Neurocutaneous Syndromes (NF1, NF2, Tuberous Sclerosis)

What are neurocutaneous syndromes and what are NF1, NF2 & TSC?

A group of inherited conditions in which cutaneous and neurologic manifestations coexist: skin findings are often the first sign of underlying involvement of the central nervous system or peripheral nerves.

In simple terms, neurocutaneous syndromes are disorders in which a genetic alteration leads to the development of benign or malignant tumors, skin lesions, and abnormalities in multiple organs. The most common syndromes in children are:

• Neurofibromatosis type 1 (NF1) — also known as von Recklinghausen disease. Characterized by café-au-lait macules, cutaneous and subcutaneous neurofibromas, optic pathway gliomas, and, in a small percentage, malignant peripheral nerve sheath tumors (MPNST).
• Neurofibromatosis type 2 (NF2) — much rarer, classically associated with bilateral vestibular schwannomas (tumors of the auditory nerves) and multiple schwannomas and meningiomas of the CNS.
• Tuberous Sclerosis Complex (TSC) — characterized by hamartomatous lesions in the brain (cortical tubers, subependymal nodules), subependymal giant cell astrocytoma (SEGA), epilepsy, and characteristic cutaneous angiofibromas.

A unifying principle across all three is that early recognition enables better prevention and management of neurosurgical complications.

How common are they and at what ages do they present?

Rare diseases, yet relatively “frequent” in pediatric neurology and neurosurgery — most are diagnosed during childhood.

• NF1: approximately 1 in 2,500–3,000 live births. Early findings (café-au-lait macules, axillary/inguinal freckling) typically appear in the first years of life.
• NF2: far rarer, approximately 1 in 40,000–50,000 children. Symptoms (e.g., hearing loss) most often arise in adolescence or early adulthood, but diagnosis can occur in childhood, especially in familial cases.
• TSC: approximately 1 in 6,000 children. Frequently presents in infancy with skin findings, cardiac rhabdomyomas, or early-onset epilepsy.

All three syndromes are autosomal dominant, but in approximately 50% of NF1/NF2 and about two-thirds of TSC cases, the mutation occurs de novo, without prior family history.

What are the key features of NF1 in children?

NF1 is the most common genetic neurocutaneous disorder, characterized by cutaneous findings and neurofibromas, but it can also affect the brain, vasculature, and skeleton.

Common features of Neurofibromatosis type 1 (NF1) include:

• ≥ 6 café-au-lait macules (light brown patches).
• Axillary or inguinal freckling.
• Neurofibromas — benign nerve sheath tumors, cutaneous or subcutaneous.
• Plexiform neurofibromas — extensive lesions involving entire nerve bundles, which may cause asymmetry, pain, or neurologic deficit.
• Optic pathway gliomas — tumors of the optic nerve that may impair vision and cause proptosis.
• Lisch nodules of the iris (ophthalmologic finding).
• Skeletal dysplasias (e.g., sphenoid wing, spine), scoliosis.
• Vascular abnormalities (e.g., internal carotid stenosis, moyamoya disease), renal artery stenosis.
• Macrocephaly, mild learning difficulties, or behavioral challenges.

An important but rare complication in NF1 is the development of malignant peripheral nerve sheath tumor (MPNST). Any rapid growth, new pain, or change in character of a neurofibroma warrants immediate evaluation.

How does NF2 present and how does it differ from NF1?

Neurofibromatosis type 2 is characterized by tumors of nerves and meninges without the prominent cutaneous stigmata of NF1. The hallmark is bilateral vestibular schwannomas and multiple meningiomas.

Key features of Neurofibromatosis type 2 (NF2):

• Bilateral vestibular schwannomas of the auditory nerves — commonly causing hearing loss, tinnitus, and imbalance; larger tumors may compress the brainstem, leading to hydrocephalus or facial nerve dysfunction.
• Multiple schwannomas of other cranial or spinal nerves, causing neuralgias, weakness, or sensory deficits.
• Multiple meningiomas intracranially or along the spine.
• Intramedullary tumors such as ependymomas or astrocytomas of the spinal cord.
• Ocular findings: early-onset posterior subcapsular cataracts.

In contrast to NF1, NF2 typically lacks prominent cutaneous manifestations. Suspicion is often raised by early-onset hearing loss or a positive family history.

What is Tuberous Sclerosis Complex (TSC) and how does it affect the brain?

TSC is a multisystem disorder affecting the brain, skin, heart, kidneys, and eyes — with epilepsy as the most frequent neurologic manifestation.

In Tuberous Sclerosis Complex, we commonly encounter:

• Cutaneous lesions: hypomelanotic “ash-leaf” macules, shagreen patches, facial angiofibromas.
• Cardiac rhabdomyomas — often detected prenatally or in infancy.
• Renal angiomyolipomas — which may cause hematuria or hypertension.
• Cortical tubers — dysplastic lesions of the cerebral cortex that frequently serve as epileptogenic foci.
• Subependymal nodules and subependymal giant cell astrocytoma (SEGA), typically near the foramen of Monro and capable of causing obstructive hydrocephalus.
• Epilepsy, often beginning in infancy (e.g., infantile spasms), with major implications for cognitive and psychomotor development.

Early recognition and aggressive management of epilepsy and tumors (such as SEGA) are central to pediatric neurosurgical care in TSC.

Which complications require pediatric neurosurgical management?

Not all children with a neurocutaneous syndrome require surgery. There are specific complications for which neurosurgical intervention may be lifesaving or disease-modifying.

Typical neurosurgical indications include:

• Neurofibromatosis type 1 (NF1):
  • Symptomatic or progressive optic pathway gliomas with vision loss or proptosis.
  • Plexiform neurofibromas with severe pain, neurologic deficit, or significant functional/cosmetic impact.
  • Malignant peripheral nerve sheath tumor (MPNST) — requiring wide oncologic resection (sarcoma surgery).
  • Hydrocephalus or vascular complications (e.g., moyamoya disease) managed with neurosurgical procedures (bypass, shunt).
• Neurofibromatosis type 2 (NF2):
  • Vestibular schwannomas with progressive hearing loss or brainstem compression.
  • Multiple meningiomas or schwannomas causing neurologic compression.
  • Intramedullary tumors with myelopathy.
• Tuberous Sclerosis Complex (TSC):
  • SEGA causing obstruction at the foramen of Monro, hydrocephalus, and seizures.
  • Cortical tubers that are clearly epileptogenic and responsible for drug-resistant epilepsy.

Across all syndromes, the shared goal is resection and decompression of lesions that threaten vital functions (vision, hearing, motor function, intracranial pressure) with the lowest possible functional cost.

How is the diagnosis made and what is the role of genetic counseling?

Diagnosis relies on clinical examination, imaging, ophthalmologic/ENT assessment, and genetic testing.

In practice:

• NF1: often diagnosed clinically using established criteria (number of café-au-lait macules, typical neurofibromas, Lisch nodules, skeletal abnormalities, family history). Genetic testing may confirm the diagnosis and assist with family planning.
• NF2: requires brain MRI with thin-slice imaging of the internal auditory canals, audiologic testing, and ophthalmologic evaluation. Genetic testing is particularly valuable in familial cases.
• TSC: diagnosed by a constellation of cutaneous, cardiac, renal, and cerebral findings. Genetic testing (TSC1/TSC2) helps confirm the diagnosis and identify affected relatives.

Genetic counseling is essential: it explains inheritance patterns, recurrence risk in future pregnancies, and helps families make informed decisions.

How is a child with NF1, NF2, or TSC followed long-term?

Lifelong surveillance is required. Children benefit from regular evaluations at specialized centers experienced in neurocutaneous syndromes.

An individualized plan typically includes:

• Regular clinical assessments (neurologic, pediatric neurosurgical) — often every 6–12 months in childhood.
• Annual ophthalmologic exams (particularly in NF1 and TSC).
• Audiologic testing & MRI of the internal auditory canals in NF2.
• Brain MRI and, when indicated, spinal imaging at scheduled intervals or based on symptoms.
• Epilepsy monitoring (EEG, medication optimization, evaluation for surgery in drug-resistant cases).
• Renal, cardiac, and dermatologic surveillance, especially in TSC.
• Neuropsychological assessment (learning, behavior, school adaptation).

At Neuroknife, follow-up is conducted in close collaboration with pediatric neurologists, geneticists, ophthalmologists, otolaryngologists, pediatric oncologists, and specialized rehabilitation centers.

When is surgery indicated in Neurofibromatosis type 1?

In NF1, pediatric neurosurgery is highly targeted — intervention is recommended when the anticipated benefit clearly outweighs risk.

Surgical indications:

• Plexiform neurofibromas:
  • for persistent pain, neurologic deficit, or major functional/cosmetic deformity,
  • subtotal resection with meticulous planning due to proximity to critical neural structures.
• Suspected malignant transformation (MPNST):
  • rapid growth, severe pain, firm consistency, neurologic deterioration,
  • requires biopsy/oncologic resection with clear margins and often adjuvant therapy (chemotherapy/radiation); essentially sarcoma surgery.
• Optic pathway glioma:
  • most are low-grade and observed,
  • intervention (medical or surgical) is considered only when vision is threatened or there is significant mass effect with hydrocephalus.
• Hydrocephalus / vascular lesions:
  • CSF shunting or other procedures (e.g., revascularization for moyamoya disease) when indicated.

Surgical decisions are always individualized and discussed in depth with the family and the oncology team.

When is surgery indicated in Neurofibromatosis type 2?

In NF2, the central question is when and how to intervene on vestibular schwannomas and other tumors without exhausting the child’s functional reserves.

Core principles:

• Small vestibular schwannomas with preserved hearing:
  • often initial observation with MRI and audiometry,
  • intervention when clear growth or hearing decline occurs.
• Large vestibular schwannomas with brainstem compression or non-serviceable hearing:
  • surgical resection via retrosigmoid or translabyrinthine approaches,
  • consideration of auditory brainstem or cochlear implantation in selected cases.
• Other schwannomas/meningiomas/intramedullary tumors:
  • resection when they produce clear neurologic deficit or progressive compression.

Because NF2 patients often develop multiple tumors throughout the nervous system, planning is long-term and judicious: we do not operate on every lesion, but on those that determine functional trajectory.

When is surgery indicated in Tuberous Sclerosis Complex?

In TSC, two major neurosurgical pillars dominate care: subependymal giant cell astrocytoma (SEGA) with hydrocephalus, and drug-resistant epilepsy from cortical/subcortical tubers.

Subependymal Giant Cell Astrocytoma (SEGA)

SEGA typically arises near the foramen of Monro and may obstruct CSF flow, leading to hydrocephalus with headache, vomiting, somnolence, and papilledema.

• Surgical resection via transventricular or transcortical approaches, depending on location.
• Endoscopic techniques with possible endoscopic third ventriculostomy in selected cases.
• For inoperable or multifocal disease: mTOR inhibitor therapy (e.g., everolimus), which can reduce tumor size and seizure burden.

Epilepsy surgery in TSC

Many children with TSC have epilepsy that is inadequately controlled with medication. In such cases, epilepsy surgery can fundamentally alter developmental trajectory.

• Comprehensive presurgical evaluation: video-EEG, high-resolution MRI, PET/SPECT, neuropsychological testing.
• Identification of a dominant epileptogenic focus (cortical tuber) amenable to resection with acceptable functional risk.
• In selected children: resection of the tuber and surrounding epileptogenic cortex to reduce or eliminate seizures.
• Adjunct or alternative options: corpus callosotomy, vagus nerve stimulation.

Decisions regarding epilepsy surgery are made by a specialized multidisciplinary board, including pediatric neurologists, pediatric neurosurgeons, neuropsychologists, and neuroradiologists.