ORIGINAL ARTICLE

Natural history of neurofibromatosis type 2 with onsetbefore the age of 1 year

Martino Ruggieri & Anna Lia Gabriele & Agata Polizzi & Vincenzo Salpietro &

Francesco Nicita & Piero Pavone & Nunzio Platania & Pietro Milone & Angela Distefano &

Giuseppe Privitera & Giuseppe Belfiore & Francesca Granata & Rosario Caltabiano &

Vincenzo Albanese & Lorenzo Pavone & Aldo Quattrone

Received: 15 November 2012 /Accepted: 4 January 2013 /Published online: 3 February 2013# Springer-Verlag Berlin Heidelberg 2013

Abstract Neurofibromatosis type 2 (NF2) with onset be-fore the first year of life has been anecdotally reported in theliterature. We (a) prospectively (years 1997–2012) followedup three unrelated NF2 children, all harbouring NF2 genemutations whose onset of disease was before age 1 year, and(b) systematically reviewed published reports on NF2 in theyoungest age group (i.e. onset <1 year). The present threechildren had (1) small (<1 cm), bilateral vestibular schwan-nomas (VSs) detected (as an incidental finding) at magneticresonance imaging (MRI) by the age of 4 to 5 months thatwere asymptomatic for 10 to 14 years, with sudden andrapid (<12 months) progression in two cases at the age of11 and 15 years, respectively; (2) development of largenumbers of skin NF2 plaques mainly in atypical locations(i.e. face, hands, legs and knees), which reverted to normal

skin appearance at the time of VSs progression; (3) lensopacities (n=1) and NF2 retinal changes (n=2) detected asearly as age of 3-4 months; (4) diffuse (asymptomatic) highsignal lesions at brain MRI in the periventricularregions (alike cortical dysplasia); and (5) unaffectedfirst-degree relatives who did not harbour NF2 geneabnormalities. This represents the youngest NF2 groupwith the longest prospective follow-up so far reported.NF2 may present as a congenital form with bilateralVSs presenting as early as the first months of life andwith natural history different to that which occurs inclassical NF2.

Keywords Neurofibromatosis . NF2 . Childhood . Earlyonset . Vestibular schwannomas

M. Ruggieri (*)Department of Educational Sciences, University of Catania,Via Casa Nutrizione 1,95124 Catania, Italye-mail: m.ruggieri@unict.it

M. Ruggieri :N. Platania :V. AlbaneseUnit of Neurosurgery, Department of Neurosciences,University of Catania, Azienda Ospedaliera Universitaria“Policlinico-Vittorio Emanuele”, Via S. Sofia 78,95123 Catania, Italy

A. L. GabrieleUnit of Molecular Genetics, Institutes for MediterraneanAgriculture and Forest Systems (ISAFOM),National Research Council (CNR), Via Cavour 4/6,87030 Rende, Cosenza, Italy

A. Polizzi :A. DistefanoInstitute of Neurological Sciences,National Research Council (NRC),Via Paolo Gaifami 18,95126 Catania, Italy

V. SalpietroUnit of Genetics and Paediatric Immunology,Department of Paediatrics, University of Messina, PoliclinicoUniversitario “Gaetano Martino”, Via Consolare Valeria 1,98125 Messina, Italy

F. NicitaChild Neurology Section, Department of Pediatrics,University of Rome “La Sapienza”, Viale del Policlinico 155,00161 Rome, Italy

P. Pavone : L. PavoneUnit of Paediatrics and Paediatric Emergency “Costanza Gravina”,Azienda Ospedaliero-Universitaria “Policlinico-VittorioEmanuele” Section “Vittorio Emanuele”,Via Plebiscito 628,95122 Catania, Italy

P. MiloneUnit of Radiology, Institute of Radiology,University of Catania, Azienda Ospedaliera Universitaria“Policlinico-Vittorio Emanuele”, Via Santa Sofia 78,95123 Catania, Italy

Neurogenetics (2013) 14:89–98DOI 10.1007/s10048-013-0354-0

Introduction

Neurofibromatosis type 2 (NF2) is an autosomal dominantdisorder characterised by the development of vestibularschwannomas (VSs), schwannomas of other cranial, spinaland cutaneous nerves, cranial and spinal meningiomas,and/or other central nervous system (CNS) tumours includ-ing ependymomas and astrocytomas [1, 2]. A variety ofocular abnormalities are also common, including early-onset cataract (usually asymptomatic), optic nerve sheathmeningiomas, retinal and/or pigment epithelial hamartomas,and epithelial retinal membranes. Skin abnormalities in-clude flat dermal (NF2 plaques) and spherical subcutaneousnodular schwannomas. About 1 % of adult NF2 patientshave at least six café-au-lait spots [3].

Although classically considered a disease of adults, initialsigns and/or symptoms may be evident in childhood [2,4–11]. At least 18 % of NF2 individuals present before theage of 10 years [2, 4–6]. The pattern of presentation andnatural history of NF2 in childhood are variable and differfrom those in adulthood in many respects. For these reasons,clinically affected individuals currently fall into two maingroups: (a) mild (Gardner-type) NF2, with bilateral VSspresenting in adulthood (mean age, 22–27 years), often asthe only feature [2, 3]; and (b) severe (Wishart-type) NF2,with multiple (and rapidly progressing) CNS tumours other-than-VS, which may present first (usually in childhood) [2,4–11]. The latter group also tend to have more marked skinand eye involvement [2].

Patients may also have disease-related tumours localised toone part of the nervous system: e.g. a unilateral VS with ipsilat-eral meningiomas and/or multiple schwannomas in one part ofthe peripheral nervous system (mosaic/segmental NF2) [12].

Natural history studies have been conducted for child-hood NF2 with onset in the pre-school, toddler and child-hood age [2, 4–11] groups, but no detailed (or follow-up)data are available for NF2 with onset before the first year oflife, except for anecdotal cases in large NF2 databases [2, 6,8]. The aim of the present study was to identify the earliest

clinical presentations of NF2 in childhood (i.e. disease onset<1 year of age) and to characterise its natural history.

Materials and methods

Through the Italian national pediatric NF2 database held atthe University of Catania, we originally identified three NF2children out of the 98 (currently aged 4–22 years) diagnosedas having the disease according to the revised NF2 criteria[1], whose first disease manifestations were apparent priorto age 1 year.

These three children (one boy and two girls, currentlyaged 12, 13 and 15 years, respectively) have been prospec-tively followed up since 1997 at the Unit for Neurocutane-ous Disorders of the University of Catania, by means ofserial clinical, laboratory and imaging investigations,according to the current diagnostic and follow-up protocolfor paediatric NF2 [2]. No further NF2 child with diseaseonset before the age of 1 year was identified at the Univer-sity of Catania during the study follow-up period.

Literature review

Published reports on patients diagnosed with NF2, whosefirst symptoms appeared before the age of 18 years, wereidentified by a Medline search covering the period fromJanuary 1966 to December 2012. The search reviewedexisting articles related to this topic and examined the ref-erence lists of studies identified. We then considered onlythose cases that described NF2 children or adults whose firstdisease manifestation and/or onset of disease was at orbefore 1 year of age. Five articles [2, 4–6, 8] and oneextended abstract [7] met the above inclusion criteria, in-cluding one of our previous studies [2] that reported prelimi-nary data on two patients in the present study (current patients1 and 3, corresponding to cases 1 and 3 in our previous study).

G. PriviteraUnit of Radiotherapy, Institute of Radiology,University of Catania, Azienda Ospedaliera Universitaria“Policlinico-Vittorio Emanuele”, Via Santa Sofia 78,95123 Catania, Italy

G. BelfioreUnit of Paediatric Radiology, Institute of Radiology,University of Catania, Azienda Ospedaliera Universitaria“Policlinico-Vittorio Emanuele”, Via Santa Sofia 78,95123 Catania, Italy

F. GranataUnit of Neuroradiology, Department of Radiology, Universityof Messina, Policlinico Universitario “Gaetano Martino”,Via Consolare Valeria 1,98125 Messina, Italy

R. CaltabianoInstitute of Anatomic Pathology “G. Ingrassia”,University of Catania, via Santa Sofia 87,95123 Catania, Italy

A. QuattroneDepartment of Neurosciences, University “Magna Grecia”,Viale Europa, Località Germaneto,88100 Catanzaro, Italy

90 Neurogenetics (2013) 14:89–98

Results

The main clinical, laboratory, imaging and molecular find-ings and outcome of the three NF2 children prospectivelyfollowed up in our centres are summarised in Table 1 and inFigs. 1, 2, 3, 4, 5, 6 and 7. Here below, we briefly describethe peculiar aspects of the natural history of the disease inthe three children.

Case reports

Case 1

This 12-year-old Italian boy was born pre-term (gestationalweek 36) by complicated delivery (torsion of the umbilicalcord) after normal pregnancy. His growth parameters at birthwere in the 50th percentile for his gestational age. At birth,he had mild respiratory distress, and there was right micro-phthalmia. At age 3 months, a routine follow-up eye exam-ination revealed right lens opacity associated with pigmentretinal hyperplasia.

At the age of 4 months, brain computerised tomography(CT) and magnetic resonance imaging (MRI), obtained duringthe work-up for pre-term babies, showed left colpocephalyand bilateral high-signal (partially calcified) lesions in theposterior periventricular region. In addition, the brain MRIstudy revealed small, bilateral VSs (Fig. 1a). At that age,developmental milestones and physical examination werenormal. The child was discharged home, with serial clinicaland laboratory follow-up studies, which confirmed the previ-ous findings. Auditory evoked potentials yielded normalfindings.

The child was first referred to us at age 18 months, as hisparents had noticed a decrease in visual acuity in the lefteye. In addition, he had developed multiple, raised, round tooval, yellow/brown lesions in the hands (Fig. 2a) and legs(Fig. 2c). Skin examination confirmed the raised lesions anddisclosed additional plaques in the face (Fig. 2e) and trunkas well as café-au-lait macules over the trunk. The boy hadno neurological or hearing signs. Visual acuity was 1/50 inthe right eye and 3/10 in the left eye. Full ophthalmologicexamination revealed a pale optic disc in the left eye. Heartand abdominal ultrasound studies were negative. A histo-logical study of two raised skin lesions taken from one handand leg confirmed these to be NF2 plaques (Fig. 3). Theauditory evoked potentials yielded normal results. A repeat-ed brain and spinal MRI study confirmed the previousfindings with VSs of unmodified size and revealed left opticnerve meningioma, with no other lesion in the brain andspinal cord.

The child was followed up clinically every 3–6 monthswith serial MRI studies of the CNS every 6–12 months based

upon clinical manifestations (Fig. 1b). Clinically, he mani-fested an increase in the number of NF2 plaques, especially inthe face (Fig. 2e), hands and feet. At age 6 years, he developedneurofibromatous neuropathy in the legs, which progressedleading to right lower limb contractures: at age 7 years, heunderwent partial tendonectomy of the right Achilles tendonThe molecular study of the NF2 gene revealed a mutation incodon 94 (c.281_282 ins CCTT) of exon 3 only in theproband.

At age 11 years, he presented with progressive hearingloss, sudden gait unbalance and episodic vomiting. Uponexamination, he showed complete disappearance of the NF2plaques in the face, hands, legs and trunk (Fig. 2b, d, f).There was bilateral hearing dysfunction (word recognitionscores were as low as 7 % in the right ear and 34 % in theleft ear) with abnormal auditory evoked potentials. Therewas cerebellar ataxia with frequent falls, nystagmus andpositive Romberg sign. He presented three episodes of gen-eralised tonic-clonic seizures lasting a few minutes. EEGrecordings were normal. After his second episode, he wasput under treatment with sodium valproate (20 mg/kg/day).At his last follow-up control, the seizures had not recurred.The brain and spinal MRI showed marked progression ofthe VSs with mass effect and displacement of the brainstemand mild increase in the size of the optic nerve meningioma.The child underwent surgery with left VS excision andclinical improvement (Fig. 4). Pharmacological treatmentwith Avastin (bevacizumab) [5 mg/kg intravenously every15 days] has been started since middle September 2012because of a decrease in right hearing parameters: afteradministration of seven i.v. doses (i.e. after 75 days oftherapy), clinical improvement has been recorded consistingin disappearance of cerebellar signs and amelioration ofhearing function. Specifically, the cerebellar signs startedto disappear 2 days after the initiation of therapy, and thechild's word recognition scores increased from 9 % to 67 %:the improvement in word recognition began 3 days after theinitiation of treatment and continued to improve as long asthe 75th day of therapy. First control CNS imaging studiesare planned at day 90.

Case 2

This 13-year-old Italian girl was born at term by spontane-ous delivery after normal pregnancy. Growth parameters atbirth were in the 50th percentile with normal general andneurological examination and uneventful neonatal period.

At age 3 months, she presented with right asymmetricalprotrusion of the tongue. After 2 weeks, the tongue asymmetrywas stable: the child underwent a brain MRI study, whichshowed small, bilateral VSs (Fig. 5a) and bilateral high-signallesions (with spots of calcifications) in the posterior periven-tricular temporal regions (Fig. 6), with no apparent lesion in the

Neurogenetics (2013) 14:89–98 91

Tab

le1

Clin

ical

andim

agingfind

ings

andou

tcom

ein

NF2child

renwith

onsetof

diseasebefore

1year

ofage

Mainfeatures*

12

3Mautner

(case9)

Evans

(case1)

Evans

(case2)

Nun

es(case1)

Nun

es(case2)

Nun

es(case3)

Sex

MF

FM

MM

NS

NS

NS

Current

agea

1213

1514

143

NS

NS

NS

Fam

ilial

NF2

−−

−NS

NS

NS

NS

NS

NS

Atfirstsign

s

Age

3mon

ths

3mon

ths

4mon

ths

1year

0.75

years

0.65

years

<1year

<1year

<1year

Signs/sym

ptom

sRcataract,Rpigm

ent

RTon

gue

asym

metry

Pigmentretin

alhy

perplasia

Rem

oval

ofNFs

chestandkn

eeSeizures

Nystagm

usFacialpalsy

Arm plegia

Nystagm

us

MRIfind

ings

bVSs(4

mon

ths),Bcortical

high

sign

allesion

sVSs(5

mon

ths)

Bcortical

high

sig-

nal

lesion

s

VSs(4

mon

ths)

cortical

high

sign

allesion

s

NP

NS

NS

Atdiagno

sis

Age

(years)

18mon

ths

18mon

ths

710

1.25

27

177

Signs/sym

ptom

sVisualloss,MRIreview

RXIInervepalsy,

MRIreview

3CAL2NF2

plaque,MRI

review

Tetraparesis,

remov

alependy

mom

a

Meningiom

aRetinal

hamartoma

Current

NF2features

Ocular

Cataract

+(severe)

−−

+(Bilateral)

Retinal

++

+NS

Skin

Tum

ours

Tum

ours

Tum

ours

CALspots

38

10NS

NF2plaques

>20

(disappeared

atage11

years)

1812

(disappeared

atage15

years)

NS

NF1-lik

eNFs

53

2+

Nod

ular

schw

anno

ma

2−

−Rpalm

CNS(brain)

−

VSun

ilateral

−−

−−

−−

VSbilateral

++

+−

−−

Meningiom

a−

−−

−

Astrocytoma

−−

−−

Epend

ymom

a−

−−

−

Cortexdy

splasia

Occipital

Tem

poral

Parieto-tem

poral

−

Cranial

nerves

V,VII

V,XII

IX,XI

−+

++

CNS(spine)

Tum

ours

Tum

ours

Tum

ours

Astrocytoma

−−

−−

92 Neurogenetics (2013) 14:89–98

Tab

le1

(con

tinued)

Mainfeatures*

12

3Mautner

(case9)

Evans

(case1)

Evans

(case2)

Nun

es(case1)

Nun

es(case2)

Nun

es(case3)

Epend

ymom

a−

−−

+

Schwanno

ma

−−

Th,

L−

Meningiom

aOPM

−C

−

PNS

Neuropathy

+−

+−

Other

−2PelvicPSW

Surgery

LVSremov

al(atage11

years)

NP

Cspinal

meningiom

a,pelvic

masses

Spinal

ependy

mom

aRem

oval

ofL,VS

Rem

oval

ofR,

VSat

age

8years

Outcome

Blin

d;prog

ressionof

righ

tVS

(avastin)

Cranial

nerve

palsy,

lack

ofprog

ression

ofVSs

Progression

ofVSs(avastin)

Goo

dVSsno

tpresent

VSsno

tpresent

Hearing

loss

atage

6years

No hearing

loss

Hearing

loss

atage

8years

DNA

analysis

Exo

n3(cod

on94

)5(cod

on93

)13

NS

+(N

S)

Sequence

InsCCTT

InsCCTT

Q47

0XNS

+(N

S)

FSP

SP

MacCollin

andMautner[5]repo

rted

onebo

y(diedatage2years)who

experienced,by

theageof

1year,progressive

hearingloss

andwho

seradiog

raph

icinvestigation(don

eatthesameageof

first

diseasemanifestatio

ns)revealed

VSsandspinal

andderm

altumou

rswith

nootherintracranial

tumou

rs

NSinform

ationno

tspecified,

Mmales,F

females,L

left,R

righ

t,CALspotscafé-au-laitspots,CNScentralnervou

ssystem

,PSperiph

eralnervou

ssystem

,NPno

tperformed,N

Fsneurofibromas,

OPM

optic

pathway

meningiom

a,PSW

plexiform

schw

anno

ma,Pparietal,Ttempo

ral,O

occipital,Ccervical,Ththoracic,Llumbar,SP

splicing,

FSfram

eshift,IF

infram

e

*Mautner

etal.[4],Evans

etal.[6]andNun

eset

al.[8]

aFor

casesrepo

rted

intheliterature,currentageindicatestheageat

thetim

eof

article

publication

bIn

case

3,MRIwas

performed

becauseof

asuspectedpastperinatalasph

yxia

Neurogenetics (2013) 14:89–98 93

XII cranial nerve. At that age, developmental milestones werenormal. The diagnosis of NF2 was made, and the child wasdischarged home with follow-up controls.

At age 18 months, she had developed multiple NF2 plaqueson the trunk and extremities. General examination was unre-vealing. Skin examination (and histological studies) confirmed

Fig. 1 Patient 1: axial (a, b)T1-weighted magnetic reso-nance images of the brainobtained at age 4 months (a)and 9 years (b) reveal bilateralVIII cranial nerve lesions (whitearrows). Note that the vestibu-lar lesions did not progress overtime

Fig. 2 Patient 1: skin NF2plaques in the right hand (a),right leg (c) and face (e) asrecorded at first referral; notethe disappearance of thesecutaneous NF2 plaques (b, d, f)at the time of vestibularschwannoma progression(see also text)

94 Neurogenetics (2013) 14:89–98

the plaques and revealed more than six café-au-lait spots (withirregular margins and a pale colour) on the trunk. Neurologi-cally, the girl had mild right XII cranial nerve palsy, with nosigns of hearing disorders. Full ophthalmologic examinationrevealed right retinal pigment hyperplasia with a normal opticdisc. Visual acuity was normal. Heart and abdominal ultra-sound studies were normal. Auditory evoked potentials yieldednormal results. A repeated brain and spinal MRI study con-firmed the previous findings, which were unmodified.

A molecular study of the NF2 gene revealed a mutationin codon 93 (c.281_282 ins CCTT) of exon 5 only in theproband (Table 1).

The child was followed up clinically every 3–6 monthswith serial MRI studies of the CNS every 6–12 monthsdepending on clinical findings. At her last work-up, at age13 years, she was clinically stable with no increase in theright XII cranial nerve palsy or appearance of new neuro-logical or general signs. Hearing function was preserved,and the auditory evoked potentials yielded normal results.The brain and spinal MRI showed no progression of the VSs(Fig. 5b) or the high-signal lesions in the temporal region,and no other lesions in the CNS.

Case 3

This 15-year-old Italian girl was born at term by spontane-ous delivery after a pregnancy complicated by threatenedmiscarriage at the 27th week of gestation. Growth parame-ters at birth were in the 50th percentile: general and neuro-logical examinations were unrevealing. At age 4 months, aroutine ophthalmologic examination revealed pigment reti-nal hyperplasia that was misdiagnosed as segmental retinalfolds because of the mother's threatened miscarriage. At age5 months, she underwent a cranial CT in the suspicion of aprevious perinatal asphyxia, which revealed bilateral spotsof calcification in the parietal and temporal regions and aMRI study of the brain that showed small bilateral VSs(Fig. 7a). At that age, developmental milestones werenormal.

The girl was first referred to our institutions at age 7 yearsfor a pelvic mass, which turned out to be a large (>10 cm)bilateral plexiform schwannoma,whichwas resected 6monthsafter initial diagnosis. At that age, the child had multiple NF2plaques in her four limbs, and a full head and spinal MRI scanrevealed no progression of the bilateral VSs or the high-signallesions in the periventricular regions, and the presence of acervical meningioma that compressed the spinal cord. Thecervical meningioma was successfully completely removed.

The child was followed up clinically every 3–6 monthswith serial MRI studies of the CNS every 6–12 months(Fig. 7b). Molecular genetic analysis revealed a mutationQ470X in exon 13 of the NF2 gene only in the proband.

At age 15 years, she presented with progressive hearing lossand sudden gait unbalance. She showed disappearance of theNF2 plaques in the face, hands and knees. There was hearingdysfunction with abnormal auditory evoked potentials. Neuro-logical examination revealed cerebellar ataxia with frequentfalls, nystagmus and positive Romberg sign. The brain andspinal MRI showed marked progression of the VSs with masseffect and displacement of the brainstem and mild increase inthe size of the optic nerve meningioma (data not shown).Pharmacological treatment with Avastin (bevacizumab)[5 mg/kg intravenously every 15 days] was started: after ad-ministration of seven i.v. doses (i.e. after 75 days of therapy),clinical improvement has been recorded consisting in almost

Fig. 3 Patient 1: histological aspect of one skin lesion which turnedout to be a peripheral schwannoma (NF2 plaque)

Fig. 4 Patient 1: axial T2-weighted magnetic resonance image of thebrain obtained at age 11 years reveals progression of the right VIIIcranial nerve lesion (the left VIII cranial nerve lesion was removedmonths prior to the present scan)

Neurogenetics (2013) 14:89–98 95

total disappearance of cerebellar signs and amelioration ofhearing function. The child's word recognition score increasedfrom 36 % to 87 %: the improvement in word recognitionbegan 2 weeks after the initiation of treatment and continuedto improve as long as the 75th day of therapy. First control CNSimaging studies are planned at day 90.

Literature review

The literature review revealed six NF2 children with onset ofdisease at age ≤1 year; their data are summarised in Table 1.

Discussion

This is the youngest NF2 group so far recorded (with mo-lecular confirmation), with the longest prospective follow-up. According to the present study, the pattern of presenta-tion and natural history of NF2 in children with very earlyonset of disease (i.e. before 1 year of age) are variable anddiffer from those in patients with later onset NF2 in middleand late childhood, in adolescence [2, 4–8, 11] and adult-hood [2, 13].

The most striking aspect, shared by the present cases, wasthe presence of bilateral VS, recorded (incidentally) at 4–5 months of age, which is earlier than previously reported.Previously, VSs had been seen at ages of 6–7 months [6]and around 1 year of age [4, 8] (Table 1). Thus, whateveronset age we consider, it is noteworthy that NF2, a disorderclassically viewed as a (young) adult, or more rarely, achildhood/adolescent disease, may be evident at a veryyoung age, even before the age of 1 year. In addition, asbilateral VSs have been demonstrated at a very early age(see Table 1), we hypothesize that the VIII cranial nervelesions can occur as congenital lesions, in the setting ofNF2, in a similar manner to optic pathway gliomas in someNF1 patients or giant cell astrocytomas in some patientswith tuberous sclerosis [14]. Alternatively, this may repre-sent a separate (extremely early onset) form of NF2.

Another important aspect is that in all three of our chil-dren, we (incidentally) recorded bilateral VIII cranial nervelesions as their first nervous system manifestation of thedisease. This differs from NF2 in middle and late childhoodand adolescents, who manifest other nervous systemtumours long before VIII cranial nerve lesions [2, 4–8,11]. More importantly, the vestibular tumours in these NF2children did not progress for a relatively long period of 11–

Fig. 5 Patient 2: axial (a, b)T1-weighted magnetic reso-nance images of the brainobtained at age 5 months (a)and 13 years (b) reveal bilateralVIII cranial nerve lesions (whitearrows). Note that the vestibu-lar lesions did not progress overtime

Fig. 6 Patient 2: axial (a) T2-weighted magnetic resonance images ofthe brain reveal high signal lesions in the posterior periventricularparamedian cortical regions (white arrows)

96 Neurogenetics (2013) 14:89–98

14 years, which encompassed the pre-pubertal period, cou-pled with lack of development of hearing or vestibulardysfunction, as recorded by clinical and laboratory testing.Of note, two of the three children hereby reported had asudden progression of the vestibular lesions either clinicallyand radiologically in coincidence with the pubertal period.

Previous reports of children with onset of NF2 before1 year of age recorded [4] lack of development of VS(s) upto the age of 14 years, and in one case of Nunes et al. [8],there was no hearing dysfunction until the last work-upperformed at the age of 17 years (see Table 1). Of note,two cases of Evans et al. [6] did not present VS at any stageof their follow-up.

Even when we consider the variability in growth rate ofthe VSs in the setting of NF2 [1, 3, 13], all the present NF2children had small VSs, which remained at the same sizeand volume for 11 to 14 years (see Figs. 1, 5 and 7). Unliketo what was recorded previously for late childhood NF2 [2,4–8, 11], in whom VSs usually had a larger size (and amultilobulated microscopic appearance), rapid progression,and tended to cause symptoms at younger ages, two out ofthe three present patients had stable lesions for a relativelylong period with subsequent sudden, rapid and dramaticincrease of vestibular lesions and appearance of clinicalsymptoms and signs. We hypothesise that puberty, like itoccurs for peripheral neurofibromas in NF1 [14], may act asa trigger for intracranial schwannomas in this congenitalform of NF2.

An additional and peculiar finding was that all three ofour NF2 children rapidly developed large numbers of smallskin NF2 plaques mainly in atypical locations (i.e. hands,legs, knees and face; see Fig. 2a, c, e). Strikingly, the twochildren (cases 1 and 3) who developed sudden and rapidprogression of their VSs after years of anatomical stablenessmanifested reversion of their NF2 plaques (see Fig. 2b, d, f)

in coincidence with the VSs progression, a finding notpreviously recorded in pediatric NF2 [2, 4–11]. In addition,all had large café-au-lait spots with irregular margins, and allpresented with small lens opacity and/or retinal changes astheir earliest disease manifestations (Table 1). The latterfindings have previously been recorded in larger late child-hood NF2 series [2].

Of note, all the present children had high-signal lesions inthe periventricular regions (Fig. 6), associated with smallareas of intracranial calcification in the surrounding areas.This has previously been reported in association with NF2irrespective of age, and attributed either to meningoangio-matosis or to hamartomatous (or cortical) dysplastic lesions.Even though we could not further define the nature of thesecortical lesions, it was of interest that the recorded abnor-malities in the present study were asymptomatic in cases 2and 3: the only patient who manifested seizures in thepresent study was the 15-year-old boy (case 1) who hadhowever negative EEG findings and was seizure-free afterinitiation of therapy [15]. Similar findings were reported infour of 11 NF2 cases that had meningoangiomatosis [13]and in other previous childhood NF2 [2, 7] or NF1 cases[16].

Of interest, two out of the three children were put undertreatment with Avastin (bevacizumab) with (neurologicaland) hearing improvement, which began earlier than previ-ously recorded in NF2 patients, irrespective to age [17–19].

In conclusion, according to the present findings, wecould hypothesize that (1) NF2, a disorder classicallyviewed as a (young) adult or, less frequently a childhood/a-dolescent disease, may present as a congenital form withbilateral VSs presenting as early as the first months of life;and (2) some disease features (e.g. skin lesions and VSs)and the natural history at this young age are different tothose which occur in classical NF2. Most importantly, if the

Fig. 7 Patient 3: axial postgadolinium T2- (a) and T1- (b)weighted magnetic resonanceimages of the brain obtained atage 4 months (a) and 14 years(b) reveal bilateral extracanalar(black arrows) and leftintracanalar (white arrows) VIIIcranial nerve lesions. Note thatthe vestibular lesions did notprogress over 14 years; theasterisk indicates a largearachnoid cyst in the right polartemporal area.

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current pattern of anatomical stableness of VSs with latersudden and rapid progression of lesions could be confirmedby further studies, closer follow-ups and/or earlier (pre-symptomatic; surgical or pharmacological) interventionsmight be warranted in these (extremely early onset) NF2forms.

Acknowledgments The authors wish to thank Mr. Marco Di Mauro(University of Catania) and Mr. Francesco Marino (CNR, Catania) fortheir skilful technical assistance.

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