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Review
. 2016 Oct;36(5):345-367.
doi: 10.14639/0392-100X-1093.

Childhood neurofibromatosis type 2 (NF2) and related disorders: from bench to bedside and biologically targeted therapies

M Ruggieri  1 , A D Praticò  1   2 , A Serra  3 , L Maiolino  3 , S Cocuzza  3 , P Di Mauro  3 , L Licciardello  3 , P Milone  4 , G Privitera  4 , G Belfiore  5 , M Di Pietro  6 , F Di Raimondo  7 , A Romano  7 , A Chiarenza  7 , M Muglia  8 , A Polizzi  9   10 , D G Evans  11
Affiliations
Review

Childhood neurofibromatosis type 2 (NF2) and related disorders: from bench to bedside and biologically targeted therapies

M Ruggieri et al. Acta Otorhinolaryngol Ital. 2016 Oct.

Abstract
in English, Italian

Neurofibromatosis type 2 [NF2; MIM # 101000] is an autosomal dominant disorder characterised 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) tumours (e.g., ependymomas, astrocytomas). Additional features include early onset cataracts, optic nerve sheath meningiomas, 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-two decades and suddenly progress; and (2) severe pre-pubertal (Wishart type) NF2- with multiple (and rapidly progressive) CNS tumours other-than-VS, which usually present first, years before VSs [vs. the classical 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 localised to one part of the peripheral nervous system [i.e., mosaic 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 exrin-readixin-moesin (ERM) proteins; mosaicNF2 is due to mosaic phenomena for the NF2 gene, whilst 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 [e.g., post-translational and upstream/downstream regulation] allowed biologically targeted treatment strategies [e.g., Lapatinib, Erlotinib, Bevacizumab] aimed to multiple tumour shrinkage and/or regression and tumour arrest of progression with functional improvement.

La neurofibromatosi tipo 2 [NF2] è una malattia genetica a trasmissione autosomica dominante [MIM # 101000]. Clinicamente è caratterizzata da: (1) schwannomi bilaterali del (VIII) nervo acustico/vestibolare; (2) cataratta giovanile o amartomi retinici; (3) schwannomi a carico dei nervi periferici e dei nervi cranici; (4) tumori multipli del sistema nervoso centrale (es., meningiomi, astrocitomi, ependimomi); (5) lesioni cutanee: (a) placche NF2 (schwannomi cutanei); (b) (poche) macchie caffellatte; (6) “malformazioni dello sviluppo corticale cerebrale”. La prevalenza della (forma sintomatica di) NF2 nella popolazione generale è di 1 su 100.000-200.000 individui con un’incidenza di 1 su 33.000 nati. La forma classica a esordio nel giovane adulto è conosciuta come forma di Gardner, (esordio intorno ai 20-30 anni d’età) con manifestazioni legate agli schwannomi bilaterali del nervo acustico/vestibolare (diminuzione/perdita progressiva dell’udito, tinnito, vertigini) e/o più raramente con manifestazioni da (altri) tumori del sistema nervoso centrale e/o periferico. In età pediatrica il fenotipo è diverso (forma di Wishart): per primi compaiono abitualmente i tumori del sistema nervoso centrale in assenza di schwannomi vestibolari; si possono avere macchie caffellatte e placche NF2 e solo dopo anni i tumori del nervo cranico VIII e di altri nervi cranici. Il quadro è più grave. Esiste anche una forma “congenita” ad esordio nei primi giorni/mesi di vita, con schwannomi vestibolari di piccole dimensioni (stabili nel tempo: anche per anni/decenni ma con improvvisa e rapida progressione) e numerose placche NF2; in questa forma le altre manifestazioni (es. meningiomi, altri tumori, altri schwannomi) sono spesso più gravi e progressive delle altre forme. Il gene responsabile della NF2 è localizzato sul cromosoma 22q12.1. Il prodotto genico della NF2 è conosciuto con il nome di schwannomina o merlina [dalla famiglia di proteine 4.1 del tipo moesina-ezrina-radixina/ERM alla quale appartiene il gene della NF2) e ha funzioni di regolazione della crescita e del rimodellamento cellulare (soppressione della crescita cellulare e della tumorigenesi)]. Alcune persone possono presentare tutte le (o parte delle) manifestazioni della NF2 in un emilato o in segmenti corporei circoscritti [NF2 a mosaico]. Altre persone presentano schwannomi (confermati istologicamente) dei nervi periferici (non intradermici) e/o delle radici gangliari in assenza di tumori del nervo vestibolare (o di altri nervi cranici: anche se in alcuni casi vi possono essere anche tumori unilaterali o bilaterali del nervo acustico/vestibolare e/o dei nervi cranici misti) o di altri segni diagnostici per la NF2 [Schwannomatosi, SWNTS]. L’esordio in questa forma è intorno ai 30 anni d’età (sono conosciuti casi in età pediatrica) con tumori in svariate sedi (abitualmente tronco e arti). Si conoscono due forme principali: (1) SWNTS1 [MIM # 162091] causata da alterazioni del gene SMARCB1 [regolatore della cromatina actina-dipendente associato alla matrice e correlato alle proteina SWI/SBF, sub-famiglia B, membro di tipo 1; MIM # 601607], sul cromosoma 22q11.23 (posizione centromerica rispetto al gene della NF2); (2) SWNTS2 [MIM # 615670] causata da alterazioni del gene LZTR1 [regolatore della trascrizione di tipo 1 legato alla Leucina; MIM # 600574], cromosoma 22q11.21 (posizione centromerica rispetto al gene SMARCB1) che codifica per una proteina, membro della super-famiglia BTB-kelch. Il meccanismo molecolare della Schwannomatosi comprende: (1) mutazione germinale del gene SMARCB1 o del gene LZTR1; (2) ampia delezione all’interno del cromosoma 22 (con perdita del gene NF2 e dell’allele intatto SMARCB1 o LZTR1); e (3) mutazione somatica dell’allele intatto del gene NF2 [meccanismo conosciuto come “four hits”: “Quadrupla alterazione” (su entrambi gli alleli dei due geni SWNTS/NF2), con tre passaggi consecutivi]. Negli ultimi anni, accanto alle tradizionali terapie chirurgiche e/o radioterapiche sono stati anche impiegati diversi farmaci “biologici” (es., Lapatinib e Bevacizumab) con effetti di riduzione/arresto della crescita dei tipici tumori NF2.

Keywords: Childhood NF2; Congenital NF2; Eearly onset NF2; Merlin; Mosaic NF2; Paediatric NF2; Schwannomatosis.

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Figures

Fig. 1.
Fig. 1.
Close view up of the skin of a child with NF2 showing multiple café-au-lait spots of different size and shape (the largest are indicated by white arrows): note the paler brownish colour and the irregular size and margins.
Fig. 2.
Fig. 2.
Close view up of the skin of a toddler with "congenital" onset NF2 showing classical NF2 plaques (in atypical locations) over (A) the fingers (black arrows) and (B) the knee (white arrows).
Fig. 2.
Fig. 2.
Close view up of the skin of a toddler with "congenital" onset NF2 showing classical NF2 plaques (in atypical locations) over (A) the fingers (black arrows) and (B) the knee (white arrows).
Fig. 3.
Fig. 3.
(A) Magnified view of the eye in an NF2 child showing subcapsular lens opacities (white arrow); and (B) Axial T2- weighted magnetic resonance image of the brain in a child with "congenital" NF2 showing a hypointense area (white arrows) in the intra-orbital region ("intra-orbital meningioma").
Fig. 3.
Fig. 3.
(A) Magnified view of the eye in an NF2 child showing subcapsular lens opacities (white arrow); and (B) Axial T2- weighted magnetic resonance image of the brain in a child with "congenital" NF2 showing a hypointense area (white arrows) in the intra-orbital region ("intra-orbital meningioma").
Fig. 4.
Fig. 4.
Axial T2-weighted (A) and T1-weighted contrast enhanced (gadolinium) (B) magnetic resonance images of the brain in an adolescent with Nf2 showing bilateral schwannomas (as hypointense lesions: white arrows) with intracanalar extension (outer white arrows); (C) Coronal T1-weighted contrast enhanced (gadolinium) magnetic resonance image of the brain in a child with NF2 showing bilateral schwannomas (as hyperintense lesions: white arrows) and multiple meningiomas (black arrows).
Fig. 4.
Fig. 4.
Axial T2-weighted (A) and T1-weighted contrast enhanced (gadolinium) (B) magnetic resonance images of the brain in an adolescent with Nf2 showing bilateral schwannomas (as hypointense lesions: white arrows) with intracanalar extension (outer white arrows); (C) Coronal T1-weighted contrast enhanced (gadolinium) magnetic resonance image of the brain in a child with NF2 showing bilateral schwannomas (as hyperintense lesions: white arrows) and multiple meningiomas (black arrows).
Fig. 4.
Fig. 4.
Axial T2-weighted (A) and T1-weighted contrast enhanced (gadolinium) (B) magnetic resonance images of the brain in an adolescent with Nf2 showing bilateral schwannomas (as hypointense lesions: white arrows) with intracanalar extension (outer white arrows); (C) Coronal T1-weighted contrast enhanced (gadolinium) magnetic resonance image of the brain in a child with NF2 showing bilateral schwannomas (as hyperintense lesions: white arrows) and multiple meningiomas (black arrows).
Fig. 5.
Fig. 5.
Coronal T2-weighted magnetic resonance image of the brain showing a hyperintense aspect of the right hemi-tongue (seen in the left side of the Fig.: white arrows), which is atrophic because of a schwannoma of the 12th cranial nerve (note the normal aspect of the contralateral tongue delineated by the dashed white arrows).
Fig. 6.
Fig. 6.
Axial T1-weighted contrast enhanced (gadolinium) (A-B) magnetic resonance images of the brain showing multiple meningiomas as hyperintense lesions ("meningiomatosis").
Fig. 6.
Fig. 6.
Axial T1-weighted contrast enhanced (gadolinium) (A-B) magnetic resonance images of the brain showing multiple meningiomas as hyperintense lesions ("meningiomatosis").
Fig. 7.
Fig. 7.
Sagittal (A) and axial (B) T2-weighted magnetic resonance images of the spinal cord in a child with NF2 showing round hyperintense lesions of the cervical cord at the C1 level (intraspinal ependymoma).
Fig. 7.
Fig. 7.
Sagittal (A) and axial (B) T2-weighted magnetic resonance images of the spinal cord in a child with NF2 showing round hyperintense lesions of the cervical cord at the C1 level (intraspinal ependymoma).
Fig. 8.
Fig. 8.
Axial T1-weighted contrast enhanced (gadolinium) (A-B) magnetic resonance images of the spinal cord in an adolescent with NF2, showing (A) an intradural meningioma (white arrow) and (B) two schwannomas of the spinal nerves (white arrows).
Fig. 8.
Fig. 8.
Axial T1-weighted contrast enhanced (gadolinium) (A-B) magnetic resonance images of the spinal cord in an adolescent with NF2, showing (A) an intradural meningioma (white arrow) and (B) two schwannomas of the spinal nerves (white arrows).
Fig. 9.
Fig. 9.
Axial T1-weighted magnetic resonance image of the brain in a child with a congenital form of NF2 obtained at age 4 months showing bilateral vestibular schwannomas (case 1, ref. 34).
Fig. 10.
Fig. 10.
Merlin-signalling pathway - In more recent years, several lines of evidence have suggested that Merlin exists in multiple states, which vary from "fully open" to "fully closed" [including "more closed" and "more open" states (see text for further explanation)]. In its "more closed" frame Merlin is hyperphosphorylated (has many "P" groups) and connected to cytoskeletal actin (because of an increase in intra-molecular bounds - secondary to the increased "P" groups - which contribute to fold the protein structure) (inactive Merlin): thus, the mitogen-signalling pathway [activated via the PAK and PKA pathways], is active and increases the cellular proliferative phenomena; in its "more open" frame Merlin is dephosphorylated (has less "P" groups) and is disconnected from actin (active Merlin): thus, the mitogen-signalling pathway, is inactive and decreases cellular growth, survival and cellular motility. In proliferating cells: (a) interactions between the extracellular matrix and the GFR/RTK/integrin proteins (and their membrane receptors) trigger the Rac1/PAK pathway; and (b) interactions between the GPCR receptors and c-AMP trigger the PKA pathway, both activating in turn the structural changes of Merlin [i.e., phosphorylation, increase in intra-cellular bounds and protein folding], which switches to a "more closed" (inactive) state [A: inactivating pathway]. In contact-inhibited cells, different phosphatases (mediated by the adhesion junctions' molecules and by HA bounds to CD44 receptors), via activation of the MYPT1 dephosphorylation and inhibition of the PAK/PKA pathway, dephosphorylate Merlin (→ switching to active form), which in turn leads to decreased cellular growth [B: activating pathway]. AJs = adhesion junction proteins; c-AMP = cyclic AMP; CD44 = antigen CD44; C-term = carboxy-terminal hydrophilic tail of the Merlin protein; coiledcoil = a structural motif (part) of the Merlin protein in which alpha-helices are coiled together like the strands of a rope; ERM = Ezrinradixin- moesin proteins; FERM = (F)-Four-point-one (4.1) protein-ERM domain of the Merlin protein (amino-terminal); GFR = growth factor receptor; GPCR = G-protein-coupled receptor; HA = hyaluronic acid; MYPT1 = myosin phosphatase target, subunit 1; P = phosphorylation groups; PAK = serine/threonine p21-activated kinase; PKA = protein kinase A enzyme; Rac1 = Rho family small GTP binding proteins; Rho = RAS homologue gene family; RTK = receptor tyrosine kinase; Ser-518 = Serine-518; Thr-230 = Threonine 230; + + + = stimulation; - - - = inhibition (from Ruggieri et al., 2015 and Ruggieri et al., 2015 , adapted and modified).
Fig. 11.
Fig. 11.
Diagram showing the PIK3/AKT/MAPK signalling pathway (see text for explanation): AKT, AK (Akr mouse) strain transforming; BRAF, B-raf (rapidly accelerated fibrosarcoma); CRAF, C-raf (rapidly accelerated fibrosarcoma); CREB, cAMP response element-binding protein; 4EBP1, Eukaryotic translation initiation factor 4E-binding protein 1; ERK1, extracellular signal regulated kinase 1; ERK2, extracellular signal regulated kinase 2; GSK3, glycogen synthase kinase 3; HRAS, Harvey rat sarcoma viral (Vras) oncogene homolog; HRAS-GTP, Harvey rat sarcoma viral (V-ras) oncogene homolog glucose triphosphate; KRAS, Kirsten rat sarcoma viral (V-ras) oncogene homolog; KRAS-GTP, Kirsten rat sarcoma viral (V-ras) oncogene homolog glucose triphosphate; GF, growth factor; MAP2K1, mitogen activated protein 2 kinase 1; MAP2K2, mitogen activated protein 2 kinase 2; MDM2, mouse double minute 2 homolog; MEK1, MAPK-extracellular kinase 1; MEK2, MAPK-extracellular kinase 2; mTORC1, mammalian target of rapamycin complex-1; mTORC2, mammalian target of rapamycin complex-2; NFkb, nuclear factor kappa-light-chain-enhancer of activated B cells; NRAS, Neuroblastoma rat sarcoma viral (V-ras) oncogene homolog; NRAS-GTP, Neuroblastoma rat sarcoma viral (V-ras) oncogene homolog glucose triphosphate; p70S6K, protein 70 serine/threonine 6 kinase; p120-GAP, p120-GTPase activating protein; PDK1, Phosphoinositide dependent kinase 1; PIK3, phosphatidylinositol-3-kinase; PIK3CA, phosphatidylinositol- 3-kinase catalytic a subunit; PIK3R, phosphatidylinositol-3-kinase regulatory subunit; PIP2, phosphatidylinositol bi-phosphate; PIP3, phosphatidylinositol tri-phosphate; PP1C, protein phosphatase 1 catalytic subunit C; PTEN, phosphatase and tensin homolog; RAF, rapidly accelerated fibrosarcoma protein; Raptor, regulatory associated protein of mTOR; RAS-GTP, rat sarcoma viral (V-ras) oncogene homolog glucose triphosphate; RASA1, rat sarcoma viral (V-ras) oncogene homolog GTPase activating protein 1; Rictor, rapamycin insensitive companion of mTOR; RTK, tyrosine kinase receptor; SHOC1, suppressor of C. elegans homolog 1 protein; SHOC2, suppressor of C. elegans homolog 2 protein; SOS1, son of Sevenless 1 homolog; SPRED, Sprouty-related EVH1 domain-containing protein 1 (from Ruggieri et al., 2015 , adapted and modified).
Fig. 12.
Fig. 12.
The four hits-three steps model of tumourigenesis in schwannomatosis [in the Fig. the SMARCB1 gene is represented, but the model is alike for the LZTR1 gene]: (1) during the first step the constitutive SMARCB1 gene is inactivated (1st hit); (2) in addition to the constitutional SMARCB1 mutation, a second step consists in the loss of chromosome 22q, or a segment of it, involving the two loci [i.e., the wild-type SMARCB1 gene and the constitutional NF2 gene] (2nd and 3rd hits); followed (3) by a somatic mutation of the remaining wild-type NF2 allele that constitutes the third step (4th hit) giving rise to the local growth of the schwannoma (from Ruggieri et al., 2015 , adapted and modified).
Fig. 13.
Fig. 13.
VEGF/VEGFR signalling pathway in normal vs. NF2 Schwann cells [Avastin]: in normal Schwann cells VEGF (vascular endothelial growth factor), SEMA3A (semaphorin 3 A) and SEMAF (semaphorin F) molecules and VEGFR (VEGF receptors), NRP (neuropilin) and Plexin receptors are normally expressed; in NF2 Schwann cells VEGF are normally expressed vs. lower expressed VEGFR; in addition to that, in NF2 Schwann cells NRP and Plexin receptors are normally expressed vs. lower expressed SEMA3A and SEMAF molecules (see boxes). VEGF typically binds to VEGFR2 [Panel 1] inducing endothelial proliferation, migration and permeability; VEGF can also compete with SEMA3A to bind to Neuropilin (NRP) receptors directly or can form a bridge between VEGFR2 and NRP potentiating its signalling via VEGFR2 [Panel 2]; SEMA3A and SEMAF bind NRP1 and NRP2, respectively, to induce endothelial cell regression and diminished permeability [Panel 3]. Thus, Avastin [an anti-VEGF antibody], when administered in NF2 patients acts not only via VEGFR inhibition (as VEGFR are lower expressed in NF2 Schwann cells) but also because it displaces VEGF from binding to NRP and Plexin receptor, thus allowing SEMA3A and SEMAF to bind to these receptors inducing endothelial cell regression and diminished permeability [see Panel 3 (from Ruggieri et al., 2015 and Ruggieri et al., 2015 , adapted and modified).
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