Noonan Syndrome: Clinical Features, Diagnosis, and Management Guidelines

Home , Cherubism, Costello syndrome, Cubitus valgus, Noonan syndrome

AUTHORS: Alicia A. Romano, MD,a Judith E. Allanson, MD,b + abstract Jovanna Dahlgren, MD,c Bruce D. Gelb, MD,d Bryan Hall, MD,e Mary Ella Pierpont, MD,f,g Amy E. Roberts, MD,h Noonan syndrome (NS) is a common, clinically and genetically hetero- Wanda Robinson,i Clifford M. Takemoto, MD,j and geneous condition characterized by distinctive facial features, short Jacqueline A. Noonan, MDk stature, chest deformity, congenital heart disease, and other comor- aDivision of Pediatric Endocrinology, Department of Pediatrics, bidities. Gene mutations identified in individuals with the NS phenotype New York Medical College, Valhalla, New York; bDepartment of are involved in the Ras/MAPK (mitogen-activated protein kinase) signal Genetics, Children’s Hospital of Eastern Ontario, Ottawa, Ontario, c transduction pathway and currently explain ϳ61% of NS cases. Thus, Canada; Göteborg Pediatric Growth Research Center, Institute for Clinical Sciences, Queen Silvia Children’s Hospital, Göteborg, NS frequently remains a clinical diagnosis. Because of the variability in Sweden; dCenter for Molecular Cardiology and Department of presentation and the need for multidisciplinary care, it is essential that Pediatrics, Mount Sinai School of Medicine, New York, New York; the condition be identified and managed comprehensively. The Noonan eDepartment of Pediatrics, University of Kentucky Medical Center, Lexington, Kentucky; fDivision of Genetics, Children’s Syndrome Support Group (NSSG) is a nonprofit organization commit- Hospital and Clinics of Minnesota, Minneapolis, Minnesota; ted to providing support, current information, and understanding to gDepartment of Pediatrics, University of Minnesota, Minneapolis, those affected by NS. The NSSG convened a conference of health care Minnesota; hDepartment of Cardiology and Division of Genetics, Children’s Hospital Boston, Boston, Massachusetts; iNoonan providers, all involved in various aspects of NS, to develop these guide- Syndrome Support Group, Baltimore, Maryland; jDivision of lines for use by pediatricians in the diagnosis and management of Pediatric Hematology, Johns Hopkins Hospital, Baltimore, individuals with NS and to provide updated genetic findings. Pediatrics Maryland; and kDivision of Pediatric Cardiology, University of 2010;126:746–759 Kentucky Medical Center, Lexington, Kentucky KEY WORDS Noonan syndrome, PTPN11, SOS1, BRAF, KRAS, NRAS, RAF1, SHOC2, Ras/MAPK signal transduction, congenital heart disease, short stature ABBREVIATIONS NS—Noonan syndrome CFC—cardiofaciocutaneous MAPK—mitogen-activated protein kinase LEOPARD—lentigines, electrocardiographic anomalies, ocular hypertelorism, pulmonary stenosis, abnormal genitalia, and deafness PTPN11—protein tyrosine phosphatase non–receptor type 11 gene PVS—pulmonary valve stenosis GH—growth hormone ASD—atrial septal defect HCM—hypertrophic cardiomyopathy MPD—myeloproliferative 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 of Pediatrics, Munger Pavilion, Room 123, New York Medical College, Valhalla, NY 10595. E-mail: [email protected] (Continued on last page)

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Noonan syndrome (NS) is a relatively CLINICAL DESCRIPTION AND Hair may be wispy in the toddler, common congenital genetic disorder DIFFERENTIAL DIAGNOSIS whereas it is often curly or wooly in the with an estimated prevalence of 1 in Facial and musculoskeletal features older child and adolescent. Regardless 1000 to 1 in 2500 live births.1 Charac- most often lead to the diagnosis of NS. of age, eyes are frequently pale blue or teristic findings include distinctive The facial appearance is most charac- blue-green and much lighter in color facial features, short stature, chest teristic in infancy (Fig 1) and early-to- than expected for family background. deformity, and congenital heart dis- middle childhood and becomes more A characteristic pectus deformity of ease. It is an autosomal dominant subtle in adulthood4 (Fig 1B). In the the chest with pectus carinatum supe- disorder with complete penetrance newborn infant with NS, the head is riorly and pectus excavatum inferiorly but variable expressivity. Until re- large with a small face tucked beneath is seen in most individuals. Also, nip- cently, diagnosis was based solely on a large cranium, a tall forehead, and ples are wide-spaced and low-set, and clinical findings, but genetic muta- narrowing at the temples. The eyes are rounded shoulders are common.5 Sco- tions are identifiable in ϳ61% of the wide-spaced and prominent with epi- liosis is reported in 10% to 15%.6 Other patients. Because of the difficulty in canthal folds, ptosis, and horizontal less common spinal abnormalities in- establishing a diagnosis of NS, the or down-slanting palpebral fissures clude kyphosis, spina bifida, vertebral Noonan Syndrome Support Group co- (95%). There may be telecanthus as and rib abnormalities, and genu val- ordinated a meeting of health care well as hypertelorism. The nose is gum. Talipes equinovarus is de- providers with expertise in various short and broad with a depressed root scribed in 10% to 15%, other joint aspects of the disorder with the aim and full tip. The ears are low-set, are contractures in 4%, radio-ulnar syn- of developing guidelines for its diag- posteriorly rotated, and have an oval ostosis in 2%, and cervical spine fu- nosis and management. This report shape and thickening of the helix sion in 2%. Abnormal forearm carry- is the result of those efforts and is (90%). The upper lip is distinctive with ing angles (cubitus valgus) are found intended to provide the pediatrician a deeply grooved philtrum with high, in more than half the males (10–11°) with key clinical features of NS, to wide peaks to the vermillion of the up- and females (14–15°).7 Hyperexten- provide an update of currently un- per lip (95%), and full lips. Generally, sibility is common.7 derstood genetic causes, and to the neck is short with excess skin and Because of differences in prognosis, present management recommenda- a low posterior hairline (55%). In recurrence concerns, and treatment, tions (Table 1). middle-to-late childhood, facial ap- accurate diagnosis is essential. There pearance often lacks expression and A description of the meeting method- are several disorders with significant resembles the face of an individual ology is provided in Supplemental phenotypic overlap with NS, such as with a myopathy. By adolescence, face Turner syndrome (Table 2).8–17 For Information. shape is an inverted triangle, wide at many years, before our understanding HISTORY OF NS the forehead and tapered to a pointed of their underlying genetic causes, car- chin. Eyes are less prominent. Fea- diofaciocutaneous (CFC) syndrome In 1962, Jacqueline Noonan, a pediat- tures are sharper. There is a narrow and Costello syndrome were often con- ric cardiologist, identified 9 patients nasal root with a thin bridge. The neck fused for NS, particularly in the new- whose faces were remarkably simi- is longer, accentuating skin webbing born period. Therefore, it was not sur- lar and who, in addition, had short or prominence of the trapezius mus- prising that they, like NS, were found to stature, significant chest deformi- cle. The adult face may be quite unre- be caused by mutations in genes of the ties, and pulmonary stenosis.1 In markable, although the same individ- Ras/MAPK (mitogen-activated protein 1968 Dr Noonan published a case se- ual may have had more obvious kinase) pathway. Other disorders with ries with these 9 plus an additional features as an infant. Some adults, significant phenotypic overlap with 10 patients.2 The eponym “Noonan however, have typical features includ- NS include neurofibromatosis type 1, syndrome” was adopted in recogni- ing ptosis, wide-spaced eyes, low-set LEOPARD (lentigines, electrocardio- tion of Dr Noonan, because she was ears with posterior rotation and thick- graphic anomalies, ocular hypertelor- the first to indicate that this condi- ened helix, and broad or webbed neck. ism, pulmonary stenosis, abnormal tion occurred in both genders, was In the older adult, nasolabial folds are genitalia, and deafness) syndrome, associated with normal chromo- more prominent than one would ex- Aarskog syndrome, fetal alcohol syn- somes, included congenital heart de- pect for that person’s age, and the skin drome, mosaic trisomy 22, and fects, and could be familial.3 appears transparent and thin. Baraitser-Winter syndrome. Molecular

PEDIATRICS Volume 126, Number 4, October 2010 747 Downloaded from pediatrics.aappublications.org by guest on January 22, 2015 TABLE 1 Management Recommendations Clinical Specialty Issue Recommendations Genotype/phenotype Genetics consultation and follow-up issues Decision whether to perform gene testing in individuals with NS phenotype should take into consideration: Positive gene testing can confirm NS diagnosis Negative test results cannot exclude the diagnosis Expected frequency of mutations among patients with definite NS by sequencing the 6 genes known to date is ϳ60% If sequential molecular testing is determined to be indicated (rather than simultaneous chip based analysis): PTPN11 sequencing should be performed first, because this gene explains the highest number of cases If normal, phenotype should be used to guide the choice of the next gene to sequence If developmental delays are absent or mild, CFC syndrome–like skin and hair findings are present, and/or patient is of normal stature, consider SOS1 sequencing If HCM is present, consider RAF1 sequencing For significant developmental delays or cognitive issues, consider KRAS sequencing For sparse, thin, slow-growing hair, consider SHOC2 sequencing If a variant is found, consider testing the parents to provide accurate recurrence risks Cardiovascular issues All individuals should undergo a cardiac evaluation by a cardiologist at the time of diagnosis, including an electrocardiogram and echocardiogram Those found to have cardiac problems should have regular follow-up at intervals determined by the cardiologist; cardiac care should be individualized according to the specific disorder(s) present Some will require treatment such as balloon valvuloplasty or surgery; long-term reevaluation of these patients after treatment is essential (specifically, after successful cardiac surgery, cardiac care should not be discontinued) Individuals without heart disease on their initial evaluation should have cardiac reevaluation every 5 y Adults should not discontinue periodic cardiac evaluations even if their evaluations in childhood or adolescence were normal; unexpected cardiac findings can occur at any point in time Growth and endocrine Children should be weighed and measured regularly by the primary care provider, and the data should be plotted on appropriate issues growth charts (thrice yearly for the first3yoflife and yearly thereafter) Children with evidence of growth failure (growth deceleration, height less than Ϫ2 SDs, or height inappropriate for genetic background) that cannot be explained by a comorbidity should be monitored more often, have nutrition optimized, have baseline 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 by 14 y of age) should be referred to a pediatric endocrinologist Therapeutic interventions as indicated (GH for growth failure, thyroid hormone replacement for hypothyroidism, estrogen or testosterone 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 findings issues 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 infection Orchiopexy should be performed by the age of1yiftesticles remain undescended at that time Gastrointestinal issues Pediatric gastroenterology/nutrition consultation for feeding difficulties/recurrent vomiting Further testing as indicated (upper-gastrointestinal series, upper endoscopy, pH studies, etc) Therapeutic interventions as indicated (antireflux 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 6–12 mo of age if initial screen performed in infancy Bleeding symptoms First tier: CBC with differential count and prothrombin time/activated partial thromboplastin time Second tier (in consultation with hematologist): specific factor activity (factor XI, factor XII, factor IX, factor VIII, von Willebrand factor) and platelet function (bleeding time or platelet aggregation) Surgery: preoperative evaluation (first- and second-tier testing) of bleeding risk; hematology consultation as needed for management of bleeding risk Splenomegaly: CBC with differential count Hepatosplenomegaly: CBC with differential count, liver-function tests Avoidance of aspirin and aspirin-containing medications Neurological, cognitive, Developmental screening annually and behavioral Complete neuropsychological testing if screening result is abnormal issues Evaluations for speech pathology, PT, and OT if delays in speech, gross motor, and fine motor skills, respectively Early-intervention programs beginning in infancy if delays noted Speech therapy for speech and articulation issues, PT and OT for gross and fine motor delays Regular, detailed developmental evaluations throughout childhood Individualized education plan for school-aged children Electroencephalography and referral to neurology if seizures suspected Brain and upper-spine MRI with any neurologic problem (headaches, weakness, numbness, poor balance, etc), cranial size aberration Magnetic resonance angiography (after MRI) if focal/sudden neurologic signs

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TABLE 1 Continued Clinical Specialty Issue Recommendations Eye and ear issues Detailed eye examination in infancy and/or at diagnosis Eye reevaluations as indicated if problems found or at least every 2 y thereafter Hearing test in infancy and/or at diagnosis with annual hearing test throughout early childhood Attentive management of ear infections to minimize hearing loss Orthopedic and dental Annual examination of chest and back, radiography if abnormal issues Careful oral exam at each visit Dental referral between the ages of 1 and 2 y and yearly visits thereafter Dental radiography as indicated Lymphatic issues Referral of those with peripheral lymphedema to specialty lymphedema clinics For 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 anesthesia Avoidance of anesthetics associated with malignant hyperthermia in those individuals with NS-like phenotype, a skeletal myopathy, and normal to modestly elevated creatine phosphokinase level and HCM Skeletal muscle biopsy should be considered to look for excess muscle spindles (suspect diagnosis of congenital myopathy with excess muscle spindles) in those with NS-like phenotype, a skeletal myopathy, and normal to modestly elevated creatine phosphokinase level and HCM CBC indicates complete blood count; PT, physical therapy; OT, occupational therapy.

genetic testing will aid in the differentiation of NS from CFC syndrome, Costello syndrome, LEOPARD syndrome, neuroﬁbromatosis type 1, or Aarskog syndrome. A karyotype will differentiate Turner syndrome from mosaic trisomy 22. A discussion of scoring systems as algo- rithms of diagnostic criteria is provided in Supplemental Information.7,18,19

HISTORY OF MOLECULAR GENETIC TESTING AND GENETIC RESEARCH In 1994, linkage analysis of a large family inheriting NS established definitive linkage to the first NS locus, defined as chromosomal bands 12q22-qter and named NS1.19,20 Genetic heterogeneity was subsequently established. In 2001, Tartaglia and co-workers21 identified missense mutations in the protein tyrosine phosphatase non– receptor type 11 gene (PTPN11)asthe first molecular causes of NS. This discovery was enabled by the observa- tions that PTPN11 resided within the NS1 critical region and that studies with a mouse model of PTPN11 deficiency revealed that its protein prod- uct, SHP-2, was critical for the embry- ologic development of the semilunar FIGURE 1 22 A, Patient with NS at (from left to right) 10 days, 6 months, and 2 years of age. B, Patient with NS at cardiac valves. Because pulmonary (from left to right) 4 months and 1, 2, 5, 9, and 21 years of age. valve stenosis (PVS) is a prominent

PEDIATRICS Volume 126, Number 4, October 2010 749 Downloaded from pediatrics.aappublications.org by guest on January 22, 2015 TABLE 2 Differential Diagnosis: Similarities and Differences Between NS and Other Disorders Syndrome Similarities With NS Differences From NS Aarskog syndrome Similarities in NS and Aarskog syndrome are primarily facial With Aarskog syndrome, no cardiovascular malformations (faciogenital dysplasia) and skeletal (hypertelorism, down-slanting palpebral but shawl scrotum is present; this is an X-linked fissures, and short stature).15 recessive disorder caused by FGD1 gene mutations. Baraitser-Winter syndrome Features common to both NS and Baraitser-Winter syndrome With Baraitser-Winter syndrome, there can be iris include hypertelorism, eyelid ptosis, short neck, short coloboma, pachygyria, lissencephaly, bicuspid aortic stature, and cognitive delays. valve stenosis, and aortic stenosis17 CFC syndrome Common facial, skeletal, and cardiac features in both NS and With CFC syndrome, coarser facial features, severe CFC syndrome include hypertelorism with down-slanting feeding problems, follicular hyperkeratosis, sparse palpebral fissures, epicanthal folds, and eyelid ptosis, eyebrows and eyelashes, ichthyosis, and ulerythema depressed nasal root, short stature, relative ophryogenes; majority have moderate retardation13; macrocephaly, PVS, HCM, and ASDs.9 KRAS or BRAF may be caused by MEK1 or MEK2 mutations10–12 mutations and rarely SOS1 or MEK1 mutations have been seen in patients with NS and those with CFC syndrome.10–12,138 Costello syndrome Many features common to both Costello syndrome and NS With Costello syndrome, coarse facial features, wide nasal include curly hair, wide nasal bridge, eyelid ptosis, down- bridge, loose skin, increased pigmentation with age, slanting palpebral fissures, epicanthal folds, PVS, HCM, deep palmar and plantar creases, papillomata of the pectus deformity, and Chiari I malformation. face or perianal region, premature aging and hair loss, multifocal atrial tachycardia, moderate mental retardation, and ulnar deviation of the wrist and fingers14; caused by HRAS mutations Fetal alcohol syndrome Common features to both NS and fetal alcohol syndrome With fetal alcohol syndrome, born small for gestational include growth delay, developmental delay, hypertelorism, age, microcephaly, cleft palate, small palpebral epicanthal folds, PVS, and ASD. fissures, smooth philtrum, thin-lip vermilion, and a wider range of cardiac defects including ventricular septal defect, endocardial cushion defect, conotruncal abnormalities, and coarctation of the aorta LEOPARD syndrome Common features to LEOPARD syndrome and NS include With LEOPARD syndrome: Sensorineural deafness, multiple hypertelorism, PVS, HCM, and short stature; caused by skin lentigines, pigmented lesions, conduction PTPN11, RAF1, or BRAF gene mutations abnormalities, 30% have mental retardation Mosaic trisomy 22 Similar facial features include hypertelorism and ptosis. In mosaic trisomy 22: No congenital heart defects are seen,16 and cognitive development more impaired. Neurofibromatosis type 1 Some people with neurofibromatosis type 1 gene mutations With neurofibromatosis type 1, multiple café au lait, have NS-like facial features and PVS axillary, and inguinal freckling, cutaneous neurofibroma, and iris Lisch nodules Turner syndrome Girls with NS and Turner syndrome can have short stature, Cardiac features are typically left-sided in Turner eyelid ptosis, increased internipple distance, webbed syndrome but right-sided in NS; coarctation of the neck, and kidney malformations.8 aorta and/or bicuspid aortic valve are more characteristic of Turner syndrome; girls have gonadal dysgenesis in Turner syndrome; normal fertility in girls with NS. Turner syndrome is attributable to loss of 1 sex chromosome.

feature of NS, these investigators somatic growth). The reasoning of not to be allelic.23–26 LEOPARD syn- reasoned that PTPN11 was a leading these investigators proved correct, be- drome, on the other hand, proved to be positional candidate gene in NS1.Inad- cause they observed PTPN11 missense allelic with PTPN11; mutations account dition, Tartaglia and co-workers recog- mutations in 2 medium-sized families for ϳ90% of cases, and speciﬁc muta- nized that SHP-2, a protein tyrosine inheriting NS in a pattern consistent tions, particularly Y259C and T468M, phosphatase with largely positive reg- with linkage to NS1 and then additional are prevalent only in LEOPARD syn- ulatory roles in Ras/MAPK signaling, mutations in approximately half of a drome.27,28 Other Ras/MAPK genes participated in signaling downstream small number of sporadic cases or were then considered as candidate from several ligand-receptor com- small families with NS. genes that might be mutated in pa- plexes with possible relevance to the tients with NS that is not explained by pleiomorphic abnormalities observed Subsequent molecular discovery indi- PTPN11. HRAS mutations were shown in NS (eg, ﬁbroblast growth factor for cated that other genetic syndromes to cause Costello syndrome, and 4 Ras/ bone development, growth hormone that resembled NS phenotypically, MAPK genes (KRAS, BRAF, MEK1, and [GH] and insulin-like growth factor for Costello and CFC syndromes, proved MEK2) were mutated in CFC syn-

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TABLE 3 Summary of Postnatal Mutation Testing for NS Gene Total No. of No. of Mutation-Positive % of All Cases Comments Subjects Studies Patients, n (% of Genotyped Study Cohort) PTPN1112,25,26,30–33,45,51–53,139 877 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 broadly spread mutations SOS1 30,49,53,59,139 311 5 60 (19.3) 11.1 Subjects were PTPN11- and KRAS-negative RAF117,30,53,140 304 4 31 (10.2) 4.7 Subjects were PTPN11-, KRAS-, and SOS1-negative BRAF 55,139,140 334 3 6 (1.8) 0.8 Subjects were PTPN11-, KRAS-, SOS1-, RAF1-negative SHOC2 34 96 1 4 (4.2) 1.7 Subjects were PTPN11-, KRAS-, SOS1-, RAF1-, and BRAF-negative NRAS 35 733 1 4 (0.5) 0.2 Subjects were PTPN11-, KRAS-, SOS1-, RAF1-, and BRAF-negative Total a 32 a 61 — Shown are results of postnatal mutation testing from studies that included Ն20 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). drome.10,11,29 By using this candidate cluding the heterogeneity in NS diag- found exclusively among 1 genotype, gene approach, 6 additional Ras/MAPK nostic clinical criteria, the occurrence probably because of genetic and epige- candidate genes were identified from of phenotyping at different ages, and a netic factors that influence both pen- 2006 to the present: KRAS, NRAS, SOS1, case-mix sensitivity (the rate of etrance and expressivity. Table 4 sum- RAF1, BRAF, and SHOC2.12,30–35 PTPN11 mutations among familial marizes some genotype/phenotype correlations that may be useful for cli- Genetic Testing for NS cases of NS is nearly double that among sporadic cases42). Mutations in nicians, but note that there are no phe- The currently available commercial the 7 genes identified for NS to date notypic features exclusive to a specific tests use different technologies account for 61% of postnatal cases. genotype. There are, however, signifi- (dideoxynucleotide sequencing, dena- cant differences in the risk of various There is currently no information con- turing high-performance liquid chro- NS manifestations based on the caus- cerning the number of cases, if any, matography, and oligonucleotide- ative gene. based microarray sequencing) that that harbor more than 1 mutation for PTPN11 mutations have been consis- fundamentally are based on the pres- NS because all studies took a sequen- tently associated with the presence of ence of missense or small insertions/ tial genotyping approach. Because 1 a pectus deformity, easy bruising, the deletions in the coding regions and center recently introduced the use characteristic facial appearance, and flanking intron boundaries of genes of microarray-based sequencing in short stature.49,50,59 Children with SOS1- that cause NS. Although gross chromo- which all relevant genes are analyzed associated NS are more likely to have somal abnormalities (interstitial dele- in parallel, it will be of interest to dis- CFC syndrome–like skin findings (ker- tions, duplications, and balanced cover whether multiple hits are ob- atosis pilaris, sparse hair, curly hair, translocations) have rarely been iden- served in some subset of patients with sparse eyebrows)53 and less likely to tified in patients with phenotypes that NS. have short stature53 or impaired cog- closely resembled (or were) NS,36–41 A suggested algorithm for individual nitive functioning.53,60 Patients with NS routine karyotyping or copy-number genotyping is shown in Table 1. The caused by missense mutations in analysis is not recommended at this rationale for this algorithm and a dis- PTPN11 are more likely to have PVS and time for typical NS cases. It may be con- cussion of prenatal mutation testing atrial septal defects (ASDs) and less sidered for atypical cases or when in NS is provided in Supplemental likely to have hypertrophic cardiomy- there is particularly severe neurocog- Information56–58). opathy (HCM) than people with NS nitive involvement. without a PTPN11 mutation.21,42,49,50 GENOTYPE/PHENOTYPE Postnatal Mutation Testing for NS Those with a pathogenic SOS1 muta- CORRELATIONS Table 312,30–35,42–55 summarizes the stud- tion are more likely to have PVS than ies that comprised Ն20 subjects of Among the mutated genes that ac- those with NS who have neither an postnatal mutation testing for NS since count for NS, many different genotype/ SOS1 nor a PTPN11 mutation.33 It is re- 2001. There are important limitations phenotype correlations have been markable that 80% to 95% of children in the interpretation of these data, in- made. No phenotypic features are with RAF1 mutations have HCM.31,32 Pa-

PEDIATRICS Volume 126, Number 4, October 2010 751 Downloaded from pediatrics.aappublications.org by guest on January 22, 2015 TABLE 4 Genotype/Phenotype Correlations Gene Most Common Cardiovascular Most Common Growth Most Common Most Common Skin/Hair Features Most Common Features Features Developmental Features Other Features PTPN11 PVS Overrepresentation of N308D and N308S: little or no —— short stature cognitive delays Underrepresentation of HCM Lower IGF-1 levels — — — KRAS — — More severe cognitive delay CFC syndrome–like skin and hair findings — SOS1 — Lower prevalence of Lower prevalence of CFC syndrome–like skin and hair findings — short stature cognitive delays RAF1 Overrepresentation of HCM — — — — SHOC2 Overrepresentation of mitral valve Higher prevalence GH Distinctive hyperactive Easily pluckable, sparse, thin, slow Hypernasal speech prolapse and septal defects deficiency behavior growing hair Darkly pigmented skin eczema icthyosis 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. tients with the SHOC2 S2G mutation ized by left-axis deviation, an abnormal for any patient with HCM and may in- have a distinctive phenotype, initially R/S ratio over the left precordial leads, clude the use of ␤-blocker medications termed Noonan-like syndrome, with and an abnormal Q wave.67 Many pa- or surgical myomectomy to reduce loose anagen hair.61 In addition to the tients have mild PVS that requires only outflow obstruction.62 hair findings, the phenotype may include periodic reevaluation. If the PVS is or It is important for adults with NS to mitral valve and cardiac septal defects, becomes clinically significant, initial have lifetime cardiac follow-up. Left- GH deficiency, ectodermal abnormalities treatment is usually pulmonary bal- sided obstructive lesions may develop with darkly pigmented ichthyotic skin, loon valvuloplasty, but it may be unsuc- in adulthood.68 Pulmonary valve insuf- hypernasal voice, and developmental is- cessful if the valve is dysplastic. With ficiency and right ventricular dysfunc- 34 sues with hyperactivity. severe dysplasia, a pulmonary valvec- tion are potential problems after ear- In a study of 45 patients with NS, both tomy or pulmonary homograft may be lier pulmonary valve surgery. Cardiac bleeding diathesis and juvenile my- needed in childhood. The other cardiac arrhythmias have been rare in the lim- elomonocytic leukemia were found ex- defects can be treated in the standard ited reports available about long-term ways. clusively in patients with specific PTPN11 follow-up of adults.6,69 mutations.49 Familial cases of NS are HCM is present in ϳ20% of patients more likely than sporadic cases to be with NS overall but is particularly fre- GROWTH AND ENDOCRINE ISSUES caused by a PTPN11 mutation.42 NS at- quent with RAF1 mutations,31,32 and it is Growth tributable to KRAS mutations seems to variable in severity and natural his- confer a more severe phenotype with tory. In some infants with HCM the con- Approximately 50% to 70% of individu- more significant learning issues and de- dition resolves, whereas in others it als with NS have short stature.7,70,71 Al- velopmental delays.50 becomes rapidly progressive and may though short stature is a main charac- have a fatal outcome. Others develop teristic of this condition, some CARDIOVASCULAR ISSUES HCM after infancy. The course may be individuals will have normal growth More than 80% of patients with NS stable or progressive, or it may im- and stature. Birth weight and length have an abnormality of the cardiovas- prove. Management is similar to that are typically normal, but there is a sub- cular system.7,62–64 PVS is the most common. The valve may be dysplastic TABLE 5 Cardiac Conditions in NS in 25% to 35% of those with PVS64–66 and is often associated with an ASD. Frequent Occasional Rare Isolated ASDs and partial atrioventric- PVS Aortic valvular stenosis Pulmonary hypertension Secundum ASD Supravalvular pulmonary stenosis Aortic root dilation ular canal defects are also relatively HCM Bicuspid aortic valve Aortic dissection common. A broad spectrum of cardiac Partial atrioventricular Patent ductus arteriosus Restrictive cardiomyopathy abnormalities has been reported, as canal defect Branch pulmonary artery stenosis Dilated cardiomyopathy Mitral valve anomalies Ebstein’s anomaly of tricuspid valve noted in Table 5. Approximately 50% of Ventricular septal defect Pulmonary atresia patients with NS have an unusual elec- Tetralogy of Fallot Coronary artery abnormalities trocardiographic pattern character- Coarctation of aorta

752 ROMANO et al Downloaded from pediatrics.aappublications.org by guest on January 22, 2015 STATE-OF-THE-ART REVIEW ARTICLE sequent deceleration of height and These studies resulted in improved data from comparisons of adult weight to the third centile or less. The growth velocity without significant ad- heights for those treated with GH mean delay of bone age is ϳ2 years.7,72 verse effects.78–80,84–86 Although most among those who were PTPN11 NS-specific growth charts have been studies have excluded patients with mutation-positive with those who published.72,73 HCM, left ventricular wall thickness re- were mutation-negative revealed no Mean adult heights of European indi- mained normal when prospectively difference in outcome.90 Additional viduals with NS have been reported for measured in patients with NS on studies may clarify the role of the women as ϳ153.0 cm and for men as GH.76–78 In addition, among the com- different RAS/MAPK pathway ab- 162.5 and 169.8 cm.6,72 The mean adult bined 889 patients from 6 articles that errations in growth and GH height of North American individuals is reported adult-height outcomes in pa- responsiveness. less than the third centile in 54.5% of tients with NS on GH,84,88–92 there were women (Ͻ151 cm) and 38% of men only 5 reported cardiac events (2 mild Other Endocrine and Autoimmune (Ͻ163.2 cm).74,75 A higher prevalence progressions of PVS, 1 HCM, 1 in- Issues of short stature has been found in creased biventricular hypertrophy, Puberty is typically, but not universally, PTPN11 mutation-positive subjects and 1 cardiac decompensation). delayed for both boys and girls with NS than in mutation-negative subjects, The efficacy of GH in NS can be as- and is characterized by a diminished and a lower prevalence of short stat- sessed by considering adult-height pubertal growth spurt.72 The mean age ure has been described for those with data (Table 6).84,88–91 Although different of pubertal onset is 13.5 to 14.5 years SOS1-associated NS.50,51 parameters were reported in these in boys and 13 to 14 years in girls. Pu- Reports of GH-secretory dynamics studies (ie, median versus mean val- berty may progress with a rapid tempo have been inconsistent and are likely a ues, height SD scores based on popu- (Ͻ2 years).92 Pubertal induction may reflection of the genotypic heterogene- lation standards versus the NS- be instituted (with careful consider- ity of NS. There have been reports of specific standards, varied doses, etc), ation of timing for optimal height po- GH deficiency (45% [n ϭ 150]96 37% it seems that improved outcomes (⌬ tential) for no secondary sexual char- [n ϭ 27]77), neurosecretory dysfunc- height SD score: 1.3–1.7; mean height acteristics in boys at 14 years tion,78–80 and completely normal GH se- gain: 9.5–13 cm for boys and 9.0–9.8 (testosterone induction) and girls at cretion.81,82 Insulin-like growth factor 1 cm for girls89,90,92) occur with earlier 13 years (estrogen induction). levels are frequently low and were initiation and longer duration of GH Thyroid antibodies are commonly significantly lower in the PTPN11 therapy, as has been demonstrated for found, but hypothyroidism is likely no mutation-positive than mutation- other conditions such as Turner more common in those with NS than in negative patients.81–83 syndrome.93,94 the general population.7,95–97 There Until recently, most experience with GH Initial short-term data have sug- have been case reports of the occur- in NS has been reported in studies that gested that PTPN11-positive patients rence of other autoimmune condi- involved small numbers of patients responded “less efficiently” to GH tions, such as systemic lupus erythem- with varied enrollment ages, treat- than did the PTPN11-negative pa- atosus and celiac disease, but their ment durations, doses, and responses. tients.48 In contrast, longer-term frequency is unknown.98–100

TABLE 6 Baseline and Treatment Growth Data From Studies That Reported Adult-Height Outcomes in Individuals With NS Treated With GH Reference Patients, Baseline Age, y Baseline SDSa GH Dose, mg/kg per wk Duration Delta Height Gain n (n Female) Therapy, y Height SDS 88 4 (4) 13.5 (Ϫ0.6) 0.19 for 1 y, then 0.31 3.5 (0.48) NA 84 10 (4) 12 Ϫ3.1 (Ϫ0.7) 0.30 5.3 3.1 cm 89 18 (11) 8.6 (boys), 7.7 (girls) Ϫ2.9 (Ϫ0.3) 0.23 (n ϭ 10), 0.46 (n ϭ 15) for 7.5 1.7 13 cm (boys), 9.8 cm (girls) 2 y, then dose titrationb 91 24 (NA) 10.2 (median) Ϫ3.24 (median) 0.24 (median [range: 0.17–0.77]) 7.59 (median) 0.61 (0.97) NA 90 29 (8) 11 Ϫ2.8 (0.0) 0.35 6.4 (median) 1.3 (1.3) 9.5 cm (boys), 9.0 cm (girls) 92 65 (30) 11.6 Ϫ3.5 0.33 5.6 1.4 10.9 cm (boys) 9.2 cm (girls) Results are mean values unless speciﬁed 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.

PEDIATRICS Volume 126, Number 4, October 2010 753 Downloaded from pediatrics.aappublications.org by guest on January 22, 2015 RENAL AND GENITOURINARY ISSUES in patients with NS and can contribute abilities, an increased incidence of 105,108 Renal anomalies occur in 10% to 11% to bleeding risk. brain abnormalities, and a wide array of those with NS and are usually of lit- Both thrombocytopenia and platelet of other neurologic problems. In a tle significance.7,98,99 Solitary kidney, dysfunction have been described in pa- study of 151 subjects with NS, 76% had renal pelvis dilation, and duplicated tients with NS. The etiology of the feeding difficulties, 94% had ocular collecting system have been reported. thrombocytopenia is probably multi- problems, 50% had hypermobility of Cryptorchidism occurs in up to 80% of factorial and can be associated with a joints/hypotonia, 13% had recurrent boys, and surgical orchiopexy is re- defect in platelet production caused by seizures, 3% had hearing loss, and 3% 7 quired. Recent evidence suggests ser- a decrease in megakaryocytes.108 had peripheral neuropathy. There toli cell dysfunction101 rather than Splenomegaly may also cause mild-to- was also a general delay in the mean cryptorchidism as the etiology of male moderate thrombocytopenia and is age of motor milestones; sitting alone gonadal dysfunction. Fertility does not found by ultrasound in up to 52% of occurred at 10 months, walking oc- seem to be affected in women. patients with NS.109 Splenomegaly may curred at 21 months, and speaking be isolated or associated with hepato- 2-word sentences occurred at 31 HEMATOLOGY AND ONCOLOGY ISSUES megaly. In some patients, hepato- months.7 Another study revealed that splenomegaly or splenomegaly may be 84% had some type of neurologic Disordered bleeding has been re- caused by NS/myeloproliferative dis- problem.113 ported for 30% to 65% of individuals order (MPD). with NS.7,102 Although the symptoms Structural malformations and defor- are often mild, such as excessive NS/MPD is a condition seen in infants mations of the central nervous system bruising, epistaxis, or menorrhagia, with NS that is characterized by leuko- and spinal cord are found at relatively bleeding with surgical procedures cytosis with monocytosis, thrombocy- low frequency. The most common de- can be significant. A number of topenia, and hepatosplenomegaly. Al- fects are Arnold-Chiari malformation coagulation-factor deficiencies (iso- though the clinical picture of NS/MPD type I and hydrocephalus. The mean lated and combined), thrombocytope- resembles that of juvenile myelomono- head circumference is at the 50th per- nia, and platelet dysfunction have been cytic leukemia, infants with NS/MPD centile; however, some individuals described. Elevation of the activated seem to have a favorable prognosis. with NS can be microcephalic or 7 partial thromboplastin time is fre- Although some infants with NS/MPD macrocephalic. quent. Approximately 25% of individu- have been reported to develop aggres- Most people with NS have normal in- als with NS have partial factor XI defi- sive leukemia, the majority with this telligence, but 10% to 40% require ciency.102–107 The bleeding symptoms condition present in the first few special education.7,114,115 Even among do not correlate well with the degree months of life and will remain stable or those of normal intelligence, IQ has of deficiency. A number of other coag- improve by 1 year of age without spe- been shown to be 10 points less than 110,111 ulation factors can be depressed, and cific therapy. unaffected family members or 1 SD low factor XII and factor VIII activity are Despite the role of somatic PTPN11 and below that of the general popula- the next most frequent depres- KRAS mutations in the development of tion.114 The observed heterogeneity sions.105–107 It is important to note that malignancies, the incidence of cancer in cognitive abilities in syndromes of although factor XII deficiency can pro- in older children and adults with NS the Ras/MAPK signaling cascade in- long the activated partial thrombo- has not been shown to be increased cluding NS can be at least partially plastin time, it does not result in clini- over that of the general population.6,112 ascribed to the individual affected cal bleeding. Low factor VIII levels can However, additional studies are genes and the type of mutation.116 For be seen with von Willebrand disease, needed to accurately assess the risk of example, SOS1 mutations53,60,116 and which is a common bleeding disorder malignancy in individuals with NS. specific PTPN11 mutations42,60,116,117 in the general population; although have been associated with no or mild both low factor VIII and von Willebrand NEUROLOGIC, COGNITIVE, AND cognitive delays. factor have been reported in NS, an ac- BEHAVIORAL ISSUES Children with NS have a higher rate of curate estimate of the prevalence of The neurologic, cognitive, and behav- clumsiness, poor coordination, stub- von Willebrand disease in patients with ioral aspects of individuals with NS are bornness, and irritability.118 Body- NS has not yet been determined.105–107 poorly understood and extremely vari- image problems and poor self-esteem, Less commonly, factor IX and factor II able. There is an increased incidence depression, and social inadequacy have also been reported to be deficient of cognitive issues and learning dis- have been noted to occur in adults with

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NS.69 Limited data are available on the TABLE 7 Support Organizations for NS psychological and psychiatric charac- Organization Contact Information teristics of patients with NS. Psychiat- Noonan Syndrome Support Group Internet: www.noonansyndrome.org; telephone: 888-686-2224 or ric problems are rarely found, and 410-374-5245; address: PO Box 145, Upperco, MD 21155 Magic Foundation Internet: www.magicfoundation.org; telephone: 800-362-4423 or qualitative data in a study of 112 708-383-0808; Address: 6645 W North Ave, Oak Park, IL 60302 adults6 with NS revealed their report- NORD: National Organization for Internet: www.rarediseases.org; telephone: 203-744-0100; ing an inability to fit in but an overall Rare Disorders address: 55 Kenosia Ave, PO Box 1968, Danbury, CT good or satisfactory quality of life. In 06813-1968 Human Growth Foundation Internet: www.hgfound.org; telephone: 800-451-6434; address: addition, the majority of adults with NS 997 Glen Cove Ave, Suite 5, Glen Head, NY 11545 finished high school and had paying BDF Newlife Internet: www.bdfnewlife.co.uk; telephone: 01543 468888; jobs.6,69 address: Hemlock Business Park, Hemlock Way, Cannock, Staffordshire WS11 7GF, United Kingdom GASTROINTESTINAL AND FEEDING ISSUES LYMPHATIC ISSUES involved in the care of and research on Most infants (75%) with NS have feed- NS is associated with a generalized individuals with NS. Our goal was to ing difficulties; poor suck with pro- disorder of lymphatic development, provide the pediatrician with new in- longed feeding time (15%), very poor which has manifestations in fetal life formation and accrued experience to suck and slow feeding with recurrent through adulthood.128,129 The overall in- promote the correct diagnosis and vomiting (38%), and severe feeding cidence of lymphatic manifestations in best care of those with NS. Recognizing problems that require tube-feeding for all age groups of those with NS is un- that NS is a clinically and genetically Ն 2 weeks (24%) have been de- known, but it is estimated to be ϳ20%. heterogeneous condition character- 6,7 scribed. Investigation of some chil- Peripheral lymphedema, the most ized by congenital heart disease, dis- dren with poor feeding has revealed common lymphatic manifestation, is tinct facial features, short stature, and immaturity of gut motility and delayed seen most frequently in young infants. many other potential comorbidities, 119 gastrointestinal motor development. It typically resolves in the first few patients do require multidisciplinary Gastroesophageal reflux is common, years. Adolescents and adults can de- evaluations and regular follow-up care and there have been a few reports of velop peripheral lymphedema.130 for their identified issues. Certainly, malrotation.109,120 Typically, the period many questions remain unanswered Other types of lymphatic involvement of failure to thrive is self-limited, al- regarding the optimal care of these in- that have been described in patients though poor weight gain may persist dividuals not only in childhood but with NS include hydrops, chylous pleu- for up to 18 months. throughout adulthood. Therefore, it is ral effusions, chylothorax, pulmonary important to recognize that the recom- lymphangiectasis, intestinal lymphan- ORAL AND DENTAL ISSUES mendations in this report are based on giectasia, hypoplastic leg lymphatics, Oral findings in patients with NS in- the authors’ best judgments and the anomalous lymphatic vessels in the clude a high arched palate (55%– current available medical knowledge. thoracic cage and aplasia or absence 100%),37,72,121 dental malocclusion of the thoracic duct, hypoplastic in- (50%–67%),6,120–123 articulation diffi- ACKNOWLEDGMENTS guinal and iliac lymphatic vessels, culties (72%),71 and micrognathia This article was developed through a (33%–43%). Some individuals with NS and testicular lymphangiectasis. conference organized by the Noonan develop mandibular cysts, which can Management of these conditions can Syndrome Support Group. The funding be difficult.131,132 mimic cherubism.124,125 The pathology for the conference was provided by an of these lesions in individuals with NS A discussion of malignant hyperther- independent medical education grant is characterized by multinucleated gi- mia in patients with NS is provided in from Novo Nordisk, Inc to the Noonan ant cells within a fibrous stroma and is Supplemental Information.133–137 Syndrome Support Group. Representa- indistinguishable from cherubism. Table 7 lists support organizations tives from Novo Nordisk, Inc did not par- These 2 conditions, however, are ge- that may serve as additional resources ticipate in any scientific deliberations, netically distinct; SH3BP2 gene muta- regarding NS. did not contribute to the content of this tions are found in individuals with report, and did not review or comment cherubism, whereas PTPN11126 and CONCLUSIONS on this report before publication. SOS1127 mutations are found in pa- These guidelines were developed from We thank Dr Mignon Loh for helpful dis- tients with NS with giant cell lesions. an interdisciplinary meeting of experts cussion about NS/MPD.

PEDIATRICS Volume 126, Number 4, October 2010 755 Downloaded from pediatrics.aappublications.org by guest on January 22, 2015 REFERENCES

1. Noonan JA, Ehmke DA. Associated noncar- 18. Duncan WJ, Fowler RS, Farkas LG, et al. A vere Noonan syndrome phenotype. Am J diac malformations in children with con- comprehensive scoring system for evalu- Hum Genet. 2006;79(1):129–135 genital heart disease. J Pediatr. 1963;31: ating Noonan syndrome. Am J Med Genet. 31. Pandit B, Sarkozy A, Pennacchio LA, et al. 150–153 1981;10(1):37–50 Gain-of-function RAF1 mutations cause 2. Noonan JA. Hypertelorism with Turner 19. van der Burgt I, Berends E, Lommen E, van Noonan and LEOPARD syndromes with hy- phenotype. Am J Dis Child. 1968;116(4): Beersum S, Hamel B, Mariman E. Clinical pertrophic cardiomyopathy. Nat Genet. 373–380 and molecular studies in a large Dutch 2007;39(8):1007–1012 3. Opitz JM. The Noonan syndrome. Am J Med family with Noonan syndrome. Am J Med 32. Razzaque MA, Nishizawa T, Komoike Y, et al. Genet. 1985;21(3):515–518 Genet. 1994;53(2):187–191 Germline gain-of-function mutations in 4. Allanson JE, Hall JG, Hughes HE, Preus M, 20. Jamieson CR, van der Burgt I, Brady AF, et RAF1 cause Noonan syndrome. Nat Genet. Witt RD. Noonan syndrome: the changing al. Mapping a gene for Noonan syndrome 2007;39(8):1013–1017 phenotype. Am J Med Genet. 1985;21(3): to the long arm of chromosome 12. Nat 33. Roberts AE, Araki T, Swanson KD, et al. 507–514 Genet. 1994;8(4):357–360 Germline gain-of-function mutations in 5. Allanson JE. Noonan syndrome. J Med 21. Tartaglia M, Mehler EL, Goldberg R, et al. SOS1 cause Noonan syndrome. Nat Genet. Genet. 1987;24(1):9–13 Mutations in PTPN11, encoding the protein 2007;39(1):70–74 6. Shaw AC, Kalidas K, Crosby AH, Jeffery S, tyrosine phosphatase SHP-2, cause 34. Cordeddu V, Di Schiavi E, Pennacchio LA, et Patton MA. The natural history of Noonan Noonan syndrome. Nat Genet. 2001;29(4): al. Mutation of SHOC2 promotes aberrant syndrome: a long-term follow-up study. 465–468 protein N-myristoylation and causes Arch Dis Child. 2007;92(2):128–132 22. Chen B, Bronson RT, Klaman LD, et al. Mice Noonan-like syndrome with loose anagen hair. Nat Genet. 2009;41(9):1022–1026 7. Sharland M, Burch M, McKenna WM, Pat- mutant for Egfr and Shp2 have defective ton MA. A clinical study of Noonan syn- cardiac semilunar valvulogenesis. Nat 35. Cirstea IC, Kutsche K, Dvorsky R, et al. A drome. Arch Dis Child. 1992;67(2):178–183 Genet. 2000;24(3):296–299 restricted spectrum of NRAS mutations cause Noonan syndrome. Nat Genet. 2010; 8. Loscalzo ML. Turner syndrome. Pediatr 23. Ion A, Tartaglia M, Song X, et al. Absence of 42(1):27–29 Rev. 2008;29(7):219–227 PTPN11 mutations in 28 cases of cardiofa- 9. Roberts A, Allanson J, Jadico SK, et al. The ciocutaneous (CFC) syndrome. Hum Genet. 36. Caballín MR, Miró R, Egozcue J. Abnormal cardiofaciocutaneous syndrome. J Med 2002;111(4–5):421–427 phenotype in a child with the same bal- Genet. 2006;43(11):833–842 anced translocation (5;7)(p15;q22) as his 24. Kavamura MI, Pomponi MG, Zollino M, et al. father. Clin Genet. 1981;20(6):428–431 10. Niihori T, Aoki Y, Narumi Y, et al. Germline PTPN11 mutations are not responsible for 37. Chery M, Philippe C, Worms AM, Gilgen- KRAS and BRAF mutations in cardio-facio- the cardiofaciocutaneous (CFC) syn- krantz S. The Noonan syndrome: the Nancy cutaneous syndrome. Nat Genet. 2006; drome. Eur J Hum Genet. 2003;11(1): experience revisited. Genet Couns. 1993; 38(3):294–296 64–68 11. Rodriguez-Viciana P, Tetsu O, Tidyman WE, 4(2):113–118 25. Tartaglia M, Cotter PD, Zampino G, Gelb BD, et al. Germline mutations in genes within 38. Legius E, Wlodarska I, Selleri L, et al. De Rauen KA. Exclusion of PTPN11 mutations the MAPK pathway cause cardio-facio- novo 46,XX, dir dup (11)(q133.3¡q14.2) in in Costello syndrome: further evidence for cutaneous syndrome. Science. 2006; a patient with mental retardation, congen- distinct genetic etiologies of Noonan, 311(5765):1287–1290 ital cardiopathy and thrombopenia. Clin cardio-facio-cutaneous, and Costello syn- Genet. 1996;49(4):206–210 12. Schubbert S, Zenker M, Rowe SL, et al. dromes. Clin Genet. 2003;63(5):423–426 Germline KRAS mutations cause Noonan 39. Onufer CN, Stephan MJ, Thuline HC, Char F. 26. Tröger B, Kutsche K, Bolz H, et al. No muta- syndrome. Nat Genet. 2006;38(3):331–336 Chromosome 13 long arm interstitial dele- tion in the gene for Noonan syndrome, 13. Kavamura MI, Peres CA, Alchorne MMA, tion associated with features of Noonan PTPN11, in 18 patients with Costello syn- Brunoni D. CFC index for the diagnosis of phenotype. Ann Genet. 1987;30(4):236–239 drome. Am J Med Genet. 2003;121A(1): cardiofaciocutaneous syndrome. Am J 40. Shchelochkov OA, Patel A, Weissenberger 82–84 Med Genet. 2002;112(1):12–16 GM, et al. Duplication of chromosome band 27. Digilio MC, Conti E, Sarkozy A, et al. Group- 14. Hennekam RC. Costello syndrome: an over- 12q24.11q24.23 results in apparent ing of multiple-Lentigines/LEOPARD and view. Am J Med Genet C Semin Med Genet. Noonan syndrome. Am J Med Genet A. 2003;117C(1):42–48 Noonan syndromes on the PTPN11 gene. 2008;146A(8):1042–1048 Am J Hum Genet. 2002;71(2):389–394 15. Reddy P, Kharbanda OP, Kabra M, Duggal R. 41. Tonoki H, Saitoh S, Kobayashi K. Patient Dental and craniofacial features of Aars- 28. Legius E, Schrander-Stumpel C, Schollen E, with del(12)(q12q13.12) manifesting ab- kog syndrome: report of a case and review Pulles-Heintzberger C, Gewillig M, Fryns normalities compatible with Noonan syn- of literature. J Clin Pediatr Dent. 1999; JP. PTPN11 mutations in LEOPARD syndrome. Am J Med Genet. 1998;75(4): 23(2):155–159 drome. J Med Genet. 2002;39(8):571–574 416–418 16. Florez L, Lacassie Y. Mosaic trisomy 22: re- 29. Aoki Y, Niihori T, Kawame H, et al. Germline 42. Tartaglia M, Kalidas K, Shaw A, et al. port of a patient with normal intelligence. mutations in HRAS proto-oncogene cause PTPN11 mutations in Noonan syndrome: Am J Med Genet A. 2005;132A(2):223–225 Costello syndrome. Nat Genet. 2005;37(10): molecular spectrum, genotype-phenotype 17. Ganesh A, Al-Kindi A, Jain R, Raeburn S. The 1038–1040 correlation, and phenotypic heterogene- phenotypic spectrum of Baraitser-Winter 30. Carta C, Pantaleoni F, Bocchinfuso G, et al. ity. Am J Hum Genet. 2002;70(6):1555–1563 syndrome: a new case and review of liter- Germline missense mutations affecting 43. Bertola DR, Pereira AC, Albano LM, De Ol- ature. J AAPOS. 2005;9(6):604–606 KRAS isoform B are associated with a se- iveira PS, Kim CA, Krieger JE. PTPN11 gene

756 ROMANO et al Downloaded from pediatrics.aappublications.org by guest on January 22, 2015 STATE-OF-THE-ART REVIEW ARTICLE

analysis in 74 Brazilian patients with and cardiofaciocutaneous syndromes: 67. Raaijmakers R, Noordam C, Noonan JA, Noonan syndrome or Noonan-like pheno- molecular diversity and associated pheno- Croonen EA, van der Burgt CJ, Draaisma type. Genet Test. 2006;10(3):186–191 typic spectrum. Hum Mutat. 2009;30(4): JM. Are ECG abnormalities in Noonan syn- 44. Ferrero GB, Baldassarre G, Delmonaco AG, 695–702 drome characteristic for the syndrome? et al. Clinical and molecular characteriza- 56. Lee K, Williams B, Roza K, et al. PTPN11 Eur J Pediatr. 2008;167(12):1363–1367 tion of 40 patients with Noonan syndrome. analysis for the prenatal diagnosis of 68. Danetz JS, Donofrio MT, Embrey RP. Multi- Eur J Med Genet. 2008;51(6):566–572 Noonan syndrome in fetuses with abnor- ple left-sided cardiac lesions in one of 45. Hung CS, Lin JL, Lee YJ, Lin SP, Chao MC, Lo mal ultrasound findings. Clin Genet. 2009; Noonan’s original patients. Cardiol Young. FS. Mutational analysis of PTPN11 gene in 75(2):190–194 1999;9(6):610–612 Taiwanese children with Noonan syn- 57. Levaillant JM, Gerard-Blanluet M, Holder- 69. Noonan JA. Noonan syndrome. In: Gold- drome. J Formos Med Assoc. 2007;106(2): Espinasse M, et al. Prenatal phenotypic stein S, Reynolds CR, eds. Handbook of 169–172 overlap of Costello syndrome and severe Neurodevelopmental and Genetic Disor- 46. Jongmans M, Sistermans EA, Rikken A, et Noonan syndrome by tri-dimensional ul- ders in Adults. New York, NY: Guilford al. Genotypic and phenotypic characteriza- trasonography. Prenat Diagn. 2006;26(4): Press; 2005:308–319 tion of Noonan syndrome: new data and 340–344 70. Mendez HMM, Opitz JM. Noonan syndrome: review of the literature. Am J Med Genet A. 58. Schlüter G, Steckel M, Schiffmann H, et al. a review. Am J Med Genet. 1985;21(3): 2005;134A(2):165–170 Prenatal DNA diagnosis of Noonan syn- 493–506 drome in a fetus with massive hygroma 47. Musante L, Kehl HG, Majewski F, et al. Spec- 71. Nora JJ, Nora AH, Sinha AK, Spangler RD, colli, pleural effusion and ascites. Prenat trum of mutations in PTPN11 and Lubs HA. The Ullrich-Noonan syndrome Diagn. 2005;25(7):574–576 genotype-phenotype correlation in 96 pa- (Turner phenotype). Am J Dis Child. 1974; tients with Noonan syndrome and five pa- 59. Jongmans M, Otten B, Noordam K, van der 127(1):48–55 tients with cardio-facio-cutaneous syn- Burgt I. Genetics and variation in pheno- 72. Ranke MB, Heidemann P, Kunpfer C, End- drome. Eur J Hum Genet. 2003;11(2): type in Noonan syndrome. Horm Res. 2004; ers H, Schmaltz AA, Bierich JR. Noonan 201–206 62(suppl 3):56–59 syndrome: growth and clinical manifesta- 48. Sarkozy A, Conti E, Seripa D, et al. Correla- 60. Pierpont EI, Pierpont ME, Mendelsohn NJ, tions in 144 cases. Eur J Pediatr. 1988; tion between PTPN11 gene mutations and Roberts AE, Tworog-Dube E, Seidenberg 148(3):220–227 congenital heart defects in Noonan and MS. Genotype differences in cognitive 73. Witt DR, Kenna BA, Hall JG, Allanson JE. LEOPARD syndromes. J Med Genet. 2003; functioning in Noonan syndrome. Genes Growth curves for height in Noonan syn- 40(9):704–708 Brain Behav. 2009;8(3):275–282 drome. Clin Genet. 1986;30(3):150–153 49. Yoshida R, Hasegawa T, Hasegawa Y, et al. 61. Mazzanti L, Cacciari E, Cicognani A, Berga- 74. Noonan JA, Raaijmakers R, Hall BD. Adult Protein-tyrosine phosphatase, nonrecep- maschi R, Scarano E, Forabosco A. tor type 11 mutation analysis and clinical Noonan-like syndrome with loose anagen height in Noonan syndrome. Am J Med assessment in 45 patients with Noonan hair: a new syndrome? Am J Med Genet A. Genet. 2003;123A(1):68–71 syndrome. J Clin Endocrinol Metab. 2004; 2003;118A(3):279–286 75. Kuczmarski RJ, Ogden CL, Guo SS, et al. CDC 89(7):3359–3364 62. Noonan JA. Noonan syndrome and related growth charts for the United States: meth- 50. Zenker M, Buheitel G, Rauch R, et al. disorders. Prog Pediatr Cardiol. 2005; ods and development. Vital Health Stat 11. Genotype-phenotype correlations in 20(2):177–185 2002;(246):1–190 Noonan syndrome. J Pediatr. 2004;144(3): 63. Marino B, Diglio MC, Toscano A, Giannotti A, 76. Romano AA, Blethen SL, Dana K, Noto R. 368–374 Dallapiccola B. Congenital heart diseases Growth hormone treatment in Noonan 51. Ko JM, Kim JM, Kim GH, Yoo HW. PTPN11, in children with Noonan syndrome: an ex- syndrome: the National Cooperative SOS1, KRAS, and RAF1 gene analysis, and panded cardiac spectrum with high prev- Growth Study experience. J Pediatr. 1996; genotype-phenotype correlation in Korean alence of atrioventricular canal. J Pediatr. 128(5 pt 2):S18–S21 patients with Noonan syndrome. J Hum 1999;135(6):703–706 77. Cotterill AM, McKenna WJ, Brady AF, et al. Genet. 2008;53(11–12):999–1006 64. Burch M, Sharland M, Shinebourne E, The short term effects of growth hormone 52. Zenker M, Lehmann K, Schulz AL, et al. Ex- Smith G, Patton MA, McKenna WJ. Cardio- therapy on height velocity and cardiac ven- pansion of the genotypic and phenotypic logic abnormalities in Noonan syndrome: tricular wall thickness in children with spectrum in patients with KRAS germline phenotypic diagnosis and echocardio- Noonan’s syndrome. J Clin Endocrinol mutations. J Med Genet. 2007;44(2): graphic assessment of 118 patients. JAm Metab. 1996;81(6):2291–2297 131–135 Coll Cardiol. 1993;22(4):1189–1192 78. Ahmed ML, Foot AB, Edge JA, Lamkin VA, 53. Tartaglia M, Pennacchio LA, Zhao C, et al. 65. Ishizawa A, Oho S, Dodo H, Katori T, Homma Savage MO, Dunger DB. Noonan’s Gain-of-function SOS1 mutations cause a S. Cardiovascular abnormalities in syndrome: abnormalities of the growth distinctive form of Noonan syndrome. Nat Noonan syndrome: the clinical findings hormone/IGF-1 axis and the response to Genet. 2007;39(1):75–79 and treatments. Acta Paediatr Jpn. 1996; treatment with human biosynthetic 54. Zenker M, Horn D, Wieczorek D, et al. SOS1 38(1):84–90 growth hormone. Acta Paediatr Scand. is the second most common Noonan gene 66. Sznajer Y, Keren B, Baumann C, et al. The 1991;80(4):446–450 but plays no major role in cardio-facio- spectrum of cardiac anomalies in Noonan 79. Noordam C, van der Burgt I, Sweep CG, cutaneous syndrome. J Med Genet. 2007; syndrome as a result of mutations in Delemarre-van de Waal HA, Sengers RC, Ot- 44(10):651–656 the PTPN11 gene. Pediatrics. 2007;119(6). ten BJ. Growth hormone (GH) secretion in 55. Sarkozy A, Carta C, Moretti S, et al. Germ- Available at: http://www.pediatrics.org/ children with Noonan syndrome: fre- line BRAF mutations in Noonan, LEOPARD, cgi/content/full/119/6/e1325 quently abnormal without consequences

PEDIATRICS Volume 126, Number 4, October 2010 757 Downloaded from pediatrics.aappublications.org by guest on January 22, 2015 for growth or response to GH treatment. 91. Raaijmakers R, Noordam C, Karagiannis G, ciency. Am J Med Genet. 1988;29(2): Clin Endocrinol (Oxf). 2001;54(1):53–59 et al. Response to growth hormone treat- 277–282 80. Tanaka K, Sato A, Naito T, Kuramochi K, Ita- ment and final height in Noonan syndrome 105. Bertola DR, Carneiro JD, D’Amico EA, et al. bashi H, Takemura Y. Noonan syndrome in a large cohort of patients in the KIGS Hematological findings in Noonan syn- presenting growth hormone neurosecre- database. J Pediatr Endocrinol Metab. drome. Rev Hosp Clin Fac Med Sao Paulo. tory dysfunction. Intern Med. 1992;31(7): 2008;21(3):267–273 2003;58(1):5–8 908–911 92. Romano AA, Dana K, Bakker B, et al. Growth 106. Massarano AA, Wood A, Tait RC, Stevens R, 81. Limal JM, Parfait B, Cabrol S, et al. Noonan response, near-adult height, and patterns Super M. Noonan syndrome: coagulation syndrome: relationships between geno- of growth and puberty in patients with and clinical aspects. Acta Paediatr. 1996; type, growth, and growth factors. J Clin Noonan syndrome treated with growth 85(10):1181–1185 Endocrinol Metab. 2006;91(1):300–306 hormone. J Clin Endocrinol Metab. 2009; 107. Sharland M, Patton MA, Talbot S, Chitolie A, 94(7):2338–2344 82. Ferreira LV, Souza SA, Arnhold IJ, Men- Bevan DH. Coagulation-factor deficiencies donca BB, Jorge AA. PTPN 11 (protein ty- 93. Reiter EO, Blethen SL, Baptista J, Price L. and abnormal bleeding in Noonan’s syn- rosine phosphatase, nonreceptor type 11) Early initiation of growth hormone treat- drome. Lancet. 1992;339(8784):19–21 mutations and response to growth hor- ment allows age appropriate estrogen use 108. Singer ST, Hurst D, Addiego JE Jr. Bleeding mone therapy in children with Noonan syn- in Turner’s syndrome. J Clin Endocrinol disorders in Noonan syndrome: three case drome. J Clin Endocrinol Metab. 2005; Metab. 2001;86(5):1936–1941 reports and review of the literature. J Pe- 90(9):5156–5160 94. Bechtold S, Dalla Pozza R, Schmidt H, Bon- diatr Hematol Oncol. 1997;19(2):130–134 83. Binder G, Neuer K, Ranke MB, Wittekindt fig W, Schwarz HP. Pubertal height gain in 109. George CD, Patton MA, el Sawi M, Sharland NE. PTPN11 mutations are associated with Ullrich-Turner syndrome. J Pediatr Endo- M, Adam EJ. Abdominal ultrasound in mild growth hormone resistance in indi- crinol Metab. 2006;19(8):987–993 Noonan syndrome: a study of 44 patients. viduals with Noonan syndrome. J Clin En- 95. Vesterhus P, Aarskog D. Noonan’s syn- Pediatr Radiol. 1993;23(4):316–318 docrinol Metab. 2005;90(9):5377–5381 drome and autoimmune thyroiditis. J Pe- 110. Kratz CP, Niemeyer CM, Castleberry RP, et 84. Kirk JMW, Betts PR, Butler GE, et al; UK KIGS diatr. 1973;83(2):237–240 al. The mutational spectrum of PTPN11 in Executive Group on Behalf of the Partici- 96. Allanson JE. Noonan syndrome. Am J Med juvenile myelomonocytic leukemia and pating Centres. Short stature in Noonan Genet C Semin Med Genet. 2007;145C(3): Noonan syndrome/myeloproliferative dis- syndrome: response to growth hormone 274–279 ease. Blood. 2005;106(6):2183–2185 therapy. Arch Dis Child. 2001;84(5): 97. Svensson J, Carlsson A, Ericsson UB, West- 111. Choong K, Freedman MH, Chitayat D, Kelly 440–443 phal O, Ivarsson SA. Noonan’s syndrome EN, Taylor G, Zipursky A. Juvenile my- 85. MacFarlane CE, Brown DC, Johnston LB, et and autoimmune diseases. J Pediatr Endo- elomonocytic leukemia and Noonan syn- al. Growth hormone therapy and growth in crinol Metab. 2003;16(2):217–218 drome. J Pediatr Hematol Oncol. 1999; children with Noonan’s syndrome: results 98. Alanay Y, Balci S, Ozen S. Noonan syndrome 21(6):523–527 of 3 years’ follow-up. J Clin Endocrinol and systemic lupus erythematosus: pre- 112. Merks JH, Caron HN, Hennekam RC. High Metab. 2001;86(5):1953–1956 sentation in childhood. Clin Dysmorphol. incidence of malformation syndromes in a 86. Ogawa M, Moriya N, Ikeda H, et al. Clinical 2004;13(3):161–163 series of 1,073 children with cancer. Am J evaluation of recombinant human growth 99. Lopez-Rangel E, Malleson PN, Lirenman DS, Med Genet A. 2005;134A(2):132–143 hormone in Noonan syndrome. Endocr J. Roa B, Wiszniewska J, Lewis ME. Systemic 113. Duenas DA, Preissig S, Summitt RL, Wilroy 2004;51(1):61–68 lupus erythematosus and other autoim- RS, Lemmi H, Dews JE. Neurologic manifes- 87. Noordam C, Draaisma JM, van den Nieu- mune disorders in children with Noonan tations of Noonan syndrome. South Med J. wenhof J, van der Burgt I, Otten BJ, Daniels syndrome. Am J Med Genet A. 2005;139(3): 1973;66(2):193–196 O. Effects of growth hormone treatment on 239–242 114. van der Burgt I, Thoonen G, Roosenboom N, left ventricular dimensions in children 100. Amoroso A, Garzia P, Vadacca M, et al. The et al. Patterns of cognitive functioning in with Noonan’s syndrome. Horm Res. 2001; unusual association of three autoimmune school-aged children with Noonan syn- 56(3–4):110–113 diseases in a patient with Noonan syndrome associated with variability in phe- 88. Municchi G, Pasquino AM, Pucarelli I, Cian- drome. J Adolesc Health. 2003;32(1):94–97 notypic expression. J Pediatr. 1999;135(6): farani S, Passeri F. Growth hormone treat- 101. Marcus KA, Sweep CG, van der Burgt I, 707–713 ment in Noonan syndrome: report of four Noordam C. Impaired Sertoli cell function 115. Lee DA, Portnoy S, Hill P, Patton MA. Psyco- cases who reached final height. Horm Res. in males diagnosed with Noonan syn- logical profile of children with Noonan syn- 1995;44(4):164–167 drome. J Pediatr Endocrinol Metab. 2008; drome. Dev Med Child Neurol. 2005;47(1): 89. Osio D, Dahlgren J, Wikland KA, Westphal O. 21(11):1079–1084 35–38 Improved final height with long term 102. Witt DR, McGillivray BC, Allanson JE, et al. 116. Cesarini L, Alfieri A, Pantaleoni F, et al. Cog- growth hormone treatment in Noonan syn- Bleeding diathesis in Noonan syndrome: a nitive profile of disorders associated with drome. Acta Paediatr. 2005;94(9): common association. Am J Med Genet. dysregulation of the RAS/MAPK signaling 1232–1237 1988;31(2):305–317 cascade. Am J Med Genet A. 2009;149A(2): 90. Noordam K, Peer N, Francois I, DeSchepper 103. Kitchens CS, Alexander JA. Partial defi- 140–146 J, Burgt I, Otten B. Long term growth hor- ciency of coagulation factor XI as a newly 117. Jongmans M, Sistermans E, Rikken A, et al. mone treatment improves adult height in recognized feature of Noonan syndrome. J Genotypic and phenotypic characteriza- children with Noonan syndrome with and Pediatr. 1983;102(2):224–227 tion of Noonan syndrome: New data and without mutations in PTPN 11. Eur J Endo- 104. de Haan M, vd Kamp JJ, Briet E, Dubbeldam review of the literature. Am J Med Genet. crinol. 2008;159(3):203–208 J. Noonan syndrome: partial factor XI defi- 2005;134A(2):165–170

758 ROMANO et al Downloaded from pediatrics.aappublications.org by guest on January 22, 2015 STATE-OF-THE-ART REVIEW ARTICLE

118. Wood A, Massarano A, Super M, Harrington 126. Lee JS, Tartaglia M, Gelb BD, et al. Pheno- malignant hyperthermia. Lancet. 1972; R. Behavioral aspects and psychiatric find- typic and genotypic characterisation of 2(7773):383 ings in Noonan syndrome. Arch Dis Child. Noonan- like/multiple giant cell lesion syn- 135. Hunter A, Pinsky L. An evaluation of the pos- 1995;72(2):153–155 drome. J Med Genet. 2005;42(2):e11 sible association of malignant hyperpyr- 119. Shah N, Rodriguez M, St Louis D, Lindley K, 127. Neumann TE, Allanson J, Kavamura I, et al. exia with the Noonan syndrome using se- Milla PJ. Feeding difficulties and foregut Multiple giant cell lesions in patients with rum creatine phosphokinase levels. J dysmotility in Noonan’s syndrome. Arch Noonan syndrome and cardio-facio- Pediatr. 1975;86(3):412–415 Dis Child. 1999;81(1):28–31 cutaneous syndrome. Eur J Hum Genet. 136. de Boode WP, Semmekrot BA, ter Laak HJ, 120. Ahmed S, Patel RG. Intramural jejunal 2009;17(4):420–425 et al. Myopathology in patients with a haematoma after peroral mucosal biopsy 128. Witt DR, Hoyme HE, Zonana J, et al. Noonan phenotype. Acta Neuropathol in a child with intestinal malrotation. Arch Lymphedema in Noonan syndrome: clues (Berl). 1996;92(6):597–602 Dis Child. 1971;46(249):723–724 to pathogenesis and prenatal diagnosis 137. van der Burgt I, Kupsky W, Stassou S, et al. 121. Collins E, Turner G. The Noonan syndrome: and review of the literature. Am J Med Myopathy caused by HRAS germline a review of the clinical and genetic fea- Genet. 1987;27(4):841–856 mutations: implications for disturbed tures in 27 cases. J Pediatr. 1973;83(6): 129. Bloomfield FH, Hadden W, Gunn TR. Lym- myogenic differentiation in the presence 941–950 phatic dysplasia in a neonate with Noon- of constitutive HRas activation. J Med 122. Horowitz SL, Morishima A. Palatal abnor- an’s syndrome. Pediatr Radiol. 1997;27(4): Genet. 2007;44(7):459–462 malities in the syndrome of gonadal dys- 321–323 genesis and its variants and in Noonan 138. Nava C, Hanna N, Michot C, et al. Cardio- 130. Miller M, Motulsky AC. Noonan syndrome syndrome. Oral Surg. 1974;38(6):839–844 facio-cutaneous and Noonan syndromes in a adult family presenting with chronic due to mutations in the RAS/MAPK sig- 123. Wilroy RS Jr, Summitt RL, Tipton RE, Primm lymphedema. Am J Med. 1978;65(2): naling pathway: genotype-phenotype re- PA, Martens PR. Phenotypic heterogeneity 379–383 lationships and overlap with Costello in the Noonan syndrome. Birth Defects. 131. Goens MB, Campbell D, Wiggins JW. Spon- 1979;15(5B):305–311 syndrome. J Med Genet. 2007;44(12): taneous chylothorax in Noonan syndrome: 763–771 124. Jafarov T, Ferimazova N, Reichenberger E. treatment with prednisone. Am J Dis Child. Noonan-like syndrome mutations in 139. Sharland M, Taylor R, Patton MA, Jeffery S. 1992;146(12):1453–1456 PTPN11 in patients diagnosed with Absence of linkage of Noonan syndrome to cherubism. Clin Genet. 2005;68(2): 132. Pardo JM, Chua C. Spontaneous chylotho- the neurofibromatosis type 1 locus. J Med 190–191 rax in a male newborn with Noonan syn- Genet. 1992;29(3):188–190 drome. Int Pediatr. 1994;9(1):55–58 125. Bertola DR, Kim CA, Pereira AC, et al. Are 140. Flintoff WF, Bahuau M, Lyonnet S, et al. No Noonan syndrome and Noonan-like/ 133. King JO, Denborough MA, Zapf PW. Inheri- evidence for linkage to the type 1 or type 2 multiple giant cell lesion syndrome distance of malignant hyperpyrexia. Lancet. neurofibromatosis loci in Noonan syn- tinct entities? Am J Med Genet. 2001;98(3): 1972;1(7746):365–370 drome families. Am J Med Genet. 1993; 230–234 134. Pinsky L. The XX-XY Turner phenotype and 46(6):700–705

(Continued from ﬁrst 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 speaker’s bureaus of both companies; Dr Dahlgren received grants in 2008 from Novo Nordisk, Inc for genetic analysis of individuals with NS; Dr Gelb currently has SOS1, RAF1, and SHOC2 gene patents pending and receives royalties for PTPN11 mutation testing from GeneDx, Correlegan, Prevention Genetics, Baylor College of Medicine, and Harvard Partners; and Dr Roberts currently has an SOS1 gene patent pending. The other authors have indicated they have no ﬁnancial relationships relevant to this article to disclose.

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Noonan Syndrome: Clinical Features, Diagnosis, and Management Guidelines Alicia A. Romano, Judith E. Allanson, Jovanna Dahlgren, Bruce D. Gelb, Bryan Hall, Mary Ella Pierpont, Amy E. Roberts, Wanda Robinson, Clifford M. Takemoto and Jacqueline A. Noonan Pediatrics 2010;126;746; originally published online September 27, 2010; DOI: 10.1542/peds.2009-3207 Updated Information & including high resolution figures, can be found at: Services http://pediatrics.aappublications.org/content/126/4/746.full.ht ml Supplementary Material Supplementary material can be found at: http://pediatrics.aappublications.org/content/suppl/2010/09/15 /peds.2009-3207.DC1.html References This article cites 137 articles, 20 of which can be accessed free at: http://pediatrics.aappublications.org/content/126/4/746.full.ht ml#ref-list-1 Citations This article has been cited by 21 HighWire-hosted articles: http://pediatrics.aappublications.org/content/126/4/746.full.ht ml#related-urls Subspecialty Collections This article, along with others on similar topics, appears in the following collection(s): Genetics http://pediatrics.aappublications.org/cgi/collection/genetics_s ub Permissions & Licensing Information about reproducing this article in parts (figures, tables) or in its entirety can be found online at: http://pediatrics.aappublications.org/site/misc/Permissions.xht ml Reprints Information about ordering reprints can be found online: http://pediatrics.aappublications.org/site/misc/reprints.xhtml

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