Neurofibromatosis Type I (NF1)

Content of This Page

 1- Introduction

2- Causes

3- Symptoms

4- Investigations & Lab Results

5- Complications

6- Treatment

Introduction

Neurofibromatosis Type I (NF1), also known as von Recklinghausen disease, is a common autosomal dominant genetic disorder that primarily affects the nervous system, skin, and eyes. It is characterized by the development of multiple benign nerve sheath tumors (neurofibromas) and distinctive skin findings, including café-au-lait spots and axillary/inguinal freckling.

NF1 is caused by mutations in the NF1 gene located on chromosome 17, which encodes the neurofibromin protein, a tumor suppressor that regulates cell growth. Loss of neurofibromin function leads to uncontrolled cell proliferation and tumor formation.

© image from Wikimedia Commons

Causes

1. Genetic Cause

  • NF1 gene mutation:

    • This gene encodes neurofibromin, a tumor suppressor protein that helps regulate cell growth by inhibiting the RAS signaling pathway.

    • A mutation leads to loss of neurofibromin function, resulting in uncontrolled cell division and tumor formation, especially in nerve tissue.

2. Inheritance Pattern

  • Autosomal Dominant Inheritance:

    • Each child of an affected parent has a 50% chance of inheriting the condition.

    • The disease shows variable expressivity, meaning symptoms can vary widely even among family members with the same mutation.

3. Sporadic Mutations

  • Approximately 50% of cases are due to new (de novo) mutations, meaning they occur spontaneously without a family history.

  • These mutations happen during early embryonic development or in the germ cells of one parent.

© image from www.researchgate.net

Symptoms

1 . Dermatologic Features

  • Café-au-lait spots

    • Flat, light-brown skin patches

    • Usually >6 lesions >5 mm in prepubertal children or >15 mm in postpubertal individuals

  • Axillary or inguinal freckling

    • Clusters of freckles in armpits or groin (Crowe’s sign)

  • Cutaneous neurofibromas

    • Soft, benign tumors on or under the skin

    • May increase in number and size with age

  • Plexiform neurofibromas

    • Larger, deeper tumors along nerves

    • Often congenital and may cause disfigurement or compression of nearby structures

2. Neurological Features

  • Learning disabilities (seen in ~50% of children)

    • Often mild but may affect academic performance

  • Attention-deficit/hyperactivity disorder (ADHD)

  • Seizures (less common)

  • Headaches

3. Ophthalmologic Features

  • Lisch nodules

    • Benign pigmented iris hamartomas

    • Asymptomatic and detectable on slit-lamp examination

  • Optic pathway gliomas

    • Tumors of the optic nerve

    • May cause vision loss or proptosis (bulging eye)

4. Skeletal Abnormalities

  • Scoliosis (curvature of the spine)

  • Long bone dysplasia

    • Especially tibial bowing or pseudarthrosis (non-healing fracture)

  • Short stature

5. Other Possible Symptoms

  • Hypertension (can result from renal artery stenosis or pheochromocytoma)

  • Macrocephaly (large head size)

  • Delayed or early puberty

Investigations & Lab Results

1. Clinical Diagnosis

  • Diagnosis is based on the National Institutes of Health (NIH) criteria requiring two or more of the following:

    • Six or more café-au-lait spots (≥5 mm in children, ≥15 mm in adults)

    • Two or more neurofibromas or one plexiform neurofibroma

    • Axillary or inguinal freckling

    • Optic glioma

    • Two or more Lisch nodules (iris hamartomas)

    • A distinctive bone lesion (e.g., sphenoid dysplasia, tibial pseudarthrosis)

    • A first-degree relative with NF1

2. Imaging Studies

  • MRI of the brain and spine:

    • To detect optic pathway gliomas, plexiform neurofibromas, and other CNS tumors

    • Assess for skeletal abnormalities or spinal cord involvement

  • X-rays:

    • To evaluate bone dysplasia, scoliosis, or pseudarthrosis

  • Ultrasound or CT scan:

    • If visceral neurofibromas or vascular abnormalities are suspected

3. Ophthalmologic Examination

  • Slit-lamp exam:

    • To identify Lisch nodules (pigmented iris hamartomas)

  • Visual field testing and fundus exam:

    • To assess optic nerve function, especially if optic glioma is suspected

4. Genetic Testing

  • NF1 gene mutation analysis:

    • Useful in unclear or early cases, prenatal diagnosis, or family counseling

    • Can confirm diagnosis but not always necessary due to clinical criteria

5. Other Laboratory Tests

  • Generally not required for diagnosis

  • May be done to evaluate associated conditions (e.g., hypertension workup, endocrine evaluation)

Complications

1. Tumor-related Complications

  • Malignant Peripheral Nerve Sheath Tumors (MPNST):

    • Malignant transformation of plexiform neurofibromas (rare but serious)

    • Presents with rapid growth, pain, or neurological deficits

  • Plexiform neurofibromas:

    • Can cause disfigurement, pain, and functional impairment

    • Difficult to completely remove surgically

  • Optic pathway gliomas:

    • May cause vision loss or blindness if untreated

2. Neurological Complications

  • Seizures (rare)

  • Headaches and migraines

  • Cognitive impairment and learning disabilities

  • Developmental delays and behavioral problems

3. Skeletal Complications

  • Scoliosis:

    • May progress and cause deformity or respiratory problems

  • Tibial dysplasia and pseudarthrosis:

    • Leads to bone fragility, fractures, and non-healing wounds

  • Other bone abnormalities:

    • Sphenoid wing dysplasia causing orbital defects

    • Short stature or macrocephaly

4. Vascular Complications

  • Hypertension:

    • Due to renal artery stenosis or pheochromocytoma (rare tumor of adrenal glands)

  • Vascular stenosis or aneurysms:

    • Can lead to strokes or hemorrhage

5. Psychological and Social Impact

  • Disfigurement from tumors may cause social stigma and low self-esteem

  • Learning difficulties can impact education and employment

  • Emotional and behavioral issues may occur

Treatment

1. General Management

  • Regular monitoring and follow-up with a multidisciplinary team (neurology, dermatology, ophthalmology, orthopedics, genetics)

  • Early intervention for complications such as learning disabilities, tumors, or skeletal abnormalities

  • Genetic counseling for affected individuals and families

2. Management of Skin Lesions

  • Observation: Most cutaneous neurofibromas are benign and don’t require treatment

  • Surgical removal: For symptomatic, disfiguring, or problematic neurofibromas (painful, bleeding, or impairing function)

  • Laser therapy: Sometimes used for superficial lesions

3. Treatment of Plexiform Neurofibromas

  • Surgery: When possible, but complete excision is often difficult due to nerve involvement

  • Targeted therapies:

    • MEK inhibitors (e.g., selumetinib): Recently approved for shrinking inoperable plexiform neurofibromas, especially in children

  • Clinical trials: May be considered for novel therapies

4. Management of Optic Pathway Gliomas

  • Observation: Many are stable and asymptomatic, especially in young children

  • Chemotherapy: For progressive tumors causing vision problems (usually carboplatin and vincristine)

  • Radiation therapy: Used cautiously due to risks in children

5. Skeletal Abnormalities

  • Orthopedic interventions:

    • Bracing or surgery for scoliosis

    • Surgical stabilization for tibial pseudarthrosis

  • Physical therapy: To maintain mobility and function

6. Neurological and Learning Support

  • Educational support: For learning disabilities and cognitive challenges

  • Behavioral therapy: For ADHD or emotional issues

  • Seizure management: With antiepileptic drugs if needed

7. Management of Hypertension and Vascular Issues

  • Regular screening for hypertension

  • Treatment of underlying causes (renal artery stenosis, pheochromocytoma) as appropriate

Scroll to Top