Biochemical Insights into Merlin/NF2 Pathophysiology and Biologically Targeted Therapies in Childhood NF2 and Related Forms

Abstract Neurofibromatosis type 2 (NF2; MIM # 101000) is an autosomal dominant disorder characterized 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) tumors (e.g., ependymomas, astrocytomas). Additional features include early-onset cataracts, optic nerve sheath meningiomas and 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 to two decades and suddenly progress; and (2) severe prepubertal (Wishart type) NF2, with multiple (and rapidly progressive) CNS tumors other than VS, which usually present first, years before VSs (vs. the classic 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 localized to one part of the peripheral nervous system (i.e., mosaic/segmental 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 ezrin-radixin-moesin (ERM) proteins; mosaic NF2 is due to mosaic phenomena for the NF2 gene, whereas 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 allowed biologically targeted treatment strategies (e.g., lapatinib, erlotinib, bevacizumab) aimed to multiple tumor shrinkage and/or regression and tumor arrest of progression with functional improvement. In the present review we focus on the pathophysiology of merlin structure and function and on its posttranslational and upstream/downstream regulation in the different forms of NF2 in the pediatric age.