Diagnosis, management and new therapeutic options in childhood neurofibromatosis type 2 and related disorders

Neurofibromatosis type 2 [NF2; MIM # 101000] is an autosomal dominant disorder characterised by the development 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 eye [e.g., early onset cataracts, optic nerve sheath meningiomas, retinal and/or pigment epithelial hamartomas and epithelial retinal membranes] and skin abnormalities [e.g., flat dermal (NF2-plaques) and/or spherical subcutaneous nodular schwannomas and few, atypical 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 tumors other-than-VS, which usually present first, years before VSs, both associated with more marked skin and eye involvement [vs. the classical mild adult (Gardner type) NF2, with bilateral VSs presenting in young adulthood, sometimes as the only disease feature]. Individuals manifesting unilateral VS associated to ipsilateral meningiomas or multiple schwannomas localised to one part of the peripheral nervous system have mosaic/segmental NF2; individuals developing multiple non-VS, non-intradermal cranial, spinal and peripheral schwannomas [histologically proven] have 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; mosaic/segmental NF2 is due to mosaic phenomena for the NF2 gene, whilst schwannomatosis is caused by germline and possibly mosaic mutations either in the SMARCB1 gene [SWNTS1; MIM # 162091] or the LZTR1 gene [SWNTS2; MIM # 615670] both falling within the 22q region. Data driven from in vitro and animal studies on the merlin pathway allowed biologically targeted treatment strategies [employing Lapatinib, Erlotinib, Everolimus, Picropodophyllin, OSU.03012, Imatinib, Sorafenib, Bevacizumab] aimed to multiple tumor shrinkage and/or regression and tumor arrest of progression with functional improvement.