Neurofibromatosis

Question 1

What is neurofibromatosis (NF)?

Answer 1

A genetic disorder characterized by the development of benign and malignant tumors along nerves, as well as other systemic abnormalities.

Question 2

What are the two major types of neurofibromatosis?

Answer 2

Neurofibromatosis Type 1 (NF1) (Von Recklinghausen disease).

Neurofibromatosis Type 2 (NF2).

Question 3

What is the key difference between NF1 and NF2?

Answer 3

NF1: Affects the skin, peripheral nerves, and other tissues; characterized by café-au-lait spots and neurofibromas.

NF2: Affects the central nervous system; characterized by bilateral vestibular schwannomas and other intracranial or spinal tumors.

Question 4

What is the mode of inheritance for both NF1 and NF2?

Answer 4

Autosomal dominant.

Question 5

What is the mutation responsible for NF1?

Answer 5

Mutation in the NF1 gene on chromosome 17, which encodes neurofibromin, a tumor suppressor protein.

Question 6

What is the mutation responsible for NF2?

Answer 6

Mutation in the NF2 gene on chromosome 22, which encodes merlin (schwannomin), a tumor suppressor protein.

Question 7

What is the role of neurofibromin in NF1?

Answer 7

Neurofibromin regulates the RAS/MAPK pathway to suppress cell proliferation; its loss leads to uncontrolled cell growth.

Question 8

What is the role of merlin in NF2?

Answer 8

Merlin regulates cell growth and adhesion; its loss leads to tumor formation, particularly in Schwann cells.

Question 9

What are the major diagnostic criteria for NF1?

Answer 9

Presence of two or more of the following:

1. ≥6 café-au-lait spots (>5 mm in prepubertal or >15 mm in postpubertal individuals).
2. ≥2 neurofibromas or 1 plexiform neurofibroma.
3. Axillary or inguinal freckling.
4. Optic glioma.
5. ≥2 Lisch nodules (iris hamartomas).
6. Bony dysplasia (e.g., sphenoid wing dysplasia or pseudoarthrosis).
7. First-degree relative with NF1.

Question 10

What skin findings are characteristic of NF1?

Answer 10

Café-au-lait macules.

Axillary and inguinal freckling.

Cutaneous and subcutaneous neurofibromas.

Question 11

What are plexiform neurofibromas in NF1?

Answer 11

Large, diffuse neurofibromas involving multiple nerve branches, often causing disfigurement or compressive symptoms.

Question 12

What are common ocular findings in NF1?

Answer 12

Lisch nodules (benign pigmented hamartomas of the iris).

Optic pathway gliomas.

Question 13

What are skeletal abnormalities in NF1?

Answer 13

Scoliosis.

Pseudoarthrosis (nonunion of long bones).

Sphenoid wing dysplasia.

Question 14

What is the hallmark feature of NF2?

Answer 14

Bilateral vestibular schwannomas, leading to hearing loss, tinnitus, and balance issues.

Question 15

What are other tumors associated with NF2?

Answer 15

Meningiomas.

Ependymomas.

Schwannomas of other cranial or spinal nerves.

Question 16

What ocular findings are seen in NF2?

Answer 16

Juvenile cataracts.

Retinal hamartomas.

Question 17

How is NF1 diagnosed?

Answer 17

Based on clinical criteria; genetic testing for NF1 gene mutations can confirm the diagnosis in uncertain cases.

Question 18

How is NF2 diagnosed?

Answer 18

Based on clinical features (e.g., bilateral vestibular schwannomas or a combination of cranial and spinal tumors) and confirmed with NF2 gene mutation testing.

Question 19

What is the primary treatment approach for NF1?

Answer 19

Supportive care and management of complications:

• Annual exams for growth, blood pressure, and vision.
• Surgical removal of symptomatic neurofibromas.
• Treatment of scoliosis or other skeletal abnormalities.
• Monitoring for optic gliomas or malignancies.

Question 20

What targeted therapy is approved for NF1?

Answer 20

Selumetinib, a MEK inhibitor, is approved for inoperable plexiform neurofibromas.

Question 21

What is the primary treatment approach for NF2?

Answer 21

Surgical resection of symptomatic vestibular schwannomas or other tumors.

Cochlear implants for hearing loss.

Radiation therapy or radiosurgery for inoperable tumors.

Question 22

What is a targeted therapy under investigation for NF2?

Answer 22

Bevacizumab (anti-VEGF monoclonal antibody) to reduce tumor size and improve hearing.

Question 23

What are the major complications of NF1?

Answer 23

Malignant peripheral nerve sheath tumors (MPNSTs).

Optic gliomas leading to vision loss.

Scoliosis or other skeletal deformities.

Hypertension (often secondary to renal artery stenosis).

Question 24

What are the major complications of NF2?

Answer 24

Hearing loss and vestibular dysfunction.

Neurological deficits from meningiomas or spinal tumors.

Brainstem compression