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Noonan Syndrome: Clinical Features, Diagnosis, and Management Guidelines

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Noonan Syndrome: Clinical Features, Diagnosis, and Management Guidelines Noonan Syndrome: Clinical Features, Diagnosis, and Management Guidelines 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) 746 ROMANO et al Downloaded from pediatrics.aappublications.org by guest on January 22, 2015 STATE-OF-THE-ART REVIEW ARTICLE 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
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