phakomatoses

Phakomatoses, or neuro-oculo-cutaneous syndromes, are a group of hereditary or sporadic disorders characterized by hamartomas and benign or malignant tumors that affect the nervous system, skin, and eyes. They are usually genetic with autosomal dominant or sporadic mutations; expressivity ranges from mild to severe and somatic mosaicism can occur.

Neurofibromatosis type 1 (NF1) results from mutations in the NF1 gene on chromosome 17. Features include multiple café-au-lait macules, axillary/inguinal freckling, cutaneous neurofibromas, and Lisch nodules in the iris. Learning difficulties and skeletal abnormalities may occur.

Neurofibromatosis type 2 (NF2) involves mutations in the NF2 gene on chromosome 22. It is marked by bilateral vestibular schwannomas, NF2-associated meningiomas and ependymomas; skin findings are less prominent than in NF1.

Von Hippel-Lindau disease is caused by VHL mutations on chromosome 3p; it predisposes to retinal and central nervous system hemangioblastomas, clear cell renal cell carcinoma, and pheochromocytoma; regular surveillance is essential.

Tuberous sclerosis complex (TSC) involves TSC1 or TSC2 mutations; hallmarks include cortical tubers and subependymal nodules with potential subependymal giant cell astrocytoma, facial angiofibromas, shagreen patches, ungual fibromas, renal angiomyolipomas, and cardiac rhabdomyomas.

Sturge-Weber syndrome is usually sporadic due to somatic GNAQ mutations; characterized by a unilateral facial port-wine stain in the trigeminal distribution and leptomeningeal vascular malformations causing seizures, stroke-like episodes, cognitive impairment, and glaucoma.

Diagnosis relies on clinical evaluation supported by genetics and imaging; management is multidisciplinary: surveillance for tumors, seizure control, treatment of cutaneous lesions, laser therapy for skin lesions, and counseling on inheritance and recurrence risk.