CLINICAL REPORT Guidance for the Clinician in Rendering Pediatric Care

Health Supervision for Children WithNeurofibromatosis Type 1David T. Miller, MD, PhD, FAAP,a Debra Freedenberg, MD, PhD, FAAP,b Elizabeth Schorry, MD,c Nicole J. Ullrich, MD, PhD,d

David Viskochil, MD, PhD,e Bruce R. Korf, MD, PhD, FAAP,f COUNCIL ON GENETICS, AMERICAN COLLEGE OF MEDICAL GENETICS ANDGENOMICS

abstractNeurofibromatosis type 1 (NF1) is a multisystem disorder that primarilyinvolves the skin and peripheral nervous system. Its population prevalence isapproximately 1 in 3000. The condition is usually recognized in early childhood,when pigmentary manifestations emerge. Although NF1 is associated withmarked clinical variability, most children affected follow patterns of growthand development within the normal range. Some features of NF1 can bepresent at birth, but most manifestations emerge with age, necessitatingperiodic monitoring to address ongoing health and developmental needs andminimize the risk of serious medical complications. In this report, we providea review of the clinical criteria needed to establish a diagnosis, theinheritance pattern of NF1, its major clinical and developmentalmanifestations, and guidelines for monitoring and providing intervention tomaximize the health and quality of life of a child affected.

INTRODUCTION

Neurofibromatosis type 1 (NF1) is 1 of the most common inherited geneticconditions, affecting approximately 1 in 3000 individuals.1 NF1 isa multisystem disorder in which some features may be present at birth butmost are age-related manifestations. Since the publication of the article“Health Supervision for Children With Neurofibromatosis,” the healthsupervision and treatment rationale has evolved, necessitating thisupdate.2 In this report, we only address issues concerning the diagnosisand management of NF1, which should not be confused withneurofibromatosis type 2, a separate and distinct disorder that typicallypresents in childhood and adolescence with cutaneous and vestibularschwannomas and has an incidence of 1 in 33 000 and a prevalence of lessthan 1 in 50 000.1 Most pediatricians and pediatric medical subspecialistsfollow multiple children with NF1 in their practices, and NF1 has a widespectrum of health implications. This document seeks to educate andprovide guidance for the clinician on the current understanding of the

aDivision of Genetics and Genomics and dDepartment of Neurology,Harvard Medical School, Harvard University and Boston Children’sHospital, Boston, Massachusetts; bTexas Department of State HealthServices, Austin, Texas; cDivision of Human Genetics, CincinnatiChildren’s Hospital Medical Center, Cincinnati, Ohio; eDivision ofMedical Genetics, Department of Pediatrics, University of Utah, SaltLake City, Utah; and fDepartment of Genetics, University of Alabama atBirmingham, Birmingham, Alabama

Dr Miller led the working group, served as liaison between theworking group and the American College of Medical Genetics, reviewedand updated literature references, and drafted several sections; DrFreedenberg served as liaison between the working group and theAmerican Academy of Pediatrics; Drs Schorry, Ullrich, and Viskochilreviewed and updated literature references and drafted severalsections; Dr Korf cochaired the working group, reviewed and updatedliterature references, and drafted several sections; and all authorsapproved the final manuscript as submitted and agree to beaccountable for all aspects of the work. This document is copyrightedand is property of the American Academy of Pediatrics and its Boardof Directors. All authors have filed conflict of interest statements withthe American Academy of Pediatrics. Any conflicts have been resolvedthrough a process approved by the Board of Directors. The AmericanAcademy of Pediatrics has neither solicited nor accepted anycommercial involvement in the development of the content of thispublication.

Clinical reports from the American Academy of Pediatrics benefit fromexpertise and resources of liaisons and internal (AAP) and externalreviewers. However, clinical reports from the American Academy ofPediatrics may not reflect the views of the liaisons or theorganizations or government agencies that they represent.

The guidance in this report does not indicate an exclusive course oftreatment or serve as a standard of medical care. Variations, takinginto account individual circumstances, may be appropriate.

To cite: Miller DT, Freedenberg D, Schorry E, et al. AAPCOUNCIL ON GENETICS, AAP AMERICAN COLLEGE OF MEDICALGENETICS AND GENOMICS. Health Supervision for ChildrenWith Neurofibromatosis Type 1. Pediatrics. 2019;143(5):e20190660

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pathophysiology of NF1, healthsupervision for children with NF1,and the role of the medical home incaring for children with NF1.

DIAGNOSIS AND DIFFERENTIALDIAGNOSIS

In a National Institutes of Health(NIH) consensus developmentconference regarding NF1, 7 criteriawere demarcated, of which 2 or moreare required to establish thediagnosis of NF1 (see Table 1).3–6 Thediagnosis of NF1 in nonfamilialpediatric cases may be difficultbecause certain clinicalmanifestations are age dependent.The variability of clinical expressivity

in NF1 also makes it difficult topredict future manifestations of NF1in a child who is affected.

The diagnosis of NF1 in a child isusually first suspected on the basis ofcafé-au-lait macules (CALMs) (Fig 2).The differential diagnosis (Table 2)includes other conditions that presentwith CALMs or other pigmentarymanifestations. In general, CALMs inNF1 have uniform and regularborders (“coast of California”).Atypical CALMs that are irregularlyshaped (“coast of Maine”) or haveheavy pigment compared withadjacent skin may be seen in NF1, butif typical CALMs are not also present,other conditions should be

considered. Other signs andsymptoms delineate these conditions,and referral to a specialistexperienced in diagnosing NF1 andrelated conditions (usually a medicalgeneticist, dermatologist, orneurologist) may be helpful toestablish a diagnosis. Finally, thereare individuals who have faircomplexion with up to 6 lightlypigmented, irregularly marginatedCALMs who may have a pigmentarydysplasia unrelated to an underlyingmedical condition.7

There are families in whichindividuals have typical multipleCALMs inherited as an autosomaldominant trait with no othermanifestations of NF1. Some of these

TABLE 1 NIH Consensus Development Conference Criteria

Clinical Criteria Clinical Pearls

1. Six or more CALMs equal to or greater than5 mm in longest diameter in prepubertalpatients and 15 mm in longest diameter inpostpubertal patients

• 2–3 or fewer CALMs are normal in thepopulation

• Typically, CALMs are present since infancy inpeople with NF1

• Typically have smooth edges2. Two or more neurofibromas of any type or 1plexiform neurofibroma

• Dermal and subcutaneous neurofibromas nottypically detectable until later in childhood

• Plexiform neurofibroma typically changes thecolor and/or texture of overlying skin

3. Freckling in the axillary or inguinal regions(Crowe sign)

• Not typically detectable until age 5 or later

• Freckling in areas not exposed to the sun isunexpected in people without NF1

4. Optic glioma (OPG) • Not detectable without direct ophthalmoscopy• May be present in infancy• Early detection critical for preserving vision

5. Two or more iris hamartomas (Lisch nodules)(Fig 1)

• Occurrence is age related (rarely present ininfants and toddlers; present in about half ofchildren by school age; present in mostteenagers)

• Not detectable (without slit-lamp examination)• Does not affect vision

6. A distinctive osseous lesion, such as sphenoidwing dysplasia or long-bone dysplasia (withassociated cortical thickening and medullarycanal narrowing), with or withoutpseudoarthrosis

• Tibial dysplasia is the most common type ofbone dysplasia

• Infants and toddlers with anterior-lateral tibialbowing on examination should have tibialradiographs and referral to orthopedics

7. A first-degree relative (parent, sibling, or child)with NF1 according to the aforementionedcriteria

• Parent who is affected should have somesymptoms even if mildly affected (100%penetrance)

• NF1 does not skip a generation

Two or more criteria are required to establish the diagnosis of NF1. Adapted from Neurofibromatosis. Conferencestatement. National Institutes of Health Consensus Development Conference. Arch Neurol. 1988;45(5):575–578; NationalInstitutes of Health Consensus Development Conference Statement: neurofibromatosis. Bethesda, Md., USA, July 13-15,1987. Neurofibromatosis. 1988;1(3):172–178; and DeBella K, Szudek J, Friedman JM. Use of the national institutes of healthcriteria for diagnosis of neurofibromatosis 1 in children. Pediatrics. 2000;105(3, pt 1):608–614.

FIGURE 1Multiple CALMs over the back and cutaneousneurofibromas below the right scapula andright side of the lower back.

FIGURE 2Axillary freckling.

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families are genetically linked to theNF1 locus and carry an NF1pathogenic variant. There are alsoother, less common, conditionsassociated with CALMs. The conditionthat could appear most similar to NF1is Legius syndrome, which is causedby pathogenic variants in SPRED1,which encodes a protein that alsofunctions within the Ras signalingpathway. People with Legiussyndrome have multiple CALMs,intertriginous freckling (Fig 3),learning disabilities, and relativemacrocephaly that isindistinguishable from findings inmild cases of NF1.8 Other

manifestations of NF1, such asneurofibromas or other tumors,ophthalmologic findings, and skeletalmanifestations, are not present infamilies with Legius syndrome.9 Theabsence of neurofibromas in adultswith multiple CALMs in an extendedpedigree is helpful to establisha diagnosis of Legius syndromeversus NF1, and molecular testing forSPRED1 versus NF1 should beconsidered in these cases.9

GENETICS

NF1 is inherited in an autosomaldominant fashion, although

approximately half of individualsaffected have sporadic cases causedby a new (or de novo) NF1 genemutation, hereafter calleda pathogenic sequence variant (PSV).There is complete penetrance (ie,everyone with a pathogenic change inthe NF1 gene will show some featuresof NF1), although expression isextremely variable, even withinmembers of the same family. Anindividual with NF1 (whether familialor de novo) has a 50% chance ofhaving a child with NF1 with eachpregnancy. In contrast, unaffectedparents of a child with a new PSVhave a low risk of recurrence insiblings of the child who is affected.The NF1 gene encodes a proteincalled neurofibromin, which functionsto regulate the Ras signaling pathwaythat controls cell proliferation. Cellsin tumors associated with NF1, suchas Schwann cells in neurofibromas,have a PSV of both NF1 alleles: thegerm-line PSV and a somaticallyacquired PSV of the other allele. NF1,therefore, functions as a tumor-suppressor gene.

Role of Genetic Testing in Diagnosis

Molecular diagnosis of NF1 isavailable on the basis of analysis ofDNA for a pathogenic variant in theNF1 gene. Testing can be performed

TABLE 2 Differential Diagnosis of Patients With CALMs

Diagnosis Clinical Features

Legius syndrome • Typical NF1-like CALMs; mild freckling• No neurofibromas or OPGs• Similar cognitive impairment

McCune-Albright syndrome • Jagged (coast of Maine) CALMs• Polyostotic fibrous dysplasia with fracture• Precocious puberty or other tumors• No neurofibromas

Noonan syndrome • Typical CALMs but fewer• Lentigines rather than Crowe sign freckling• Pulmonic valve stenosis with neck webbing• Short stature, cryptorchidism, pectusexcavatum, curly hair, distinctive facialgestalt

Silver-Russell syndrome • Typical CALMs but fewer; no freckling• Intrauterine growth retardation withpostnatal growth retardation, normocephaly

• Fifth digit clinodactyly, hypospadias, bodyasymmetry

Chromosomal or DNA instability syndromes: FS, BS,MMRCS

• Atypical CALMs; no freckles

• Postnatal growth retardation withmicrocephaly

• UV sensitivity (BS), brain and blood cancers(MMRCS), congenital malformations (FS)

PTEN hamartoma tumor syndrome • Typical CALMs but fewer; no freckles• CALMs of the glans and/or penile shaft inmales

• Macrocephaly ($3 SD from mean)• Hypotonia, family history of thyroid andbreast cancer

Chromosomal mosaicism and ring chromosomes • Atypical CALMs; pigmentary dysplasia• Intellectual disability• Growth retardation with microcephaly• Body asymmetry

Sotos syndrome, Nevoid basal cell carcinomasyndrome, neurofibromatosis type 2, epidermalnevus syndrome, Carney syndrome

• Atypical CALMs; no freckling

• Physical manifestations distinct from NF1

BS, Bloom syndrome; FS, Fanconi syndrome; MMRCS, mismatch repair cancer syndrome; PTEN, Phosphatase and tensinhomolog.

FIGURE 3Close-up of a 9 mm sessile cutaneous neuro-fibroma (cNF; inset) and 12mm globular cNFfrom the same individual. The globular cNFprotrudes further from the surrounding skinsurface, but both are benign lesions.

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on any source of DNA, usually a bloodspecimen. Thousands of distinct PSVshave been identified in differentpatients; most lead to loss of functionof the gene product, as expected fora tumor-suppressor gene.10,11

Thus far, only 4 genotype-phenotypecorrelations have been established:

1. A deletion of the entire NF1 geneand more than 10 surroundinggenes, comprising 1.4 to 1.5 Mb ofDNA, leads to a severe phenotypewith intellectual disability, a largeburden of neurofibromas, andincreased risk of malignantperipheral nerve sheath tumors(MPNSTs) and cardiovascularmalformations.12

2. A specific 3-base deletion in exon22 (National Center forBiotechnology Informationnomenclature) of the NF1 gene(c.2970-2972 delAAT) leads toa mild phenotype characterized byCALMs and skinfold freckles withno neurofibromas.13

3. Amino acid substitution at codon1809 (which encodes arginine) isassociated with pigmentaryfeatures but not neurofibromas,although these patients may alsohave a Noonan syndrome–likephenotype, including pulmonicstenosis and short stature.14

4. Some missense or splicing variantsare associated with “spinal NF1,” inwhich there are often fewpigmentary findings, few or nodermal neurofibromas, and normalcognitive ability but large numbersof internal tumors involving spinalnerve roots and deep peripheralnerves.15

NF1 genetic testing may beperformed for purposes of diagnosisor to assist in genetic counseling andfamily planning. If a child fulfillsdiagnostic criteria for NF1, moleculargenetic confirmation is usuallyunnecessary. For a young child whopresents only with CALMs, NF1genetic testing can confirma suspected diagnosis before a second

feature, such as skinfold freckling,appears. Some families may wish toestablish a definitive diagnosis assoon as possible and not wait for thissecond feature, and genetic testingcan usually resolve the issue. Witha sensitivity rate of 95%, genetictesting is considered highly reliable,although a negative test does notcompletely rule out the condition.

In rare instances, CALMs may beassociated with either of the 2specific NF1 PSVs noted above, inwhich case neurofibromas areunlikely to occur. Also, Legiussyndrome, associated with theSPRED1 gene, can present withmultiple CALMs, sometimes withskinfold freckling, but without otherfeatures of NF1.8,9 Some laboratorieswill initially perform NF1 testing ona child with multiple CALMs and thentest for SPRED1 if NF1 testing isnegative. It is also possible to testonly for SPRED1 and then to assumethat NF1 is most likely if SPRED1testing is negative,16 although manyparents whose child is undergoinggenetic testing might prefer to havea definitive diagnosis. Genetic testingfor the NF1 gene can also be helpfulin children who present with atypicalfeatures such as isolated plexiformneurofibromas, optic glioma, or tibialdysplasia. Blood testing in suchinstances is usually negative becausethe genetic changes may haveoccurred only in the affected tissue.In such cases, testing of tissueobtained from a lesion might bepositive and indicative of somaticmosaicism. Children who presentwith “segmental NF1” (who usuallyhave a limited distribution of CALMsand/or skinfold freckles or,sometimes, of neurofibromas) canalso be diagnosed with somaticmosaicism after a biopsy of affectedtissue and molecular testing of eithermelanocytes from CALMs or Schwanncells from neurofibromas.17 Thisprotocol usually does not guideclinical management, so it is rarelyfollowed, although it can be helpful

for adults who are concerned aboutthe possibility of genetic transmissionby way of gonadal NF1 mutationmosaicism and wish to identify thespecific PSV for future prenataltesting.

Knowledge of the NF1 PSV can enabletesting of other family members andprenatal diagnostic testing. Becausethe penetrance of NF1 is essentially100% by adolescence, a carefulphysical examination usually sufficesto establish the diagnosis in a relativeat risk for having inherited themutant allele. People with NF1 havea 50% risk for each of their offspringto be affected and can be offeredprenatal testing or preimplantationgenetic diagnosis. Prenatal testingrequires previous knowledge of thespecific PSV in the affected individual.The unaffected parents of a child whois sporadically affected have a lowprobability of having another childwho is affected, barring theoccurrence of germ-line mosaicism ora new de novo PSV in a subsequentpregnancy. The latter scenario hasbeen reported but is expected tooccur less often than germ-linemosaicism.18 Prenatal testing couldbe performed if the PSV of the childwho is sporadically affected is known.Typically, families are counseled thatthe recurrence risk is 1% or less forparents who are clinically unaffected.

Summary and RecommendationsAbout Genetic Testing

The following can be summarizedabout genetic testing:

• can confirm a suspected diagnosisbefore a clinical diagnosis ispossible;

• can differentiate NF1 from Legiussyndrome;

• may be helpful in children whopresent with atypical features;

• usually does not predict futurecomplications; and

• may not detect all cases of NF1;a negative genetic test rules out

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a diagnosis of NF1 with 95% (butnot 100%) sensitivity.

SKIN

Cutaneous pigmentary manifestationsare the most common and most well-recognized features of NF1 inchildren. The morphology andsignificance of CALMs have alreadybeen noted. Axillary and inguinalfreckles (Fig 3), commonly referred toas Crowe sign, are small (1–2 mm)pigmented macules that appear inskinfold regions (eg, axillae, inguinalregions, and the neck), typicallybeginning at about 3 to 5 years of age.In some cases, there may be similardiffuse freckling all over the body. Theonly importance of skinfold frecklingis as 1 of the diagnostic criteria forNF1. Additional skin manifestationsinclude juvenile xanthogranulomas(JXGs) and nevus anemicus.19 JXGsare small, waxy, yellowish nodulesthat appear on the skin in a smallpercentage of young children withNF1. They typically resolvespontaneously. It has been suggestedthat JXGs might be associated withleukemia in children with NF1,20 butstudies reveal that either they are nota risk factor for leukemia or the riskis too low to warrant surveillance forleukemia.19,21 Nevus anemicus isa flat skin macule that is paler thansurrounding skin; unlike surroundingskin, it will not turn red when rubbed.Nevus anemicus may occur in up tohalf of individuals with NF1.22

Pruritus is a common symptom inindividuals with NF1, and topicallotions and antihistamines areminimally effective. In older children,gabapentin can be helpful.

NEUROFIBROMAS

Nonmalignant Cutaneous andSubcutaneous Neurofibromas

Various types of neurofibromas arecommon manifestations of NF1.Cutaneous neurofibromas typicallyemerge in the teenage years andincrease in numbers with increasing

age (Fig 4). Sometimes they may beseen in younger children, often visiblewith side lighting as subtle skinbumps. Neurofibromas are present inalmost all adults with NF1 (althoughthe numbers vary greatly), and theyusually first appear on the trunk andthen extend to the extremities, neck,and face. Some people may haverelatively low numbers of smallcutaneous neurofibromas, and othersmay be carpeted with hundreds oreven thousands. They often havea mild purplish coloration and mayeither be raised above the skin orpucker subcutaneously. Cutaneousneurofibromas are benign tumors;however, by virtue of sheer numbersand ready visualization, these tumorscan significantly affect quality of life.Removal of neurofibromas bya plastic surgeon or dermatologistcan be recommended if they rub onclothing or cause discomfort. Lasersurgery and electrodessication havebeen used by some providers,although long-term outcome data arenot available.

Summary and RecommendationsAbout Skin and CutaneousNeurofibromas

The following can be summarizedabout skin and cutaneousneurofibromas:

• cutaneous manifestations are theusual presenting symptoms of NF1;

• pruritus is common among patientswith NF1;

• the number of CALMs does notpredict severity of NF1;

• cutaneous neurofibromas (otherthan cutaneous plexiformneurofibromas) are not at risk formalignant transformation but mayhave significant impact on qualityof life; and

• in a child with NF1, it is notpossible to predict futureneurofibroma burden.

Plexiform Neurofibromas

Plexiform neurofibromas area distinct type of neurofibroma thatarise from 1 or multiple nerve trunksor branches (Fig 5). Unlike cutaneousneurofibromas, plexiformneurofibromas often come toattention early in childhood and arebelieved to be congenital lesions.Plexiform neurofibromas are found inapproximately 50% of individualswith NF1 by whole-body MRI inadults, but less than 20% ofindividuals will require anyintervention during childhood.23–25

Plexiform neurofibromas may haveoverlying skin manifestations (suchas thickened orange-peel overlyingskin with a purplish browncoloration), may also have an

FIGURE 4Plexiform neurofibroma adjacent to the leftaxilla.

FIGURE 5OPG affecting the right (greater than left) opticpathway (arrow).

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associated hairy patch or region ofhyperpigmentation, and may tend tohave a heterogeneous texture ornodularity on palpation. Plexiformneurofibromas can occur in any areaof the body, including the head andneck, orbit, extremities, thorax,paraspinal nerve roots, abdomen, andpelvis. These tumors may beasymptomatic or can cause pain andmorbidity by compression of adjacentstructures. Plexiform neurofibromasare usually difficult to remove in theirentirety because of interdigitationinto normal tissues and peripheralnerves. Persistent pain at the site ofa plexiform neurofibroma mayindicate transformation to an MPNST(see Malignancies Related to NF1).Nodular neurofibromas are a subtypeof plexiform neurofibromas that havea relatively homogenous appearanceon MRI and are more likely to have anatypical histology on biopsy; thesetumors may be a precursor toMPNSTs.

Summary and RecommendationsAbout Plexiform Neurofibromas

The following can be summarizedabout plexiform neurofibromas:

• believed to be congenital lesions;

• are present in approximately 50%of people with NF1, but less than20% will require any interventionduring childhood; and

• are benign tumors that maytransform into MPNSTs (usuallyaccompanied by symptoms such aspain, rapid growth, or neurologicdysfunction).

GLIOMAS OF THE CENTRAL NERVOUSSYSTEM

Optic Pathway Gliomas

Optic pathway gliomas (OPGs) (Fig 6)are the most common central nervoussystem (CNS)–associated tumor seenin children with NF1 and can bedetected in approximately 15% to20% of pediatric patients withNF1.26,27 Symptomatic OPGs are mostcommonly detected in children

younger than 6 years duringophthalmologic surveillance (beforeany vision complaint). The majority ofOPGs are classified as pilocyticastrocytomas (World HealthOrganization grade 1). The largemajority of these lesions remainindolent without effect on vision;however, a small percentage can leadto vision loss and other morbiditysuch as precocious puberty. There isno way to reliably predict whichtumors will result in a decrease invisual acuity or visual function.Lesions located in the optic chiasmand posterior optic tracts appearmore likely to require treatment thanthose in the prechiasmatic opticnerve. Lesions located close to orinvolving the hypothalamus are morelikely to result in precociouspuberty.27 Data also have revealedthat female patients with OPGs aremore likely to progress and requiretreatment, but both male and femalepatients should have the samesurveillance.28–30

Children with known or suspectedNF1 should undergo screening andsurveillance ophthalmologicexaminations at least annually fromthe time of diagnosis of NF1 orsuspected NF1 by an ophthalmologist

familiar with management of NF1,and this examination should beperformed more frequently orrepeated if there is concern. OPGsmost often develop before 6 yearsof age, when it may be difficult toobtain a reliable ophthalmologicevaluation and when children are lesslikely to complain of visualsymptoms. For these reasons, therehas been some suggestion to screenmore frequently, such as every 6months, before 6 years of age, but thishas not yet become standardpractice.31 The use of screening andsurveillance neuroimaging in thesetting of NF1 also is controversial;the Optic Pathway Task Force hasrecommended against the use ofscreening MRI,26 but others havesuggested that outcomes may beimproved by early detection in youngchildren.32,33 Because of the potentialfor glioma to have contiguousinvolvement of the hypothalamus,regular monitoring for early pubertaldevelopment and monitoring foracceleration in linear growth isrecommended for all patients. Thereis consensus that ophthalmologicexamination should be performed atleast annually, and decisions aboutmore frequent surveillance or the useof diagnostic imaging in the child whois asymptomatic are best made by theophthalmologist and clinicians caringfor each patient.

OPGs in people with NF1 havea better prognosis than sporadicOPGs in people without NF1.Treatment is considered when thereis decrease of visual function such asdecrease in visual acuity, constrictionof visual fields, change in color vision,or afferent pupillary defect. Aftertreatment, two-thirds of people havestabilization or improvement ofvision. Traditional chemotherapy(vincristine and carboplatin) is oftenused initially, although there arenewer targeted, NF1-specifictreatments in the pipeline that maybe used in cases of progression orrecurrence. Radiotherapy and surgery

FIGURE 6Anterior bowing of the left tibia. Note corticalthickening with medullary narrowing proximalto the segment of anterior bowing. The fibula isalso bowed.

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are usually contraindicated except inrare situations.

Summary and RecommendationsAbout OPGs

The following can be summarizedabout OPGs:

• highest morbidity is in childrenyounger than 6 years, but youngchildren are not likely to reportsymptoms;

• less than half of patients with OPGsdevelop vision loss or othersymptoms;

• changes in linear growth rate mayreveal the presence of OPGsaffecting the hypothalamic-pituitary axis, but this can betreated by an endocrinologist (ifneeded) and is not an indication forchemotherapy;

• treatment with modifiedchemotherapy is often effective inhalting further vision loss and/orimproving vision, so earlytreatment is crucial;

• surveillance by a pediatricophthalmologist familiar with NF1(at least annually); and

• neuroimaging is an option asa baseline study and is mandatoryfor signs and symptoms outlined inTable 3.

Characteristic MRI Findings,Low-Grade Gliomas, and BrainstemExpansions

One of the most frequent findings inpatients with NF1 is the occurrence ofhyperintense lesions on T2-weighted

MRI of the brain. These are locatedpredominantly in the basal ganglia,brainstem, and cerebellum. They havebeen called “unidentified brightobjects,” “focal areas of signalintensity [FASI],” “NF[neurofibromatosis] spots,” or“spongiform changes” because thetrue nature and significance of theselesions is still undetermined. Themost proper designation at this timeis “T2 hyperintensities.” These lesionsbecome evident between 2 and10 years of age, and then regress bythe second decade.

If an MRI-based T2-weightedhyperintensity reveals contrastenhancement or mass effect, a low-grade glioma should be suspected.Low-grade gliomas in people withNF1 can occur anywhere in thebrain.34 The brainstem is a commonregion to have both T2-weightedhyperintensities and low-gradegliomas; the latter are oftenaccompanied by expansion of thebrainstem with or withoutenhancement. Similar to OPGs,a biopsy is rarely performed onbrainstem gliomas to avoid iatrogenicsymptoms. Brainstem gliomas aretypically benign and progressclinically in only one-third or fewer ofcases.35 Children with NF1 anda known brainstem-expansive lesionare monitored for development ofclinical symptoms referable to thelocation such as headache,hydrocephalus, or cranial nervedysfunction. Similar to OPGs, NF1-associated brainstem gliomas are

more indolent than those notassociated with NF1 and most oftendo not require clinical intervention ortreatment, suggesting thatconservative management is optimal.

Malignancies Related to NF1

The most frequent neoplasmsassociated with NF1 in children areMPNSTs, gliomas,pheochromocytomas, and leukemia.Malignant tumors are the mostworrisome complications of NF1.Malignancy, mainly MPNSTs, andcardiovascular complications are themajor causes of reduced lifeexpectancy in NF1, but this isreflective mostly of adults. Lifeexpectancy is decreased by 8 to15 years.36,37

MPNSTs usually arise by malignanttransformation of an existingplexiform or nodular neurofibroma.For individuals with NF1, there isa lifetime risk of 8% to 13% todevelop an MPNST, which typicallydevelops during or after youngadulthood.38 Treatment involvessurgical resection, radiotherapy, andchemotherapy; however, 5-yearsurvival remains at less than 20%.The primary care provider should bealert to the possibility of malignanttransformation in a patient who hasa known plexiform neurofibromawith the development of pain(especially persistent pain or painthat wakes the patient from sleep),rapid growth, or change inconsistency (eg, from soft and pliableto firm and hard). Patients andfamilies should also be educated inreporting such symptoms forpotential referral to a sarcomaspecialist. Patients who aresymptomatic should undergo MRI ofthe affected area and consideration ofa positron emission tomography withradiographic computed tomography(PET-CT) scan, which, in some largerstudies, has been shown to help indistinguishing benign neurofibromasfrom MPNSTs.39,40 These tumors arestaged and treated as malignant soft-

TABLE 3 Indications for Neuroimaging Studies in Children With NF1

Indications for Consideration of Neuroimaging Studies

• Focal sensory or motor symptoms• New onset of seizures• Headaches that are increasing in frequency or severity• Signs of increased intracranial pressure (headaches, visual disturbance, increased lethargy)• Transient ischemic attack or stroke-like symptoms• Decline in visual acuity or visual fields• Precocious puberty or accelerated growth• Head and neck plexiform neurofibromas increasing in size or with new development of pain• Encephalopathy or cognitive deterioration• Extremity asymmetry (ie, leg-length discrepancy)

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tissue sarcomas, preferably ata dedicated sarcoma center. Targetedmedical therapies for MPNSTs areunder exploration but have not beenas effective as wide surgical resectionand are only used as adjuvant therapyfor surgery.

Other pediatric malignancies occurless frequently in NF1, includinglow- to high-grade astrocytomas,rhabdomyosarcoma,pheochromocytoma, and juvenilemyelomonocytic leukemia.41 High-grade astrocytomas tend to occur inolder people, and low-gradeastrocystomas and/or gliomas of theposterior fossa can be symptomatic.Pheochromocytomas can lead toincreased catecholamineconcentrations and consequenthypertension but are rare in childrenwith NF1. Most experts recommendscreening for pheochromocytoma ifthere is an acute and dramaticincrease in heart rate and/or bloodpressure. Pheochromocytoma is oftendiagnosed incidentally in patientswith NF1 because of a higherfrequency of imaging for otherneoplasms.42 Breast cancer occursmore frequently in young adults withNF1 than in the generalpopulation.43,44

Summary and RecommendationsAbout Malignancies Related to NF1

The following can be summarizedabout malignancies related to NF1:

• MPNSTs most often develop withina plexiform neurofibroma;

• diagnostic imaging is an option toassess the extent of a plexiformneurofibroma at the time ofdiagnosis and is clinically indicatedfor signs and symptoms outlinedthis section above and/or inTable 3; a fludeoxyglucose PET-CTscan may be useful in detectingmalignant transformation ofa plexiform neurofibroma;

• hypertension may be indicative ofpheochromocytoma, but most

hypertension is detectedincidentally;

• there is an increased risk of breastcancer in young adults with NF1;and

• other types of malignancy mayoccur in NF1.

NEUROLOGIC MANIFESTATIONS

Individuals with NF1 are moresusceptible to developingheadaches, particularly commonmigraine headaches.45 Brain MRImay be indicated depending on theacuity of symptoms but is notnecessary if the headaches areeasily controlled and if neurologicexamination is normal. Brain MRIwould be indicated for signs orsymptoms suggestive of a newintracranial mass such as symptomsof increased intracranial pressure,a new neurologic deficit withapparent or possible CNS origin, ornew onset of seizures (Table 3).Once an acute process is ruled out,headaches in NF1 can be managedas they would be for similar-typeheadaches in the generalpopulation. A referral to a headachespecialist may be indicated forheadaches that are frequent and/ordifficult to control withnonprescription medication. Typicallifestyle modifications for sufferersof common migraines should beoffered to the person with NF1 andheadaches once more-acutepathology has been ruled out.

Individuals with NF1 are moresusceptible to developing seizurescompared with the generalpopulation. This higher risk ofseizures may be attributable, at leastin part, to structural or vascularchanges in the individual with NF1.46

Seizures can occur at any age, areusually focal, and warrant concernabout a focal CNS lesion;neuroimaging with brain MRI isrecommended at presentation withnew onset of seizure.

SUMMARY AND RECOMMENDATIONSABOUT HEADACHES AND SEIZURES

The following can be summarizedabout headaches and seizures:

• headaches (often migraine) aremore common among individualswith NF1;

• imaging is often not needed fora headache that can be controlledwith nonprescription medication ifneurologic examination is normal,and the approach to treatment isusually the same as for similar-typeheadaches in a patientwithout NF1;

• seizures are more common amongpatients with NF1, and an initialseizure should prompt considerationfor neuroimaging; and

• other indications for neuroimagingare summarized in Table 3.

IMAGING CONSIDERATIONS

As described in preceding sections,diagnostic imaging is often used in thecare of patients with NF1 forapplications such as tumor surveillance(assessment of burden of tumor andprogression). It has been standardpractice to use clinical assessment todetermine if, when, and where to image.MRI is the most common modality forimaging of plexiform neurofibromas andbrain lesions such as OPGs and low-grade gliomas. In addition to MRI, PET-CT may be indicated in the assessmentof possible malignant transformation ofa neurofibroma. The value of imaging toassess the extent of a plexiformneurofibroma in the absence ofevidence of progression is debatablebecause treatment decisions aretypically based on clinical, and notradiographic, progression. Therefore,decisions about whether, when, andwhere to image are judgments best leftto providers experienced in caring forchildren with NF1.

NEURODEVELOPMENTAL

Infants and toddlers with NF1 mayhave mild motor developmental

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delays, such as muscular hypotonia,which typically improves slowlythrough childhood. The NF1population has an increasedincidence of speech and languageissues (particularly oromotor deficits,including speech dyspraxia, whichcan improve with appropriate speechtherapy), velopharyngealinsufficiency, misarticulation, anddisfluency.47,48 Problems withhearing are not typical for patientswith NF1, and any suspicion abouthearing problems should beapproached as they would be for anyother pediatric patient.

Approximately 50% of individuals withNF1 have some type of learningproblem.49,50 Intellectual disabilityoccurs in a minority of patients at a rateslightly higher than that in the generalpopulation. Intellectual disability shouldincrease suspicion for chromosome 17microdeletion involving the NF1 locus,and the microdeletion has otherimplications such as increased tumorburden and risk of malignancy(including MPNSTs). Typical learningdifficulties include problems withexecutive function and nonverballearning disabilities such as reducedprocessing speed. Attention-deficit/hyperactivity disorder also occurs in atleast 50% of individuals with NF1, andapproaches to treatment are akin tothose used in the general population.49

Having a diagnosis of NF1 does notresult in a predictable pattern oflearning disability, so each person withNF1 should be carefully monitored andoffered psychoeducational and/orneuropsychological and academictesting at the first sign of any academicor social concerns. The goal of suchtesting is to determine specific areas ofstrength and weakness and to provideappropriate interventions such as a 504plan or an individualized educationprogram. A diagnosis of NF1 may helpunderscore the need for speech,occupational, and/or physical therapy.

Some studies have suggested thatNF1 increases susceptibility to autismspectrum disorder, especially in the

realm of communication skills.51–53

Many individuals with NF1,particularly teenagers, demonstratedifficulty with social pragmatics, andthis can adversely affect socialadjustment, even without a formaldiagnosis of autism spectrumdisorder. Individuals with NF1typically have a personality profilewith delayed social maturitycompared with peers. For this, andperhaps other reasons, they oftenexperience anxiety. Efforts to help inlearning coping skills for socialanxiety are often indicated.

SUMMARY AND RECOMMENDATIONSABOUT DEVELOPMENTAL ISSUES

The following can be summarizedabout developmental issues:

• learning difficulties are commonamong patients with NF1 andtypically are more severe amongpatients with an NF1 microdeletionor complete gene deletion;

• speech articulation difficulties arecommon, and many patients withNF1 require speech therapy;

• executive function and attentionare often affected, andneuropsychological testing isdesirable to identify the particularchallenges faced by each individual;

• a 504 accommodation plan and/oran individualized educationprogram can be considered forschool;

• social difficulties are common, butthe rate of autism is unknown;consider referral to psychotherapyfor social anxiety or copingdifficulties;

• the evaluating therapists andeducators must communicate backto the primary care providerregarding developmental andeducational progress andadditional recommendations; and

• support adherence with “2017Recommendations for PreventivePediatric Health Care” from theAmerican Academy of Pediatrics.54

SKELETAL GROWTH

NF1-related skeletal abnormalitiesinclude macrocephaly, short stature,and osteopenia as well as localizedbone dysplasias. Macrocephaly andrelative macrocephaly (ie, head sizedisproportionately larger than height)typically require no special follow-up.Congenital hydrocephalus is not morecommon in NF1, but acquiredhydrocephalus attributable toaqueductal stenosis can occur.Postnatal growth delay is seen inapproximately one-third of children,and the pubertal growth spurt isslightly reduced. Height growthvelocity is typically normal for bothsexes during childhood, and growthcharts made specifically for childrenwith NF1 are available.55

The etiologies of relative macrocephalyand short stature are not understood.Some children have responded togrowth-hormone therapy to treat shortstature. Although short-term tumorinduction has not been observed inthose treated with growth hormone, thepresence of insulin-like growth factorreceptors in Schwann cells is concerningfor long-term induction of tumors iftreated with growth-hormone therapy.Growth-hormone therapy in NF1 isimplemented cautiously and is generallyreserved for people who have poorgrowth velocity and documented testresults of low growth-hormonestimulation (ie, ,5 ng/mL). Childrenwith NF1 who have accelerated growthvelocity or tall stature in childhood withor without precocious puberty should beevaluated for associated gliomas (OPGs)involving the chiasm and/orhypothalamic-pituitary axis.Disproportionate growth of theextremities, including leg-lengthdiscrepancy, is generally associated withplexiform neurofibromas causing localbone growth acceleration and soft-tissuehypertrophy.

Childhood osteopenia is frequent inNF1, but there is only a slightlyincreased risk for fractures.56 Theetiology of osteopenia is unknown,

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although it may be related todecreased musculoskeletal strengthand poor neuromuscularcoordination, leading to decreasedbone remodeling. Children with NF1have a higher prevalence ofinsufficient concentrations of serum(25-hydroxycholecalciferol) vitaminD, which modulates calcium andphosphorus bone metabolism(important in bone deposition).Periodic assessment of vitamin Dconcentrations, especially in higherlatitudes, cultures without vitamin Dfortification of food, and children whohave less sun exposure, are helpful indetermining the need for and dosingof vitamin D supplementation.

A few distinctive skeletal manifestationsare part of the NF1 diagnostic criteria(sphenoid wing dysplasia, dystrophicscoliosis, and long-bone dysplasia57,58).Although each of these is relativelyuncommon, individually occurring infewer than 10% of individuals with NF1,each can cause significant morbidity,underscoring the need for carefulsurveillance. These skeletal anomaliesarise as focal manifestations, usuallyunilateral or involving a short segmentof the spine. Sphenoid wing dysplasia istypically congenital, and at least half ofcases develop ipsilateral periorbitalplexiform neurofibromas. Long-bonedysplasia (especially of the tibia),defined on radiographs as a thickenedcortex with a narrowed medullarycavity with or without cysts, usuallyemerges in late infancy or in toddlerswith both anterior and lateral bowing(Fig 7). This dysplasia can progress tofracture with poor bone healing,resulting in pseudarthrosis; therefore,tibial radiography is recommended inchildren with anterior tibial bowingbefore they begin to walk. More thantwo-thirds of infants presenting withcongenital pseudarthrosis of the tibiahave NF1.

In addition to typical scoliosis thatusually arises in early adolescence,children with NF1 also can havedystrophic scoliosis (Fig 8), which isa short-segment, sharply angulated

curve associated with underlyingvertebral-body and rib abnormalitiesand sometimes with adjacentplexiform neurofibromas. Specificfeatures of dystrophic scoliosisinclude vertebral scalloping, pencilingof ribs, spindling of transverseprocesses, and wedging of one ormore vertebral bodies. This conditiongenerally presents in early childhoodand progresses rapidly over a fewyears, requiring surgical interventionwith spine appliances through thegrowth years until definitive spinalfusion can be performed. Otherdistinctive focal skeletalmanifestations include nonossifyingfibromas of the distal femur orproximal tibia, cranial bone defects,giant-cell tumor of the jaw, andossifying subperiosteal hematomas.

Chest-wall deformities, such as pectusexcavatum or carinatum, occur inapproximately one-third ofindividuals with NF1; thismanifestation overlaps with otherRASopathy conditions, primarilyNoonan syndrome. Localized boneerosions and/or bone dysplasia(sphenoid wing dysplasia) can occurwith adjacent growth of plexiformneurofibromas, especially scalpneurofibromas. Dental abnormalitiesand increased caries may also occur.59

Summary and Recommendations ofSkeletal Features

General Skeletal Features

The following can be summarizedabout general skeletal features:

• macrocephaly is typically benign;

• short stature may necessitate anendocrinology referral;

• accelerated growth and/or earlypuberty indicates referral toendocrinology and brain MRI fora hypothalamic tumor; and

• osteopenia and vitamin Dinsufficiency is frequent in NF1 inchildren.

Specific Skeletal Features

The following can be summarizedabout specific skeletal features:

FIGURE 7Dystrophic scoliosis in a patient with NF1. The image on the left shows a computed tomographyreconstruction of the vertebral column revealing acute angle kyphoscoliosis. The image on the right,from the same patient, reveals a relatively large paraspinal plexiform neurofibroma in the area ofspinal deformity.

FIGURE 8Multiple Lisch nodules with peripheral clus-tering between 3:30 and 8:30.

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• sphenoid wing dysplasia is oftenassociated with unilateral periorbitalplexiform neurofibromas;

• dystrophic scoliosis and long-bonedysplasia require clinicalsurveillance and early orthopedicreferral; and

• nonossifying fibromas, pectusanomalies, and cranial bone defectsdo not usually require intervention.

Other Medical Complications

Approximately one-third of patientswith NF1 develop serious medicalcomplications; however, with thevariability of clinical manifestations andthe progressive nature of NF1, it is notpossible to determine the prognosisafter establishing a diagnosis, especiallyat a young age. The reported incidenceof complications in NF1 varies fromstudy to study, mostly because ofbiased patient selection by age andspecialty referral but also because ofinconsistent use of diagnostic criteriaand variable use of imaging. The rate ofcomplications is often overestimatedbecause most studies involve patientsin hospitals or referral clinics.

VASCULAR

A wide range of congenital cardiacanomalies, vascular stenoses andaneurysms, and cerebrovascularlesions are associated with NF1. NF1vasculopathy can involve different-sized vessels, ranging from smallarterioles to the aorta, and, in manycases, remains asymptomatic.60 Renalartery stenosis, with and withoutinternal renal arteriopathy, is themost frequent site of symptomaticvasculopathy and can be animportant cause of hypertension inchildren with NF1.60 The prevalenceof hypertension in children andteenagers with NF1 is higher thanthat in the general population and isoften related to vascular lesions(renal artery stenosis, aortic stenosis,and coarctation).61 The trueprevalence may be lower thanreported in studies that are based on

patients at specialty clinics but stillnecessitates regular assessment ofblood pressure in patients with NF1.

Essential hypertension is alsoa frequent occurrence in teenagepatients with NF1. Workup ofhypertension in the pediatric agegroup should include Dopplerultrasonography of the aorta andrenal arteries, renal arteriography, ormagnetic resonance angiography.

Congenital heart disease occurs morecommonly in patients with NF1 than inthe general population, witha frequency of 2% reported in a largeinternational NF1 database. Pulmonicstenosis is by far the most commoncongenital heart defect seen inNF1.60,62 Other cardiac malformationsinclude atrial septal defect, ventricularseptal defect, aortic coarctation,tetralogy of Fallot, mitral valveprolapse, and hypertrophiccardiomyopathy.62,63 Congenital cardiacmalformations and hypertrophiccardiomyopathy may be more commonin patients with large NF1 deletions.64

Children with NF1 and a cardiacmurmur or those with microdeletion ofthe NF1 locus should be evaluated witha cardiology examination andechocardiography. It remains unclearwhether screening of all patients withNF1 with echocardiography isindicated; however, those with a largedeletion should be evaluated.64

Cerebrovascular abnormalities are seenin 2.5% to 6% of children with NF1screened by MRI or magnetic resonanceangiography of the brain.65 Stenoticlesions, particularly of the internalcarotid, middle cerebral, or anteriorcerebral arteries, are most common,although aneurysms can also be seen.Lesions may remain stable andasymptomatic but can also developprogressive narrowing over time,leading to an increased risk for strokeand focal neurologic signs. Moyamoyasyndrome, a progressive stenosis ofinternal carotid arteries withconcomitant formation of tortuousarterial collaterals, occurs in a subset of

patients, particularly those witha history of cranial radiotherapy.66

Outcomes of NF1 cerebrovasculardisease may be improved by treatmentwith antiplatelet agents such as aspirinand revascularization surgery for thosewith progressive lesions.66 Radiotherapyto the brain should be avoided when atall possible for children with NF1because of the risk of moyamoyasyndrome.

SUMMARY AND RECOMMENDATIONSFOR VASCULAR COMPLICATIONS

The following can be summarizedabout vascular complications:

• Examination of the newborn shouldinclude attention to the increasedrisk of congenital heartmalformations such as pulmonicstenosis. Referral to cardiologyand/or consideration for anechocardiogram should be basedon the clinical examination.

• Blood pressure should bemonitored at least annually.

• Persistent hypertension requiresassessment of large vessels,including renal arteries.

• Moyamoya syndrome respondswell to revascularization surgery,but patients should continuereceiving prophylactic-aspirintherapy under the direction ofa neurosurgeon even aftersuccessful surgery.

• Neuroimaging is an option asa baseline study and is mandatoryfor signs and symptoms outlined inTable 3.

GASTROINTESTINAL

Constipation and midgastric abdominalpain are common in children with NF1.A recent study revealed that 30% ofa small group of children with NF1 metdiagnostic criteria for constipation,including an enlarged rectal diameter.67

Management with diet modificationand gentle stool softeners, such aspolyethylene glycol, is often helpful.Abdominal migraine has been reported

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as a cause of episodic abdominal painin children with NF1 and may be morecommon than anatomic causes ofabdominal pain.68 Treatment withmigraine medications, such aspropranolol and cyproheptadine, canbe helpful. Plexiform neurofibromasinvolving the mesentery orretroperitoneum are only rarelya source of abdominal pain, vomiting,and abdominal mass. Intestinal polypsoccasionally occur, with pathologyconsistent with neurofibromas orschwannomas. Gastrointestinal stromaltumors (GISTs) are benign tumors ofthe small intestine that can causegastrointestinal bleeding andabdominal pain in patients with NF1.69

GISTs are rare in childhood and do notrespond to tyrosine kinase inhibitors,

unlike some GISTs that occur in thegeneral population and can be treatedby these medications.

SUMMARY AND RECOMMENDATIONSFOR GASTROINTESTINALCOMPLICATIONS

The following can be summarizedabout gastrointestinal complications:

• Constipation is common in childrenwith NF1, but treatment does notdiffer from other children.

• Midgastric abdominal pain is morecommon in children with NF1, andabdominal migraine should beconsidered as a possible cause;abdominal tumors are a lesscommon cause of abdominal pain.

MEDICAL HOME AND TRANSITION

The primary care medical home isvaluable for children with NF1. Inaddition to the broad principles of themedical home, surveillance plans formedical, developmental, andbehavioral issues are important inNF1, especially during childhood.Determination of appropriate referralsto pediatric medical subspecialists arealso important to optimize care.70,71

Health supervision guidance isoutlined in several sections in thisdocument and in Table 4. Referral toand coordination with community-based services, especially educationaland behavioral services, are frequentlynecessary. Collaboration with pediatricmedical subspecialists and programs,

TABLE 4 Health Supervision Guidelines for Children With NF1

Infancy, 1 mo to 1 y Early Childhood, 1–5 y Late Childhood 5 y toPuberty

Adolescence and YoungAdulthood (Postpubertal)

Genetic counselingGenetic etiology Xa — — Xb

Genetic testing As neededc As neededc As neededc As neededc

Future reproductive planning Xa — Xb Xd

Medical evaluation and treatmente

Monitor growth rate X Annual Annualf AnnualMeasure head circumference X X X —

Blood pressure — Annual Annualfg Annualf

Attention to cardiacexamination

X — — —

Skin examination X Annual Annual AnnualBone examination or scoliosis

examinationXb Annual Annualf Annualf

Neurologic examination X Annual Annualf Annualf

Ophthalmologic examination Annual Annual Annual As neededMonitor precocious puberty — Annualf Annualf —

Diagnostic imaging examinationse As needede As needede As needede As needede

Developmental and psychosocialevaluationg

X X X X

Anticipatory guidance;phenotype reviewh

Xa Xb Xb Xb

Family support X X X XSupport groups X X Xb Xb

Long-term planning X X Xb Xb

Sexual and reproductiveissues

— — Xb X

X indicates to be performed; —, not applicable.a Or at the time of diagnosis.b At least once in this time period.c See discussion.d Before transition to adult care.e As needed for significant abnormalities and/or new signs.f Advise for more frequent visits as indicated.g Ensure compliance with “2017 Recommendations for Preventive Pediatric Health Care” from the American Academy of Pediatrics.54 “Developmental and psychosocial evaluation” in thistable should follow the standard recommendations for pediatric preventive care.h Anticipatory guidance; phenotype review: review age-related medical and developmental issues of NF1 with the patient and family, including the following: issues related to motor andlanguage development and potential need for early intervention (eg, speech therapy); learning and behavioral problems (eg, attention-deficit/hyperactivity disorder), school performance,and potential need for neuropsychological testing; and anticipatory guidance about concerning signs and symptoms related to plexiform neurofibromas.

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particularly genetics, neurology,ophthalmology, orthopedics, oncology,and dermatology, at regional referralcenters on an ongoing basis can behelpful for primary care clinicians andfamilies.

NF1 is a lifelong condition, and some ofthe complications are more likely tooccur among adults with the disorder.These include many of the tumor-related complications, ranging fromquality-of-life concerns to potentiallylife-threatening complications. Adultswith NF1 also may continue to facesocial and vocational challenges becauseof the cognitive profile associated withthe disorder. Medical and psychosocialsupports should be continued for youngadults. The American Academy ofPediatrics offers detailed guidance onhow to plan and execute better healthcare transitions for all patients,72

including a step-by-step algorithm.Patients with NF1 benefit from avoidinga gap in care during the transition frompediatric to adult providers.73

INTO THE FUTURE: PROSPECTS FORMEDICAL TREATMENT OF NF1

The mechanisms that underlie variouscomplications of NF1 are graduallycoming to light, and this is leading to thedevelopment of new approaches totherapy. Examples are drugs that targetthe Ras signaling mechanism that isregulated by the NF1 gene product ormolecules that mediate communicationbetween cells that are important intumor formation. Preclinical studies andhuman clinical trials are underway, forthe most part, by using drugs that wereoriginally developed for treatment ofother disorders that involve aberrantcell signaling such as cancer.74 Medicaltherapy for various features of NF1 arelikely to become increasingly available;clinical trials can be identified throughClinicalTrials.gov, and sources such asthe Children’s Tumor Foundation (www.ctf.org) provide up-to-date informationon current treatment. This is a time ofgreat hope for individuals with NF1 andtheir families, with the prospect of newtreatments that will significantly

improve quality of life and health in theyears to come.

Pediatricians can play a critical role inimproving outcomes by identifyingsigns that can lead to a diagnosis andby conducting appropriate surveillance.There are also potential new therapies,primarily for tumor-related aspects ofNF1, that are currently in clinical trialsand not yet part of standard clinicalpractice. A few key areas that willbenefit from future efforts towarda systematic review to facilitateevidence-based practice guidelinesinclude the following: optimalophthalmologic, orthopedic, andneuropsychological assessments fortimely interventions. Likewise, moredata are needed to determine if andwhen to perform surveillance imagingby whole-body or regional MRI forroutine tumor surveillance.23,24,75

SUPPORT GROUPS AND RESOURCES

The following are support groups andresources:

Children’s Tumor Foundation(includes information about NF1clinic locations): 120 Wall Street,New York, New York 10005-3904(phone: 800-323-7938 [toll free] or212-344-6633; fax: 212-747-0004;e-mail: info@ctf.org; Web site:www.ctf.org);

Neurofibromatosis Network: 213South Wheaton Avenue, Wheaton,Illinois 60187 (phone: 800-942-6825; fax: 630-510-8508; e-mail:admin@nfnetwork.org; Web site:www.nfnetwork.org); and

ClinicalTrials.gov: a service of the USNIH, ClinicalTrials.gov is a registryand results database of publiclyand privately supported clinicalstudies of human participantsconducted around the world (Website: https://clinicaltrials.gov/).

LEAD AUTHORS

David T. Miller, MD, PhD, FAAPDebra Freedenberg, MD, PhD, FAAPElizabeth Schorry, MDNicole J. Ullrich, MD, PhD

David Viskochil, MD, PhDBruce R. Korf, MD, PhD, FAAP

COUNCIL ON GENETICS EXECUTIVECOMMITTEE, 2018–2019

Emily Chen, MD, PhD, FAAP, Co-ChairpersonTracy L. Trotter, MD, FAAP, Co-ChairpersonSusan A. Berry, MD, FAAPLeah W. Burke, MD, FAAPTimothy A. Geleske, MD, FAAPRizwan Hamid, MD, FAAPRobert J. Hopkin, MD, FAAPWendy J. Introne, MD, FAAPMichael J. Lyons, MD, FAAPAngela E. Scheuerle, MD, FAAPJoan M. Stoler, MD, FAAP

FORMER COUNCIL ON GENETICS EXECUTIVECOMMITTEE MEMBERS

Debra Freedenberg, MD, PhD, FAAPMarilyn C. Jones, MD, FAAP

LIAISONS

Katrina M. Dipple, MD, PhD – AmericanCollege of Medical GeneticsMelissa A. Parisi, MD, PhD – Eunice KennedyShriver National Institute of Child Health andHuman DevelopmentBritton D. Rink, MD – American College ofObstetricians and GynecologistsJoan A. Scott, MS, CGC – Health Resources andServices Administration, Maternal and ChildHealth BureauStuart K. Shapira, MD, PhD – Centers forDisease Control and Prevention

STAFF

Paul Spire

ABBREVIATIONS

CALM: café-au-lait maculeCNS: central nervous systemGIST: gastrointestinal

stromal tumorJXG: juvenile xanthogranulomaMPNST: malignant peripheral

nerve sheath tumorNF1: neurofibromatosis type 1NIH: National Institutes of HealthOPG: optic pathway gliomaPET-CT: positron emission

tomography withradiographic computedtomography

PSV: pathogenic sequence variant

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All clinical reports from the American Academy of Pediatrics automatically expire 5 years after publication unless reaffirmed, revised, or retired at or before

that time.

DOI: https://doi.org/10.1542/peds.2019-0660

Address correspondence to David T. Miller, MD, PhD, FAAP. Email: David.Miller2@childrens.harvard.edu

PEDIATRICS (ISSN Numbers: Print, 0031-4005; Online, 1098-4275).

Copyright © 2019 by the American Academy of Pediatrics

FINANCIAL DISCLOSURE: Dr Korf has consulting or advisory committee relationships with Accolade, AstraZeneca, Envision Genomics, Genome Medical,

Neurofibromatosis Initiative, the Neurofibromatosis Therapeutic Acceleration Project, and Novartis and serves as an editor with the American Society of Human

Genetics; Dr Miller had a part-time clinical consulting relationship with Claritas Genomics, which concluded in August 2017; Dr Viskochil has a consulting

relationship with Genzyme-Sanofi and research relationships with Armagen, Shire, and Ultragenyx; and Drs Freedenberg, Schorry, and Ullrich have indicated they

have no financial relationships relevant to this article to disclose.

FUNDING: No external funding.

POTENTIAL CONFLICT OF INTEREST: The authors have indicated they have no potential conflicts of interest to disclose.

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