neurofibroma 1

7/29/2019 neurofibroma 1

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a b o u t

n e u r o f i b r o

m a t o

s i s 1

NF1



About Neurobromatosis 1OriginaleditionwrittenbyBruceKorf,MD,Ph.D.

Updatedin007byRosalieFerner,MDandBruceKorf,

MD,Ph.D.withmembersoftheClinicalCareAdvisory

BoardoftheChildren’sTumorFoundation:

JanM.Friedman,MD,Ph.D.

University of British Columbia

DavidH.Gutmann,MD,Ph.D.,Co-Chair Washington University School of Medicine

BruceR.Korf,MD,Ph.D.

University of Alabama at Birmingham School of Medicine

RobertMiyamoto,ConsumerRepresentative

University of Washington

ScottR.Plotkin,MD,Ph.D.

Harvard Medical School/Massachusetts General Hospital

TenaRosser,MD

Children’s Hospital Los Angeles/University of Southern

California

ElizabethK.Schorry,MD Cincinnati Children’s Hospital

WilliamH.SlatteryIII,MD

House Ear Institute

DavidViskochil,MD,Ph.D.,Co-Chair

University of Utah

MedicalillustrationscourtesyofSarahBuono

© 007Children’sTumorFoundation. Allrightsreserved.



Contents About Neurobromatosis (NF) 2

CommonSignsofNF1 4

DiagnosisofNF1 7

VariabilityofNF1 9

OtherPotentialManifestationsofNF1 10

LessCommonComplicationsofNF1 14CosmeticConcerns 16

FindingMedicalCareforNF1 17

MedicalEvaluation&Follow-Up:Children17

MedicalEvaluation&Follow-Up:Adults 18TreatingTumorsinNF1 19

Psychological&SocialIssuesofNF1 0

DecidingWhethertoHaveaChild 1

TheGeneticsofNF1:APrimer GlossaryofMedicalTerms 9

Children’sTumorFoundation



THISBROCHUREISINTENDEDTOPROVIDE

an introductory overview of neurobromatosis

type 1 (NF1) for patients, families, and healthcare

providerswiththehopethatreaderswillseek

additionalinformationaboutthedisorderaccording

totheirownindividualneeds.Physiciansknowl-

edgeableaboutNF,localgeneticsclinics,special-

izedNFclinicsthroughoutthecountry,andthe

Children’sTumorFoundationallserveashelpful

sourcesofaccurate,up-to-dateinformation.

ThankstoadvancesinNF1research,new

discoveriesaboutthedisorderarebeingmade

everyyear.Weencourageyoutostayinformed

throughtheFoundation’sregularlyupdatedweb-site (www.ctf.org), quarterly newsletter, research

E-NewsBlast,andbrochurescoveringawide

varietyoftopics.PhysicianswhoseeNFpatients

areencouragedtoattendtheFoundation’s

annualNFConferenceandtovisitourwebsite

tolearnabouttheNFClinicNetwork.

MuchcanbedonetoeffectivelymanageNF1

andhelpaffectedindividualsleadfull,healthylives.

Wehopethispublicationwillanswermanyofyour

questions. If you need further assistance, we wel-comeyoutocontacttheFoundationattheaddress,

phonenumber,ore-mailaddresslistedherein. ABOUT

NEUROFIBROMATOSIS (NF)Neurobromatosis (NF) is the term for a set

ofdistinctgeneticdisorderscharacterizedby

their tendency to cause multiple, benign (non-

cancerous) tumors to grow on nerves. NF

affectsroughly100,000individualsintheU.S.alone.Itstrikespeopleofallracesandethnic

origins worldwide, and both sexes, equally.



Halfofallcasesaretheresultofinheritance

fromaparentwhohasNF,whiletheother50%

occurinfamilieswithnohistoryofthedisorder.

Neurobromatosis 1 (NF1)isthemostcommonformofNF,affectingoneinevery

,000births.Itisoneofthemostprevalent

geneticdisordersandthemostcommonof

the neurocutaneous disorders (conditions that

affect both the skin and nervous system). NF1wasformerlyknownasperipheralNForvon

Recklinghausen’sdisease,namedafterthe

Germanphysicianwhorecognizedtheneuro-

logicalcomponentofthedisorderin188.

NF1ischaracterizedbypigmentedspotsonthe

skin (café-au-lait spots) and tumors that develop

onnervesanywhereinthebody.Insomecases,

tumorscanariseinthebrainoronthespinal

cord.Thedisorderalsocancausenon-tumorous

complicationssuchaslearningdisabilities–whichaffectupto60%ofallindividualswithNF1–as

wellasboneorskeletalabnormalitiesandcertain

cardiovasculardefects.

Neurobromatosis 2 (NF2),formerlycalled

centralorbilateralacousticNF,isestimatedto

affectoneinevery5,000births.Thedisorderis

characterized by tumors (vestibular schwanno-

mas, also called acoustic neuromas) on the

eighthcranialnervesofthebrain–thosethat

controlhearing.NFcanresultinhearingloss.

AdditionalfeaturesofNFcanincludeother

braintumors,suchasmeningiomas,andspinal

cordtumors.

NF1 and NF2 are quite different disorders, causedbymutationsofdifferentgenesondifferentchro-

mosomes,despitethesimilarityintheirnames.



4

Schwannomatosisisamorerecentlyrecog-nizedformofNFthatsharescertain,butnot

other,featuresofNF.Itgenerallydoesnot

causehearinglossandischaracterizedby

chronic pain due to tumors (schwannomas)

thatgrowonnervesanywhereinthebody.The

incidenceofSchwannomatosisisestimatedto

beoneinevery40,000births.Itisbelievedto

be predominantly spontaneous (non-inherited),

withonlyanestimated10%ofcasesbeingfamilial.Littleisknownabouttheunderlying

causes of Schwannomatosis; however, the rst

candidategeneforthedisorderwasreportedin

007,whichshouldhelpaccelerateprogressin

understandingofthedisorder.

ThisbrochurewillfocusonNF1.Separatepub-

licationsareavailablefromtheChildren’sTumor

Foundationwhichprovidemoreinformation

aboutNFandSchwannomatosis.These,as

wellasbrochuresonadditionaltopicsrelevant

toNF1,arelistedonthebackofthisbrochure.

COMMON SIGNS OF NF1

AnumberoffeaturescommonlyassociatedwithNF1aredescribedbelow.Anindividualwith

NF1may,butwillnotnecessarily,developallof

thesefeatures.

Café-au-lait spots,oneofthemostcommon

signs of NF1, are at,

pigmentedspotsonthe

skinnamedafterthe

Frenchtermforcoffee

(café) with milk (lait).

Theytendtobeafewshadesdarkerthanthe

usualcolorofaperson’s



5

skin.Thesespotsareharmlessandoften

helpdeterminethediagnosisofNF1.There

isnocorrelationbetweenthenumberof

café-au-lait spots that an individual has and

the severity, or specic manifestations, of

hisorherNF1.Ingeneral,NF1tumorsare

notmorelikelytoappearonregionsofthe

body where there are café-au-lait spots.

PeoplewithNF1almostalwayshavesixor more café-au-lait spots, which usually

arepresentatbirthorappearwithinthe

rst several years of life. (Fewer café-au-

laitspotsmayoccurinpeoplewhodonot

haveNF1;indeed,about10%ofthegeneralpopulation has one or two café-au-lait

spots.) The size of the spots that identify

NF1variesfrom1/4inchinchildrento

severalinchesindiameter,andoccasionally

may be quite large.

The number of café-au-lait spots that an

individualwithNF1hasmayincreasein

childhoodand,occasionally,laterinlife.

Theymaybeverylightincolorininfants,

darkeningasthechildgetsolderorwithsunexposure. For some individuals, café-au-lait

spotsmayfadeduringadulthood.

Freckling in specic body areas may also

occurinindividualswithNF1.Inthosewho

donothaveNF1,frecklingusuallyoccurs

inareasofskinexposedtosun;withNF1,

frecklingcanbepresentinotherareas,

including the armpit (axillary freckling) and

the groin (inguinal freckling). The freckles are

often rst noted around three or four yearsofage.Suchfrecklingisnotseeninevery

personwithNF1,butwhenpresentitiscon-

sideredstrongevidenceofthedisorder.



6

Lisch nodules areclumpsofpigmentinthe colored part of the eye (iris) that usually

appeararoundpuberty.Theydonotcause

medicalproblemsoraffectvision.Thepresence

of Lisch nodules can be helpful in conrming a

diagnosisofNF1.Lischnodulescanbedistin-

guished from iris freckles (commonly seen in

people without NF) by a simple procedure called

aslit-lampexamination.Thisistypicallyper-

formedbyanophthalmologist.

Neurobromas,themostcommontumorsin

NF1,arebenigngrowthsthattypicallydevelop

on,orjustunderneath,thesurfaceoftheskin;

however,theymayalsooccurindeeperareasof the body. Neurobromas are composed of

tissue from the nervous system (neuro) and

brous tissue (broma). There are two major

types of neurobromas.

Dermal neurobromas,alsoknownascutane-ous neurobromas,

aresmall,nodule-like

tumorsonthesurface

of the skin (pictured

here). These may ap-pearatanyage,though

aremostlikelytostart

developinginadoles-

cence. Dermal neurobromas rarely, if ever,

becomecancerous.

Plexiform neurobromasgrowdiffuselyoras

nodulesundertheskinsurfaceordeeperinthe

body.Theymaybepresentfrombirth,butnot

initially be noticeable. Plexiform neurobromas

candevelopinanypartofthebodyandtendtogrowandintertwinewithnormalbodytissues.

Theyhaveapproximatelya10%chanceof



7

becomingcancerous.Suddengrowthorpain

in a plexiform neurobroma can be a sign of

malignancy.

The presence of multiple neurobromas is an important diagnostic sign of NF1. (A single

neurobroma may occur in a person who does

not have NF.) The number of neurobromas

varieswidelyamongaffectedindividuals–from

onlyafewto,inrarecases,thousands.

Atpresent,thereisnowaytopredicthowmany

neurobromas a person will develop. In some

people, the size or number of neurobromas in-

creases during puberty and pregnancy, reecting

apossiblehormonaleffect.Ingeneral,thenum-

ber of dermal neurobromas tends to increase

withage.Thereisnoevidencethatdiet,exercise,

or vitamins affect the growth of neurobromas.

DIAGNOSIS OF NF1Primarycarephysicianswillreferpatientstoa

geneticist, neurologist, or NF clinic to conrm

thediagnosisofNF1.Thedisorderisdiagnosed

bythepresenceoftwoormoreofthefollowing

criteria,providedthatnootherdiseaseaccountsfor the ndings:

• Six or more café-au-lait spots, each over

5 mm (1/5 inch) in greatest diameter among

childrenwhohavenotyetreachedpuberty;or

each over 15 mm (2/3 inch) in greatest diameter

amongpost-pubertalindividuals.

•Two or more neurobromas of any type, or

one plexiform neurobroma.

• Multiple freckles in the axillary (armpit) or

inguinal (groin) regions.



8

• A distinctive osseous (bone) lesion, such as

sphenoid dysplasia (absence of bone surround-

ing the eye) or bowing of the tibia of the lower

leg with or without pseudarthrosis (incomplete

healing of a fracture).

• Optic glioma (tumor of the optic nerve).

• Two or more Lisch nodules (in the iris of the

eye) on slit-lamp examination.

• A rst-degree relative (parent, sibling, or off -

spring) with NF1, diagnosed by the above criteria.

Occasionally,thesignsofNF1arenoteasyto

identify.MembersoffamiliesinwhichNF1hasoccurredareoftenconcernedaboutwhether

they may have inherited the disorder (or whether

they may have passed on NF1 to their children),

eveniftheyhavenoobvioussigns.Anexamina-

tionbyaphysicianfamiliarwiththesignsofNF1

isusuallythebestwaytodeterminewhetherthe

disorderispresent.

Ifafamilymemberisfoundtohaveafewfeatures

of NF1 but not enough to make a diagnosis (for

example, two or three café-au-lait spots only), itmaybehelpfultoperformadirectgenetest.How-

ever,itisextremelyrareforanindividualtoinherit

NF1yetshownodetectablesignsofthedisorder.

Genetic Testing

Inmostaffectedindividuals,NF1canbediag-

nosedbytheaboveclinicalcriteria.Inthese

casesagenetictestisnotnecessary.Inother

cases,genetictestingofthepatient’sbloodmay

be useful to conrm a diagnosis. Laboratory testsarenowavailabletodeterminepre-symptomatic

(when the individual has no clinical symptoms of

NF1) and prenatal diagnosis. Direct gene testing



9

fromabloodsampleisavailablefordiagnosing

NF1.Atpresent,thetestis95%effectivein

diagnosingthedisorder.However,thetest

cannotdeterminetheseverityofNF1orthe

likelihood of any specic physical symptoms

developing.TolearnthelatestaboutNFtest-

ing,wesuggestthatyouconsultyourphysician,

theChildren’sTumorFoundation,yournearest

geneticscenter,oradesignatedNFclinic.

VARIABILITY OF NF1

SymptomsofNF1arehighlyvariablefromone

persontoanother.Atpresent,thereisnowayto

predicthowseriousacaseofNF1anindividual

willhave.Theseverityrangesfromverymildcasesinwhichtheonlysignsofthedisorderin

adulthood may be multiple café-au-lait spots

and a few dermal neurobromas, to more

severecasesinwhichotherkindsoftumorsor

othermoreseriouscomplicationsmaydevelop.

NF1isacongenitaldisorder;thatis,ithasits

originsasthechilddevelopsbeforebirth.Many

oftheseriousproblemsinNF1mentionedbelow

areevidentatbirthordeveloppriortoadoles-

cence.PeoplewithNF1whohavereached

adulthoodwithouthavingcertainproblemsare

unlikelytodevelopthem.Theseincludecurva-

ture of the spine (scoliosis); congenital defects

ofthebone;problemsassociatedwithpuberty,

growth, or head size; and optic glioma (a tumor

on the nerve that controls vision). Neurological

impairmentleadingtolearningdisabilities,and

inrarecasesmentalretardation,isalsotypically

evidentinearlychildhood.

Itisimportanttonotethatthemajorityofpeople

withNF1leadhealthy,productivelives.Formany,

copingwiththeuncertaintiessurroundingNF1

presents a unique, yet conquerable challenge.



10

OTHER POTENTIALMANIFESTATIONS OF NF1

Learning Disabilities

Learning disabilities are approximately ve

timesmorecommoninchildrenwithNF1than

inotherchildrenandmaybeassociatedwith

speech problems, motor decits, or Attention

Decit Hyperactivity Disorder (ADHD). About

50-60%ofchildrenwithNF1willhavelearning

difculties of some type requiring special assis-

tanceatschool.Atthesametime,itisimportant

torememberthatroughlyhalfofallindividuals

withNF1willnot havelearningdisabilities.

NF1-associatedlearningdisabilitiesareoften

rst noticed when a child starts school. There are

specic characteristic problems performing tasks

suchasreading,writing,ortheuseofnumbers.

TheseissuescanoccurinchildrenwithNF1whohavenormal,orevenaboveaverage,intelligence.

AchildwithNF1whoissuspectedofhaving

alearningproblemshouldbeevaluatedatthe

youngestpossibleagebyapsychologist,

pediatricneurologist,developmentalpediatri-

cian,orotherprofessionalwithspecialknow-

ledgeoflearningdisabilities.Manyschool

systemsprovidereferralstosuchspecialists,

anddevelopmentalservicesareavailableeven

forinfantsandpre-schoolers.

Althoughalearningdisabilityisalifelongcondi-

tion,manyadultshavefoundwaystoadaptand

successfully overcome specic decits. Additional

brochuresareavailablefromtheChildren’sTumor

Foundation with specic information about NF1,

learningdisabilities,andenhancingsuccessin

school,forusebyparentsandeducators.



11

Optic Glioma

Anopticgliomaisatumoroftheopticnervein

thebrainwhichcontrolsvision.Thiskindoftumor

occursinabout15%ofpatientswithNF1and

usuallyappearsinchild-

hood,withapeakonset

ageofabout-4years

old.Opticgliomasmaybesuspectedbecause

offailingvisionoran

abnormaleyeexam,

andtheyaredetectedbymeansofascreening

MRIscan.Therefore,childrenwithNF1should

haveroutineeyeexams–atleastannually–by

anophthalmologistwhoisfamiliarwithNF1and

opticgliomas.Fortunately,themajorityofoptic

nervegliomasneveraffectvisionanddonot

require any treatment. If there is evidence that

the optic glioma is progressing (getting worse or

affecting vision), the current most common treat-

mentrecommendedischemotherapy.

Bone Defects

Abnormalbonedevelopmentoccursinapproxi-

mately14%ofindividualswithNF1.Mostbone

defectsofNF1willbeevidentatbirthorshortly

thereafter (some, such as vertebral defects, can

occur later). They can occur in almost any bone,

butareseenmostoftenintheskullandlimbs.

Theyinclude:

• Congenitalabsence,orpartialabsence,ofthesphenoid bone (the bone normally surrounding

the orbit of the eye), also known as sphenoidwingdysplasia.Thismaycauseslightbulgingof

theskinaroundtheeye.

Optic Nerve



1

• Congenitalbowingofthelegbones,calledtibialdysplasia,canoccurinthebonesofthe

lower leg (tibia or bula). This affects about 3-5%

ofpeoplewithNF1.Tibialdysplasiaisusually

noticed in the rst year of life, so children older

thanthisareveryunlikelytodevelopit.The

affectedbonesmaybethinnerthannormal.Ifa

fractureoccurs,healingmaybesloworincom-

plete, causing pseudarthrosis (a “false joint” or

non-healing fracture). In rare cases, pseudar -

throsismayinvolveotherbonessuchastheulna

oftheforearm.Managementofpseudarthrosis

is a difcult problem, requiring the supervision of

anorthopedicsurgeonwhoisfamiliarwithNF1.

NFresearchisunderwaytodeterminethebest

waytomanagepseudarthrosis.

• Bonecystsoccasionallyoccurattheendofbonesinthearmsandlegs,andtheycansome-

timescausepainordiscomfort.

• Osteopenia (decreased bone density), which

istheprimarycauseofosteoporosis,ismore

commoninindividualswithNF1thaninthose

ofthegeneralpopulation.Preventionstrategies

canbediscussedwithone’sdoctor.

Scoliosis

Scoliosis,orlateralcurvatureofthespine,

isrelativelycommoninNF1

–occurringinabout10%of

patients.Inmostcasesthe

scoliosisismildandappears

inearlychildhood.Asubset

ofchildrenwithNF1may

developanunusualtypeofscoliosiswithasharpangle

tothecurveratherthana



1

smoothS-shapedcurve.Achildwithscoliosis

willneedperiodicspinalimagingandphysical

examinationstodeterminewhethercorrective

measuresareneeded.Insomecases,abrace

maybeusedtopreventprogressionoftheprob-

lem.Thesharplyangulatedformofscoliosisis

more likely to require correction by surgery.

Large Head Size

ChildrenandadultswithNF1oftenhavelarge

headcircumference.Thisusuallydoesnot

indicate any signicant medical problem. Rarely,

largeheadcircumferenceresultsfromhydro-

cephalus, a serious condition which may require

surgery.ImagingofthebrainwithCTscanor

MRIcanhelpdetermineifheadenlargementis

seriousornot.Headcircumferenceinchildren

withNFIshouldbeperiodicallymeasured.

Headache & Other PainMany people with NF1 have frequent head-

aches,particularlymigraineheadaches.

Featuresmayincludethrobbingpainonone

sideofthehead,nausea,andsensitivitytolight.

Migrainecanalsocausestomachpain,withorwithoutheadache.Thesecanberelievedusing

thesametypesofmedicationsusedtotreat

migrainesinpersonswithoutNF1.Severeor

recurrentpainofanytype,anywhereinthe

body,shouldbeevaluatedbyaphysician.

Painisatreatableconditionandmanydifferent

therapeuticoptionsareavailableforitsman-

agement.Importantly,newpaininaplexiform

neurobroma can be a sign of malignancy and

shouldbeevaluatedrightaway.



14

High Blood Pressure (Hypertension)

PeoplewithNF1canhavehypertensionfor

reasonscompletelyunrelatedtoNF1.However,

tworareproblemsassociatedwithNF1mayresultinhypertension:renalarterystenosis

(narrowing of the artery to the kidney) and pheo-

chromocytoma (a rare and usually benign tumor

of the adrenal gland). Both of these problems

aretreatable.ItisimportantthatroutinephysicalexamsforchildrenandadultswithNF1include

bloodpressurechecks.

LESS COMMONCOMPLICATIONS OF NF1

Thecomplicationsmentionedbelowmayoccur

inNF1,butusuallyinlessthan10%ofpatients.

Itshouldbeemphasizedthatmostpeoplewith

NF1willnot experiencethesesymptoms.Many

aretreatable.

• Early or late onset of puberty (can be associ-

ated with optic glioma).

• Problems with growth (individual is too short or

too tall). It is important to note that, as a group,peoplewithNF1areslightlyshorterthanthegen-

eralpopulation–withaverageheightaroundthe

5thpercentileratherthanthe50thpercentile.

• Mental retardation (this is seen in 5-8%

ofthosewithNF1,comparedto-5%inthegeneral population).

• Epilepsy (seizure disorder).

• Cerebrovascular occlusion (stroke), due to

blockageofthebloodvesselssupplyingthe

brain.



15

• Abnormalitiesofbloodvessels,includinganeurysm (weakening of the blood vessel wall,

resulting in bulging) in the renal arteries or in the

brain.

• Congenitalheartdefects,suchasasmallholebetween chambers of the heart (VSD) or narrow-

ing of the pulmonary artery (pulmonic stenosis).

• Malignant tumors (cancer). NF1-related malignancyisestimatedtooccurinabout7-1%

ofaffectedindividuals.PeoplewithNF1havea

somewhathigherriskforcertainraremalignant

tumorsthatoccuralongperipheralnerves,in

the brain, or in the spinal cord. One specic

type, called MPNST (malignant peripheral nerve

sheath tumor), can grow within a plexiform

neurobroma. NF1 patients probably have the

same risk for certain common cancers (such as

cancer of the lung or colon) as does the general

population.However,earlyresearchindicates

apossibleincreaseintheincidenceofbreast

canceramongwomenwithNF1.

• Brain tumors (other than optic glioma), such

asastrocytomasorbrainstemgliomas.

• Leukemia.ChildrenwithNF1havemorethana00-foldincreaseintheriskofdeveloping

anuncommontypeofleukemiacalledjuvenile

myelomonocytic leukemia (JMML). This affects

lessthan1%ofNF1patients.AdultswithNF1

arenotatincreasedriskofdevelopingleukemia

orrelatedcancers.

• Neurological dysfunction (motor or sensory).

• Itching of the skin (pruritis).



16

COSMETIC CONCERNS

In some cases, NF1 can be disguring. Some

adultsmayhavelargeenoughnumbersofder-

mal neurobromas to cause cosmetic problems.Occasionally, large plexiform neurobromas

maygrowaroundtheeyeoreyelid,oraffectone

sideoftheface.Scoliosiscanaffectappearance

whenitissevere.Growthscanoccuraround

the nipple (areolar neurobromas), which maybedistressing.Rarely,anovergrowthofskinor

bonecausesenlargementofanarmorleg.

Disgurement, and the fear of becoming dis-

gured in the future, is often a major concern

forthosewithNF1.Yetnoteveryonereactsthe

samewaytocomplicationsthataffectappear -

ance. Some people nd that café-au-lait spots

or a small number of neurobromas on the skin

arehardtolivewith,whileothersareableto

copewellwithmoresevereinvolvement.

Mostphysiciansdonotrecommendroutine

removal of dermal neurobromas, unless they

arecausingpain,rubbingagainstclothing,or

causing signicant cosmetic concern. If desired,aplasticsurgeonmaybeconsultedtodeter-

minewhetheraparticulartumororgroupof

tumorscanberemovedbyconventionalorlaser

surgery.Somepatientsareexploringthetech-

nique of electro-dessication, or use of an electric

current to dry out and remove dermal neuro-

bromas.Alloftheseproceduresposetheriskof

possiblescarring,andnonehavebeenprovento

resultinpermanenttumorremoval.Theyshould

alwaysbeperformedbyaphysicianwhoisex-

periencedintreatingpatientswithNF1.



17

Plexiform neurobromas around the eye are

often managed jointly by an eye (ophthalmic)

surgeonandaplasticsurgeon.Largeplexiform

neurobromas are often difcult to remove com-

pletely,sincetheyareenmeshedwithnormal

tissuessuchasnervesandbloodvessels.

FINDING MEDICAL CAREFOR NF1

IndividualswithNF1shouldregularlyseea

physicianforevaluationandfollow-upcarewho

isknowledgeableaboutthedisorderandits

complications–orisatleastwillingtolearnand

identify colleagues with the required expertise

asneeded.Specialistsfrommanydisciplines

may be knowledgeable about specic aspects

ofNF1;thosemostlikelytobefamiliarwiththe

disorderasawholeincludegeneticists,neurolo-

gists,andpediatricneurologists.

TheChildren’sTumorFoundationhasestab-

lishedanNFClinicNetworkthatincludesmajor

centersforNFcarethroughouttheU.S.For

moreinformationaboutwheretoseekhelp,con-

tact the Foundation’s national headquarters or

your local chapter or afliate, or visit www.ctf.org.

MEDICAL EVALUATION & FOLLOW-UP:CHILDREN

Theroleofthepediatricianwhofollowsachild

withNF1istomonitorthechild’sgrowthand

developmentmuchasisordinarilydoneforany

otherchild.Thephysicianideallywillbeable

toaccomplishthiswithoutundulyemphasiz-

ing potential difculties, which may or may not

becomeproblemsforanygivenchild.Amedical

evaluationforanyonewithNF1shouldinclude

lookingatfamilymedicalhistory.



18

HealthychildrenwithNF1areusuallyexamined

at6-or1-monthintervalsforheight,weight,

andheadcircumference;bloodpressure;vision

andhearing;evidenceofnormalsexualdevel-

opment;signsoflearningdisability,hyperactiv-

ity, or speech and motor decits; evidence of

scoliosis; and for café-au-lait spots and neuro-

bromas. The causes of any unusual growth

patternaregenerallyinvestigated.Further

diagnosticevaluations,includingbloodtestsandimaging,areusuallyneededonlytoinvestigate

suspectedproblems.

ManyNFspecialistsfeelthereisnoneedto

doroutinescreeningMRIscansofthebrainorspineinhealthypatientswithNF1whohave

no symptoms. Others will recommend a “base-

line” MRI scan in children to check for optic

nervegliomasorspinaltumorsandforuseas

areferencepointtocomparefuturescans.All

physiciansareinagreementthatMRIscans

andotherimagingshouldbeusedifpatientsare

having specic symptoms.

MEDICAL EVALUATION & FOLLOW-UP:

ADULTSInadditiontothestandardphysicalevaluation,

routinecheck-upsforadultswithNF1generally

includeanexaminationoftheskin,thespine

(for scoliosis), blood pressure, vision, and hear -

ing.Attentionisgiventoanymassthatisrapidly

enlargingorcausingnewpain,asthesesigns

can indicate malignancy. Specic tests can be

performedifamedicalproblemdevelops.Adults

withNF1whoareotherwisehealthyusually

havecheck-upsat1-monthintervals.



19

TREATING TUMORS IN NF1

Neurobromas, depending on their location and

size,cansometimesberemovedsurgicallyifthey

becomepainful,invasive,infected,orcosmeticallytroublesome.Atumorsometimesappearswhere

onehasbeenremoved,particularlyifthattumor

wasnotremovedcompletely.Thereisnoevi-

dence that removal of dermal neurobromas will

increasetherateofappearanceofnewgrowths,orcauseincompletelyremovedtumorstochange

frombenigntocancerous.

Subcutaneous (under the skin) neurobromas

are more difcult to remove completely. This is

especially the case for plexiform neurobromas.

Partialremovalmayberecommendedifthey

arecausingsymptomsorpushingonimportant

structures,whichcanresultinlossofneurologi-

calfunction.

World-classNFresearchisunderwaytoidentify

andtestcandidatedrugsthatcouldpotentially

leadtotreatmentsthatenableshrinkingorstop-

pingthegrowthoftumorsassociatedwithNF1.

ThespeedofprogressinNF1research,fromdiscoveryoftheNF1genein1990tothestartof

clinicaltrialsmorerecently,shouldgiveindividu-

alswiththedisordergoodreasonforoptimism.

InformationaboutcurrentNF1clinicaltrialscan

befoundontheChildren’sTumorFoundationwebsite.TheFoundationfundspioneeringNF

researchthroughitsYoungInvestigatorAwards,

DrugDiscoveryInitiativeAwards,NFPreclinical

Consortium, and special awards for specic areas

ofstudy.ThroughitsannualNFConferenceandother scientic meetings, the Foundation also

fostersvitalresearchcollaborations.



0

PSYCHOLOGICAL & SOCIALISSUES OF NF1

Thepotentialcomplicationsanduncertain-

tiesofNF1canbestressfulformanyaffectedindividuals.Decisionsaboutwhether,orwhat,

totellfriends,teachersandemployers–and

whethertohavechildren–areexamplesof

concernsexpressedbymany.Anxietyaboutthe

needformedicaltreatments,asenseoflosingcontrol,andthefeelingofbeingdifferentfrom

othersalsoarecommon.Becauseofthestress

ofmedicalproblemsandlearningdisabilities

associatedwithNF1,socialandpsychological

problemsmayalsodevelop.

Thedisordercanplaceemotionalburdensnot

onlyontheindividualaffected,butalsoonthe

wholefamily–includingunaffectedsiblings.

Parentsmaybetroubledbyunfounded,yet

natural feelings of guilt about the child’s difcul-ties. The nancial cost of caring for a child with

NF1complicationscanbeconsiderable.Indi-

vidualorfamilycounselingbyasocialworkeror

psychotherapistisoftenhelpful.

Tohelpeasethesemultiplepressures,the

Children’sTumorFoundationanditslocal

chapters and afliates have organized sup-

portgroupsthathelpthosewithNFovercome

theirsenseofisolation.Supportgroupsoffer

anopportunitytosharefeelingsandlearnmore

aboutthedisorderinanatmosphereofmutual

understanding.Manypeoplereportthatbecom-

ingactivelyinvolvedineffortstoadvanceNF

research,providesupportservices,orraise

awarenessofNFcanbringanaddedsenseof

hope,community,andempowerment.



1

DECIDINGWHETHER TO HAVE A CHILD

ForcouplesinwhichonepersonhasNF1,there

isa50-50chanceofpassingonthedisorderwitheachpregnancy.Thedecisionwhethertocon-

ceivechildrenwillinvolveemotionalintrospection

aswellasthegatheringoffacts.Noonecan

makethispersonaldecisionforanyoneelse.

Manyinthispositionchoosetoconceiveand

feel condent that, whether or not their child is

bornwithNF1,theyhavemadethedecision

thatisrightforthem.Othersmaydecideto

haveprenataltestingtodeterminewhetherthe

unbornchildhasNF1.

Thistestingisavailableeitherbyamniocentesis

(performed at 15-16 weeks in the pregnancy)

or by chorionic villous sampling (performed at

10-12 weeks). Unfortunately, prenatal testingcanonlytellwhetherthechildhasinheritedNF1

fromtheparent;itdoesnotgiveanyinformation

abouttheexpecteddegreeofseverity.

Some couples have chosen “preimplantation

genetic diagnosis,” a complicated and expen-

siveprocedureusingin vitrofertilizationtech-

niques. Eggs are fertilized outside the body and

thosethatdonothaveanNF1mutationare

selectedtoimplantbackintotheuterus.

The “50-50 Risk”

Witheverypregnancy,anindividualwithNF1

facesa50%riskofconceivingachildwiththe

disorder – the same odds as ipping a coin. This

riskcanbecomparedtothe4-7%riskthatanycoupleinthegeneralpopulationfacesofbear-

ingachildwithaseriousmedicalproblem.



Unaffectedparentswhohaveachildbornwith

NF1 because of a “spontaneous genetic muta-

tion” do not havea50%riskinfuturepregnan-

cies.Theirchanceofbearinganotherchildwith

NF1isaboutthatofanycoupleinthegeneral

population (some studies show a slightly higher

risk). For NF1, this chance is one in 6,000. (One

additionalbirthinevery6,000resultsinachild

whohasinheritedNF1fromaparentwiththe

disorder.Thus,atotaloftwochildrenin6,000 – or one in 3,000 – are born with NF1.)

However,inorderforunaffectedparentswho

haveachildwithNF1toaccuratelyassesstheir

riskofconceivinganotherchildwithNF1,itisessentialtoknowforcertainwhethertheythem-

selvesinfacthaveNF1.Theseparentsshould

beexaminedbyaknowledgeablephysicianto

makesurethatneitherofthemhasamild,

undiagnosedcaseofNF1.

Help with Making the Decision

Geneticcounselingcanhelpcoupleswork

throughthedecision-makingprocess.Counsel-

orsdonottellanyonewhattodo;rather,theyprovide information, clarify issues, answer ques-

tions,andexplainpossibleoptionsincluding

prenatal testing, adoption, or articial insemina-

tion.Thecounselorencouragesthecoupleto

arriveatadecisionthatisrightforthem.Most

majorhospitalsanduniversity-basedmedical

centersoffergeneticcounselingservices.

∫



THE GENETICS OF NF1:A PRIMER

NF1 is caused by a change (mutation) in a single

genelocatedonchromosome17.AnotherformofNF,calledNF,iscausedbyamutationinan

entirelydifferentgenelocatedonchromosome.

Theoddsofoneperson,ormembersofonefam-

ily,havingbothNF1andNFareextremelylow;

thispossibilityshouldnotbeofconcern.Anindi-vidualwithNF1cannotpassonNFtohisorher

child,norcansomeonewithNFpassonNF1.

WhenapersonwithNF1issaidtohavetheNF1

gene,whatthisreallymeansisthattheindividual

hasamutationinatleastoneofthetwocop-

iesoftheNF1genethatpeoplenormallyhave.

IndividualswhowerenotbornwithNF1havetwo

normal (or unaffected) copies of the NF1 gene.

TheNF1genecanbeinheritedfromanaffectedparent (who has NF1) or it may arise by chance

inanindividualwithnofamilyhistoryofNF1.In

thelattercase,NF1resultsfromachangeinthe

genecalledaspontaneousmutation.Abouthalf

ofthosewithNF1haveinheriteditfromaparentwhohasthedisorder;theotherhalfareaffected

becauseofaspontaneousmutationandhaveno

affectedparent.NF1hasanunusuallyhighspon-

taneousmutationrate.Itcanappearinany family,

regardlessofraceorethnicity.

OnceanindividualhasachangeintheNF1

gene–whetherbyinheritanceorbecauseof

aspontaneousmutation–thereisa50-50

chance,eachtimeheorshehasachild,that

thechangedgenewillbepassedon.Thereisalsoa50-50chance,eachtime,thatthe

changedgenewillnot bepassedon.Inthis



4

lattercase,thechildwillbecompletelyfreeof

NF1andwillneverdevelopsignsofthedis-

ease.Thischild,therefore,cannotpassonthe

disorder; NF1 cannot “skip a generation.”

Variability

TheextremevariabilityinNF1symptomsis

seenevenwithinfamilies.ThesameNF1gene

mutationpresentindifferentmembersofthe

samefamily–brothersandsisters,grandpar-

ents,parentsandchildren–canresultinNF1

caseswithwidelyvaryingdegreesofseverity

andverydifferentsymptoms.Forexample,a

parentwhohasamildcaseofNF1mayhave

aseverelyaffectedchild.Thereversesituation

canalsooccur:aseverelyaffectedparentmay

haveachildwithverymildNF1.Atpresent,

thereisnowaytopredicthowseriouslyaffected

anypersoninanyfamilywithNF1willbe,or

whichNF1complicationsmaydevelop.

Genes

Ourbodyismadeupoftrillionsofcells.Each

cellnucleuscontainsasetofchemicalstructures

knownaschromosomes.Thereare46chromo-somes,arrangedinpairs,ineachcellofthe

body.Onechromosomeofeachpairwascontrib-

utedbythefather,andtheotherbythemother.

AgeneisasmallsectionofachromosomecomposedofDNA,amoleculethatencodesthe

buildingblocksofproteinsthatdirectourcells.

Justasthechromosomesoccurinpairs,genes

alsocomeinpairs.Anestimated0,000genes

are arranged in a very specic order on the 23

chromosomepairs.Oneofthesepairs,called

thesexchromosomes,differsinmalesand



5

females;theotherpairs,calledautosomes,

arethesameinbothsexes.

What Genes Do

Whenageneisactivated,avarietyofevents

canoccurinthecell,dependingonthepar-

ticularfunctionofthatgene.Somegenesare

responsibleforobvioustraitssuchaseyecolor;

otherscontroltheproductionofsubstances

essentialtochemicalprocessesinsideourbod-

ies.Certaingenessimplyactason-offswitches

forothergenes.Thesumtotalofthesereac-

tions–whicharelikeorderstothecell–are

all the instructions needed for the rst cell to

developintoahumanbeingandforthebodyto

carryonallthefunctionsoflife.

Gene Mutation

Amutationissimplyachangeoralteration.

Genemutationshaveoccurredsincethebegin-

ningoftimeandcontinuetodoso.Mostarenot

detectable,andmanyarenotharmful.Infact,

gene mutations can be benecial in allowing

speciestoadaptandultimatelysurvivechanges

intheenvironment.Whenamutationoccursinagene,itcanalterthestructureofthegene,and

the gene’s “instructions” to the cell are changed

orevenstoppedcompletely.Analterationofthis

kindcanhaveseriouseffects,andmayresultin

ageneticdisorder.

NF1istheresultofsuchachangedgene.

Thischangeisnotcausedbyanyfactorun-

deraperson’scontrol,suchasdrugorX-ray

exposure;rather,itiscausedbyanerrorinthe

processofcopyinggeneticinformation,typically

whenspermoreggcellsform.



6

Duetoadvancesinresearch,muchinformation

isnowknownabouthowtheNF1geneactsata

molecularlevel.TheNF1genenormallyproduc-

es a protein called “neurobromin,” which acts

through a pathway in the cell (called the Ras

pathway) to signal cells whether to keep dividing

andmultiplying.Thistypeofgeneisalsocalled

a “tumor suppressor” gene.

Mosaic or Segmental NFOccasionally,amutationintheNF1genecan

occurafterconception,laterinembryonicdevel-

opment.Itthereforeaffectsonlyacertainper-

centageofcellsinthebody,butnotothers.Such

cases,whichalwaysresultfromaspontaneous

mutation,arecalledmosaicNF1.SegmentalNF1

isaformofmosaicisminwhichonlyoneportion

ofthebodyisaffectedwithfeaturesofNF1.

Autosomal Dominant DisordersNF1isanautosomaldominantdisorder.Autoso-

malmeansthegeneislocatedononeofthe

numberedpairsofchromosomescalledauto-

somes.Sincethesechromosomesarethesame

inmalesandfemales,thegenecanbepresentineithersex,anditcanbepassedonfrom

eitheramotherorafathertoasonoradaugh-

ter.Thetermdominantmeansthatthepresence

ofonlyonechangedoraffectedgenecauses

thedisordertoappear;theactionoftheunaf-fectedgenewhichispairedwiththedominant

genecannotpreventthedisorder.Becauseone

geneisenoughtocausethedisorder,NF1can

bepassedfromonegenerationtothenextwhen

onlyoneparenthasthegene.



7

The 50-50 Odds of Passing on NF1

WhyaretheoddsofachildinheritingNF1

fromanaffectedparent50-50?

Theexplanationforthisliesintheprocessthat

bringseggcellsandspermcellstomaturity.

Thesecellscarryourgeneticheritagefromone

generationtothenext.Beforereachingmaturity

eachofthesespermandeggcellscontains

pairsofchromosomes,thefullcomplementof

geneticmaterialjustlikeanyotherbodycell.As

theyapproachmaturity,however,thesecellsgo

through a special cell division process (meio-

sis) that results in each egg or sperm having a

singlechromosomefromeachpair–orhalfof

itsoriginalgeneticmaterial.Ithappensthisway:

Whenaneggandsperm–eachwithsingle

chromosomes–unite,anewcellisformed

which contains the 46 chromosomes (23 pairs)

required for normal human development.

1.Chromosomeslineupinpairsinsidetheeggorspermcell.

.Thepairsseparate.

.Thecelldivides.

4.Twocellsareproduced,eachwithone

memberofeverychromosomepair.



8

Thisdiagramshowstheonlypairofchromo-

someswhichincludetheNF1geneandits

unaffectedpartner:

ApersonwhohasNF1makestwodifferentkinds

ofreproductivecells,onewhichwill–ifithappens

tobeusedinconception–causeachildtohave

NF1,andtheotherwhichwillproduceanunaffect-edchildifitistheonethathappenstobeused.

WhenapersonwithNFhaschildrenwithan

unaffectedindividual,therearefourpossible

combinationsofcells.Twowillyieldachildwith

NF1,andtwowillyieldanunaffectedchild.Thisishowithappens:

Thus,thereisa50%chancewitheachpregnan-cyforthechildtoreceivetheNF1gene;thereis

alsoa50%chanceforthechildtoreceivetwo

unaffectedgenesandbefreeofNF1.

AffectedNF1gene

Whenthispairof

chromosomes

dividesduring

reproductiononeeggorsperm

willcontaintheunaffectedgene

onewillcontainthe

affectedNF1gene

Unaffectedgene

← ←

Twounaffected

cellsmay

unite:

Unaffected

child

Twounaffected

cellsmay

unite:

Unaffected

child

NF1cellmay

unitewith

unaffectedcell:

Causes

NF1 in child

NF1cellmay

unitewith

unaffectedcell:

Causes

NF1 in child

ReproductivecellsofparentwithNF1

Reproductivecellsofunaffectedparent

PossibleCombinations



9

GLOSSARY OF MEDICAL TERMSRELATING TO NF1

ASTROCYTOMATumorsthatarisefrombraincellscalledastrocytes.

AUTOSOMAL DOMINANT INHERITANCETheprocessbywhichonegeneofapaircausestheexpres-

sionofatraitordisorder.Suchagenehasa50%chanceof

beingpassedontoeachchildofanaffectedparent.

CAFÉ-AU-LAIT SPOTSPigmented, at spots which are variable in shape and size.

SixormorespotsareusuallyasignofNF1.

CHEMOTHERAPYTreatmentoftumorgrowthbychemicalagents.

CHROMOSOMESBearersofgenes,thebasicunitsofheredity.Thenucleus

ofeachbodycellcontainspairsofchromosomes.

COMPUTERIZED TOMOGRAPHY(Also known as CT or CAT scan) A computerized X-ray,

whichprovidesdetailedimagesofinternalorgans,head

andlimbs.

DOMINANTPertainstoagene,whichbyitselfcausestheexpression

ofatraitordisorder.Anidentical,pairedgeneneednotbe

present.

FIBROMA A tumor composed mainly of brous or connective tissue.

GENEThebasicunitofheredity.Thousandsofgenes,arranged

in specic linear order, form a chromosome. Genes, like

chromosomes,comeinpairs;oneofeachpairislocated

ononechromosome,withthematchinggeneontheotherchromosomeofthatpair.

GLIOMA Atypeofbraintumor.

GLIOBLASTOMA

Atypeofmalignantbraintumor.



0

HAMARTOMA Abenigngrowthconsistingofanovergrowthofthetissues

which normally occur in an area. A neurobroma is an

exampleofahamartoma.

HEMIHYPERTROPHYOvergrowthofonehalfofthebodyorofapartofthebody,

suchastheface.Rarely,thismayoccurinNF1.

LEARNING DISABILITY A problem with a specic cognitive function necessary for

learninginspiteofaverageoraboveaverageintelligence.

Learningdisabilitiescanaffectone’sabilitytolisten,think,read,write,spell,speakand/orcomputemath.

LISCH NODULESSmall,harmlessclumpsofpigmentontheirisoftheeye,

oftenseeninNF1.Theydonotcauseproblemswithvision.

MAGNETIC RESONANCE IMAGING (MRI) A diagnostic technique which uses magnetic energy to

imagethebrainandbody.

MENINGIOMA Abenigntumorofthecoveringofthebrain.

MUTATION Apermanentchangeingeneticmaterial,usuallyina

singlegene.

NEURODenotesrelationshiptoanerveornerves,ortothener-

voussystem.

NEUROFIBROMA AbenigntumorcausedbyproliferationofSchwanncells

and broblasts.

NEUROFIBROMATOSIS TYPE 1 (NF1)(pronounced neuro-fbroma-tosis)

Ageneticdisordercharacterizedbydevelopmentalchang-

esinthenervoussystem,muscles,bonesandskinand

marked supercially by the formation of multiple soft tumors

(neurobromas) and by areas of pigmentation (café-au-lait

spots). Formerly called von Recklinghausen’s disease.

NEURONSElectricallyactivecellsofthenervoussystemresponsible

forcontrollingbehaviorandbodyfunction.



1

OPTIC GLIOMATumor affecting the optic (visual) nerve.

ORBITBonycavityoftheskullinwhichtheeyeballislocated.

PLEXIFORM NEUROFIBROMA A diffuse, at type of growth. Usually occurs below the skin

internally.

PERIPHERALSituatedawayfromthecenterofthecentralnervous

system,towardthesurfaceofthebody.

PIGMENTEDHaving color, in the case of café-au-lait spots a few shades

darkerthanone’sregularskincolor.

PSEUDARTHROSIS

Failure of a fracture to heal, resulting in a “false joint.”

RECESSIVEPertaining to a gene, a pair of which is generally required

forfullexpressionofatraitordisorder.

SARCOMA

Malignantsofttissuetumor.

SCHWANN CELLThe cell of which myelin (the insulation of peripheral

nerves) is composed.

SCHWANNOMA

AbenigntumorcausedbyproliferationofSchwanncells.

SCOLIOSISLateraldeviationinthenormallystraightverticallineof

thespine.

SPONTANEOUS MUTATION

A change in a gene, occurring with no identiable cause.

VESTIBULAR SCHWANNOMA(ACOUSTIC NEUROMA)Benigntumoroftheeighthcranialnervethatcauses

hearingimpairment,acommontumorinNF.

VON RECKLINGHAUSEN’S DISEASE AnothernameforNF1.



CHILDREN’S TUMOR FOUNDATION

ThemissionoftheFoundationisto:

• FindeffectivetreatmentsandacureforNFbysponsoringworld-classresearchandpromoting

collaboration between scientists in the eld;

• ImproveclinicalcareforpatientswithNFandencouragethedevelopmentofNFclinics

nationwide;

• Provideinformationandsupportservicesforaffectedpatientsandfamilies,includingyouth

programs;

• RaisepublicawarenessofNFtogeneratebetterunderstandingandresourcestoimprove

thelivesofthosebornwiththedisorder.

Become Involved!

Yourparticipation,whetherasavolunteerordonor, will help “solve the NF puzzle” by enabling

pioneeringresearchaimedatendingNF.Untila

cureisfound,youalsowillbehelpingtoprovide

hopeandsupportforthosewithNF.

Tobecomeinvolvedandlearnaboutlocal

Foundationactivitiesinyourarea,pleasevisitour

websiteorcontactusattheaddressornumber

onthebackofthisbrochure.



Brochures Available

• AboutNF1

• AboutNF• AboutSchwannomatosis• TheChildwithNF1• NF1:ForAdults• NF1:ForTeens• NF1:ForEducators• NF1:AboutLearningDisabilities

• NF:ForTeens• NF:AboutHearingLoss• NF:GeneticTesting• Mosaic&SegmentalNF

• Children’sTumorFoundation:AboutUs

Other Resources

Stayup-to-dateoninformationaboutNF:

• Visitourwebsiteathttp://www.ctf.org

• Contact us (see back) to receive our quarterly

newsletterandregulare-mailnewsupdates!



Children’s Tumor Foundation95 Pine Street, 16th Floor New York, NY 10005

Tel. 212-344-6633 or 800-323-7938 Fax 212-747-0004 E-mail [email protected] http://www.ctf.org

Founded in 1978, the

Children’s Tumor Foundationis a national, not-for-prot

health organization dedicatedto meeting the unique needs of individuals with neurobromatosis

(NF) and their families.

neurofibroma 1

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