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1090-3798/$ - see frodoi:10.1016/j.ejpn.20

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Official Journal of the European Paediatric Neurology Society

Case study

Stroke in a child with neurofibromatosis type 2

Joanne Nga,�, Santosh R. Mordekara, Daniel J.A. Connollyb, Peter Baxtera

aDepartment of Paediatric Neurology, Sheffield Children’s Hospital, Western Bank, Sheffield S10 2TH, UKbDepartment of Neuroradiology, Sheffield Children’s Hospital, Sheffield, UK

a r t i c l e i n f o

Article history:

Received 21 August 2007

Received in revised form

31 January 2008

Accepted 5 February 2008

Keywords:

Neurofibromatosis type 1

Neurofibromatosis type 2

Stroke

Vasculopathy

Moya–moya disease

nt matter & 2008 Europe08.02.007

thor. Tel.: +44 1142717000drjoanneng@doctors.org.

a b s t r a c t

Neurofibromatosis types 1 (NF1) and 2 (NF2) are genetically distinct conditions caused by

mutations in tumour suppressor genes that share a number of phenotypic features.

Childhood stroke and vasculopathy have been associated with NF1, but not with NF2. We

describe a case of brainstem stroke in a child with NF2.

& 2008 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights reserved.

1. Introduction

Neurofibromatosis type 2 (NF2) is an autosomal dominant

disorder causing a predisposition to nervous system tumours,

with an incidence of 1 in 30,000–50,000. NF2 patients may

develop schwannomas, meningiomas, ependymomas and

astrocytomas but bilateral vestibular schwannomas are felt to

be the hallmark of the disease. There are also associated skin

and ocular abnormalities such as flat dermal NF2 plaques,

spherical subcutaneous schwannomas and early onset catar-

acts. Mononeuropathy in childhood is increasingly recognised

in NF2 and frequently presents as a persistent facial palsy, third

nerve palsy or hand or foot drop. NF2 has a wide range of

phenotypic variability ranging from mild (Gardner) forms where

there is late onset bilateral vestibular schwannomas, often as

the only feature. The severe (Wishart) form has an early onset of

vestibular schwannomas before the age of 25 years and they

also present with other tumours. The NF2 gene is a tumour

suppressor gene located on chromosome 22q12 and encodes for

an Paediatric Neurology S

; fax: +44 1142678296.uk (J. Ng).

the proteins merlin or schwannomin. Mutational analysis

studies of the NF2 gene have suggested a correlation between

severe phenotype and inheritance of truncating mutations.1In contrast, features of NF1 include optic glioma, pigmented

cutaneous lesions, neurofibromas, scoliosis, hydrocephalus,

epilepsy and learning difficulties. The NF1 gene is located on

chromosome 17q11.2 and encodes for a large tumour

suppressor protein called neurofibromin.2 NF1 is also distin-

guished by an association with large vessel vasculopathy that

can cause stroke and Moya–moya syndrome. The latter has

not been described in NF2. We describe an unusual case of

brainstem stroke in a child with NF2.

2. Case study

A boy with known NF2 presented with stroke at age 15 years.

He is the third generation of this family, known to be affected.

He had bilateral vestibular schwannomas and a left-sided

ociety. Published by Elsevier Ltd. All rights reserved.

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trigeminal schwannoma (Fig. 1). Genetic testing at 6 years of

age revealed that he had inherited the 448–1G4A point

mutation, confirming NF2.

At 15 years of age he became unwell with gastroenteritis

and on day 4 of this illness, he developed acute right-sided

weakness. He was normotensive with no history of trauma or

recent infection with chicken pox. Examination showed

bilateral horizontal nystagmus; right facial palsy, mild tongue

deviation to the right and a dense right hemiparesis. There

was no dysarthria or dysphasia. Cardiovascular examination

and hydration were normal. Magnetic resonance imaging

(MRI) [Philips Infinion 1.5T, Best (The Netherlands)] revealed a

large left-sided lesion extending from the midbrain to the

pons. The lesion was of intermediate to low signal intensity

on T1 without evidence of enhancement after gadolinium

administration. The brainstem lesion also demonstrated a

low apparent diffusion coefficient (ADC) and a high diffusion

weighted imaging (DWI) trace consistent with an acute

infarct (Fig. 1). Magnetic resonance angiography (MRA)

showed a normal posterior circulation with no evidence of

dissection or stenosis. Full blood count, ESR, clotting,

thrombophilia screen, iron, folate, urea and electrolytes, liver

function, amino acids, lactate cholesterol, triglycerides,

mycoplasma serology, autoantibody screen, antiphospholi-

pid, anticardiolipin antibodies, thyroid function, homocys-

teine and CSF lactate were all normal or negative. His

transthoracic echocardiogram and electrocardiogram were

unremarkable.

He was commenced on aspirin for stroke prophylaxis and

received multidisciplinary neurorehabilitation. Speech and

language assessment confirmed difficulties with eating, which

resolved over 48 h. At 4 months follow-up his facial weakness

had resolved, but unfortunately the hemiparesis did not resolve.

3. Discussion

To our knowledge this is the first reported case of a child with

NF2 and brainstem stroke. Vasculopathy is not a known

Fig. 1 – Axial ADC map (A) and diffusion weighted image (DWI) t

acute stroke.

manifestation of NF2, although there has been one report of

an adult with NF2 with intracerebral vascular dysplasia

leading to left middle cerebral artery (LMCA) infarction due

to a diffuse narrowing and irregularity of the LMCA on MRA.

She had a different NF2 gene mutation, to our case,

600–2A4G.3 There has been another case report in an adult

patient with NF2 that was found to have a middle meningeal

artery aneurysm.4 No genetic mutation was documented in

this case. These authors suggested that NF2 might be a risk

factor for the development of intracranial aneurysms. In a

separate case report, a child was found to have renal vascular

disease with NF2. This child was found to have

c.288_290delCTT .F96del NF2 gene mutation.5 Our patient

was normotensive with a normal renal ultrasound. The

pathogenesis of brain stem stroke is difficult to explain in

our case, as there was no evidence of a dissection or any other

detectable risk factor. Although we did not pursue an

aggressive diagnostic work-up to ascertain the exact cause

for vasculopathy, in view of the cases above, vasculopathy

would be a plausible suggestion. The three cases described

previously have different NF2 gene mutations, and a correla-

tion cannot be inferred between a specific gene mutation and

associated vasculopathy in NF2.

The association of stroke and Moya–moya disease with NF1,

although rare, is well recognised.6 The underlying pathophy-

siology of vasculopathy in NF1 is incompletely understood.

Both gene mutations encode for tumour suppressor proteins

and these proteins may have a role in regulation of vascular

development. Claudio et al. demonstrated the expression of

the mouse schwannomin protein in mice with the NF2 gene,

located on mouse chromosome 11. They showed the protein

was distributed in the brain, spinal cord and non-neural

tissues including the lungs, kidneys, heart, spleen and

intestine. They also demonstrated the presence of the

schwannomin protein in the tunica intima of the endothelial

lining of blood vessels.7 This finding could explain the

pathogenesis of vasculopathy in NF2. Our case along with

the other case reports, suggest that vasculopathy may be

associated with NF2, as well as NF1.

race (B) demonstrate low ADC and high DWI consistent with

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