Phakomatoses (neurocutaneous syndromes) are a group of hereditary disorders that affect both the central nervous system and the skin, eye, or other organs. The classical phakomatoses — neurofibromatosis 1 and 2, tuberous sclerosis complex, von Hippel-Lindau disease, and Sturge-Weber syndrome — each have distinctive genetics, characteristic CNS pathology, and associated systemic manifestations. Many are now treatable with targeted therapies that have transformed prognosis. This page covers the major phakomatoses; NF1 and NF2 details are also in the Schwannoma/NF tumor page.

Tuberous Sclerosis Complex (TSC)

Genetics

  • Autosomal dominant.
  • TSC1 (hamartin, chromosome 9q34) or TSC2 (tuberin, 16p13.3).
  • Both encode proteins that inhibit mTOR signaling.
  • ~2/3 sporadic mutations.
  • TSC2 generally more severe than TSC1.

CNS Pathology

  • Cortical tubers: well-circumscribed cortical lesions; dysmorphic neurons + balloon cells (similar to FCD IIb); often calcified.
  • Subependymal nodules: along ventricular walls; can calcify (“candle drippings” or “candle gutter” appearance on imaging).
  • Subependymal giant cell astrocytoma (SEGA): at the foramen of Monro; can cause obstructive hydrocephalus; CNS WHO grade 1.
  • White matter lesions: radial migration lines.

Systemic Features

  • Skin: facial angiofibromas (adenoma sebaceum), ash-leaf macules (hypomelanotic), shagreen patches, periungual fibromas, café-au-lait macules.
  • Eye: retinal hamartomas.
  • Heart: rhabdomyomas (often regress).
  • Kidney: angiomyolipomas, renal cysts.
  • Lungs: lymphangioleiomyomatosis (women).
  • Mouth: dental pits, oral fibromas.

Clinical Features

  • Seizures (~80%): often early-onset infantile spasms; later focal seizures.
  • Autism spectrum (~50%).
  • Intellectual disability (~50%).
  • TAND (TSC-Associated Neuropsychiatric Disorders).
  • Sudden unexpected death in epilepsy (SUDEP) risk.

Treatment

  • Anti-epileptic drugs; vigabatrin first-line for infantile spasms.
  • mTOR inhibitors (everolimus, sirolimus): approved for SEGA, angiomyolipoma, refractory epilepsy. Transformative.
  • Epilepsy surgery for refractory focal seizures.
  • Multidisciplinary care.
  • Cannabidiol for refractory seizures (approved).

von Hippel-Lindau Disease (VHL)

Genetics

  • Autosomal dominant.
  • VHL gene (3p25); tumor suppressor.
  • VHL protein regulates HIF (hypoxia-inducible factor); loss of VHL increases HIF signaling and vascularization.

CNS Tumors

  • Hemangioblastomas: cerebellum (most common), brainstem, spinal cord, supratentorial (rare).
    • Cystic mass with mural nodule.
    • Histology: thin-walled vessels + lipid-laden stromal cells.
    • Inhibin alpha positive.
    • Multiple lesions common.
  • Endolymphatic sac tumors: rare; hearing loss.

Systemic Features

  • Retinal hemangioblastomas.
  • Renal cell carcinoma (clear cell): major cause of mortality.
  • Pheochromocytoma.
  • Pancreatic cysts and tumors (neuroendocrine).
  • Inner ear tumors.
  • Epididymal cysts.

Treatment

  • Surgical resection of CNS hemangioblastomas; some can be observed.
  • Stereotactic radiosurgery.
  • Belzutifan: HIF-2α inhibitor approved 2021 for VHL-associated tumors (renal cell carcinoma, hemangioblastomas, pancreatic neuroendocrine tumors). Transformative for VHL.
  • Screening surveillance for RCC, pheochromocytoma.

Sturge-Weber Syndrome

Genetics

  • Sporadic; somatic GNAQ mutations (most cases) or GNA11 mutations.
  • Mutations affect a subset of cells; explains the segmental distribution.

CNS Pathology

  • Leptomeningeal venous angioma: abnormal capillary-venous network in pia, usually unilateral.
  • Underlying cortical atrophy and “tram-track” calcifications (bilateral gyral calcifications adjacent to angioma).
  • Chronic ischemia from venous hypertension + impaired venous drainage.

Clinical Features

  • Port-wine stain (nevus flammeus): facial, V1 distribution especially (ophthalmic branch of trigeminal); sometimes V2.
  • Seizures (refractory in many).
  • Hemiparesis (contralateral to lesion).
  • Visual field defects.
  • Cognitive impairment.
  • Glaucoma (ipsilateral).

Treatment

  • Anti-epileptic drugs.
  • Epilepsy surgery (hemispherectomy in severe cases).
  • Aspirin (theoretically for venous thrombosis prevention).
  • Glaucoma management.
  • Cosmetic management of port-wine stain (laser).

Ataxia-Telangiectasia (AT)

Genetics

  • Autosomal recessive.
  • ATM gene; involved in DNA damage response.

Features

  • Progressive cerebellar ataxia (early childhood).
  • Ocular telangiectasias.
  • Immunodeficiency.
  • Malignancy risk (lymphoma, leukemia).
  • Radiation hypersensitivity.
  • Elevated serum AFP (alpha-fetoprotein).

Other Phakomatoses

  • PHACE syndrome: Posterior fossa anomalies + Hemangiomas + Arterial anomalies + Cardiac + Eye + Sternal defects.
  • Klippel-Trenaunay-Weber syndrome: vascular malformations + soft tissue/bony overgrowth.
  • Cowden syndrome: PTEN mutations; Lhermitte-Duclos disease (dysplastic gangliocytoma of cerebellum); macrocephaly; benign tumors.
  • Gorlin syndrome (Basal cell nevus): PTCH1 mutations; basal cell carcinomas + medulloblastomas + odontogenic keratocysts.
  • Wyburn-Mason syndrome: retinal + cerebral AVMs.
  • Incontinentia pigmenti: X-linked dominant; skin + CNS + dental + eye.

NF1 and NF2 (Brief Recap)

Discussed in detail in Schwannoma & NF page.

  • NF1: café-au-lait + freckling + Lisch nodules + cutaneous/plexiform NFs + optic pathway glioma.
  • NF2: bilateral vestibular schwannomas + multiple meningiomas + ependymomas.

🔍 Did You Know?

The transformation of tuberous sclerosis complex (TSC) management has been one of the most dramatic in pediatric neurology. Before the introduction of mTOR inhibitors, TSC management was largely reactive: SEGAs that obstructed CSF flow were surgically resected; angiomyolipomas were embolized or resected when bleeding; refractory epilepsy was managed with anti-epileptic drugs and sometimes epilepsy surgery. The 2010 EXIST-1 trial showed that everolimus shrinks SEGAs, often eliminating the need for surgical resection. Subsequent trials demonstrated benefit for angiomyolipomas (EXIST-2) and for TSC-associated refractory epilepsy (EXIST-3). The mechanism is direct: TSC1 and TSC2 are negative regulators of mTOR, so loss of TSC1/2 function produces hyperactive mTOR signaling that drives tumor growth and epileptogenesis. mTOR inhibitors directly block this overactive signaling. The treatment paradigm shifted from reactive to proactive — many SEGAs are now managed entirely without surgery, and angiomyolipomas are treated before they bleed. The same mTOR pathway is implicated in FCD type II (somatic mosaic mutations) and hemimegalencephaly, opening targeted therapy possibilities there as well. The story illustrates a powerful principle: understanding the molecular pathway of a genetic disease often reveals existing drugs that can be repurposed for transformative therapy. TSC went from a syndrome with limited options to a treatable condition; FCD and hemimegalencephaly may follow the same trajectory.

Pitfalls and Pearls

  • TSC: TSC1 (hamartin) or TSC2 (tuberin); mTOR pathway; cortical tubers + SEGA + skin + heart + kidney.
  • Cortical tuber: dysmorphic neurons + balloon cells; like FCD IIb.
  • SEGA: foramen of Monro; mTOR inhibitors shrink.
  • mTOR inhibitors (everolimus, sirolimus): TSC SEGAs, angiomyolipomas, epilepsy.
  • VHL: VHL gene; hemangioblastoma (CNS, retina) + RCC + pheochromocytoma + pancreatic.
  • Hemangioblastoma: cystic + mural nodule; inhibin α positive.
  • Belzutifan (HIF-2α inhibitor): approved 2021 for VHL tumors.
  • Sturge-Weber: GNAQ somatic; leptomeningeal angioma + port-wine stain + seizures + glaucoma; tram-track calcifications.
  • NF1: NF1 gene; café-au-lait + neurofibromas + Lisch + optic pathway glioma; selumetinib for plexiform NF.
  • NF2: NF2 gene; bilateral vestibular schwannomas + meningiomas; bevacizumab for VS.
  • Ataxia-telangiectasia: ATM gene; cerebellar ataxia + telangiectasias + immunodeficiency + cancer + radiation sensitivity.
  • Cowden syndrome: PTEN; Lhermitte-Duclos.
  • Gorlin syndrome: PTCH1; basal cell carcinomas + medulloblastomas (SHH).
  • PHACE syndrome: posterior fossa anomalies + hemangiomas + arterial + cardiac.

References

  1. Northrup H, Aronow ME, Bebin EM, et al. Updated international tuberous sclerosis complex diagnostic criteria and surveillance recommendations. Pediatr Neurol. 2021;123:50-66.
  2. Krueger DA, Care MM, Holland K, et al. Everolimus for subependymal giant-cell astrocytomas in tuberous sclerosis. N Engl J Med. 2010;363(19):1801-1811.
  3. Maher ER, Neumann HP, Richard S. von Hippel-Lindau disease: a clinical and scientific review. Eur J Hum Genet. 2011;19(6):617-623.
  4. Jonasch E, Donskov F, Iliopoulos O, et al. Belzutifan for renal cell carcinoma in von Hippel-Lindau disease. N Engl J Med. 2021;385(22):2036-2046.
  5. Shirley MD, Tang H, Gallione CJ, et al. Sturge-Weber syndrome and port-wine stains caused by somatic mutation in GNAQ. N Engl J Med. 2013;368(21):1971-1979.
  6. French JA, Lawson JA, Yapici Z, et al. Adjunctive everolimus therapy for treatment-resistant focal-onset seizures associated with tuberous sclerosis (EXIST-3). Lancet. 2016;388(10056):2153-2163.