The Phakomatoses

Abstract

The term “phakomatosis” encompasses a set of dominantly inherited disorders characterized by the tendency to develop hamartomas as well as benign or malignant tumors, with prominent effects on the nervous system. Neurofibromatosis describes three distinct conditions, neurofibromatosis type 1 (NF1), neurofibromatosis type 2 (NF2), and schwannomatosis. All are characterized by nerve sheath tumors: neurofibromas in the case of NF1, schwannomas for NF2 and schwannomatosis. NF1 is a multisystem disorder with manifestations including skeletal dysplasia, learning disabilities, and risk of gliomas or malignant peripheral nerve sheath tumors. NF2 is associated with bilateral vestibular schwannomas, schwannomas of other cranial and peripheral nerves, ependymomas, gliomas, and meningiomas, as well as cataracts. Schwannomastosis is associated with multiple schwannomas, often leading to chronic pain. Tuberous sclerosis complex includes hamartomas of the brain, leading to seizures and impaired intellectual development, as well as renal angiomyolipomas, cardiac rhabdomyomas, and multiple cutaneous hamartomas. von Hippel–Lindau syndrome is characterized by hemangioblastomas of the brain, spinal cord, and retina, as well as risk of pheochromocytoma, renal cysts and/or carcinoma, and endolymphatic sac tumors. The genes for all of these disorders have been identified; each functions by a tumor suppressor mechanism, although haploinsufficiency may play a role in some of the phenotypic features as well. In addition to these disorders, there are a number of other conditions associated with “patchy” manifestations and prominent effects on the nervous system, including Proteus syndrome, Sturge–Weber syndrome, and several other very rare conditions. Insights into pathogenesis of this group of disorders is beginning to suggest avenues of treatment, with clinical trials underway and some examples of success, particularly for tuberous sclerosis complex, already changing the approach to treatment.