title: Childhood neurofibromatosis type 2 (NF2) and related disorders: from bench to bedside and biologically targeted therapies.
abstract: Neurofibromatosis type 2 [NF2; MIM # 101000] is an autosomal dominant disorder characterised by the occurrence of vestibular schwannomas (VSs), schwannomas of other cranial, spinal and cutaneous nerves, cranial and spinal meningiomas and/or other central nervous system (CNS) tumours (e.g., ependymomas, astrocytomas). Additional features include early onset cataracts, optic nerve sheath meningiomas, retinal hamartomas, dermal schwannomas (i.e., NF2-plaques), and (few) café-au-lait spots. Clinically, NF2 children fall into two main groups: (1) congenital NF2 - with bilateral VSs detected as early as the first days to months of life, which can be stable/asymptomatic for one-two decades and suddenly progress; and (2) severe pre-pubertal (Wishart type) NF2- with multiple (and rapidly progressive) CNS tumours other-than-VS, which usually present first, years before VSs [vs. the classical adult (Gardner type) NF2, with bilateral VSs presenting in young adulthood, sometimes as the only disease feature]. Some individuals can develop unilateral VS associated with ipsilateral meningiomas or multiple schwannomas localised to one part of the peripheral nervous system [i.e., mosaic NF2] or multiple non-VS, non-intradermal cranial, spinal and peripheral schwannomas (histologically proven) [schwannomatosis]. NF2 is caused by mutations in the NF2 gene at chromosome 22q12.1, which encodes for a protein called merlin or schwannomin, most similar to the exrin-readixin-moesin (ERM) proteins; mosaicNF2 is due to mosaic phenomena for the NF2 gene, whilst schwannomatosis is caused by coupled germ-line and mosaic mutations either in the SMARCB1 gene [SWNTS1; MIM # 162091] or the LZTR1 gene [SWNTS2; MIM # 615670] both falling within the 22q region and the NF2 gene. Data driven from in vitro and animal studies on the merlin pathway [e.g., post-translational and upstream/downstream regulation] allowed biologically targeted treatment strategies [e.g., Lapatinib, Erlotinib, Bevacizumab] aimed to multiple tumour shrinkage and/or regression and tumour arrest of progression with functional improvement.
authors.affiliation: Unit of Rare Diseases of the Nervous System in Childhood, Department of Clinical and Experimental Medicine, Section of Pediatrics and Child Neuropsychiatry, University of Catania, Italy.
authors.forename: M
authors.initials: M
authors.lastname: Ruggieri
authors.affiliation: Unit of Rare Diseases of the Nervous System in Childhood, Department of Clinical and Experimental Medicine, Section of Pediatrics and Child Neuropsychiatry, University of Catania, Italy.|Department of Biomedical and Biotechnological Sciences, University of Catania, Italy.
authors.forename: A D
authors.initials: AD
authors.lastname: Praticò
authors.affiliation: Department of Medical and Surgical Sciences and Advanced Technologies "G. Ingrassia", Institute of Otorhinolaryngology, University of Catania, Italy.
authors.forename: A
authors.initials: A
authors.lastname: Serra
authors.affiliation: Department of Medical and Surgical Sciences and Advanced Technologies "G. Ingrassia", Institute of Otorhinolaryngology, University of Catania, Italy.
authors.forename: L
authors.initials: L
authors.lastname: Maiolino
authors.affiliation: Department of Medical and Surgical Sciences and Advanced Technologies "G. Ingrassia", Institute of Otorhinolaryngology, University of Catania, Italy.
authors.forename: S
authors.initials: S
authors.lastname: Cocuzza
authors.affiliation: Department of Medical and Surgical Sciences and Advanced Technologies "G. Ingrassia", Institute of Otorhinolaryngology, University of Catania, Italy.
authors.forename: P
authors.initials: P
authors.lastname: Di Mauro
authors.affiliation: Department of Medical and Surgical Sciences and Advanced Technologies "G. Ingrassia", Institute of Otorhinolaryngology, University of Catania, Italy.
authors.forename: L
authors.initials: L
authors.lastname: Licciardello
authors.affiliation: Department of Medical and Surgical Sciences and Advanced Technologies "G. Ingrassia", Institute of Radiology, University of Catania, Italy.
authors.forename: P
authors.initials: P
authors.lastname: Milone
authors.affiliation: Department of Medical and Surgical Sciences and Advanced Technologies "G. Ingrassia", Institute of Radiology, University of Catania, Italy.
authors.forename: G
authors.initials: G
authors.lastname: Privitera
authors.affiliation: Unit of Paediatric Radiology, AOU "Policlinico-Vittorio Emanuele", Catania, Italy.
authors.forename: G
authors.initials: G
authors.lastname: Belfiore
authors.affiliation: Department of Medical and Surgical Sciences and Advanced Technologies "G. Ingrassia", Institute of Ophthalmology, University of Catania, Italy.
authors.forename: M
authors.initials: M
authors.lastname: Di Pietro
authors.affiliation: Division of Hematology, AOU "Policlinico-Vittorio Emanuele", University of Catania, Italy.
authors.forename: F
authors.initials: F
authors.lastname: Di Raimondo
authors.affiliation: Division of Hematology, AOU "Policlinico-Vittorio Emanuele", University of Catania, Italy.
authors.forename: A
authors.initials: A
authors.lastname: Romano
authors.affiliation: Division of Hematology, AOU "Policlinico-Vittorio Emanuele", University of Catania, Italy.
authors.forename: A
authors.initials: A
authors.lastname: Chiarenza
authors.affiliation: Unit of Genetics, Institute of Neurological Sciences, National Research Council, Piano Lago di Mangone, Italy.
authors.forename: M
authors.initials: M
authors.lastname: Muglia
authors.affiliation: National Centre for Rare Disease, Istituto Superiore di Sanità, Rome, Italy.|Institute of Neurological Sciences, National Research Council, Catania, Italy.
authors.forename: A
authors.initials: A
authors.lastname: Polizzi
authors.affiliation: Genomic Medicine, University of Manchester, Manchester Academic Health Science Centre, Institute of Human Development, Central Manchester NHS Foundation Trust, Manchester Royal Infirmary, Manchester, UK.
authors.forename: D G
authors.initials: DG
authors.lastname: Evans
mesh_terms: D001691:Biological Therapy; D002648:Child; D006801:Humans; D016518:Neurofibromatosis 2 / Q000150:complications / Q000175:diagnosis / Q000235:genetics / Q000628:therapy*
keywords: Childhood NF2; Congenital NF2; Eearly onset NF2; Merlin; Mosaic NF2; Paediatric NF2; Schwannomatosis