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Journal of Pediatric Biochemistry 2015; 05(04): 120-130
DOI: 10.1055/s-0036-1572361
Review Article
Georg Thieme Verlag KG Stuttgart · New York

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

Martino Ruggieri
1   Department of Clinical and Experimental Medicine, Section of Pediatrics and Child Neuropsychiatry, University of Catania, Italy
,
Andrea Domenico Praticò
1   Department of Clinical and Experimental Medicine, Section of Pediatrics and Child Neuropsychiatry, University of Catania, Italy
2   Department of Biomedical and Biotechnological Sciences, University of Catania, Italy
,
Mariella Muglia
3   Unit of Genetics, Institute of Neurological Sciences, National Research Council, Piano Lago di Mangone, Italy
,
Luigi Maiolino
4   Department of Medical and Surgical Sciences and Advanced Technologies “G. Ingrassia,” Section of Otolaryngology, University of Catania, Italy
,
Gaetano Magro
5   Department of Medical and Surgical Sciences and Advanced Technologies “G. Ingrassia”, Section of Anatomic Pathology, University of Catania, Italy
,
Dafydd Gareth Evans
6   Genomic Medicine, University of Manchester, Manchester Academic Health Science Centre, Institute of Human Development, Central Manchester NHS Foundation Trust, Manchester Royal Infirmary, Manchester, United Kingdom
› Author Affiliations
Further Information

Publication History

23 December 2015

31 December 2015

Publication Date:
15 February 2016 (online)

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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.

Keywords

neurofibromatosis type 2 - NF2 - childhood NF2 - pediatric NF2 - schwannomatosis - mosaic NF2 - merlin - schwannomin - NF2 pathogenesis - Avastin - bevacizumab
 

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