Pediatrics 2010 Romano 746 59 Noonan

DOI: 10.1542/peds.2009-3207; originally published online September 27, 2010; 2010;126;746Pediatrics

Jacqueline A. NoonanMary Ella Pierpont, Amy E. Roberts, Wanda Robinson, Clifford M. Takemoto and

Alicia A. Romano, Judith E. Allanson, Jovanna Dahlgren, Bruce D. Gelb, Bryan Hall,Noonan Syndrome: Clinical Features, Diagnosis, and Management Guidelines

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The online version of this article, along with updated information and services, is

of Pediatrics. All rights reserved. Print ISSN: 0031-4005. Online ISSN: 1098-4275.Boulevard, Elk Grove Village, Illinois, 60007. Copyright 2010 by the American Academy published, and trademarked by the American Academy of Pediatrics, 141 Northwest Pointpublication, it has been published continuously since 1948. PEDIATRICS is owned, PEDIATRICS is the official journal of the American Academy of Pediatrics. A monthly

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Noonan Syndrome: Clinical Features, Diagnosis, andManagement Guidelines

abstract +Noonan syndrome (NS) is a common, clinically and genetically hetero-geneous condition characterized by distinctive facial features, shortstature, chest deformity, congenital heart disease, and other comor-bidities. Genemutations identied in individuals with the NS phenotypeare involved in the Ras/MAPK (mitogen-activated protein kinase) signaltransduction pathway and currently explain61% of NS cases. Thus,NS frequently remains a clinical diagnosis. Because of the variability inpresentation and the need formultidisciplinary care, it is essential thatthe condition be identied and managed comprehensively. The NoonanSyndrome Support Group (NSSG) is a nonprot organization commit-ted to providing support, current information, and understanding tothose affected by NS. The NSSG convened a conference of health careproviders, all involved in various aspects of NS, to develop these guide-lines for use by pediatricians in the diagnosis and management ofindividuals with NS and to provide updated genetic ndings. Pediatrics2010;126:746759

AUTHORS: Alicia A. Romano, MD,a Judith E. Allanson, MD,b

Jovanna Dahlgren, MD,c Bruce D. Gelb, MD,d Bryan Hall,MD,e Mary Ella Pierpont, MD,f,g Amy E. Roberts, MD,h

Wanda Robinson,i Clifford M. Takemoto, MD,j andJacqueline A. Noonan, MDk

aDivision of Pediatric Endocrinology, Department of Pediatrics,New York Medical College, Valhalla, New York; bDepartment ofGenetics, Childrens Hospital of Eastern Ontario, Ottawa, Ontario,Canada; cGteborg Pediatric Growth Research Center, Institutefor Clinical Sciences, Queen Silvia Childrens Hospital, Gteborg,Sweden; dCenter for Molecular Cardiology and Department ofPediatrics, Mount Sinai School of Medicine, New York, New York;eDepartment of Pediatrics, University of Kentucky MedicalCenter, Lexington, Kentucky; fDivision of Genetics, ChildrensHospital and Clinics of Minnesota, Minneapolis, Minnesota;gDepartment of Pediatrics, University of Minnesota, Minneapolis,Minnesota; hDepartment of Cardiology and Division of Genetics,Childrens Hospital Boston, Boston, Massachusetts; iNoonanSyndrome Support Group, Baltimore, Maryland; jDivision ofPediatric Hematology, Johns Hopkins Hospital, Baltimore,Maryland; and kDivision of Pediatric Cardiology, University ofKentucky Medical Center, Lexington, Kentucky

KEY WORDSNoonan syndrome, PTPN11, SOS1, BRAF, KRAS, NRAS, RAF1,SHOC2, Ras/MAPK signal transduction, congenital heart disease,short stature

ABBREVIATIONSNSNoonan syndromeCFCcardiofaciocutaneousMAPKmitogen-activated protein kinaseLEOPARDlentigines, electrocardiographic anomalies, ocularhypertelorism, pulmonary stenosis, abnormal genitalia, anddeafnessPTPN11protein tyrosine phosphatase nonreceptor type 11genePVSpulmonary valve stenosisGHgrowth hormoneASDatrial septal defectHCMhypertrophic cardiomyopathyMPDmyeloproliferative disorder

www.pediatrics.org/cgi/doi/10.1542/peds.2009-3207

doi:10.1542/peds.2009-3207

Accepted for publication Jul 23, 2010

Address correspondence to Alicia A. Romano, MD, Department ofPediatrics, Munger Pavilion, Room 123, New York MedicalCollege, Valhalla, NY 10595. E-mail: [email protected]

(Continued on last page)

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Noonan syndrome (NS) is a relativelycommon congenital genetic disorderwith an estimated prevalence of 1 in1000 to 1 in 2500 live births.1 Charac-teristic ndings include distinctivefacial features, short stature, chestdeformity, and congenital heart dis-ease. It is an autosomal dominantdisorder with complete penetrancebut variable expressivity. Until re-cently, diagnosis was based solely onclinical ndings, but genetic muta-tions are identiable in 61% of thepatients. Because of the difculty inestablishing a diagnosis of NS, theNoonan Syndrome Support Group co-ordinated a meeting of health careproviders with expertise in variousaspects of the disorder with the aimof developing guidelines for its diag-nosis and management. This reportis the result of those efforts and isintended to provide the pediatricianwith key clinical features of NS, toprovide an update of currently un-derstood genetic causes, and topresent management recommenda-tions (Table 1).

A description of the meeting method-ology is provided in SupplementalInformation.

HISTORY OF NS

In 1962, Jacqueline Noonan, a pediat-ric cardiologist, identied 9 patientswhose faces were remarkably simi-lar and who, in addition, had shortstature, signicant chest deformi-ties, and pulmonary stenosis.1 In1968 Dr Noonan published a case se-ries with these 9 plus an additional10 patients.2 The eponym Noonansyndrome was adopted in recogni-tion of Dr Noonan, because she wasthe rst to indicate that this condi-tion occurred in both genders, wasassociated with normal chromo-somes, included congenital heart de-fects, and could be familial.3

CLINICAL DESCRIPTION ANDDIFFERENTIAL DIAGNOSIS

Facial and musculoskeletal featuresmost often lead to the diagnosis of NS.The facial appearance is most charac-teristic in infancy (Fig 1) and early-to-middle childhood and becomes moresubtle in adulthood4 (Fig 1B). In thenewborn infant with NS, the head islarge with a small face tucked beneatha large cranium, a tall forehead, andnarrowing at the temples. The eyes arewide-spaced and prominent with epi-canthal folds, ptosis, and horizontalor down-slanting palpebral ssures(95%). There may be telecanthus aswell as hypertelorism. The nose isshort and broad with a depressed rootand full tip. The ears are low-set, areposteriorly rotated, and have an ovalshape and thickening of the helix(90%). The upper lip is distinctive witha deeply grooved philtrum with high,wide peaks to the vermillion of the up-per lip (95%), and full lips. Generally,the neck is short with excess skin anda low posterior hairline (55%). Inmiddle-to-late childhood, facial ap-pearance often lacks expression andresembles the face of an individualwith a myopathy. By adolescence, faceshape is an inverted triangle, wide atthe forehead and tapered to a pointedchin. Eyes are less prominent. Fea-tures are sharper. There is a narrownasal root with a thin bridge. The neckis longer, accentuating skin webbingor prominence of the trapezius mus-cle. The adult face may be quite unre-markable, although the same individ-ual may have had more obviousfeatures as an infant. Some adults,however, have typical features includ-ing ptosis, wide-spaced eyes, low-setears with posterior rotation and thick-ened helix, and broad or webbed neck.In the older adult, nasolabial folds aremore prominent than one would ex-pect for that persons age, and the skinappears transparent and thin.

Hair may be wispy in the toddler,whereas it is often curly or wooly in theolder child and adolescent. Regardlessof age, eyes are frequently pale blue orblue-green and much lighter in colorthan expected for family background.

A characteristic pectus deformity ofthe chest with pectus carinatum supe-riorly and pectus excavatum inferiorlyis seen in most individuals. Also, nip-ples are wide-spaced and low-set, androunded shoulders are common.5 Sco-liosis is reported in 10% to 15%.6 Otherless common spinal abnormalities in-clude kyphosis, spina bida, vertebraland rib abnormalities, and genu val-gum. Talipes equinovarus is de-scribed in 10% to 15%, other jointcontractures in 4%, radio-ulnar syn-ostosis in 2%, and cervical spine fu-sion in 2%. Abnormal forearm carry-ing angles (cubitus valgus) are foundin more than half the males (10 11)and females (14 15).7 Hyperexten-sibility is common.7

Because of differences in prognosis,recurrence concerns, and treatment,accurate diagnosis is essential. Thereare several disorders with signicantphenotypic overlap with NS, such asTurner syndrome (Table 2).817 Formany years, before our understandingof their underlying genetic causes, car-diofaciocutaneous (CFC) syndromeand Costello syndromewere often con-fused for NS, particularly in the new-born period. Therefore, it was not sur-prising that they, like NS, were found tobe caused by mutations in genes of theRas/MAPK (mitogen-activated proteinkinase) pathway. Other disorders withsignicant phenotypic overlap withNS include neurobromatosis type 1,LEOPARD (lentigines, electrocardio-graphic anomalies, ocular hypertelor-ism, pulmonary stenosis, abnormalgenitalia, and deafness) syndrome,Aarskog syndrome, fetal alcohol syn-drome, mosaic trisomy 22, andBaraitser-Winter syndrome. Molecular

STATE-OF-THE-ART REVIEW ARTICLE

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TABLE 1 Management Recommendations

Clinical Specialty Issue Recommendations

Genotype/phenotype Genetics consultation and follow-upissues Decision whether to perform gene testing in individuals with NS phenotype should take into consideration:

Positive gene testing can conrm NS diagnosisNegative test results cannot exclude the diagnosisExpected frequency of mutations among patients with denite NS by sequencing the 6 genes known to date is60%

If sequential molecular testing is determined to be indicated (rather than simultaneous chip based analysis):PTPN11 sequencing should be performed rst, because this gene explains the highest number of casesIf normal, phenotype should be used to guide the choice of the next gene to sequenceIf developmental delays are absent or mild, CFC syndromelike skin and hair ndings are present, and/or patient is of normalstature, consider SOS1 sequencing

If HCM is present, consider RAF1 sequencingFor signicant developmental delays or cognitive issues, consider KRAS sequencingFor sparse, thin, slow-growing hair, consider SHOC2 sequencing

If a variant is found, consider testing the parents to provide accurate recurrence risksCardiovascular issues All individuals should undergo a cardiac evaluation by a cardiologist at the time of diagnosis, including an electrocardiogram and

echocardiogramThose found to have cardiac problems should have regular follow-up at intervals determined by the cardiologist; cardiac care

should be individualized according to the specic disorder(s) presentSome will require treatment such as balloon valvuloplasty or surgery; long-term reevaluation of these patients after treatment is

essential (specically, after successful cardiac surgery, cardiac care should not be discontinued)Individuals without heart disease on their initial evaluation should have cardiac reevaluation every 5 yAdults should not discontinue periodic cardiac evaluations even if their evaluations in childhood or adolescence were normal;

unexpected cardiac ndings can occur at any point in timeGrowth and endocrineissues

Children should be weighed and measured regularly by the primary care provider, and the data should be plotted on appropriategrowth charts (thrice yearly for the rst 3 y of life and yearly thereafter)

Children with evidence of growth failure (growth deceleration, height less than2 SDs, or height inappropriate for geneticbackground) that cannot be explained by a comorbidity should be monitored more often, have nutrition optimized, havebaseline laboratory tests run, and/or be referred to a pediatric endocrinologist

Thyroid-function tests and antibodies should be obtained from any child with a goiter and/or symptoms of hypothyroidism(fatigue, constipation, poor growth, etc)

Children with evidence of delayed puberty (no breast development in girls by the age of 13 y, no testicular enlargement in boys by14 y of age) should be referred to a pediatric endocrinologist

Therapeutic interventions as indicated (GH for growth failure, thyroid hormone replacement for hypothyroidism, estrogen ortestosterone for pubertal delay)

Renal and genitourinary All individuals should have a kidney ultrasound at the time of diagnosis; a repeat test may be needed depending on initial ndingsissues Individuals may be at increased risk of urinary tract infections if a structural abnormality is present

Antibiotic prophylaxis may be considered for hydronephrosis and/or recurrent urinary tract infectionOrchiopexy should be performed by the age of 1 y if testicles remain undescended at that time

Gastrointestinal issues Pediatric gastroenterology/nutrition consultation for feeding difculties/recurrent vomitingFurther testing as indicated (upper-gastrointestinal series, upper endoscopy, pH studies, etc)Therapeutic interventions as indicated (antireux medications, feeding therapy, feeding tube, surgical consult if malrotation

suspected, etc)Hematology issues Screening CBC with differential and prothrombin time/activated partial thromboplastin time at diagnosis and after 612 mo of

age if initial screen performed in infancyBleeding symptomsFirst tier: CBC with differential count and prothrombin time/activated partial thromboplastin timeSecond tier (in consultation with hematologist): specic factor activity (factor XI, factor XII, factor IX, factor VIII, von Willebrandfactor) and platelet function (bleeding time or platelet aggregation)

Surgery: preoperative evaluation (rst- and second-tier testing) of bleeding risk; hematology consultation as needed formanagement of bleeding risk

Splenomegaly: CBC with differential countHepatosplenomegaly: CBC with differential count, liver-function testsAvoidance of aspirin and aspirin-containing medications

Neurological, cognitive, Developmental screening annuallyand behavioral Complete neuropsychological testing if screening result is abnormalissues Evaluations for speech pathology, PT, and OT if delays in speech, gross motor, and ne motor skills, respectively

Early-intervention programs beginning in infancy if delays notedSpeech therapy for speech and articulation issues, PT and OT for gross and ne motor delaysRegular, detailed developmental evaluations throughout childhoodIndividualized education plan for school-aged childrenElectroencephalography and referral to neurology if seizures suspectedBrain and upper-spine MRI with any neurologic problem (headaches, weakness, numbness, poor balance, etc), cranial size

aberrationMagnetic resonance angiography (after MRI) if focal/sudden neurologic signs


genetic testing will aid in the differen-tiation of NS from CFC syndrome,Costello syndrome, LEOPARD syn-drome, neurobromatosis type 1, orAarskog syndrome. A karyotype willdifferentiate Turner syndrome frommosaic trisomy 22.

A discussion of scoring systems as algo-rithms of diagnostic criteria is providedin Supplemental Information.7,18,19

HISTORY OF MOLECULAR GENETICTESTING AND GENETIC RESEARCH

In 1994, linkage analysis of a large fam-ily inheriting NS established denitivelinkage to the rst NS locus, dened aschromosomal bands 12q22-qter andnamed NS1.19,20 Genetic heterogeneitywas subsequently established.

In 2001, Tartaglia and co-workers21

identied missense mutations in theprotein tyrosine phosphatase nonreceptor type 11 gene (PTPN11) as therst molecular causes of NS. This dis-covery was enabled by the observa-tions that PTPN11 resided within theNS1 critical region and that studieswith a mouse model of PTPN11 de-ciency revealed that its protein prod-uct, SHP-2, was critical for the embry-ologic development of the semilunarcardiac valves.22 Because pulmonaryvalve stenosis (PVS) is a prominent

FIGURE 1A, Patient with NS at (from left to right) 10 days, 6 months, and 2 years of age. B, Patient with NS at(from left to right) 4 months and 1, 2, 5, 9, and 21 years of age.

TABLE 1 Continued

Clinical Specialty Issue Recommendations

Eye and ear issues Detailed eye examination in infancy and/or at diagnosisEye reevaluations as indicated if problems found or at least every 2 y thereafterHearing test in infancy and/or at diagnosis with annual hearing test throughout early childhoodAttentive management of ear infections to minimize hearing loss

Orthopedic and dentalissues

Annual examination of chest and back, radiography if abnormalCareful oral exam at each visitDental referral between the ages of 1 and 2 y and yearly visits thereafterDental radiography as indicated

Lymphatic issues Referral of those with peripheral lymphedema to specialty lymphedema clinicsFor more information, contact the National Lymphedema Network (www.lymphnet.org)

Anesthesia risk Individuals with NS should be considered at standard risk for malignant hyperthermia when receiving general anesthesiaAvoidance of anesthetics associated with malignant hyperthermia in those individuals with NS-like phenotype, a skeletalmyopathy, and normal to modestly elevated creatine phosphokinase level and HCMSkeletal muscle biopsy should be considered to look for excess muscle spindles (suspect diagnosis of congenital myopathy withexcess muscle spindles) in those with NS-like phenotype, a skeletal myopathy, and normal to modestly elevated creatinephosphokinase level and HCM

CBC indicates complete blood count; PT, physical therapy; OT, occupational therapy.



feature of NS, these investigatorsreasoned that PTPN11 was a leadingpositional candidate gene in NS1. In ad-dition, Tartaglia and co-workers recog-nized that SHP-2, a protein tyrosinephosphatase with largely positive reg-ulatory roles in Ras/MAPK signaling,participated in signaling downstreamfrom several ligand-receptor com-plexes with possible relevance to thepleiomorphic abnormalities observedin NS (eg, broblast growth factor forbone development, growth hormone[GH] and insulin-like growth factor for

somatic growth). The reasoning ofthese investigators proved correct, be-cause they observed PTPN11missensemutations in 2 medium-sized familiesinheriting NS in a pattern consistentwith linkage to NS1 and then additionalmutations in approximately half of asmall number of sporadic cases orsmall families with NS.

Subsequent molecular discovery indi-cated that other genetic syndromesthat resembled NS phenotypically,Costello and CFC syndromes, proved

not to be allelic.2326 LEOPARD syn-drome, on the other hand, proved to beallelic with PTPN11; mutations accountfor90% of cases, and specic muta-tions, particularly Y259C and T468M,are prevalent only in LEOPARD syn-drome.27,28 Other Ras/MAPK geneswere then considered as candidategenes that might be mutated in pa-tients with NS that is not explained byPTPN11. HRAS mutations were shownto cause Costello syndrome, and 4 Ras/MAPK genes (KRAS, BRAF, MEK1, andMEK2) were mutated in CFC syn-

TABLE 2 Differential Diagnosis: Similarities and Differences Between NS and Other Disorders

Syndrome Similarities With NS Differences From NS

Aarskog syndrome(faciogenital dysplasia)

Similarities in NS and Aarskog syndrome are primarily facialand skeletal (hypertelorism, down-slanting palpebralssures, and short stature).15

With Aarskog syndrome, no cardiovascular malformationsbut shawl scrotum is present; this is an X-linkedrecessive disorder caused by FGD1 gene mutations.

Baraitser-Winter syndrome Features common to both NS and Baraitser-Winter syndromeinclude hypertelorism, eyelid ptosis, short neck, shortstature, and cognitive delays.

With Baraitser-Winter syndrome, there can be iriscoloboma, pachygyria, lissencephaly, bicuspid aorticvalve stenosis, and aortic stenosis17

CFC syndrome Common facial, skeletal, and cardiac features in both NS andCFC syndrome include hypertelorism with down-slantingpalpebral ssures, epicanthal folds, and eyelid ptosis,depressed nasal root, short stature, relativemacrocephaly, PVS, HCM, and ASDs.9 KRAS or BRAFmutations and rarely SOS1 or MEK1 mutations have beenseen in patients with NS and those with CFCsyndrome.1012,138

With CFC syndrome, coarser facial features, severefeeding problems, follicular hyperkeratosis, sparseeyebrows and eyelashes, ichthyosis, and ulerythemaophryogenes; majority have moderate retardation13;may be caused by MEK1 or MEK2 mutations1012

Costello syndrome Many features common to both Costello syndrome and NSinclude curly hair, wide nasal bridge, eyelid ptosis, down-slanting palpebral ssures, epicanthal folds, PVS, HCM,pectus deformity, and Chiari I malformation.

With Costello syndrome, coarse facial features, wide nasalbridge, loose skin, increased pigmentation with age,deep palmar and plantar creases, papillomata of theface or perianal region, premature aging and hair loss,multifocal atrial tachycardia, moderate mentalretardation, and ulnar deviation of the wrist andngers14; caused by HRAS mutations

Fetal alcohol syndrome Common features to both NS and fetal alcohol syndromeinclude growth delay, developmental delay, hypertelorism,epicanthal folds, PVS, and ASD.

With fetal alcohol syndrome, born small for gestationalage, microcephaly, cleft palate, small palpebralssures, smooth philtrum, thin-lip vermilion, and awider range of cardiac defects including ventricularseptal defect, endocardial cushion defect, conotruncalabnormalities, and coarctation of the aorta

LEOPARD syndrome Common features to LEOPARD syndrome and NS includehypertelorism, PVS, HCM, and short stature; caused byPTPN11, RAF1, or BRAF gene mutations

With LEOPARD syndrome: Sensorineural deafness, multipleskin lentigines, pigmented lesions, conductionabnormalities, 30% have mental retardation

Mosaic trisomy 22 Similar facial features include hypertelorism and ptosis. In mosaic trisomy 22: No congenital heart defects areseen,16 and cognitive development more impaired.

Neurobromatosis type 1 Some people with neurobromatosis type 1 gene mutationshave NS-like facial features and PVS

With neurobromatosis type 1, multiple caf au lait,axillary, and inguinal freckling, cutaneousneurobroma, and iris Lisch nodules

Turner syndrome Girls with NS and Turner syndrome can have short stature,eyelid ptosis, increased internipple distance, webbedneck, and kidney malformations.8

Cardiac features are typically left-sided in Turnersyndrome but right-sided in NS; coarctation of theaorta and/or bicuspid aortic valve are morecharacteristic of Turner syndrome; girls have gonadaldysgenesis in Turner syndrome; normal fertility in girlswith NS. Turner syndrome is attributable to loss of 1sex chromosome.


drome.10,11,29 By using this candidategene approach, 6 additional Ras/MAPKcandidate genes were identied from2006 to the present: KRAS, NRAS, SOS1,RAF1, BRAF, and SHOC2.12,3035

Genetic Testing for NS

The currently available commercialtests use different technologies(dideoxynucleotide sequencing, dena-turing high-performance liquid chro-matography, and oligonucleotide-based microarray sequencing) thatfundamentally are based on the pres-ence of missense or small insertions/deletions in the coding regions andanking intron boundaries of genesthat cause NS. Although gross chromo-somal abnormalities (interstitial dele-tions, duplications, and balancedtranslocations) have rarely been iden-tied in patients with phenotypes thatclosely resembled (or were) NS,3641

routine karyotyping or copy-numberanalysis is not recommended at thistime for typical NS cases. It may be con-sidered for atypical cases or whenthere is particularly severe neurocog-nitive involvement.

Postnatal Mutation Testing for NS

Table 312,3035,4255 summarizes the stud-ies that comprised 20 subjects ofpostnatalmutation testing for NS since2001. There are important limitationsin the interpretation of these data, in-

cluding the heterogeneity in NS diag-nostic clinical criteria, the occurrenceof phenotyping at different ages, and acase-mix sensitivity (the rate ofPTPN11 mutations among familialcases of NS is nearly double thatamong sporadic cases42). Mutations inthe 7 genes identied for NS to dateaccount for 61% of postnatal cases.There is currently no information con-cerning the number of cases, if any,that harbor more than 1 mutation forNS because all studies took a sequen-tial genotyping approach. Because 1center recently introduced the useof microarray-based sequencing inwhich all relevant genes are analyzedin parallel, it will be of interest to dis-cover whether multiple hits are ob-served in some subset of patients withNS.

A suggested algorithm for individualgenotyping is shown in Table 1. Therationale for this algorithm and a dis-cussion of prenatal mutation testingin NS is provided in SupplementalInformation5658).

GENOTYPE/PHENOTYPECORRELATIONS

Among the mutated genes that ac-count for NS, many different genotype/phenotype correlations have beenmade. No phenotypic features are

found exclusively among 1 genotype,probably because of genetic and epige-netic factors that inuence both pen-etrance and expressivity. Table 4 sum-marizes some genotype/phenotypecorrelations that may be useful for cli-nicians, but note that there are no phe-notypic features exclusive to a specicgenotype. There are, however, signi-cant differences in the risk of variousNS manifestations based on the caus-ative gene.

PTPN11 mutations have been consis-tently associated with the presence ofa pectus deformity, easy bruising, thecharacteristic facial appearance, andshort stature.49,50,59 Childrenwith SOS1-associated NS are more likely to haveCFC syndromelike skin ndings (ker-atosis pilaris, sparse hair, curly hair,sparse eyebrows)53 and less likely tohave short stature53 or impaired cog-nitive functioning.53,60 Patients with NScaused by missense mutations inPTPN11 aremore likely to have PVS andatrial septal defects (ASDs) and lesslikely to have hypertrophic cardiomy-opathy (HCM) than people with NSwithout a PTPN11 mutation.21,42,49,50

Those with a pathogenic SOS1 muta-tion are more likely to have PVS thanthose with NS who have neither anSOS1 nor a PTPN11 mutation.33 It is re-markable that 80% to 95% of childrenwith RAF1 mutations have HCM.31,32 Pa-

TABLE 3 Summary of Postnatal Mutation Testing for NS

Gene Total No. ofSubjects

No. ofStudies

Mutation-PositivePatients, n (% ofStudy Cohort)

% of All CasesGenotyped

Comments

PTPN1112,25,26,3033,45,5153,139 877 13 359 (40.9) 40.9a 25% of mutations were Asp308

KRAS16,20,30,53,54,139 616 6 15 (2.4) 1.4 PTPN11-negative subjects had more broadlyspread mutations

SOS1 30,49,53,59,139 311 5 60 (19.3) 11.1 Subjects were PTPN11- and KRAS-negativeRAF117,30,53,140 304 4 31 (10.2) 4.7 Subjects were PTPN11-, KRAS-, and SOS1-negativeBRAF 55,139,140 334 3 6 (1.8) 0.8 Subjects were PTPN11-, KRAS-, SOS1-, RAF1-negativeSHOC2 34 96 1 4 (4.2) 1.7 Subjects were PTPN11-, KRAS-, SOS1-, RAF1-, and

BRAF-negativeNRAS 35 733 1 4 (0.5) 0.2 Subjects were PTPN11-, KRAS-, SOS1-, RAF1-, and

BRAF-negativeTotal a 32 a 61

Shown are results of postnatal mutation testing from studies that included20 patients with the NS phenotype. All studies took a sequential genotyping approach.a Total values were not calculated for columns 2 and 4 because of overlap of patients (ie, mutation-negative patients were often tested again in separate studies for subsequent mutations).



tients with the SHOC2 S2G mutationhave a distinctive phenotype, initiallytermed Noonan-like syndrome, withloose anagen hair.61 In addition to thehair ndings, the phenotypemay includemitral valve and cardiac septal defects,GH deciency, ectodermal abnormalitieswith darkly pigmented ichthyotic skin,hypernasal voice, and developmental is-sues with hyperactivity.34

In a study of 45 patients with NS, bothbleeding diathesis and juvenile my-elomonocytic leukemia were found ex-clusively in patientswith specic PTPN11mutations.49 Familial cases of NS aremore likely than sporadic cases to becaused by a PTPN11 mutation.42 NS at-tributable to KRAS mutations seems toconfer a more severe phenotype withmore signicant learning issues and de-velopmental delays.50

CARDIOVASCULAR ISSUES

More than 80% of patients with NShave an abnormality of the cardiovas-cular system.7,6264 PVS is the mostcommon. The valve may be dysplasticin 25% to 35% of those with PVS6466

and is often associated with an ASD.Isolated ASDs and partial atrioventric-ular canal defects are also relativelycommon. A broad spectrum of cardiacabnormalities has been reported, asnoted in Table 5. Approximately 50% ofpatients with NS have an unusual elec-trocardiographic pattern character-

ized by left-axis deviation, an abnormalR/S ratio over the left precordial leads,and an abnormal Q wave.67 Many pa-tients have mild PVS that requires onlyperiodic reevaluation. If the PVS is orbecomes clinically signicant, initialtreatment is usually pulmonary bal-loon valvuloplasty, but it may be unsuc-cessful if the valve is dysplastic. Withsevere dysplasia, a pulmonary valvec-tomy or pulmonary homograft may beneeded in childhood. The other cardiacdefects can be treated in the standardways.

HCM is present in 20% of patientswith NS overall but is particularly fre-quent with RAF1mutations,31,32 and it isvariable in severity and natural his-tory. In some infants with HCM the con-dition resolves, whereas in others itbecomes rapidly progressive and mayhave a fatal outcome. Others developHCM after infancy. The course may bestable or progressive, or it may im-prove. Management is similar to that

for any patient with HCM and may in-clude the use of-blockermedicationsor surgical myomectomy to reduceoutow obstruction.62

It is important for adults with NS tohave lifetime cardiac follow-up. Left-sided obstructive lesions may developin adulthood.68 Pulmonary valve insuf-ciency and right ventricular dysfunc-tion are potential problems after ear-lier pulmonary valve surgery. Cardiacarrhythmias have been rare in the lim-ited reports available about long-termfollow-up of adults.6,69

GROWTH AND ENDOCRINE ISSUES

Growth

Approximately 50% to 70% of individu-als with NS have short stature.7,70,71 Al-though short stature is a main charac-teristic of this condition, someindividuals will have normal growthand stature. Birth weight and lengthare typically normal, but there is a sub-

TABLE 4 Genotype/Phenotype Correlations

Gene Most Common CardiovascularFeatures

Most Common GrowthFeatures

Most CommonDevelopmental Features

Most Common Skin/Hair Features Most CommonOther Features

PTPN11 PVS Overrepresentation ofshort stature

N308D and N308S: little or nocognitive delays

Underrepresentation of HCM Lower IGF-1 levels KRAS More severe cognitive delay CFC syndromelike skin and hair ndings SOS1 Lower prevalence of

short statureLower prevalence ofcognitive delays

CFC syndromelike skin and hair ndings

RAF1 Overrepresentation of HCM SHOC2 Overrepresentation of mitral valve

prolapse and septal defectsHigher prevalence GHdeciency

Distinctive hyperactivebehavior

Easily pluckable, sparse, thin, slowgrowing hair Darkly pigmented skineczema icthyosis

Hypernasal speech

NRASa

Shown are the phenotypic features that have been correlated to the currently known genotypes in NS.a Too few cases for genotype/phenotype correlation analysis.

TABLE 5 Cardiac Conditions in NS

Frequent Occasional Rare

PVS Aortic valvular stenosis Pulmonary hypertensionSecundum ASD Supravalvular pulmonary stenosis Aortic root dilationHCM Bicuspid aortic valve Aortic dissectionPartial atrioventricularcanal defect

Patent ductus arteriosus Restrictive cardiomyopathyBranch pulmonary artery stenosis Dilated cardiomyopathyMitral valve anomalies Ebsteins anomaly of tricuspid valveVentricular septal defect Pulmonary atresiaTetralogy of Fallot Coronary artery abnormalitiesCoarctation of aorta


sequent deceleration of height andweight to the third centile or less. Themean delay of bone age is2 years.7,72

NS-specic growth charts have beenpublished.72,73

Mean adult heights of European indi-viduals with NS have been reported forwomen as 153.0 cm and for men as162.5 and 169.8 cm.6,72 The mean adultheight of North American individuals isless than the third centile in 54.5% ofwomen (151 cm) and 38% of men(163.2 cm).74,75 A higher prevalenceof short stature has been found inPTPN11 mutation-positive subjectsthan in mutation-negative subjects,and a lower prevalence of short stat-ure has been described for those withSOS1-associated NS.50,51

Reports of GH-secretory dynamicshave been inconsistent and are likely areection of the genotypic heterogene-ity of NS. There have been reports ofGH deciency (45% [n 150]96 37%[n 27]77), neurosecretory dysfunc-tion,7880 and completely normal GH se-cretion.81,82 Insulin-like growth factor 1levels are frequently low and weresignicantly lower in the PTPN11mutation-positive than mutation-negative patients.8183

Until recently, most experiencewith GHin NS has been reported in studies thatinvolved small numbers of patientswith varied enrollment ages, treat-ment durations, doses, and responses.

These studies resulted in improvedgrowth velocity without signicant ad-verse effects.7880,8486 Although moststudies have excluded patients withHCM, left ventricular wall thickness re-mained normal when prospectivelymeasured in patients with NS onGH.7678 In addition, among the com-bined 889 patients from 6 articles thatreported adult-height outcomes in pa-tients with NS on GH,84,8892 there wereonly 5 reported cardiac events (2 mildprogressions of PVS, 1 HCM, 1 in-creased biventricular hypertrophy,and 1 cardiac decompensation).

The efcacy of GH in NS can be as-sessed by considering adult-heightdata (Table 6).84,8891 Although differentparameters were reported in thesestudies (ie, median versus mean val-ues, height SD scores based on popu-lation standards versus the NS-specic standards, varied doses, etc),it seems that improved outcomes (height SD score: 1.31.7; mean heightgain: 9.513 cm for boys and 9.09.8cm for girls89,90,92) occur with earlierinitiation and longer duration of GHtherapy, as has been demonstrated forother conditions such as Turnersyndrome.93,94

Initial short-term data have sug-gested that PTPN11-positive patientsresponded less efciently to GHthan did the PTPN11-negative pa-tients.48 In contrast, longer-term

data from comparisons of adultheights for those treated with GHamong those who were PTPN11mutation-positive with those whowere mutation-negative revealed nodifference in outcome.90 Additionalstudies may clarify the role of thedifferent RAS/MAPK pathway ab-errations in growth and GHresponsiveness.

Other Endocrine and AutoimmuneIssues

Puberty is typically, but not universally,delayed for both boys and girls with NSand is characterized by a diminishedpubertal growth spurt.72 The mean ageof pubertal onset is 13.5 to 14.5 yearsin boys and 13 to 14 years in girls. Pu-bertymay progresswith a rapid tempo(2 years).92 Pubertal induction maybe instituted (with careful consider-ation of timing for optimal height po-tential) for no secondary sexual char-acteristics in boys at 14 years(testosterone induction) and girls at13 years (estrogen induction).

Thyroid antibodies are commonlyfound, but hypothyroidism is likely nomore common in those with NS than inthe general population.7,9597 Therehave been case reports of the occur-rence of other autoimmune condi-tions, such as systemic lupus erythem-atosus and celiac disease, but theirfrequency is unknown.98100

TABLE 6 Baseline and Treatment Growth Data From Studies That Reported Adult-Height Outcomes in Individuals With NS Treated With GH

Reference Patients,n (n Female)

Baseline Age, y Baseline SDSa GH Dose, mg/kg per wk DurationTherapy, y

DeltaHeightSDS

Height Gain

88 4 (4) 13.5 (0.6) 0.19 for 1 y, then 0.31 3.5 (0.48) NA84 10 (4) 12 3.1 (0.7) 0.30 5.3 3.1 cm89 18 (11) 8.6 (boys), 7.7 (girls) 2.9 (0.3) 0.23 (n 10), 0.46 (n 15) for

2 y, then dose titrationb7.5 1.7 13 cm (boys), 9.8 cm (girls)

91 24 (NA) 10.2 (median) 3.24 (median) 0.24 (median [range: 0.170.77]) 7.59 (median) 0.61 (0.97) NA90 29 (8) 11 2.8 (0.0) 0.35 6.4 (median) 1.3 (1.3) 9.5 cm (boys), 9.0 cm

(girls)92 65 (30) 11.6 3.5 0.33 5.6 1.4 10.9 cm (boys) 9.2 cm (girls)

Results are mean values unless specied otherwise. SDS indicates SD score; NA, not applicable.a Height SDS is reported according to population standards and/or (NS standards).b Estimated mean: 0.35 mg/kg per week.



RENAL AND GENITOURINARY ISSUES

Renal anomalies occur in 10% to 11%of those with NS and are usually of lit-tle signicance.7,98,99 Solitary kidney,renal pelvis dilation, and duplicatedcollecting system have been reported.Cryptorchidism occurs in up to 80% ofboys, and surgical orchiopexy is re-quired. Recent evidence suggests ser-toli cell dysfunction101 rather thancryptorchidism as the etiology of malegonadal dysfunction. Fertility does notseem to be affected in women.

HEMATOLOGY AND ONCOLOGY ISSUES

Disordered bleeding has been re-ported for 30% to 65% of individualswith NS.7,102 Although the symptomsare often mild, such as excessivebruising, epistaxis, or menorrhagia,bleeding with surgical procedurescan be signicant. A number ofcoagulation-factor deciencies (iso-lated and combined), thrombocytope-nia, and platelet dysfunction have beendescribed. Elevation of the activatedpartial thromboplastin time is fre-quent. Approximately 25% of individu-als with NS have partial factor XI de-ciency.102107 The bleeding symptomsdo not correlate well with the degreeof deciency. A number of other coag-ulation factors can be depressed, andlow factor XII and factor VIII activity arethe next most frequent depres-sions.105107 It is important to note thatalthough factor XII deciency can pro-long the activated partial thrombo-plastin time, it does not result in clini-cal bleeding. Low factor VIII levels canbe seen with von Willebrand disease,which is a common bleeding disorderin the general population; althoughboth low factor VIII and von Willebrandfactor have been reported in NS, an ac-curate estimate of the prevalence ofvonWillebrand disease in patientswithNS has not yet been determined.105107

Less commonly, factor IX and factor IIhave also been reported to be decient

in patients with NS and can contributeto bleeding risk.105,108

Both thrombocytopenia and plateletdysfunction have been described in pa-tients with NS. The etiology of thethrombocytopenia is probably multi-factorial and can be associated with adefect in platelet production caused bya decrease in megakaryocytes.108

Splenomegaly may also cause mild-to-moderate thrombocytopenia and isfound by ultrasound in up to 52% ofpatients with NS.109 Splenomegaly maybe isolated or associated with hepato-megaly. In some patients, hepato-splenomegaly or splenomegaly may becaused by NS/myeloproliferative dis-order (MPD).

NS/MPD is a condition seen in infantswith NS that is characterized by leuko-cytosis with monocytosis, thrombocy-topenia, and hepatosplenomegaly. Al-though the clinical picture of NS/MPDresembles that of juvenile myelomono-cytic leukemia, infants with NS/MPDseem to have a favorable prognosis.Although some infants with NS/MPDhave been reported to develop aggres-sive leukemia, the majority with thiscondition present in the rst fewmonths of life andwill remain stable orimprove by 1 year of age without spe-cic therapy.110,111

Despite the role of somatic PTPN11 andKRAS mutations in the development ofmalignancies, the incidence of cancerin older children and adults with NShas not been shown to be increasedover that of the general population.6,112

However, additional studies areneeded to accurately assess the risk ofmalignancy in individuals with NS.

NEUROLOGIC, COGNITIVE, ANDBEHAVIORAL ISSUES

The neurologic, cognitive, and behav-ioral aspects of individuals with NS arepoorly understood and extremely vari-able. There is an increased incidenceof cognitive issues and learning dis-

abilities, an increased incidence ofbrain abnormalities, and a wide arrayof other neurologic problems. In astudy of 151 subjects with NS, 76% hadfeeding difculties, 94% had ocularproblems, 50% had hypermobility ofjoints/hypotonia, 13% had recurrentseizures, 3% had hearing loss, and 3%had peripheral neuropathy.7 Therewas also a general delay in the meanage of motor milestones; sitting aloneoccurred at 10 months, walking oc-curred at 21 months, and speaking2-word sentences occurred at 31months.7 Another study revealed that84% had some type of neurologicproblem.113

Structural malformations and defor-mations of the central nervous systemand spinal cord are found at relativelylow frequency. The most common de-fects are Arnold-Chiari malformationtype I and hydrocephalus. The meanhead circumference is at the 50th per-centile; however, some individualswith NS can be microcephalic ormacrocephalic.7

Most people with NS have normal in-telligence, but 10% to 40% requirespecial education.7,114,115 Even amongthose of normal intelligence, IQ hasbeen shown to be 10 points less thanunaffected family members or 1 SDbelow that of the general popula-tion.114 The observed heterogeneityin cognitive abilities in syndromes ofthe Ras/MAPK signaling cascade in-cluding NS can be at least partiallyascribed to the individual affectedgenes and the type of mutation.116 Forexample, SOS1 mutations53,60,116 andspecic PTPN11 mutations42,60,116,117

have been associated with no or mildcognitive delays.

Children with NS have a higher rate ofclumsiness, poor coordination, stub-bornness, and irritability.118 Body-image problems and poor self-esteem,depression, and social inadequacyhave been noted to occur in adults with


NS.69 Limited data are available on thepsychological and psychiatric charac-teristics of patients with NS. Psychiat-ric problems are rarely found, andqualitative data in a study of 112adults6 with NS revealed their report-ing an inability to t in but an overallgood or satisfactory quality of life. Inaddition, the majority of adults with NSnished high school and had payingjobs.6,69

GASTROINTESTINAL AND FEEDINGISSUES

Most infants (75%) with NS have feed-ing difculties; poor suck with pro-longed feeding time (15%), very poorsuck and slow feeding with recurrentvomiting (38%), and severe feedingproblems that require tube-feeding for2 weeks (24%) have been de-scribed.6,7 Investigation of some chil-dren with poor feeding has revealedimmaturity of gut motility and delayedgastrointestinal motor development.119

Gastroesophageal reux is common,and there have been a few reports ofmalrotation.109,120 Typically, the periodof failure to thrive is self-limited, al-though poor weight gain may persistfor up to 18 months.

ORAL AND DENTAL ISSUES

Oral ndings in patients with NS in-clude a high arched palate (55%100%),37,72,121 dental malocclusion(50%67%),6,120123 articulation dif-culties (72%),71 and micrognathia(33%43%). Some individuals with NSdevelop mandibular cysts, which canmimic cherubism.124,125 The pathologyof these lesions in individuals with NSis characterized by multinucleated gi-ant cells within a brous stroma and isindistinguishable from cherubism.These 2 conditions, however, are ge-netically distinct; SH3BP2 gene muta-tions are found in individuals withcherubism, whereas PTPN11126 andSOS1127 mutations are found in pa-tients with NS with giant cell lesions.

LYMPHATIC ISSUES

NS is associated with a generalizeddisorder of lymphatic development,which has manifestations in fetal lifethrough adulthood.128,129 The overall in-cidence of lymphatic manifestations inall age groups of those with NS is un-known, but it is estimated to be20%.Peripheral lymphedema, the mostcommon lymphatic manifestation, isseen most frequently in young infants.It typically resolves in the rst fewyears. Adolescents and adults can de-velop peripheral lymphedema.130

Other types of lymphatic involvementthat have been described in patientswith NS include hydrops, chylous pleu-ral effusions, chylothorax, pulmonarylymphangiectasis, intestinal lymphan-giectasia, hypoplastic leg lymphatics,anomalous lymphatic vessels in thethoracic cage and aplasia or absenceof the thoracic duct, hypoplastic in-guinal and iliac lymphatic vessels,and testicular lymphangiectasis.Management of these conditions canbe difcult.131,132

A discussion of malignant hyperther-mia in patients with NS is provided inSupplemental Information.133137

Table 7 lists support organizationsthatmay serve as additional resourcesregarding NS.

CONCLUSIONS

These guidelines were developed froman interdisciplinarymeeting of experts

involved in the care of and research onindividuals with NS. Our goal was toprovide the pediatrician with new in-formation and accrued experience topromote the correct diagnosis andbest care of those with NS. Recognizingthat NS is a clinically and geneticallyheterogeneous condition character-ized by congenital heart disease, dis-tinct facial features, short stature, andmany other potential comorbidities,patients do require multidisciplinaryevaluations and regular follow-up carefor their identied issues. Certainly,many questions remain unansweredregarding the optimal care of these in-dividuals not only in childhood butthroughout adulthood. Therefore, it isimportant to recognize that the recom-mendations in this report are based onthe authors best judgments and thecurrent available medical knowledge.

ACKNOWLEDGMENTSThis article was developed through aconference organized by the NoonanSyndrome Support Group. The fundingfor the conference was provided by anindependent medical education grantfrom Novo Nordisk, Inc to the NoonanSyndrome Support Group. Representa-tives from Novo Nordisk, Inc did not par-ticipate in any scientic deliberations,did not contribute to the content of thisreport, and did not review or commenton this report before publication.

We thank DrMignon Loh for helpful dis-cussion about NS/MPD.

TABLE 7 Support Organizations for NS

Organization Contact Information

Noonan Syndrome Support Group Internet: www.noonansyndrome.org; telephone: 888-686-2224 or410-374-5245; address: PO Box 145, Upperco, MD 21155

Magic Foundation Internet: www.magicfoundation.org; telephone: 800-362-4423 or708-383-0808; Address: 6645 W North Ave, Oak Park, IL 60302

NORD: National Organization forRare Disorders

Internet: www.rarediseases.org; telephone: 203-744-0100;address: 55 Kenosia Ave, PO Box 1968, Danbury, CT06813-1968

Human Growth Foundation Internet: www.hgfound.org; telephone: 800-451-6434; address:997 Glen Cove Ave, Suite 5, Glen Head, NY 11545

BDF Newlife Internet: www.bdfnewlife.co.uk; telephone: 01543 468888;address: Hemlock Business Park, Hemlock Way, Cannock,Staffordshire WS11 7GF, United Kingdom



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(Continued from rst page)

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

Copyright 2010 by the American Academy of Pediatrics

FINANCIAL DISCLOSURE: Dr Romano is a consultant to both Genentech, Inc and Novo Nordisk, Inc and also participates on the speakers bureaus of bothcompanies; Dr Dahlgren received grants in 2008 from Novo Nordisk, Inc for genetic analysis of individuals with NS; Dr Gelb currently has SOS1, RAF1, and SHOC2gene patents pending and receives royalties for PTPN11 mutation testing from GeneDx, Correlegan, Prevention Genetics, Baylor College of Medicine, and HarvardPartners; and Dr Roberts currently has an SOS1 gene patent pending. The other authors have indicated they have no nancial relationships relevant to thisarticle to disclose.



DOI: 10.1542/peds.2009-3207; originally published online September 27, 2010; 2010;126;746Pediatrics

Jacqueline A. NoonanMary Ella Pierpont, Amy E. Roberts, Wanda Robinson, Clifford M. Takemoto and

Alicia A. Romano, Judith E. Allanson, Jovanna Dahlgren, Bruce D. Gelb, Bryan Hall,Noonan Syndrome: Clinical Features, Diagnosis, and Management Guidelines

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Noonan Syndrome: Clinical Features, Diagnosis, and Management GuidelinesHISTORY OF NSCLINICAL DESCRIPTION AND DIFFERENTIAL DIAGNOSISHISTORY OF MOLECULAR GENETIC TESTING AND GENETIC RESEARCHGenetic Testing for NSPostnatal Mutation Testing for NS

GENOTYPE/PHENOTYPE CORRELATIONSCARDIOVASCULAR ISSUESGROWTH AND ENDOCRINE ISSUESGrowthOther Endocrine and Autoimmune Issues

RENAL AND GENITOURINARY ISSUESHEMATOLOGY AND ONCOLOGY ISSUESNEUROLOGIC, COGNITIVE, AND BEHAVIORAL ISSUESGASTROINTESTINAL AND FEEDING ISSUESORAL AND DENTAL ISSUESLYMPHATIC ISSUESCONCLUSIONSACKNOWLEDGMENTSREFERENCES

Pediatrics 2010 Romano 746 59 Noonan

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