What is neurofibromatosis?

What is Neurofibromatosis?

Neurofibromatosis comprises a group of genetically distinct autosomal dominant disorders of the nervous system unified by the predisposition to develop nerve sheath tumors, with neurofibromatosis type 1 (NF1) being the most common neurogenetic disorder affecting 1 in 2,000-3,000 individuals worldwide, and neurofibromatosis type 2 (NF2) being much rarer at 1 in 25,000-33,000 individuals. 1, 2, 3

Neurofibromatosis Type 1 (NF1)

Genetic Basis and Pathophysiology

• NF1 is caused by mutations in the NF1 gene on chromosome 17, which encodes neurofibromin, a key negative regulator in the RAS-MAPK pathway that controls cell growth and survival. 4, 1
• The condition is inherited in autosomal dominant fashion with full penetrance but variable expressivity, meaning severity varies even within families. 2, 3

Hallmark Clinical Features

• Café au lait macules (CALMs) are typically the initial clinical manifestation, increasing in size and number throughout childhood and puberty. 2, 3
• Neurofibromas are the hallmark lesion—benign tumors derived from the nerve sheath composed of proliferating Schwann cells, fibroblasts, mast cells, and pericytes. 3
• Plexiform neurofibromas are often congenital but grow during the first two decades of life, causing disfigurement and functional impairment. 1, 2
• Optic pathway gliomas occur in 15-20% of NF1 patients, typically presenting in young children and potentially causing vision loss. 4, 1, 2
• Axillary or inguinal freckling (Crowe's sign) is highly specific for NF1. 2
• Lisch nodules (iris hamartomas) visible on slit-lamp examination. 2

NIH Diagnostic Criteria

A diagnosis of NF1 requires meeting ≥2 of the following criteria:

• ≥6 café au lait macules measuring ≥5mm prepubertal or ≥15mm postpubertal 2
• Axillary or inguinal freckling 2
• ≥2 neurofibromas or 1 plexiform neurofibroma 2
• Optic pathway glioma 2
• ≥2 Lisch nodules 2
• Distinctive bony lesions 2
• First-degree relative with NF1 2

Life-Threatening Complications

• NF1 reduces life expectancy by 8-15 years, primarily due to malignant peripheral nerve sheath tumors (MPNST) and cardiovascular disease. 2
• MPNST risk is 8.5% by age 30,12.3% by age 50, and 15.8% by age 85, with high-grade MPNSTs usually being fatal. 4, 2
• Increased risk of juvenile myelomonocytic leukemia, rhabdomyosarcoma, and neuroblastoma compared to the general population. 1
• Pheochromocytoma and renovascular hypertension require surveillance. 2
• Women with NF1 have increased breast cancer risk, warranting annual mammography starting at age 30. 2

Molecular Classification of Nerve Sheath Tumors

Recent 2025 consensus recommendations emphasize integrated histopathologic and genomic approaches for NF1-associated peripheral nerve sheath tumors:

• ANNUBP (Atypical Neurofibromatous Neoplasm of Uncertain Biologic Potential) is defined by ≥2 features: cytologic atypia, loss of neurofibroma architecture, hypercellularity, or mitotic count >1/50 HPF but <3/10 HPF, with molecular profiling showing CDKN2A/B inactivation. 4
• "Low-grade MPNST" should be renamed "ANNUBP with increased proliferation" to avoid using "malignant" terminology for tumors with unknown biologic potential. 4
• High-grade MPNST demonstrates brisk mitotic activity, tissue necrosis, and molecular features including SUZ12, EED, or TP53 inactivating mutations, or significant aneuploidy. 4

Neurofibromatosis Type 2 (NF2)

Genetic Basis

• NF2 is caused by mutations in the NF2 gene on chromosome 22, which encodes merlin (schwannomin), a tumor suppressor protein. 1
• Inherited in autosomal dominant fashion, affecting approximately 1 in 25,000-33,000 individuals. 1

Hallmark Clinical Features

• Bilateral vestibular schwannomas on the eighth cranial nerves are the defining feature, causing hearing loss, tinnitus, and balance problems. 1, 5
• Multiple meningiomas causing neurological deficits depending on location. 1, 5
• Ependymomas and other central nervous system tumors. 1, 5

Diagnostic Criteria

NF2 is diagnosed by:

• Bilateral vestibular schwannomas, OR 1, 5
• Unilateral vestibular schwannoma plus at least two other NF2-related tumors (meningiomas, ependymomas, schwannomas). 1, 5

Clinical Challenges

• Vestibular schwannomas in NF2 grow faster than sporadic counterparts. 1
• No correlation exists between tumor size and hearing loss, complicating clinical monitoring. 1
• Significant surgical morbidity including deafness and facial nerve dysfunction. 1

Management Approach

Essential Referrals

• All patients with confirmed or suspected NF1 or NF2 should be referred to a specialized neurofibromatosis clinic for coordinated care and surveillance, which significantly reduces morbidity and mortality. 2
• Genetic counseling is essential given the 50% offspring recurrence risk for autosomal dominant inheritance. 2

Surveillance Protocol for NF1

• Annual comprehensive physical examination assessing for new or rapidly growing neurofibromas, severe or progressive pain (suggesting MPNST transformation), blood pressure measurement, and symptoms of pheochromocytoma. 2
• Baseline MRI of known or suspected non-superficial plexiform neurofibromas should be considered. 2
• Symptom-directed imaging rather than routine screening is appropriate, with MRI preferred over CT to minimize radiation exposure. 2

Red Flags Requiring Urgent Evaluation

• Progressive severe pain in existing neurofibroma (MPNST). 2
• Rapid change in tumor volume (MPNST). 2
• New unexplained neurologic symptoms (MPNST, brain tumors). 2
• Diaphoresis, palpitations, or hypertensive episodes (pheochromocytoma). 2

Important Clinical Distinctions

Conditions That Mimic NF1

• Legius syndrome (SPRED1 mutations) presents with CALMs and freckling but lacks neurofibromas, optic gliomas, and tumor risks—genetic testing definitively distinguishes these conditions. 2
• RASopathies (Noonan, Costello, CBL syndromes) present with CALMs plus dysmorphic facies, congenital heart defects, short stature, and cryptorchidism. 2
• Constitutional mismatch repair deficiency syndrome presents with CALMs plus childhood leukemia, brain tumors, or GI malignancies, carrying extremely high cancer risk. 2