Neurobromatosis

Genetics in Family Medicine:

The Australian Handbook for General Practitioners
Genetics in Family Medicine: The Australian Handbook for General Practitioners 2007
2 Neurofbromatosis
Neurofibromatosis type 1 3
GPs role 3
Clinical features 3
Genetics 4
Prevalence 4
Investigations 4
Management 4
Neurofibromatosis type 2 5
Clinical features 5
Genetics 6
Prevalence 6
Investigations 6
Management 6
Implications for other family members 6
Bibliography 7
Genetics in Family Medicine: The Australian Handbook for General Practitioners 2007
Neurofbromatosis 3
Neurobromatosis
0Ps role

Where possible confrm or rule out a diagnosis in the parents of an affected individual using
the clinical diagnostic criteria listed below. If unsure of a diagnosis, refer to Genetics Services
(see Contacts, support and testing).

Refer as appropriate to specialist paediatric or adult neurology, dermatology, ophthalmology

and/or orthopaedic services.

Refer to Genetics Services for discussion of prenatal genetic testing (see Contacts, support
and testing).

Refer family to relevant support groups (see Contacts, support and testing).
Genetics in Family Medicine: The Australian Handbook for General Practitioners 2007
Neurofibromatosis tyge 1 {NF1)

AlsoknownasVonRecklinghausen'sdisease;PeripheralNeurofbromatosis;VonRecklinghausen's
Neurofbromatosis;Recklinghausen'sPhakomatosis;MultipleNeurofbroma.
Clinical features

NF1ischaracterisedbythedevelopmentofmultiplecaf-au-laitspots,inguinal/axillaryfreckling
andmultipleneurofbromas.

Symptomsusuallyappearduringchildhoodandmaybecomemorepronouncedduringpuberty,pregnancy,
orwhenhormonalchangestakeplace.

Rangeandseverityofsymptomscanvarygreatlyamongaffectedindividualsevenbetweenfamilymembers.

Rateofprogressionisnotpredictable.

Diagnosedwhentwoofthefollowingclinicalfeaturesarepresent:
> Sixormorecaf-au-laitspots,>0.5cmdiameterbeforepuberty,or>1.5cminadults
> Twoormoreneurofbromasofanytypeoroneplexiformneurofbroma
> Frecklingunderthearmsorinthegroinarea
> Benigntumouroftheopticnerve(glioma)
> TwoormoreLischnodules(irishamartomas)
> Adistinctiveosseouslesionsuchasasphenoiddysplasiaorthinningofthelongbonecortexwith
orwithoutpsuedoarthrosis
> A1
0
relative(parent,siblingoroffspring)withNF1bytheabovecriteria

Additionalbutnotdiagnosticfeatures:
> Precociouspubertyordelayedsexualdevelopmentmayoccur
> About50%havespecifclearningdisabilitiesinreading,spellingormathematics
> Growthmaybereduced
> Macrocephaly
> Scoliosis
> Hypertension
> Epilepsy
Genetics in Family Medicine: The Australian Handbook for General Practitioners 2007
4 Neurofbromatosis
Genetics

NF1iscausedbymutationsintheNF1genethatencodesaproteincalledneurofbromin,whichfunctions
asatumoursuppressor.

ManydifferentmutationsintheNF1genehavebeenidentifedinindividualswiththecondition.

Theconditionfollowsapatternofautosomaldominantinheritance.

Approximately50%ofNF1casesareinheritedfromaparent.

About50%areduetonewmutationsintheNF1geneoccurringrandomlyatoraroundconceptionfor
unknownreasons.
Prevalence

NF1affectsabout1in3000people.

Thereisawiderangeofseverityofsymptoms.

Manypeoplewiththeconditionwillonlybeaffectedmildly.

Formostpeople,NF1doesnotsignifcantlyaffecttheirhealthbutforafew,NF1cancausemajorhealth
problemsatcertainstagesoftheirlives.
Investigations

GenetictestingisnotneededtodiagnosetheconditionafterbirthbecausemostpeoplewithNF1willhave
enoughsignsoftheconditionbyage5yearsforaspecialisttodiagnosethemwithconfdence.

GenetictestingforNF1isnotwidelyavailableandiscurrentlyexpensive,butitcanbehelpfulinsome
situations,suchaswhereprenataldiagnosisisrequested.

Prenatalgenetictestingcanbedonewhereoneoftheparentsisaffectedandwantstoknowifthefetusis
affected,providedthespecifcNF1mutationintheaffectedparenthasbeenidentifed.
Management

AnannualreviewbyGPforcomplicationsoftheconditionandformanagementadvice(egreferralto
plasticsurgeon)shouldbeundertaken.

Beawarethat:
> Neurofbromascancausecosmeticproblemsandwraparoundorpenetratethenervescausingpain.
> Thereisabouta5%increaseinriskforvariouscancers,includingbraintumour.Sometimesplexiform
neurofbromasand,veryrarely,simpleneurofbromascanbecomemalignant.
> HypertensionismorecommoninNF1patientsthaninthegeneralpopulation.Atleastannualblood
pressureshouldbeundertakenonallindividualswiththiscondition.Ifhypertensionisidentifed,then
investigationsforasecondarycausesuchasrenalarterystenosisandphaeochromocytomashould
beundertaken.
> ThereisalsoanincreasedrateofscoliosisinNF1.Thisshouldbelookedforandthereshouldbe
alowthresholdforreferraltoanorthopaedicsurgeonforinvestigationandmanagement.Aswith
scoliosisinotherconditions,itmostcommonlypresentsandprogressesaroundthetimeofpuberty.

Areasofsurveillanceshouldinclude:
> Ophthalmologyforopticgliomas;growthoftheseisrareover10yearsofage.
> Education,asspecifclearningdisabilitiesinreading,spellingormathematicsmaybepresent.Children
alsomayhaveshortattentionspan,lowmuscletone,reducedco-ordinationandemotionalimmaturity.
> Monitoringofanyrapidchangesinthegrowthorsymptomsofaneurofbroma.
Genetics in Family Medicine: The Australian Handbook for General Practitioners 2007
Neurofbromatosis 5
Neurofibromatosis tyge 2 {NF2)
0Ps role
Take and update the family history (see Genetics in practice).
Inform adult patients with NF2 of the familial nature of the condition and risks to future
children and relatives.
Manage co-existent conditions.
Provide referral as appropriate to neurology and ophthalmology specialists for assessment
and surveillance.
Provide referral to Genetics Services for discussion of predictive genetic testing (see Contacts,
support and testing).
Clinical features

NF2isararegeneticconditionthatisprimarilycharacterisedbyvestibularschwannomas.

Symptomsmayinclude:
> Gradualhearingloss
> Tinnitus
> Balanceproblems

Theconditionisdiagnosedinindividualswithoneofthefollowing:
> Bilateralvestibularschwannomas
> A1
o
relativewithNF2andunilateralvestibularschwannomasoranytwoof:meningioma,
schwannoma,glioma,neurofbroma,posteriorsubcapsularlenticularopacities
> Unilateralvestibularschwannomaandanytwoof:meningioma,schwannoma,glioma,neurofbroma,
posteriorsubcapsularlenticularopacities
> Multiplemeningiomasandunilateralvestibularschwannomaoranytwoofschwannoma,glioma,
neurofbroma,cataract

Caf-au-laitspotsmaybepresentbutareusuallyfewerinnumberthaninNF1.

Benigntumoursmayalsooccurinoraroundthespinalcord.

Othertumoursofthecentralnervoussystemmayalsodevelopincludingschwannomas,meningiomas,
gliomasandrarelyneurofbromas.

Posteriorsubcapsularcataractsmaydevelopatayoungeragethanwouldotherwisebeexpected,
withsymptomsincludingimpairedand/orprogressivelossofvision.

Otherfeaturesinclude:
> Facialspasms
> Generalisedmuscleweakness,numbness,pain,and/orpartialparalysis
> Diffcultyswallowingand/orimpairedspeech
> Otherneurologicalproblemsincludingheadachesand/orseizures

Symptomsusuallydeveloparoundthetimeofpubertyorduringearlyadulthoodfromthepresenceof
benigntumoursonbothauditorynerves(acousticneuromas/vestibularschwannomas)with90%being
symptomaticbyage45.

Upto30%ofpatientspresentinthefrsttwodecadesoflifewithanon-vestibulartumoursuchas
intracranialmeningioma,astrocytomaorspinaltumour.

10%presentundertheageof10years.Earlypresentationwithanon-vestibulartumourisanadverse
prognosticindicator.
Genetics in Family Medicine: The Australian Handbook for General Practitioners 2007
6 Neurofbromatosis
Genetics

NF2iscausedbymutationsintheNF2genethatregulatestheproductionofthemerlin/schwannomin
proteinwhichfunctionsasatumoursuppressor.

Merlin/schwannominisrelatedtoaclassofproteins(ezrin-radixin-moesinproteins)thatservetolinkthe
internal,supportivesystemwithinacell(cytoskeleton)toproteinsincellmembranes.

ManydifferentmutationsintheNF2genehavebeenidentifedinindividualswiththecondition,andmay
contributetothewidevariabilityofsymptomsandfndingsinaffectedindividuals.

Theconditionfollowsapatternofautosomaldominantinheritance.

Approximately50%ofNF2casesareinheritedandabout50%areduetonewmutationsintheNF2gene.
Prevalence

NF2hasanestimatedbirthfrequencyof1in33,000to40,000.
Investigations

Genetictestingisrarelyrequiredfordiagnosis.

ThemainutilityforgenetictestingoftheNF2geneistoenablepredictivetestingandtofacilitateprenatal
testingwherethisisrequested.

Followinggeneticcounselling,genetictestingisfrstdoneonafamilymemberwithNF2andgerm-line
mutationscanbedetectedinabout60%ofthoseaffected.Thiscantakesomemonths.(SeeContacts,
support and testing).

Oncethefamilymutationhasbeenidentifed,presymptomatictestingisthenavailabletobloodrelatives
andresultsareavailableinamuchshortertimeframe.
Management

Earlydetectionofvestibularschwannomasisassociatedwithbetteroutcome.

Thediagnosisisconfrmedbyathoroughclinicalevaluationandspecialisedtestingsuchasmagnetic
resonanceimaging(MRI).

Vestibularschwannomasaresurgicallyremovedwhenpossible.Thesurgicalprocedurethatisperformed
isbaseduponthesizeandpreciselocationofthetumours.

Radiationtherapymaybeconsideredforthosewhoarenotcandidatesforsurgery.

TumoursurveillanceincarriersforanNF2mutation,affectedindividualsandat-riskindividuals.
Implications for other family members

TestingfortheNF2mutationinasymptomaticfamilymemberscanidentifythosewhomaybeatrisk
ofdevelopingtumoursandwouldbeneftfromregularscreening.

IfarelativeisfoundnottohaveinheritedthefamilyNF2mutationthennofurtherscreeningisnecessary.
Theemotionalandfnancialcostscanthereforebeavoided.
Genetics in Family Medicine: The Australian Handbook for General Practitioners 2007
Neurofbromatosis 7
Bibliography
Barlow-StewartK,2004.Neurofbromatosis type 1 (NF1).InTheAustralasian Genetics Resource Book(Ed
Barlow-StewartK),CentreforGeneticsEducation,RoyalNorthShoreHospital,SydneyNSWISBN0-9580797-2-2.
Accessible at http://www.genetics.com.au
Barlow-StewartK,2004.Neurofbromatosis type 2 (NF2).InThe Australasian Genetics Resource Book(Ed
Barlow-StewartK),CentreforGeneticsEducation,RoyalNorthShoreHospital,SydneyNSWISBN0-9580797-2-2.
Accessible at http://www.genetics.com.au
Evans,DGR,SaintoMandBaserME,2000.Neurofbromatosis type 2.JournalofMedicalGenetics,37:897-904.
NorthK,1998.Clinical aspects of neurofbromatosis type 1.EuropeanJournalofPaediatricNeurology,2:223-231.
NeurofbromatosisAssociationofAustralia(NFAA)Inc.
http://nfaa.org.au