Neurocutaneous Syndromes (Phakomatoses)

Overview and inheritance

Phakomatoses. The neurocutaneous syndromes pair lesions of the ectoderm-derived skin and eye with hamartomas and tumors of the nervous system and viscera. NF1, NF2, tuberous sclerosis complex (TSC) and von Hippel-Lindau disease (VHL) are autosomal dominant losses of a tumor-suppressor gene: every cell carries one inactivated copy, and a tumor forms wherever a somatic second hit removes the other allele. Lesions are therefore multiple, bilateral and early in onset. Sturge-Weber syndrome is the exception: a postzygotic somatic mutation makes it sporadic, mosaic and not heritable.

Sturge-Weber syndrome

Skin. Also called encephalotrigeminal angiomatosis, it is caused by a postzygotic activating GNAQ mutation (Gαq subunit) that produces capillary-venous malformations. A congenital, usually unilateral port-wine stain (nevus flammeus) follows the ophthalmic (V1) and maxillary (V2) trigeminal territories; forehead and upper-eyelid involvement carries the highest risk of brain and eye disease.

Brain and eye. An ipsilateral leptomeningeal (pial) angioma, usually parieto-occipital, causes venous stasis, cortical ischemia and atrophy. The cortex calcifies along the gyri, giving parallel curvilinear "tram-track" densities on skull film or CT. Infants develop focal seizures, then contralateral hemiparesis and intellectual disability. An episcleral hemangioma raises episcleral venous pressure and causes ipsilateral glaucoma, with an enlarged globe (buphthalmos) when present from birth.

Tuberous sclerosis complex

Mechanism. TSC1 (chromosome 9) encodes hamartin and TSC2 (chromosome 16) encodes tuberin; together they are a GTPase-activating complex for Rheb. Without it, Rheb stays GTP-bound and keeps mTORC1 active, driving cell growth and hamartomas in brain, skin, heart, kidney and lung. TSC2 mutations are more common and more severe.

Nervous system. Cortical tubers are seizure foci, and subependymal nodules calcify ("candle guttering"). Subependymal giant cell astrocytoma (SEGA) grows near the foramen of Monro and can cause obstructive hydrocephalus. Infantile spasms (West syndrome) are common, with vigabatrin the preferred first drug; intellectual disability and autism are frequent. The Vogt triad (seizures, intellectual disability, facial angiofibromas) appears in only a minority.

• Skin: hypomelanotic ash-leaf macules (brighter under a Wood lamp), lumbosacral shagreen patch, malar facial angiofibromas and periungual fibromas.
• Heart: multiple cardiac rhabdomyomas, the most common heart tumor of infancy, often seen prenatally and usually regressing (unlike the atrial myxomas of Carney complex).
• Kidney and lung: renal angiomyolipomas (vessels, smooth muscle, fat) that bleed when large; lymphangioleiomyomatosis in women.

Treatment. The mTORC1 inhibitor everolimus shrinks SEGAs and angiomyolipomas and reduces refractory seizures; sirolimus treats lymphangioleiomyomatosis.

Neurofibromatosis types 1 and 2

NF1. NF1 on chromosome 17 encodes neurofibromin, a RAS GTPase-activating protein; its loss keeps RAS GTP-bound and overdrives RAF–MEK–ERK signaling. Penetrance is complete, expressivity variable and about half of cases are de novo. Key criteria: six or more café-au-lait macules (>5 mm before puberty, >15 mm after), axillary or inguinal freckling, two or more neurofibromas or one plexiform neurofibroma, optic pathway glioma, two or more Lisch nodules (pigmented iris hamartomas, not the Brushfield spots of Down syndrome), a distinctive bone lesion such as sphenoid wing dysplasia, and an affected parent.

NF1 tumors. Neurofibromas contain Schwann cells and fibroblasts and are S-100 positive. Cutaneous ones form soft nodules; plexiform neurofibromas feel like a "bag of worms" and can become malignant peripheral nerve sheath tumors (MPNST). Other associations are optic pathway glioma (pilocytic astrocytoma) in young children, pheochromocytoma, GIST and juvenile myelomonocytic leukemia. The MEK inhibitor selumetinib shrinks symptomatic, inoperable plexiform neurofibromas in children.

NF2. NF2 on chromosome 22 encodes merlin (schwannomin), which links membrane proteins to the actin cytoskeleton and mediates contact inhibition. Bilateral vestibular schwannomas cause hearing loss, tinnitus and imbalance by young adulthood; meningiomas, spinal ependymomas and juvenile posterior subcapsular cataracts follow. Café-au-lait macules are few and Lisch nodules absent.

von Hippel-Lindau disease and surveillance

Mechanism. VHL on chromosome 3p encodes pVHL, the substrate-recognition subunit of an E3 ubiquitin ligase that binds prolyl-hydroxylated HIF-α in normal oxygen and sends it to the proteasome. Without pVHL, HIF-α accumulates as if the cell were hypoxic and switches on VEGF, PDGF and erythropoietin, producing highly vascular tumors.

• Hemangioblastomas of cerebellum, brainstem, spinal cord and retina: a cyst with a mural nodule of foamy stromal cells and capillaries; EPO secretion can cause secondary polycythemia.
• Clear cell renal cell carcinoma, bilateral and multifocal, the leading cause of death.
• Pheochromocytoma, pancreatic cysts and neuroendocrine tumors, endolymphatic sac tumors and epididymal cystadenomas.

Treatment. Belzutifan, a HIF-2α inhibitor, treats VHL-associated renal cell carcinoma, CNS hemangioblastomas and pancreatic neuroendocrine tumors.

Surveillance. Children of an affected parent have a 50% risk; Sturge-Weber carries no family risk. Carriers need lifelong screening: in VHL, yearly eye exams and metanephrines with periodic brain, spine and abdominal MRI; in TSC, serial brain and renal MRI; in NF1, yearly examination with blood pressure and childhood eye exams; in NF2, MRI and audiology.

Chromosome shortcuts: VHL has three letters (chromosome 3), "neurofibromatosis" has 17 letters (NF1) and NF2 sits on chromosome 22.