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About Neurofibromatosis 1OriginaleditionwrittenbyBruceKorf,MD,Ph.D.

Updatedin�007byRosalieFerner,MDandBruceKorf,MD,Ph.D.withmembersoftheClinicalCareAdvisoryBoardoftheChildren’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 UtahMedicalillustrationscourtesyofSarahBuono

© �007Children’sTumorFoundation.Allrightsreserved.

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Contents About Neurofibromatosis (NF) 2 CommonSignsofNF1 4DiagnosisofNF1 7VariabilityofNF1 9OtherPotentialManifestationsofNF1 10LessCommonComplicationsofNF1 14CosmeticConcerns 16FindingMedicalCareforNF1 17MedicalEvaluation&Follow-Up:Children17MedicalEvaluation&Follow-Up:Adults 18TreatingTumorsinNF1 19Psychological&SocialIssuesofNF1 �0DecidingWhethertoHaveaChild �1TheGeneticsofNF1:APrimer ��GlossaryofMedicalTerms �9Children’sTumorFoundation ��

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THISBROCHUREISINTENDEDTOPROVIDEan introductory overview of neurofibromatosis type 1 (NF1) for patients, families, and healthcare providerswiththehopethatreaderswillseekadditionalinformationaboutthedisorderaccordingtotheirownindividualneeds.Physiciansknowl-edgeableaboutNF,localgeneticsclinics,special-izedNFclinicsthroughoutthecountry,andtheChildren’sTumorFoundationallserveashelpfulsourcesofaccurate,up-to-dateinformation.

ThankstoadvancesinNF1research,newdiscoveriesaboutthedisorderarebeingmadeeveryyear.WeencourageyoutostayinformedthroughtheFoundation’sregularlyupdatedweb-site (www.ctf.org), quarterly newsletter, research E-NewsBlast,andbrochurescoveringawidevarietyoftopics.PhysicianswhoseeNFpatientsareencouragedtoattendtheFoundation’sannualNFConferenceandtovisitourwebsitetolearnabouttheNFClinicNetwork.

MuchcanbedonetoeffectivelymanageNF1andhelpaffectedindividualsleadfull,healthylives.Wehopethispublicationwillanswermanyofyourquestions. If you need further assistance, we wel-comeyoutocontacttheFoundationattheaddress,phonenumber,ore-mailaddresslistedherein. ABOUT NEUROFIBROMATOSIS (NF)

Neurofibromatosis (NF) is the term for a set ofdistinctgeneticdisorderscharacterizedbytheir tendency to cause multiple, benign (non-cancerous) tumors to grow on nerves. NF affectsroughly100,000individualsintheU.S.alone.Itstrikespeopleofallracesandethnicorigins worldwide, and both sexes, equally.

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HalfofallcasesaretheresultofinheritancefromaparentwhohasNF,whiletheother50%occurinfamilieswithnohistoryofthedisorder.

Neurofibromatosis 1 (NF1)isthemostcommonformofNF,affectingoneinevery�,000births.Itisoneofthemostprevalentgeneticdisordersandthemostcommonofthe neurocutaneous disorders (conditions that affect both the skin and nervous system). NF1 wasformerlyknownasperipheralNForvonRecklinghausen’sdisease,namedaftertheGermanphysicianwhorecognizedtheneuro-logicalcomponentofthedisorderin188�.

NF1ischaracterizedbypigmentedspotsontheskin (café-au-lait spots) and tumors that develop onnervesanywhereinthebody.Insomecases,tumorscanariseinthebrainoronthespinalcord.Thedisorderalsocancausenon-tumorouscomplicationssuchaslearningdisabilities–whichaffectupto60%ofallindividualswithNF1–aswellasboneorskeletalabnormalitiesandcertaincardiovasculardefects.

Neurofibromatosis 2 (NF2),formerlycalledcentralorbilateralacousticNF,isestimatedtoaffectoneinevery�5,000births.Thedisorderischaracterized by tumors (vestibular schwanno-mas, also called acoustic neuromas) on the eighthcranialnervesofthebrain–thosethatcontrolhearing.NF�canresultinhearingloss.AdditionalfeaturesofNF�canincludeotherbraintumors,suchasmeningiomas,andspinalcordtumors.

NF1 and NF2 are quite different disorders, caused bymutationsofdifferentgenesondifferentchro-mosomes,despitethesimilarityintheirnames.

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Schwannomatosisisamorerecentlyrecog-nizedformofNFthatsharescertain,butnotother,featuresofNF�.Itgenerallydoesnotcausehearinglossandischaracterizedbychronic pain due to tumors (schwannomas) thatgrowonnervesanywhereinthebody.TheincidenceofSchwannomatosisisestimatedtobeoneinevery40,000births.Itisbelievedtobe predominantly spontaneous (non-inherited), withonlyanestimated10%ofcasesbeingfamilial.Littleisknownabouttheunderlyingcauses of Schwannomatosis; however, the first candidategeneforthedisorderwasreportedin�007,whichshouldhelpaccelerateprogressinunderstandingofthedisorder.

ThisbrochurewillfocusonNF1.Separatepub-licationsareavailablefromtheChildren’sTumorFoundationwhichprovidemoreinformationaboutNF�andSchwannomatosis.These,aswellasbrochuresonadditionaltopicsrelevanttoNF1,arelistedonthebackofthisbrochure.COMMON SIGNS OF NF1AnumberoffeaturescommonlyassociatedwithNF1aredescribedbelow.AnindividualwithNF1may,butwillnotnecessarily,developallofthesefeatures.

Café-au-lait spots,oneofthemostcommonsigns of NF1, are flat, pigmentedspotsontheskinnamedaftertheFrenchtermforcoffee(café) with milk (lait). Theytendtobeafewshadesdarkerthantheusualcolorofaperson’s

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skin.ThesespotsareharmlessandoftenhelpdeterminethediagnosisofNF1.Thereisnocorrelationbetweenthenumberofcafé-au-lait spots that an individual has and the severity, or specific manifestations, of hisorherNF1.Ingeneral,NF1tumorsarenotmorelikelytoappearonregionsofthebody where there are café-au-lait spots.

PeoplewithNF1almostalwayshavesixor more café-au-lait spots, which usually arepresentatbirthorappearwithinthefirst several years of life. (Fewer café-au-laitspotsmayoccurinpeoplewhodonothaveNF1;indeed,about10%ofthegeneralpopulation has one or two café-au-lait spots.) The size of the spots that identify NF1variesfrom1/4inchinchildrentoseveralinchesindiameter,andoccasionallymay be quite large.

The number of café-au-lait spots that an individualwithNF1hasmayincreaseinchildhoodand,occasionally,laterinlife.Theymaybeverylightincolorininfants,darkeningasthechildgetsolderorwithsunexposure. For some individuals, café-au-lait spotsmayfadeduringadulthood.

Freckling in specific body areas may also occurinindividualswithNF1.InthosewhodonothaveNF1,frecklingusuallyoccursinareasofskinexposedtosun;withNF1,frecklingcanbepresentinotherareas,including the armpit (axillary freckling) and the groin (inguinal freckling). The freckles are often first noted around three or four years ofage.SuchfrecklingisnotseenineverypersonwithNF1,butwhenpresentitiscon-sideredstrongevidenceofthedisorder.

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Lisch nodules areclumpsofpigmentinthe colored part of the eye (iris) that usually appeararoundpuberty.Theydonotcausemedicalproblemsoraffectvision.Thepresenceof Lisch nodules can be helpful in confirming a diagnosisofNF1.Lischnodulescanbedistin-guished from iris freckles (commonly seen in people without NF) by a simple procedure called aslit-lampexamination.Thisistypicallyper-formedbyanophthalmologist.

Neurofibromas,themostcommontumorsinNF1,arebenigngrowthsthattypicallydevelopon,orjustunderneath,thesurfaceoftheskin;however,theymayalsooccurindeeperareasof the body. Neurofibromas are composed of tissue from the nervous system (neuro) and fibrous tissue (fibroma). There are two major types of neurofibromas.Dermalneurofibromas,alsoknownascutane-

ous neurofibromas, aresmall,nodule-liketumorsonthesurfaceof the skin (pictured here). These may ap-pearatanyage,thougharemostlikelytostartdevelopinginadoles-

cence. Dermal neurofibromas rarely, if ever, becomecancerous.

Plexiform neurofibromasgrowdiffuselyorasnodulesundertheskinsurfaceordeeperinthebody.Theymaybepresentfrombirth,butnotinitially be noticeable. Plexiform neurofibromas candevelopinanypartofthebodyandtendtogrowandintertwinewithnormalbodytissues.Theyhaveapproximatelya10%chanceof

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becomingcancerous.Suddengrowthorpainin a plexiform neurofibroma can be a sign of malignancy.

The presence of multiple neurofibromas is an important diagnostic sign of NF1. (A single neurofibroma may occur in a person who does not have NF.) The number of neurofibromas varieswidelyamongaffectedindividuals–fromonlyafewto,inrarecases,thousands.

Atpresent,thereisnowaytopredicthowmanyneurofibromas a person will develop. In some people, the size or number of neurofibromas in-creases during puberty and pregnancy, reflecting apossiblehormonaleffect.Ingeneral,thenum-ber of dermal neurofibromas tends to increase withage.Thereisnoevidencethatdiet,exercise,or vitamins affect the growth of neurofibromas.

DIAGNOSIS OF NF1Primarycarephysicianswillreferpatientstoageneticist, neurologist, or NF clinic to confirm thediagnosisofNF1.Thedisorderisdiagnosedbythepresenceoftwoormoreofthefollowingcriteria,providedthatnootherdiseaseaccountsfor the findings:

• Six or more café-au-lait spots, each over 5 mm (1/5 inch) in greatest diameter among childrenwhohavenotyetreachedpuberty;oreach over 15 mm (2/3 inch) in greatest diameter amongpost-pubertalindividuals.

•Two or more neurofibromas of any type, or one plexiform neurofibroma.

• Multiple freckles in the axillary (armpit) or inguinal (groin) regions.

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• 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 first-degree relative (parent, sibling, or off-spring) with NF1, diagnosed by the above criteria.

Occasionally,thesignsofNF1arenoteasytoidentify.MembersoffamiliesinwhichNF1hasoccurredareoftenconcernedaboutwhetherthey may have inherited the disorder (or whether they may have passed on NF1 to their children), eveniftheyhavenoobvioussigns.Anexamina-tionbyaphysicianfamiliarwiththesignsofNF1isusuallythebestwaytodeterminewhetherthedisorderispresent.

Ifafamilymemberisfoundtohaveafewfeaturesof NF1 but not enough to make a diagnosis (for example, two or three café-au-lait spots only), it maybehelpfultoperformadirectgenetest.How-ever,itisextremelyrareforanindividualtoinheritNF1yetshownodetectablesignsofthedisorder.

Genetic Testing

Inmostaffectedindividuals,NF1canbediag-nosedbytheaboveclinicalcriteria.Inthesecasesagenetictestisnotnecessary.Inothercases,genetictestingofthepatient’sbloodmaybe useful to confirm a diagnosis. Laboratory tests arenowavailabletodeterminepre-symptomatic(when the individual has no clinical symptoms of NF1) and prenatal diagnosis. Direct gene testing

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fromabloodsampleisavailablefordiagnosingNF1.Atpresent,thetestis95%effectiveindiagnosingthedisorder.However,thetestcannotdeterminetheseverityofNF1orthelikelihood of any specific physical symptoms developing.TolearnthelatestaboutNFtest-ing,wesuggestthatyouconsultyourphysician,theChildren’sTumorFoundation,yournearestgeneticscenter,oradesignatedNFclinic.

VARIABILITY OF NF1SymptomsofNF1arehighlyvariablefromonepersontoanother.Atpresent,thereisnowaytopredicthowseriousacaseofNF1anindividualwillhave.Theseverityrangesfromverymildcasesinwhichtheonlysignsofthedisorderinadulthood may be multiple café-au-lait spots and a few dermal neurofibromas, to more severecasesinwhichotherkindsoftumorsorothermoreseriouscomplicationsmaydevelop.

NF1isacongenitaldisorder;thatis,ithasitsoriginsasthechilddevelopsbeforebirth.ManyoftheseriousproblemsinNF1mentionedbelowareevidentatbirthordeveloppriortoadoles-cence.PeoplewithNF1whohavereachedadulthoodwithouthavingcertainproblemsareunlikelytodevelopthem.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,andinrarecasesmentalretardation,isalsotypicallyevidentinearlychildhood.

ItisimportanttonotethatthemajorityofpeoplewithNF1leadhealthy,productivelives.Formany,copingwiththeuncertaintiessurroundingNF1presents a unique, yet conquerable challenge.

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OTHER POTENTIAL MANIFESTATIONS OF NF1

Learning Disabilities

Learning disabilities are approximately five timesmorecommoninchildrenwithNF1thaninotherchildrenandmaybeassociatedwithspeech problems, motor deficits, or Attention Deficit Hyperactivity Disorder (ADHD). About 50-60%ofchildrenwithNF1willhavelearningdifficulties of some type requiring special assis-tanceatschool.Atthesametime,itisimportanttorememberthatroughlyhalfofallindividualswithNF1willnothavelearningdisabilities.

NF1-associatedlearningdisabilitiesareoftenfirst noticed when a child starts school. There are specific characteristic problems performing tasks suchasreading,writing,ortheuseofnumbers.TheseissuescanoccurinchildrenwithNF1whohavenormal,orevenaboveaverage,intelligence.

AchildwithNF1whoissuspectedofhavingalearningproblemshouldbeevaluatedattheyoungestpossibleagebyapsychologist,pediatricneurologist,developmentalpediatri-cian,orotherprofessionalwithspecialknow-ledgeoflearningdisabilities.Manyschoolsystemsprovidereferralstosuchspecialists,anddevelopmentalservicesareavailableevenforinfantsandpre-schoolers.

Althoughalearningdisabilityisalifelongcondi-tion,manyadultshavefoundwaystoadaptandsuccessfully overcome specific deficits. Additional brochuresareavailablefromtheChildren’sTumorFoundation with specific information about NF1, learningdisabilities,andenhancingsuccessinschool,forusebyparentsandeducators.

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Optic Glioma

Anopticgliomaisatumoroftheopticnerveinthebrainwhichcontrolsvision.Thiskindoftumoroccursinabout15%ofpatientswithNF1andusuallyappearsinchild-hood,withapeakonsetageofabout�-4yearsold.Opticgliomasmaybesuspectedbecauseoffailingvisionoranabnormaleyeexam,andtheyaredetectedbymeansofascreeningMRIscan.Therefore,childrenwithNF1shouldhaveroutineeyeexams–atleastannually–byanophthalmologistwhoisfamiliarwithNF1andopticgliomas.Fortunately,themajorityofopticnervegliomasneveraffectvisionanddonotrequire 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.MostbonedefectsofNF1willbeevidentatbirthorshortlythereafter (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 sphenoid wingdysplasia.Thismaycauseslightbulgingoftheskinaroundtheeye.

Optic Nerve

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• Congenitalbowingofthelegbones,calledtibialdysplasia,canoccurinthebonesofthelower leg (tibia or fibula). This affects about 3-5% ofpeoplewithNF1.Tibialdysplasiaisusuallynoticed in the first year of life, so children older thanthisareveryunlikelytodevelopit.Theaffectedbonesmaybethinnerthannormal.Ifafractureoccurs,healingmaybesloworincom-plete, causing pseudarthrosis (a “false joint” or non-healing fracture). In rare cases, pseudar-throsismayinvolveotherbonessuchastheulnaoftheforearm.Managementofpseudarthrosisis a difficult problem, requiring the supervision of anorthopedicsurgeonwhoisfamiliarwithNF1.NFresearchisunderwaytodeterminethebestwaytomanagepseudarthrosis.

• Bonecystsoccasionallyoccurattheendofbonesinthearmsandlegs,andtheycansome-timescausepainordiscomfort.

• Osteopenia (decreased bone density), which istheprimarycauseofosteoporosis,ismorecommoninindividualswithNF1thaninthoseofthegeneralpopulation.Preventionstrategiescanbediscussedwithone’sdoctor.

Scoliosis

Scoliosis,orlateralcurvatureofthespine,isrelativelycommoninNF1–occurringinabout10%ofpatients.Inmostcasesthescoliosisismildandappearsinearlychildhood.AsubsetofchildrenwithNF1maydevelopanunusualtypeofscoliosiswithasharpangletothecurveratherthana

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smoothS-shapedcurve.Achildwithscoliosiswillneedperiodicspinalimagingandphysicalexaminationstodeterminewhethercorrectivemeasuresareneeded.Insomecases,abracemaybeusedtopreventprogressionoftheprob-lem.Thesharplyangulatedformofscoliosisismore likely to require correction by surgery.

Large Head Size

ChildrenandadultswithNF1oftenhavelargeheadcircumference.Thisusuallydoesnotindicate any significant medical problem. Rarely, largeheadcircumferenceresultsfromhydro-cephalus, a serious condition which may require surgery.ImagingofthebrainwithCTscanorMRIcanhelpdetermineifheadenlargementisseriousornot.HeadcircumferenceinchildrenwithNFIshouldbeperiodicallymeasured.

Headache & Other Pain

Many people with NF1 have frequent head-aches,particularlymigraineheadaches.Featuresmayincludethrobbingpainononesideofthehead,nausea,andsensitivitytolight.Migrainecanalsocausestomachpain,withorwithoutheadache.ThesecanberelievedusingthesametypesofmedicationsusedtotreatmigrainesinpersonswithoutNF1.Severeorrecurrentpainofanytype,anywhereinthebody,shouldbeevaluatedbyaphysician.

Painisatreatableconditionandmanydifferenttherapeuticoptionsareavailableforitsman-agement.Importantly,newpaininaplexiformneurofibroma can be a sign of malignancy and shouldbeevaluatedrightaway.

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High Blood Pressure (Hypertension)

PeoplewithNF1canhavehypertensionforreasonscompletelyunrelatedtoNF1.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.ItisimportantthatroutinephysicalexamsforchildrenandadultswithNF1includebloodpressurechecks.

LESS COMMON COMPLICATIONS OF NF1ThecomplicationsmentionedbelowmayoccurinNF1,butusuallyinlessthan10%ofpatients.ItshouldbeemphasizedthatmostpeoplewithNF1willnotexperiencethesesymptoms.Manyaretreatable.

• 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 blockageofthebloodvesselssupplyingthebrain.

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• 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.PeoplewithNF1haveasomewhathigherriskforcertainraremalignanttumorsthatoccuralongperipheralnerves,inthe brain, or in the spinal cord. One specific type, called MPNST (malignant peripheral nerve sheath tumor), can grow within a plexiform neurofibroma. 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,earlyresearchindicatesapossibleincreaseintheincidenceofbreastcanceramongwomenwithNF1.

• Brain tumors (other than optic glioma), such asastrocytomasorbrainstemgliomas.

• Leukemia.ChildrenwithNF1havemorethana�00-foldincreaseintheriskofdevelopinganuncommontypeofleukemiacalledjuvenilemyelomonocytic leukemia (JMML). This affects lessthan1%ofNF1patients.AdultswithNF1arenotatincreasedriskofdevelopingleukemiaorrelatedcancers.

• Neurological dysfunction (motor or sensory).

• Itching of the skin (pruritis).

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COSMETIC CONCERNS

In some cases, NF1 can be disfiguring. Some adultsmayhavelargeenoughnumbersofder-mal neurofibromas to cause cosmetic problems. Occasionally, large plexiform neurofibromas maygrowaroundtheeyeoreyelid,oraffectonesideoftheface.Scoliosiscanaffectappearancewhenitissevere.Growthscanoccuraroundthe nipple (areolar neurofibromas), which may bedistressing.Rarely,anovergrowthofskinorbonecausesenlargementofanarmorleg.

Disfigurement, and the fear of becoming dis-figured in the future, is often a major concern forthosewithNF1.Yetnoteveryonereactsthesamewaytocomplicationsthataffectappear-ance. Some people find that café-au-lait spots or a small number of neurofibromas on the skin arehardtolivewith,whileothersareabletocopewellwithmoresevereinvolvement.

Mostphysiciansdonotrecommendroutineremoval of dermal neurofibromas, unless they arecausingpain,rubbingagainstclothing,orcausing significant cosmetic concern. If desired, aplasticsurgeonmaybeconsultedtodeter-minewhetheraparticulartumororgroupoftumorscanberemovedbyconventionalorlasersurgery.Somepatientsareexploringthetech-nique of electro-dessication, or use of an electric current to dry out and remove dermal neurofi-bromas.Alloftheseproceduresposetheriskofpossiblescarring,andnonehavebeenproventoresultinpermanenttumorremoval.Theyshouldalwaysbeperformedbyaphysicianwhoisex-periencedintreatingpatientswithNF1.

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Plexiform neurofibromas around the eye are often managed jointly by an eye (ophthalmic) surgeonandaplasticsurgeon.Largeplexiformneurofibromas are often difficult to remove com-pletely,sincetheyareenmeshedwithnormaltissuessuchasnervesandbloodvessels.

FINDING MEDICAL CARE FOR NF1

IndividualswithNF1shouldregularlyseeaphysicianforevaluationandfollow-upcarewhoisknowledgeableaboutthedisorderanditscomplications–orisatleastwillingtolearnandidentify colleagues with the required expertise asneeded.Specialistsfrommanydisciplinesmay be knowledgeable about specific aspects ofNF1;thosemostlikelytobefamiliarwiththedisorderasawholeincludegeneticists,neurolo-gists,andpediatricneurologists.

TheChildren’sTumorFoundationhasestab-lishedanNFClinicNetworkthatincludesmajorcentersforNFcarethroughouttheU.S.Formoreinformationaboutwheretoseekhelp,con-tact the Foundation’s national headquarters or your local chapter or affiliate, or visit www.ctf.org.

MEDICAL EVALUATION & FOLLOW-UP: CHILDRENTheroleofthepediatricianwhofollowsachildwithNF1istomonitorthechild’sgrowthanddevelopmentmuchasisordinarilydoneforanyotherchild.Thephysicianideallywillbeabletoaccomplishthiswithoutundulyemphasiz-ing potential difficulties, which may or may not becomeproblemsforanygivenchild.AmedicalevaluationforanyonewithNF1shouldincludelookingatfamilymedicalhistory.

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HealthychildrenwithNF1areusuallyexaminedat6-or1�-monthintervalsforheight,weight,andheadcircumference;bloodpressure;visionandhearing;evidenceofnormalsexualdevel-opment;signsoflearningdisability,hyperactiv-ity, or speech and motor deficits; evidence of scoliosis; and for café-au-lait spots and neuro-fibromas. The causes of any unusual growth patternaregenerallyinvestigated.Furtherdiagnosticevaluations,includingbloodtestsandimaging,areusuallyneededonlytoinvestigatesuspectedproblems.

ManyNFspecialistsfeelthereisnoneedtodoroutinescreeningMRIscansofthebrainorspineinhealthypatientswithNF1whohaveno symptoms. Others will recommend a “base-line” MRI scan in children to check for optic nervegliomasorspinaltumorsandforuseasareferencepointtocomparefuturescans.AllphysiciansareinagreementthatMRIscansandotherimagingshouldbeusedifpatientsarehaving specific symptoms.

MEDICAL EVALUATION & FOLLOW-UP: ADULTS

Inadditiontothestandardphysicalevaluation,routinecheck-upsforadultswithNF1generallyincludeanexaminationoftheskin,thespine(for scoliosis), blood pressure, vision, and hear-ing.Attentionisgiventoanymassthatisrapidlyenlargingorcausingnewpain,asthesesignscan indicate malignancy. Specific tests can be performedifamedicalproblemdevelops.AdultswithNF1whoareotherwisehealthyusuallyhavecheck-upsat1�-monthintervals.

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TREATING TUMORS IN NF1

Neurofibromas, depending on their location and size,cansometimesberemovedsurgicallyiftheybecomepainful,invasive,infected,orcosmeticallytroublesome.Atumorsometimesappearswhereonehasbeenremoved,particularlyifthattumorwasnotremovedcompletely.Thereisnoevi-dence that removal of dermal neurofibromas will increasetherateofappearanceofnewgrowths,orcauseincompletelyremovedtumorstochangefrombenigntocancerous.

Subcutaneous (under the skin) neurofibromas are more difficult to remove completely. This is especially the case for plexiform neurofibromas. Partialremovalmayberecommendediftheyarecausingsymptomsorpushingonimportantstructures,whichcanresultinlossofneurologi-calfunction.

World-classNFresearchisunderwaytoidentifyandtestcandidatedrugsthatcouldpotentiallyleadtotreatmentsthatenableshrinkingorstop-pingthegrowthoftumorsassociatedwithNF1.ThespeedofprogressinNF1research,fromdiscoveryoftheNF1genein1990tothestartofclinicaltrialsmorerecently,shouldgiveindividu-alswiththedisordergoodreasonforoptimism.

InformationaboutcurrentNF1clinicaltrialscanbefoundontheChildren’sTumorFoundationwebsite.TheFoundationfundspioneeringNFresearchthroughitsYoungInvestigatorAwards,DrugDiscoveryInitiativeAwards,NFPreclinicalConsortium, and special awards for specific areas ofstudy.ThroughitsannualNFConferenceandother scientific meetings, the Foundation also fostersvitalresearchcollaborations.

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PSYCHOLOGICAL & SOCIAL ISSUES OF NF1

Thepotentialcomplicationsanduncertain-tiesofNF1canbestressfulformanyaffectedindividuals.Decisionsaboutwhether,orwhat,totellfriends,teachersandemployers–andwhethertohavechildren–areexamplesofconcernsexpressedbymany.Anxietyabouttheneedformedicaltreatments,asenseoflosingcontrol,andthefeelingofbeingdifferentfromothersalsoarecommon.BecauseofthestressofmedicalproblemsandlearningdisabilitiesassociatedwithNF1,socialandpsychologicalproblemsmayalsodevelop.

Thedisordercanplaceemotionalburdensnotonlyontheindividualaffected,butalsoonthewholefamily–includingunaffectedsiblings.Parentsmaybetroubledbyunfounded,yetnatural feelings of guilt about the child’s difficul-ties. The financial cost of caring for a child with NF1complicationscanbeconsiderable.Indi-vidualorfamilycounselingbyasocialworkerorpsychotherapistisoftenhelpful.

Tohelpeasethesemultiplepressures,theChildren’sTumorFoundationanditslocalchapters and affiliates have organized sup-portgroupsthathelpthosewithNFovercometheirsenseofisolation.Supportgroupsofferanopportunitytosharefeelingsandlearnmoreaboutthedisorderinanatmosphereofmutualunderstanding.Manypeoplereportthatbecom-ingactivelyinvolvedineffortstoadvanceNFresearch,providesupportservices,orraiseawarenessofNFcanbringanaddedsenseofhope,community,andempowerment.

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DECIDING WHETHER TO HAVE A CHILD

ForcouplesinwhichonepersonhasNF1,thereisa50-50chanceofpassingonthedisorderwitheachpregnancy.Thedecisionwhethertocon-ceivechildrenwillinvolveemotionalintrospectionaswellasthegatheringoffacts.Noonecanmakethispersonaldecisionforanyoneelse.

Manyinthispositionchoosetoconceiveandfeel confident that, whether or not their child is bornwithNF1,theyhavemadethedecisionthatisrightforthem.OthersmaydecidetohaveprenataltestingtodeterminewhethertheunbornchildhasNF1.

Thistestingisavailableeitherbyamniocentesis(performed at 15-16 weeks in the pregnancy) or by chorionic villous sampling (performed at 10-12 weeks). Unfortunately, prenatal testing canonlytellwhetherthechildhasinheritedNF1fromtheparent;itdoesnotgiveanyinformationabouttheexpecteddegreeofseverity.

Some couples have chosen “preimplantation genetic diagnosis,” a complicated and expen-siveprocedureusingin vitrofertilizationtech-niques. Eggs are fertilized outside the body and thosethatdonothaveanNF1mutationareselectedtoimplantbackintotheuterus.

The “50-50 Risk”

Witheverypregnancy,anindividualwithNF1facesa50%riskofconceivingachildwiththedisorder – the same odds as flipping a coin. This riskcanbecomparedtothe4-7%riskthatanycoupleinthegeneralpopulationfacesofbear-ingachildwithaseriousmedicalproblem.

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UnaffectedparentswhohaveachildbornwithNF1 because of a “spontaneous genetic muta-tion” do nothavea50%riskinfuturepregnan-cies.TheirchanceofbearinganotherchildwithNF1isaboutthatofanycoupleinthegeneralpopulation (some studies show a slightly higher risk). For NF1, this chance is one in 6,000. (One additionalbirthinevery6,000resultsinachildwhohasinheritedNF1fromaparentwiththedisorder.Thus,atotaloftwochildrenin6,000– or one in 3,000 – are born with NF1.) However,inorderforunaffectedparentswhohaveachildwithNF1toaccuratelyassesstheirriskofconceivinganotherchildwithNF1,itisessentialtoknowforcertainwhethertheythem-selvesinfacthaveNF1.Theseparentsshouldbeexaminedbyaknowledgeablephysiciantomakesurethatneitherofthemhasamild,undiagnosedcaseofNF1.

Help with Making the Decision

Geneticcounselingcanhelpcouplesworkthroughthedecision-makingprocess.Counsel-orsdonottellanyonewhattodo;rather,theyprovide information, clarify issues, answer ques-tions,andexplainpossibleoptionsincludingprenatal testing, adoption, or artificial insemina-tion.Thecounselorencouragesthecoupletoarriveatadecisionthatisrightforthem.Mostmajorhospitalsanduniversity-basedmedicalcentersoffergeneticcounselingservices.

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THE GENETICS OF NF1: A PRIMER

NF1 is caused by a change (mutation) in a single genelocatedonchromosome17.AnotherformofNF,calledNF�,iscausedbyamutationinanentirelydifferentgenelocatedonchromosome��.Theoddsofoneperson,ormembersofonefam-ily,havingbothNF1andNF�areextremelylow;thispossibilityshouldnotbeofconcern.Anindi-vidualwithNF1cannotpassonNF�tohisorherchild,norcansomeonewithNF�passonNF1.

WhenapersonwithNF1issaidtohavetheNF1gene,whatthisreallymeansisthattheindividualhasamutationinatleastoneofthetwocop-iesoftheNF1genethatpeoplenormallyhave.IndividualswhowerenotbornwithNF1havetwonormal (or unaffected) copies of the NF1 gene.

TheNF1genecanbeinheritedfromanaffectedparent (who has NF1) or it may arise by chance inanindividualwithnofamilyhistoryofNF1.Inthelattercase,NF1resultsfromachangeinthegenecalledaspontaneousmutation.AbouthalfofthosewithNF1haveinheriteditfromaparentwhohasthedisorder;theotherhalfareaffectedbecauseofaspontaneousmutationandhavenoaffectedparent.NF1hasanunusuallyhighspon-taneousmutationrate.Itcanappearinanyfamily,regardlessofraceorethnicity.

OnceanindividualhasachangeintheNF1gene–whetherbyinheritanceorbecauseofaspontaneousmutation–thereisa50-50chance,eachtimeheorshehasachild,thatthechangedgenewillbepassedon.Thereisalsoa50-50chance,eachtime,thatthechangedgenewillnotbepassedon.Inthis

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lattercase,thechildwillbecompletelyfreeofNF1andwillneverdevelopsignsofthedis-ease.Thischild,therefore,cannotpassonthedisorder; NF1 cannot “skip a generation.”

Variability

TheextremevariabilityinNF1symptomsisseenevenwithinfamilies.ThesameNF1genemutationpresentindifferentmembersofthesamefamily–brothersandsisters,grandpar-ents,parentsandchildren–canresultinNF1caseswithwidelyvaryingdegreesofseverityandverydifferentsymptoms.Forexample,aparentwhohasamildcaseofNF1mayhaveaseverelyaffectedchild.Thereversesituationcanalsooccur:aseverelyaffectedparentmayhaveachildwithverymildNF1.Atpresent,thereisnowaytopredicthowseriouslyaffectedanypersoninanyfamilywithNF1willbe,orwhichNF1complicationsmaydevelop.

Genes

Ourbodyismadeupoftrillionsofcells.Eachcellnucleuscontainsasetofchemicalstructuresknownaschromosomes.Thereare46chromo-somes,arrangedin��pairs,ineachcellofthebody.Onechromosomeofeachpairwascontrib-utedbythefather,andtheotherbythemother.

AgeneisasmallsectionofachromosomecomposedofDNA,amoleculethatencodesthebuildingblocksofproteinsthatdirectourcells.Justasthechromosomesoccurinpairs,genesalsocomeinpairs.Anestimated�0,000genesare arranged in a very specific order on the 23 chromosomepairs.Oneofthesepairs,calledthesexchromosomes,differsinmalesand

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females;theother��pairs,calledautosomes,arethesameinbothsexes.

What Genes Do

Whenageneisactivated,avarietyofeventscanoccurinthecell,dependingonthepar-ticularfunctionofthatgene.Somegenesareresponsibleforobvioustraitssuchaseyecolor;otherscontroltheproductionofsubstancesessentialtochemicalprocessesinsideourbod-ies.Certaingenessimplyactason-offswitchesforothergenes.Thesumtotalofthesereac-tions–whicharelikeorderstothecell–areall the instructions needed for the first cell to developintoahumanbeingandforthebodytocarryonallthefunctionsoflife.

Gene Mutation

Amutationissimplyachangeoralteration.Genemutationshaveoccurredsincethebegin-ningoftimeandcontinuetodoso.Mostarenotdetectable,andmanyarenotharmful.Infact,gene mutations can be beneficial in allowing speciestoadaptandultimatelysurvivechangesintheenvironment.Whenamutationoccursinagene,itcanalterthestructureofthegene,andthe gene’s “instructions” to the cell are changed orevenstoppedcompletely.Analterationofthiskindcanhaveseriouseffects,andmayresultinageneticdisorder.

NF1istheresultofsuchachangedgene.Thischangeisnotcausedbyanyfactorun-deraperson’scontrol,suchasdrugorX-rayexposure;rather,itiscausedbyanerrorintheprocessofcopyinggeneticinformation,typicallywhenspermoreggcellsform.

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Duetoadvancesinresearch,muchinformationisnowknownabouthowtheNF1geneactsatamolecularlevel.TheNF1genenormallyproduc-es a protein called “neurofibromin,” which acts through a pathway in the cell (called the Ras pathway) to signal cells whether to keep dividing andmultiplying.Thistypeofgeneisalsocalleda “tumor suppressor” gene.

Mosaic or Segmental NF

Occasionally,amutationintheNF1genecanoccurafterconception,laterinembryonicdevel-opment.Itthereforeaffectsonlyacertainper-centageofcellsinthebody,butnotothers.Suchcases,whichalwaysresultfromaspontaneousmutation,arecalledmosaicNF1.SegmentalNF1isaformofmosaicisminwhichonlyoneportionofthebodyisaffectedwithfeaturesofNF1.

Autosomal Dominant Disorders

NF1isanautosomaldominantdisorder.Autoso-malmeansthegeneislocatedononeofthe��numberedpairsofchromosomescalledauto-somes.Sincethesechromosomesarethesameinmalesandfemales,thegenecanbepresentineithersex,anditcanbepassedonfromeitheramotherorafathertoasonoradaugh-ter.Thetermdominantmeansthatthepresenceofonlyonechangedoraffectedgenecausesthedisordertoappear;theactionoftheunaf-fectedgenewhichispairedwiththedominantgenecannotpreventthedisorder.Becauseonegeneisenoughtocausethedisorder,NF1canbepassedfromonegenerationtothenextwhenonlyoneparenthasthegene.

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The 50-50 Odds of Passing on NF1

WhyaretheoddsofachildinheritingNF1fromanaffectedparent50-50?

Theexplanationforthisliesintheprocessthatbringseggcellsandspermcellstomaturity.Thesecellscarryourgeneticheritagefromonegenerationtothenext.Beforereachingmaturityeachofthesespermandeggcellscontains��pairsofchromosomes,thefullcomplementofgeneticmaterialjustlikeanyotherbodycell.Astheyapproachmaturity,however,thesecellsgothrough a special cell division process (meio-sis) that results in each egg or sperm having a singlechromosomefromeachpair–orhalfofitsoriginalgeneticmaterial.Ithappensthisway:

Whenaneggandsperm–eachwith��singlechromosomes–unite,anewcellisformedwhich contains the 46 chromosomes (23 pairs) required for normal human development.

1.Chromosomeslineupinpairsinsidetheeggorspermcell.

�.Thepairsseparate.

�.Thecelldivides.

4.Twocellsareproduced,eachwithonememberofeverychromosomepair.

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Thisdiagramshowstheonlypairofchromo-someswhichincludetheNF1geneanditsunaffectedpartner:

ApersonwhohasNF1makestwodifferentkindsofreproductivecells,onewhichwill–ifithappenstobeusedinconception–causeachildtohaveNF1,andtheotherwhichwillproduceanunaffect-edchildifitistheonethathappenstobeused.

WhenapersonwithNFhaschildrenwithanunaffectedindividual,therearefourpossiblecombinationsofcells.TwowillyieldachildwithNF1,andtwowillyieldanunaffectedchild.Thisishowithappens:

Thus,thereisa50%chancewitheachpregnan-cyforthechildtoreceivetheNF1gene;thereisalsoa50%chanceforthechildtoreceivetwounaffectedgenesandbefreeofNF1.

AffectedNF1gene

Whenthispairof

chromosomesdividesduringreproductiononeeggorsperm

willcontaintheunaffectedgene

onewillcontaintheaffectedNF1gene

Unaffectedgene

← ←Twounaffected

cellsmayunite:

Unaffected child

Twounaffectedcellsmay

unite:Unaffected

child

NF1cellmayunitewith

unaffectedcell:Causes

NF1 in child

NF1cellmayunitewith

unaffectedcell:Causes

NF1 in child

ReproductivecellsofparentwithNF1

Reproductivecellsofunaffectedparent

PossibleCombinations

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GLOSSARY OF MEDICAL TERMS RELATING TO NF1ASTROCYTOMATumorsthatarisefrombraincellscalledastrocytes.

AUTOSOMAL DOMINANT INHERITANCETheprocessbywhichonegeneofapaircausestheexpres-sionofatraitordisorder.Suchagenehasa50%chanceofbeingpassedontoeachchildofanaffectedparent.

CAFÉ-AU-LAIT SPOTSPigmented, flat spots which are variable in shape and size. SixormorespotsareusuallyasignofNF1.

CHEMOTHERAPYTreatmentoftumorgrowthbychemicalagents.

CHROMOSOMESBearersofgenes,thebasicunitsofheredity.Thenucleusofeachbodycellcontains��pairsofchromosomes.

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

DOMINANTPertainstoagene,whichbyitselfcausestheexpressionofatraitordisorder.Anidentical,pairedgeneneednotbepresent.

FIBROMAA tumor composed mainly of fibrous or connective tissue.

GENEThebasicunitofheredity.Thousandsofgenes,arrangedin specific linear order, form a chromosome. Genes, like chromosomes,comeinpairs;oneofeachpairislocatedononechromosome,withthematchinggeneontheotherchromosomeofthatpair.

GLIOMAAtypeofbraintumor.

GLIOBLASTOMAAtypeofmalignantbraintumor.

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HAMARTOMAAbenigngrowthconsistingofanovergrowthofthetissueswhich normally occur in an area. A neurofibroma is an exampleofahamartoma.

HEMIHYPERTROPHYOvergrowthofonehalfofthebodyorofapartofthebody,suchastheface.Rarely,thismayoccurinNF1.

LEARNING DISABILITYA problem with a specific 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.

MENINGIOMAAbenigntumorofthecoveringofthebrain.

MUTATIONApermanentchangeingeneticmaterial,usuallyinasinglegene.

NEURODenotesrelationshiptoanerveornerves,ortothener-voussystem.

NEUROFIBROMAAbenigntumorcausedbyproliferationofSchwanncellsand fibroblasts.

NEUROFIBROMATOSIS TYPE 1 (NF1)(pronounced neuro-fibroma-tosis)Ageneticdisordercharacterizedbydevelopmentalchang-esinthenervoussystem,muscles,bonesandskinandmarked superficially by the formation of multiple soft tumors (neurofibromas) and by areas of pigmentation (café-au-lait spots). Formerly called von Recklinghausen’s disease.

NEURONSElectricallyactivecellsofthenervoussystemresponsibleforcontrollingbehaviorandbodyfunction.

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OPTIC GLIOMATumor affecting the optic (visual) nerve.

ORBITBonycavityoftheskullinwhichtheeyeballislocated.

PLEXIFORM NEUROFIBROMAA diffuse, flat type of growth. Usually occurs below the skin internally.

PERIPHERALSituatedawayfromthecenterofthecentralnervoussystem,towardthesurfaceofthebody.

PIGMENTEDHaving color, in the case of café-au-lait spots a few shades darkerthanone’sregularskincolor.

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

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

SARCOMAMalignantsofttissuetumor.

SCHWANN CELLThe cell of which myelin (the insulation of peripheral nerves) is composed.

SCHWANNOMAAbenigntumorcausedbyproliferationofSchwanncells.

SCOLIOSISLateraldeviationinthenormallystraightverticallineofthespine.

SPONTANEOUS MUTATIONA change in a gene, occurring with no identifiable cause.

VESTIBULAR SCHWANNOMA (ACOUSTIC NEUROMA)Benigntumoroftheeighthcranialnervethatcauseshearingimpairment,acommontumorinNF�.

VON RECKLINGHAUSEN’S DISEASEAnothernameforNF1.

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CHILDREN’S TUMOR FOUNDATION ThemissionoftheFoundationisto:

• FindeffectivetreatmentsandacureforNFbysponsoringworld-classresearchandpromotingcollaboration between scientists in the field;

• ImproveclinicalcareforpatientswithNFandencouragethedevelopmentofNFclinicsnationwide;

• Provideinformationandsupportservicesforaffectedpatientsandfamilies,includingyouthprograms;

• RaisepublicawarenessofNFtogeneratebetterunderstandingandresourcestoimprovethelivesofthosebornwiththedisorder.

Become Involved!

Yourparticipation,whetherasavolunteerordonor, will help “solve the NF puzzle” by enabling pioneeringresearchaimedatendingNF.Untilacureisfound,youalsowillbehelpingtoprovidehopeandsupportforthosewithNF.

TobecomeinvolvedandlearnaboutlocalFoundationactivitiesinyourarea,pleasevisitourwebsiteorcontactusattheaddressornumberonthebackofthisbrochure.

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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 Foundation 95 Pine Street, 16th Floor New York, NY 10005 Tel. 212-344-6633 or 800-323-7938 Fax 212-747-0004 E-mail info@ctf.org Website http://www.ctf.org

Founded in 1978, the Children’s Tumor Foundation is a national, not-for-profit health organization dedicated to meeting the unique needs of individuals with neurofibromatosis (NF) and their families.