifestyle: May help with overall well-being

Diagnosis

Diagnosing neurofibromatosis involves clinical evaluation, imaging studies, and sometimes genetic testing. Different types of NF have specific diagnostic criteria that help distinguish between the conditions.

NF1 Diagnostic Criteria

Diagnosis requires at least two of the following seven criteria:

1. Café-au-lait macules: ≥6 spots >5mm in prepubertal individuals or >15mm in postpubertal individuals
2. Neurofibromas: ≥2 neurofibromas of any type or 1 plexiform neurofibroma
3. Freckling: In axillary or inguinal regions
4. Optic glioma: Tumor of the optic pathway
5. Lisch nodules: ≥2 iris hamartomas
6. Bone lesion: Characteristic bone abnormality (sphenoid dysplasia or tibial pseudarthrosis)
7. Family history: First-degree relative with NF1 by these criteria

NF2 Diagnostic Criteria

Diagnosis is based on the Manchester criteria:

Definite NF2

• Bilateral acoustic schwannomas (acoustic neuromas) on MRI
• First-degree family history of NF2 AND unilateral acoustic schwannoma at age <30 years OR any two of: meningioma, glioma, schwannoma, juvenile posterior subcapsular cataract
• Unilateral acoustic schwannoma at age <30 years AND any two of: meningioma, glioma, schwannoma, juvenile posterior subcapsular cataract
• Multiple meningiomas (≥2) AND unilateral acoustic schwannoma at age <30 years OR any one of: glioma, schwannoma, juvenile posterior subcapsular cataract

Probable NF2

• Unilateral acoustic schwannoma at age <30 years
• Any two of: meningioma, glioma, schwannoma, juvenile posterior subcapsular cataract
• Multiple meningiomas (≥2) alone

Schwannomatosis Diagnostic Criteria

Definite Schwannomatosis

• Age ≥30 years with ≥2 non-intradermal schwannomas, at least one with histologic confirmation AND no evidence of vestibular tumor on high-quality MRI
• One pathologically confirmed non-vestibular schwannoma plus a first-degree relative meeting above criteria

Possible Schwannomatosis

• Age <30 years with ≥2 non-intradermal schwannomas, at least one with histologic confirmation AND no evidence of vestibular tumor on high-quality MRI
• Age ≥45 years with ≥2 non-intradermal schwannomas, at least one with histologic confirmation AND no evidence of vestibular tumor AND no known constitutional NF2 mutation

Clinical Evaluation

Medical History

• Family history: Three-generation pedigree analysis
• Developmental history: Learning difficulties, delays
• Symptom timeline: When features first appeared
• Previous diagnoses: Related medical conditions

Physical Examination

• Skin examination: Full body inspection for café-au-lait spots, neurofibromas, freckling
• Ophthalmologic exam: Slit-lamp examination for Lisch nodules, cataracts
• Neurological assessment: Development, coordination, reflexes
• Blood pressure: Check for hypertension
• Growth parameters: Height, weight, head circumference

Imaging Studies

Brain and Spine MRI

• Brain MRI: Screen for optic gliomas, other CNS tumors
• Spine MRI: Look for spinal neurofibromas, scoliosis
• With contrast: Better visualization of tumors
• Follow-up imaging: Monitor tumor growth over time

Other Imaging

• Audiometry: Hearing tests for NF2 suspicion
• Bone X-rays: Check for skeletal abnormalities
• CT scans: Detailed bone imaging when needed
• Ultrasound: Evaluate for masses or organ involvement

Genetic Testing

Indications for Testing

• Clinical diagnosis unclear: When criteria not fully met
• Family planning: Confirm diagnosis for counseling
• Prenatal diagnosis: For at-risk pregnancies
• Research participation: Some studies require genetic confirmation

Testing Methods

• Sequence analysis: Look for point mutations
• Deletion/duplication analysis: Detect large gene rearrangements
• Multiplex ligation-dependent probe amplification (MLPA): Screen for deletions
• Next-generation sequencing: Comprehensive gene panels

Laboratory Tests

• Routine labs: Complete blood count, basic metabolic panel
• Endocrine testing: Growth hormone, thyroid function if indicated
• Tumor markers: If malignancy suspected
• Genetic testing: Confirmatory when indicated

Differential Diagnosis

• Multiple café-au-lait spots: McCune-Albright syndrome, Legius syndrome
• Multiple tumors: Familial cancer syndromes
• Learning disabilities: Other genetic syndromes
• Hearing loss: Other causes of sensorineural hearing loss
• Schwannomas: Sporadic tumors, other genetic conditions

Prenatal Diagnosis

• Genetic testing: If family mutation known
• Fetal MRI: Limited utility in most cases
• Ultrasound: May detect some skeletal abnormalities
• Genetic counseling: Discuss options and implications

Treatment Options

While there is no cure for neurofibromatosis, treatment focuses on managing symptoms, preventing complications, and improving quality of life. A multidisciplinary approach involving various specialists is often necessary.

Surgical Management

Tumor Removal

• Indications: Tumors causing pain, functional impairment, or cosmetic concerns
• Neurofibromas: Can be surgically removed, but may recur
• Plexiform neurofibromas: Complete removal often difficult due to extensive involvement
• Acoustic neuromas: Surgical resection or stereotactic radiosurgery
• Malignant tumors: Wide excision with adjuvant therapy

Orthopedic Surgery

• Scoliosis correction: Spinal fusion for severe curves
• Bone deformities: Corrective osteotomies
• Pseudarthrosis repair: Bone grafting and fixation
• Limb length discrepancy: Lengthening procedures

Neurosurgical Procedures

• Brain tumor resection: For accessible CNS tumors
• Spinal tumor removal: Preserve neurological function
• Shunt placement: For hydrocephalus
• Nerve decompression: Relieve pressure symptoms

Medical Therapy

Targeted Therapies

• Selumetinib (Koselugo): FDA-approved MEK inhibitor for inoperable plexiform neurofibromas in children
• Mechanism: Blocks MEK protein in RAS-MAPK pathway
• Benefits: Can shrink tumors and improve symptoms
• Side effects: Skin rash, diarrhea, fatigue

Symptomatic Treatment

• Pain management: NSAIDs, anticonvulsants, opioids when needed
• Hypertension: ACE inhibitors, beta-blockers
• ADHD medications: Stimulants or non-stimulants
• Growth hormone: For short stature if deficient

Radiation Therapy

Stereotactic Radiosurgery

• Acoustic neuromas: Alternative to surgery for NF2
• Brain tumors: Precise targeting of small tumors
• Advantages: Non-invasive, outpatient procedure
• Risks: Potential for malignant transformation

Conventional Radiation

• Limited use: Generally avoided due to malignancy risk
• Optic gliomas: Sometimes used for progressive tumors
• Malignant tumors: Adjuvant therapy after surgery

Supportive Care

Educational Support

• Special education services: Individualized education plans (IEPs)
• Learning disability support: Tutoring, accommodations
• Speech therapy: For communication difficulties
• Occupational therapy: Fine motor skill development
• Physical therapy: Strength and coordination

Psychological Support

• Counseling: Individual and family therapy
• Support groups: Connect with other families
• Coping strategies: Dealing with chronic illness
• Social skills training: Especially for children

Hearing and Vision Management

Hearing Loss Treatment

• Hearing aids: For mild to moderate loss
• Cochlear implants: For severe sensorineural loss
• Brainstem implants: When cochlear implants not suitable
• Sign language: Communication alternative

Vision Problems

• Glasses or contacts: Refractive errors
• Cataract surgery: For visually significant cataracts
• Glaucoma treatment: Eye drops, surgery if needed
• Low vision aids: Magnifiers, adaptive devices

Experimental Treatments

Clinical Trials

• Novel targeted therapies: New MEK and mTOR inhibitors
• Immunotherapy: Checkpoint inhibitors for malignant tumors
• Gene therapy: Early research stages
• Combination therapies: Multiple drug approaches

Monitoring and Surveillance

Regular Assessments

• Annual comprehensive exams: Multi-specialty evaluation
• Growth monitoring: Height, weight, development
• Blood pressure checks: Screen for hypertension
• Vision screening: Annual ophthalmologic exams
• Hearing tests: For NF2 patients

Imaging Surveillance

• Brain MRI: Monitor CNS tumors
• Spine imaging: Check for spinal tumors
• Tumor assessment: Size and growth monitoring
• Malignancy screening: Watch for concerning changes

Prevention

Since neurofibromatosis is a genetic disorder, primary prevention is not possible. However, genetic counseling, early detection, and management of complications can help minimize the impact of the condition.

Genetic Counseling

Preconception Counseling

• Risk assessment: Determine likelihood of transmission
• Family planning: Discuss reproductive options
• Genetic testing: Confirm diagnosis before pregnancy
• Partner screening: Rule out unrecognized NF in partner

Prenatal Options

• Prenatal diagnosis: Testing during pregnancy if gene mutation known
• Preimplantation genetic diagnosis (PGD): IVF with genetic testing
• Sperm or egg donation: Use of unaffected gametes
• Adoption: Alternative family building option

Early Detection and Monitoring

Newborn and Infant Screening

• Skin examination: Look for café-au-lait spots
• Developmental assessment: Monitor growth and milestones
• Family history awareness: Inform healthcare providers
• Regular check-ups: Maintain consistent medical care

Childhood Surveillance

• Annual examinations: Comprehensive physical exams
• Vision screening: Early detection of optic gliomas
• Learning assessment: Educational support when needed
• Growth monitoring: Track development patterns

Complication Prevention

Malignancy Prevention

• Avoid unnecessary radiation: Minimize CT scans and X-rays
• Regular monitoring: Watch for changes in existing tumors
• Prompt evaluation: Investigate new or changing symptoms
• Lifestyle factors: Maintain healthy habits

Cardiovascular Prevention

• Blood pressure monitoring: Regular screening for hypertension
• Heart-healthy diet: Low sodium, balanced nutrition
• Regular exercise: As tolerated and appropriate
• Weight management: Maintain healthy body weight

Educational and Developmental Support

Learning Disability Prevention

• Early intervention: Start support services early
• Educational planning: Develop appropriate accommodations
• Skill building: Focus on strengths and abilities
• Social support: Encourage peer interactions

Psychosocial Prevention

• Self-esteem building: Focus on positive attributes
• Coping skills: Develop resilience strategies
• Family support: Strengthen family relationships
• Community connections: Participate in support groups

Secondary Prevention Strategies

Tumor Growth Prevention

• Hormonal considerations: Discuss risks during pregnancy
• Trauma avoidance: Protect areas with neurofibromas
• Sun protection: May help with skin changes
• Stress management: Maintain overall health

Bone Health

• Calcium and vitamin D: Adequate intake for bone health
• Weight-bearing exercise: Strengthen bones and muscles
• Fall prevention: Safety measures to prevent fractures
• Orthopedic monitoring: Regular bone health assessments

Research and Future Prevention

Clinical Research

• Participate in studies: Contribute to understanding
• Registry enrollment: Natural history studies
• Biobanking: Tissue and blood sample donation
• Clinical trials: Access to experimental treatments

Future Therapies

• Gene therapy: Potential future treatment
• Targeted prevention: Drugs to prevent tumor formation
• Biomarkers: Early detection of complications
• Personalized medicine: Individualized treatment approaches

Family and Community Prevention

• Education: Inform family members about NF
• Screening: Evaluate other family members
• Advocacy: Support research and awareness
• Resources: Connect with NF organizations

When to See a Doctor

People with neurofibromatosis require regular medical monitoring, but certain symptoms warrant immediate attention or urgent evaluation.

Seek Emergency Care Immediately

• Sudden severe headache unlike any previous headache
• Rapid onset of vision loss or double vision
• Sudden hearing loss or severe dizziness
• Seizures or loss of consciousness
• Sudden weakness or numbness in arms or legs
• Difficulty breathing or severe chest pain
• Signs of spinal cord compression (weakness, bladder/bowel problems)
• Rapidly growing mass or tumor

Schedule Urgent Appointment

• New or worsening abnormal involuntary movements
• New groin mass or rapidly enlarging existing mass
• Changes in existing neurofibromas (hardening, rapid growth, pain)
• Persistent or worsening headaches
• New vision or hearing problems
• Unexplained pain, especially nerve-related pain
• New neurological symptoms (weakness, numbness, coordination problems)
• Significant changes in abnormal appearing skin

Routine Medical Consultation

• Family history of neurofibromatosis
• Multiple café-au-lait spots in a child
• Learning difficulties or developmental delays
• Questions about genetic testing or family planning
• Need for educational support or accommodations
• Cosmetic concerns about visible tumors

Signs Requiring Medical Evaluation

In Infants and Young Children

• Six or more café-au-lait spots larger than 5mm
• Freckling in unusual areas (armpits, groin)
• Developmental delays or learning difficulties
• Vision problems or unusual eye appearance
• Bone deformities or unusual growth patterns
• Large head size (macrocephaly)

In Adolescents and Adults

• Café-au-lait spots larger than 15mm
• New soft tissue growths or masses
• Progressive hearing loss or balance problems
• Visual changes or eye problems
• High blood pressure
• Spinal curvature (scoliosis)

Follow-up Care Schedule

For Diagnosed NF Patients

• Annual comprehensive exams: Multi-specialty evaluation
• Ophthalmologic exams: Yearly vision screening
• Hearing tests: For NF2 or when indicated
• Blood pressure monitoring: Regular screening
• Growth and development: Pediatric patients
• Imaging studies: As recommended by specialists

Red Flags for Malignancy

• Rapid growth of existing neurofibroma
• Development of hard or fixed masses
• Persistent pain in tumor areas
• Neurological deficits from tumor pressure
• Changes in tumor texture or appearance
• Unexplained weight loss

Specialty Referrals

When to See Specialists

• Geneticist: Diagnosis confirmation, family planning
• Neurologist: Seizures, movement disorders, headaches
• Neurosurgeon: Brain or spinal tumors
• Ophthalmologist: Vision problems, eye tumors
• Otolaryngologist: Hearing loss, balance problems
• Orthopedist: Bone deformities, scoliosis
• Dermatologist: Skin tumor management
• Oncologist: Malignant transformation

Emergency Warning Signs

Neurological Emergencies

• Sudden onset of severe headache with neck stiffness
• Rapid changes in mental status or consciousness
• New onset seizures
• Sudden paralysis or severe weakness
• Signs of increased intracranial pressure

Spinal Cord Emergencies

• New bladder or bowel incontinence
• Progressive weakness in legs
• Saddle anesthesia (numbness in groin area)
• Severe back pain with neurological symptoms

Pregnancy Considerations

• Preconception counseling: Genetic risks and management
• Prenatal monitoring: Increased surveillance during pregnancy
• Tumor growth: Monitor for hormone-related changes
• Delivery planning: Consider tumor locations for delivery method

Related Conditions

Neurofibromatosis is associated with numerous complications and conditions that may develop over time or be part of the syndrome itself:

Neurological Complications

• Meningioma
• Schwannoma
• Glioma
• Epilepsy
• Hydrocephalus
• Peripheral neuropathy

Malignant Transformations

• Malignant peripheral nerve sheath tumor (MPNST)
• Pheochromocytoma
• Gastrointestinal stromal tumor (GIST)
• Breast cancer
• Rhabdomyosarcoma

Orthopedic Conditions

• Tibial dysplasia
• Sphenoid wing dysplasia
• Pseudarthrosis
• Kyphoscoliosis
• Osteoporosis

Ophthalmologic Conditions

• Lisch nodules
• Juvenile cataracts
• Glaucoma
• Retinal hamartoma
• Epiretinal membrane

Cardiovascular Complications

• Hypertension
• Renal artery stenosis
• Aortic coarctation
• Pulmonary stenosis
• Vasculopathy

Endocrine Disorders

• Precocious puberty
• Growth hormone deficiency
• Thyroid disorders
• Adrenal tumors

Dermatologic Manifestations

• Café-au-lait macules
• Neurofibroma
• Plexiform neurofibroma
• Juvenile xanthogranuloma

Psychiatric and Behavioral Conditions

• ADHD
• Autism spectrum disorder
• Anxiety disorders
• Depression
• Social difficulties

Gastrointestinal Complications

• Gastrointestinal neurofibromas
• Chronic constipation
• Bowel obstruction

Related Genetic Syndromes

• Legius syndrome
• Noonan syndrome
• McCune-Albright syndrome
• Watson syndrome
• Neurofibromatosis-Noonan syndrome

Frequently Asked Questions

References

1. Legius E, et al. Revised diagnostic criteria for neurofibromatosis type 1 and Legius syndrome: an international consensus recommendation. Genet Med. 2021.
2. Evans DG, et al. Consensus recommendations to accelerate clinical trials for neurofibromatosis type 2. Clin Cancer Res. 2020.
3. Plotkin SR, et al. Recommendations for screening for malignant peripheral nerve sheath tumors in patients with neurofibromatosis type 1. Am J Med Genet A. 2019.
4. Gross AM, et al. Selumetinib in children with inoperable plexiform neurofibromas. N Engl J Med. 2020.
5. National Institute of Neurological Disorders and Stroke. Neurofibromatosis Fact Sheet. NINDS. 2023.