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