Introduction to phacomatoses (neurocutaneous disorders) in childhood

The Dutch ophthalmologist,Jan van der Hoeve, first introduced the termsphakoma/phakomata(from the old Greek word phi alpha chi omicron sigma = lentil, spot, lens-shaped) to define similar retinal lesions recorded in tuberous sclerosis (1920) and in neurofibromatosis (1923). He later applied this concept: (a) to similar lesions in other organs (e.g. brain, heart and kidneys) (1932) and (b) to other disorders (i.e. von Hippel-Lindau disease and Sturge-Weber syndrome) (1933), and coined the termphakomatoses. At the same time, the American neurologistPaul Ivan Yakovlevand psychiatristRiley H. Guthrie(1931) established the key role of nervous systems and skin manifestations in these conditions and proposed to name themneurocutaneous syndromes(orectodermoses, to explain the pathogenesis). The Belgian pathologist,Ludo van Bogaert, came to similar conclusions (1935), but used the termneuro-ectodermal dysplasias. In the 1980s, the American paediatric neurologistManuel R. Gomezintroduced the concept of hamartia/hamartoma instead ofphakoma/phakomata. Genodermatoses and neurocristopathies were alternative terms still used to define these conditions. Nowadays, however, the most acclaimed terms are phacomatoses and neurocutaneous disorders, which are used interchangeably.Phacomatosesare a heterogeneous group of conditions (mainly) affecting theskin(with congenital pigmentary/vascular abnormalities and/or tumours), the central and peripheralnervous system(with congenital abnormalities and/or tumours) and theeye(with variable abnormalities). Manifestations may involve many other organs or systems including the heart, vessels, lungs, kidneys and bones. Pathogenically, they are explained by interplays between intra- and extra-neuronal signalling pathways encompassing receptor-to-protein and protein-to-protein cascades involving RAS, MAPK/MEK, ERK, mTOR, RHOA, PI3K/AKT, PTEN, GNAQ and GNA11 pathways, which shed light also to phenotypic variability and overlapping. We hereby review the history, classification, genomics, clinical manifestations, diagnostic criteria, surveillance protocols and therapies, in phacomatoses: (1)predisposingtodevelopment of tumours(i.e. the neurofibromatoses and allelic/similar disorders and schwannomatosis; tuberous sclerosis complex; Gorlin-Goltz and Lhermitte-Duclos-Cowden syndromes); (2) withvascular malformations(i.e. Sturge-Weber and Klippel-Trenaunay syndromes; megalencephaly/microcephaly-capillary malformation syndromes; CLOVES, Wyburn-Mason and mixed vascular nevus syndromes; blue rubber bleb nevus syndrome; hereditary haemorrhagic telangiectasia); (3) withvascular tumours(von Hippel-Lindau disease; PHACE(S)); (4) with pigmentary/connective tissuemosaicism(incontinentia pigmenti; pigmentary/Ito mosaicism; mTOR-related megalencephaly/focal cortical dysplasia/pigmentary mosaicism; RHOA-related ectodermal dysplasia; neurocutaneous melanocytosis; epidermal/papular spilus/Becker nevi syndromes; PENS and LEOPARD syndromes; encephalocraniocutaneous lipomatosis; lipoid proteinosis); (5) withdermal dysplasia(cerebellotrigeminal dermal dysplasia); and (6) withtwin spottingorsimilar phenomena(phacomatosis pigmentovascularis and pigmentokeratotica; and cutis tricolor).