Diagnosis, Management, and New Therapeutic Options in Childhood Neurofibromatosis Type 2 and Related Forms

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Neurofibromatosis type 2 (NF2; MIM # 101000) is an autosomal dominant disorder characterized by the development of vestibular schwannomas (VSs); schwannomas of other cranial, spinal, and cutaneous nerves; cranial and spinal meningiomas or other central nervous system tumors (eg, ependymomas and astrocytomas) or both. Additional features include eye (eg, early onset cataracts, optic nerve sheath meningiomas, retinal or pigment epithelial hamartomas or both, and epithelial retinal membranes) and skin abnormalities (eg, flat dermal [NF2 plaques] or spherical subcutaneous nodular schwannomas or both, and few, atypical café-au-lait spots). Clinically, children with NF2 fall into 2 main groups: (1) congenital NF2 with bilateral VSs detected as early as the first days to months of life, which can be stable or asymptomatic for 1-2 decades and suddenly progress; and (2) severe prepubertal (Wishart type) NF2 with multiple (and rapidly progressive) central nervous system tumors other-than-VS, which usually presents 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 with ipsilateral meningiomas or multiple schwannomas localized to a part of the peripheral nervous system have mosaic or segmental NF2; individuals developing multiple nonVS, nonintradermal cranial, spinal, and peripheral schwannomas (histologically proven) have schwannomatosis (SWNTS). 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 proteins; mosaic or segmental NF2 is because of mosaic phenomena for the NF2 gene, whereas SWNTS 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, and Bevacizumab) aimed at multiple tumor shrinkage or regression or both and tumor arrest of progression with functional improvement.

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Neurofibromatosis 2

Neurofibromatosis type 2 (NF2; MIM # 101000),1, 2, 3, 4 previously known as bilateral acoustic neurofibromatosis or central neurofibromatosis,5, 6, 7, 8 is an autosomal dominant disorder caused by mutation in the gene (NF2; MIM # 607379),9, 10 encoding neurofibromin-2 or schwannomin (SCH), which is also called merlin (moesin-ezrin-radixin-like protein), on chromosome 22q12.2.11 Clinically, NF2 is characterized by the development of vestibular schwannomas (VSs); schwannomas of other cranial,

Patterns of Initial Presentations

The pattern(s) of presentation (and the natural history) of NF2 in childhood are very protean and differ from adulthood in many respects.19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33 In addition, children with NF2 whose onset is at or before puberty usually present differently from adolescents.28, 32, 34 The most common initial symptoms in adult-onset NF2 are usually attributed to cranial nerve VIII dysfunction and include hearing loss, tinnitus, or balance dysfunction.1, 2, 3, 4,

Genotype and Molecular Phenotype: The Merlin-Signaling Pathway

NF2 is caused by mutation in the NF2 gene at chromosome 22q12.1, which encodes for a 595-amino acid protein called merlin or SCH, most similar to the exrin-readixin-moesin proteins (Fig. 12)9, 10, 11: these are membrane-cytoskeleton scaffolding proteins (ie, linking actin filaments to cell membrane or membrane glycoproteins), which act as critical regulators of contact-dependent inhibition of proliferation and function at the interface between cell-to-cell adhesion, transmembrane signaling, and

Mosaic or Segmental NF2

Some individuals may have a unilateral eighth-nerve schwannoma associated with ipsilateral meningiomas (ie, unilateral NF2 involvement of the CNS) or multiple schwannomas localized to a part of the peripheral nervous system,35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48 (the latter going into differential with SWNTS: discussed later).63 These individuals are referred to as having segmental NF2. As somatic mosaicism for the NF2 gene is the causative phenomenon, they are also referred to

Diagnosis

Clinical criteria for the diagnosis of NF2 were first formulated at the National Institutes of Health (NIH) Consensus Conference on NF1 and NF2 in 198764 and revised in 1990.65 These criteria emphasized the presence of bilateral VSs in a high percentage of patients with NF2 (Table 1). Alternatively, patients could qualify for a diagnosis of NF2 with a family history of NF2 and either unilateral VS or any 2 other tumors typically associated with NF2 (Table 1). Under NIH criteria, however,

Classical Management of Childhood NF2

The approach to management of NF2-asociated tumors has been always different from that of their sporadic counterparts. As children (but also adults) with NF2 develop multiple cranial, spinal, and peripheral nerve tumors, surgical removal of every lesion is not possible or advisable. Instead, the primary goal has been (and still is) to preserve function and to minimize quality of life.

Currently, despite frequent functional impairment, surgical removal remains the standard therapy for VSs (and

Biologically Targeted Pharmacological Strategies in Childhood NF2

Recently, following the studies on merlin pathway(s), different pharmacological strategies have been developed aimed to obtain tumor volumetric shrinkage or arrest of progression of tumors or both including a reduction in time to progression.83

Chemotherapeutic strategies have been focused on the cascades of effects caused by the loss of function of merlin, and given the complexity of the pathway(s), a number of potential targets have been proposed (Table 3) (Fig. 12).84

Mortality in Adults and Children With NF2

Overall, patients with NF2 have diminished lifespan compared with nonaffected family members76, 77, 107 with overall 5-, 10-, and 20-years survival rates after diagnosis of 85%, 67%, and 38%, respectively.107 Early age at diagnosis and the presence of intracranial meningiomas are usually associated with increased mortality, and having a mosaic, rather than nonmosaic NF2 mutation associated with reduced mortality.76 The most frequent causes of death include tumor burden, perioperative

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