Noonan syndrome (NS) is an autosomal dominant disorder characterized by short stature, facial dysmorphism, and a wide spectrum of congenital heart defects. The distinctive facial features consist of a broad forehead, hypertelorism, downslanting palpebral fissures, a high-arched palate, ... Noonan syndrome (NS) is an autosomal dominant disorder characterized by short stature, facial dysmorphism, and a wide spectrum of congenital heart defects. The distinctive facial features consist of a broad forehead, hypertelorism, downslanting palpebral fissures, a high-arched palate, and low-set, posteriorly rotated ears. Cardiac involvement is present in up to 90% of patients. Pulmonic stenosis and hypertrophic cardiomyopathy are the most common forms of cardiac disease, but a variety of other lesions are also observed. Additional relatively frequent features include multiple skeletal defects (chest and spine deformities), webbed neck, mental retardation, cryptorchidism, and bleeding diathesis (summary by Tartaglia et al., 2002). - Genetic Heterogeneity of Noonan Syndrome See also NS3 (609942), caused by mutation in the KRAS gene (190070); NS4 (610733), caused by mutation in the SOS1 gene (182530); NS5 (611553), caused by mutation in the RAF1 gene (164760); NS6 (613224), caused by mutation in the NRAS gene (164790); NS7 (613706), caused by mutation in the BRAF gene (164757); and NS8 (615355), caused by mutation in the RIT1 gene (609591). See also NS2 (605275) for a possible autosomal recessive form of NS; Noonan syndrome-like disorder with loose anagen hair (NSLH; 607721), caused by mutation in the SHOC2 gene (602775); and Noonan syndrome-like disorder with or without juvenile myelomonocytic leukemia (NSLL; 613563), caused by mutation in the CBL gene (165360). Mutations in the neurofibromin gene (NF1; 613113), which is the site of mutations causing classic neurofibromatosis type I (NF1; 162200), have been found in neurofibromatosis-Noonan syndrome (NFNS; 601321).
The disorder now known as Noonan syndrome bears similarities to the disorder described by Turner (1938) and shown by Ford et al. (1959) to have its basis in a 45,X chromosomal aberration called Turner syndrome, Ullrich-Turner syndrome (Wiedemann ... The disorder now known as Noonan syndrome bears similarities to the disorder described by Turner (1938) and shown by Ford et al. (1959) to have its basis in a 45,X chromosomal aberration called Turner syndrome, Ullrich-Turner syndrome (Wiedemann and Glatzl, 1991), or monosomy X. Migeon and Whitehouse (1967) described 2 families, each with 2 sibs with somatic features of the Turner phenotype. In 1 family, 2 brothers had webbing of the neck, coarctation of the aorta, and cryptorchidism. In the second, a brother and sister were affected. Diekmann et al. (1967) described 2 brothers and a sister, with normal and unrelated parents, who had somatic characteristics of the Turner syndrome, particularly pterygium colli and deformed sternum, and had myocardiopathy leading to death at ages 12 and 10 years in 2 of them. Noonan (1968) reported 19 patients of whom 17 had pulmonary stenosis and 2 had patent ductus arteriosus (see 607411). Twelve were males and 7 were females. Deformity of the sternum with precocious closure of sutures was a frequent feature. Among 95 male patients with pulmonary stenosis, Celermajer et al. (1968) found the Turner phenotype in 8. In 5 of these, karyotyping was performed. In 4 the chromosomes were normal; in 1, an extra acrocentric chromosome was present. Kaplan et al. (1968) described 2 brothers with Noonan syndrome and elevated alkaline phosphatase levels, one of whom also had malignant schwannoma of the forearm. Nora and Sinha (1968) observed mother-to-offspring transmission in 3 families; in 1 family, transmission was through 3 generations. Baird and De Jong (1972) described 7 cases in 3 generations. One affected woman had 5 affected children (out of 6) with 2 different husbands. Seizures and anomalous upper lateral incisors may have been coincidental. Simpson et al. (1969) reported experiences suggesting that rubella embryopathy may result in the Turner phenotype, thereby accounting for either the male Turner syndrome or the female pseudo-Turner syndrome. A particularly convincing pedigree for autosomal dominant inheritance was reported by Bolton et al. (1974), who found the condition in a man and 4 sons (in a sibship of 10). Four of the 5 affected persons had pulmonic stenosis. Father-to-son transmission was reported by Qazi et al. (1974). Koretzky et al. (1969) described an unusual type of pulmonary valvular dysplasia which showed a familial tendency with either affected parent and offspring or affected sibs. Although some relatives had pulmonary valvular stenosis of the standard dome-shaped variety, the valvular dysplasia in others was characterized by the presence of three distinct cusps and no commissural fusion. The obstructive mechanism was related to markedly thickened, immobile cusps, with disorganized myxomatous tissue. Other features were retarded growth, abnormal facies (triangular face, hypertelorism, low-set ears and ptosis of the eyelids), absence of ejection click, and unusually marked right axis deviation by electrocardiogram. It now seems clear that the patients of Koretzky et al. (1969) had Noonan syndrome. Mendez and Opitz (1985) stated that the Watson syndrome (193520) and the LEOPARD syndrome (151100) 'are essentially indistinguishable from the Noonan syndrome.' Witt et al. (1987) reviewed the occurrence of lymphedema in Noonan syndrome. When it does occur, it opens the possibility of prenatal diagnosis by imaging methods or by AFP level. Noonan syndrome was one of the causes found for posterior cervical hygroma in a series of previable fetuses studied by Kalousek and Seller (1987). The authors found, furthermore, that 45,X Turner syndrome lethal in the fetal period showed a constant association of 3 defects, posterior cervical cystic hygroma, generalized subcutaneous edema, and preductal aortic coarctation. Evans et al. (1991) found a large cutaneous lymphangioma of the right cheek and amegakaryocytic thrombocytopenia in a male infant with Noonan syndrome. Donnenfeld et al. (1991) presented a case of Noonan syndrome in which posterior nuchal cystic hygroma was diagnosed at 13 to 14 weeks of gestation by ultrasonography. The hygroma had regressed by the time of birth leaving nuchal skin fold redundancy and pterygium colli. On the basis of studies of genital tract function in 11 adult males with Noonan syndrome, Elsawi et al. (1994) concluded that bilateral testicular maldescent was a main factor in contributing to impairment of fertility. Four of the 11 men had fathered children. Lee et al. (1992) reviewed the ophthalmologic and orthoptic findings in 58 patients with Noonan syndrome. External features were hypertelorism (74%), downward sloping palpebral apertures (38%), epicanthal folds (39%), and ptosis (48%). Orthoptic examination revealed strabismus in 48%, refractive errors in 61%, amblyopia in 33%, and nystagmus in 9% of cases. Anterior segment changes, found in 63% of patients, included prominent corneal nerves (46%), anterior stromal dystrophy (4%), cataracts (8%), and panuveitis (2%). Fundal changes occurred in 20% of patients and included optic nerve head drusen, optic disc hypoplasia, colobomas, and myelinated nerve fiber layer. Lee et al. (1992) recommended early ophthalmic examination of children with Noonan syndrome. Allanson et al. (1985) studied the changes in facial appearance with age. They pointed out that the manifestations may be subtle in adults. Ranke et al. (1988) analyzed the clinical features of 144 patients from 2 West German centers. The size at birth was normal in both sexes. In both males and females, the mean height followed along the 3rd percentile until puberty, but decreased transiently due to an approximately 2-year delay in onset of puberty. Final height approaches the lower limits of normal at the end of the second decade of life. The mean adult height was 162.5 cm in males and 152.7 cm in females, respectively. Allanson (1987) provided a useful review. The fetal primidone syndrome, occurring in the offspring of mothers taking this anticonvulsant, closely simulates the Noonan syndrome. Baraitser and Patton (1986) reported 4 unrelated children (2 boys, 2 girls) with a Noonan-like syndrome associated with sparse hair as a conspicuous feature. See 115150. Leichtman (1996) reported a family suggesting that cardiofaciocutaneous syndrome (CFC; 115150) is a variable expression of Noonan syndrome. He described a 4-year-old girl who had all of the manifestations of CFC syndrome (characteristic facial and cardiac anomalies, developmental delay, hypotrichosis, eczematic eruption with resistance to treatment), whose mother had typical characteristics of Noonan syndrome. Lorenzetti and Fryns (1996) reported a 13-year-old boy with Noonan syndrome and retinitis pigmentosa. Because similar eye defects are found in CFC syndrome, the authors suggested that CFC and Noonan syndromes might be variable manifestations of the same entity. However, Neri and Zollino (1996) noted distinctions between the patient reported by Lorenzetti and Fryns (1996) and CFC syndrome, and stated that similarity of eye defects is not enough to conclude that CFC and Noonan syndromes are the same condition. Early feeding difficulties are common in Noonan syndrome but often go unrecognized. Shah et al. (1999) studied a consecutive series of children with Noonan syndrome whose diagnosis had been confirmed by a clinical geneticist. Sixteen had poor feeding (poor suck or refusal to take solids or liquids) and symptoms of gastrointestinal dysfunction (vomiting, constipation, abdominal pain, and bloating). All 16 had required nasogastric tube feeding. Seven of the 25 had foregut dysmotility and gastroesophageal reflux. In 4 of these, electrogastrography and antroduodenal manometry demonstrated immature gastric motility reminiscent of that of a preterm infant of 32 to 35 weeks' gestation. Other children had less severe forms of gastric dysmotility. The authors highlighted the importance of recognizing this common, treatable feature of Noonan syndrome. Lemire (2002) described a father, son, and daughter with an apparently autosomal dominant disorder characterized by craniofacial anomalies, coarctation of the aorta, hypertrophic cardiomyopathy, and other structural heart defects with normal psychomotor development. Some clinical features such as webbed neck, low-set ears, low posterior hairline, and widely spaced nipples suggested Noonan syndrome. Alternatively, a previously unrecognized disorder was considered. The paternal age at the father's birth was 50 years. The father presented at age 13 years when postductal coarctation of the aorta was discovered during routine physical examination. Preoperative evaluation showed hypertrophied interventricular septum with pulmonic stenosis and bicuspid aortic valve in addition to the aortic coarctation. At age 22 years, echocardiogram showed marked systolic thickening of interventricular septum and posterior wall of the left ventricle and concentric left ventricular hypertrophy. He later developed atrial flutter and congestive heart failure. His son was recognized at birth to have 2 small ventricular septal defects, mildly hypoplastic aortic arch, and coarctation of the aorta. The coarctation was repaired at age 14 days and bilateral inguinal hernias at age 5 weeks. At age 9 months, he was found to have congestive heart failure due to a restrictive cardiomyopathy. At age 10 months, studies confirmed the presence of spongy myocardium with much impaired diastolic function. He died of early acute graft failure at age 14 months after heart transplantation. Autopsy showed restrictive cardiomyopathy with generalized myocardium hypertrophy. The daughter was found at birth to have a small ventricular septal defect, small patent ductus arteriosus, aneurysm of the atrial septum, and coarctation of the aorta. Cardiomyopathy was suspected on the basis of excessive thickening of the lower two-thirds of the interventricular septum and of the free wall of the right ventricle. Coarctation of the aorta was repaired surgically at age 19 days. At age 10.5 months, she was noted to have plagiocephaly, facial asymmetry with left side smaller than the right, webbed neck, asymmetric chest with widely spaced nipples, and edema of the dorsum of the feet. At age 2 years, bicuspid aortic valve and diffuse concentric hypertrophy of the left ventricle were noted. Juvenile myelomonocytic leukemia (JMML; 607785) has been observed in some cases of Noonan syndrome (Bader-Meunier et al., 1997; Fukuda et al., 1997; Choong et al., 1999). Holder-Espinasse and Winter (2003) described a 6-year-old girl with clinical features of Noonan syndrome, short stature, and headache who was noted to have Arnold-Chiari malformation (207950) on MRI. They cited 3 previous reports of Noonan syndrome and Chiari malformation and/or syringomelia (Ball and Peiris, 1982; Gabrielli et al., 1990; Colli et al., 2001). Holder-Espinasse and Winter (2003) concluded that Chiari malformation should be considered part of the Noonan syndrome spectrum and that brain and cervical spine MRI should be required in patients with Noonan syndrome, particularly if headaches or neurologic symptoms are present. For a comprehensive review of Turner syndrome, including clinical management, see Ranke and Saenger (2001). Kondoh et al. (2003) described a transient leukemoid reaction and an apparently spontaneously regressing neuroblastoma in a 3-month-old Japanese patient with Noonan syndrome and a de novo missense mutation in the PTPN11 gene (176876.0007). Noonan et al. (2003) reported their findings in 73 adults over 21 years of age with Noonan syndrome. In 30%, adult height was in the normal range between the 10th and 90th percentiles. More than half of the females and nearly 40% of males had an adult height below the third percentile. The presence or severity of heart disease was not a factor, and none of the adults with normal height had been treated with growth hormone. Serial measurements of height over many years through childhood to adulthood were available in only a few patients, but their pattern of growth suggested that catch up may occur in late adolescence. The possible benefit of growth hormone therapy could not be evaluated. Croonen et al. (2008) evaluated ECG findings and cardiographic abnormalities in 84 patients with Noonan syndrome, 54 (67%) of whom were positive for a mutation in the PTPN11 gene. As reported previously, pulmonary stenosis was the most common cardiac abnormality, followed by atrial septal defect and hypertrophic cardiomyopathy. ECG showed at least 1 characteristic finding in 50% of cases, including left axis deviation in 38 (45%), small R waves in the left precordial leads in 20 (24%), and an abnormal Q wave in 5 (6%) Noonan patients; however, these ECG findings were not associated with a PTPN11 mutation or with a specific cardiac anomaly. Among 40 Italian patients with Noonan syndrome, Ferrero et al. (2008) found short stature in 92%, congenital heart defect in 82.5%, isolated pulmonic stenosis in 60.6%, and hypertrophic obstructive cardiomyopathy in 12.2%. Prenatal anomalies were observed in 25% of cases, with polyhydramnios being the most common. PTPN11 mutations were detected in 11 sporadic patients and 1 family, totaling 12 (31.5%) of 38 cases. One patient without a detectable mutation had a Chiari I malformation with seizures. Another of the remaining patients had a mutation in the SOS1 gene.
In more than 50% of patients with Noonan syndrome, Tartaglia et al. (2001) identified mutations in the PTPN11 gene (see, e.g., 176876.0001-176876.0003). All the PTPN11 missense mutations were clustered in the interacting portions of the amino N-SH2 (Src ... In more than 50% of patients with Noonan syndrome, Tartaglia et al. (2001) identified mutations in the PTPN11 gene (see, e.g., 176876.0001-176876.0003). All the PTPN11 missense mutations were clustered in the interacting portions of the amino N-SH2 (Src homology 2) domain and the phosphotyrosine phosphatase (PTP) domains, which are involved in switching the protein between its inactive and active conformations. An energetics-based structural analysis of 2 N-SH2 mutants indicated that in these cases there may be a significant shift of the equilibrium favoring the active conformation. The findings suggested that gain-of-function changes resulting in excessive SHP2 activity underlie the pathogenesis of Noonan syndrome. After germline mutations in PTPN11 (176876) were demonstrated in the Noonan syndrome, Tartaglia et al. (2003) investigated defects in PTPN11 in myeloid disorders including cases of juvenile myelomonocytic leukemia (JMML; 607785) in children with Noonan syndrome. Specific mutations in PTPN11 associated with isolated JMML occurred as somatic changes and had never been observed as germline defects, leading Tartaglia et al. (2003) to speculate that these molecular defects are stronger and associated with embryonic lethality. Conversely, most mutations in PTPN11 associated with Noonan syndrome, which were sufficient to perturb developmental processes, were not fully leukemogenic, suggesting a milder gain-of-function effect. In 10 affected members from a large 4-generation Belgian family with Noonan syndrome and some features suggestive of CFC syndrome, Schollen et al. (2003) identified a missense mutation in the PTPN11 gene (176876.0018). The mutation was not found in 7 unaffected relatives or 3 spouses. Musante et al. (2003) screened the PTPN11 gene for mutations in 96 familial or sporadic Noonan syndrome patients and identified 15 missense mutations in 32 patients (33%). No obvious clinical differences were detected between subgroups of patients with mutations in different PTPN11 domains. Analysis of the clinical features of their patients revealed that several patients with facial abnormalities thought to be pathognomonic for NS did not have a mutation in the PTPN11 gene. Widely varying phenotypes among the 64 patients without PTPN11 mutations indicated further genetic heterogeneity. Musante et al. (2003) also screened 5 sporadic patients with CFC syndrome and found no mutations in the PTPN11 gene. Bertola et al. (2004) described a young woman with clinical features of Noonan syndrome but with some characteristics of CFC as well, including prominent ectodermal involvement (sparse and very coarse hair, and sparse eyebrows and eyelashes), developmental delay, and mental retardation. They identified a T411M mutation in the PTPN11 gene (176876.0019); the same mutation was found in her mother and older sister, not initially considered to be affected but who had subtle clinical findings compatible with the diagnosis of Noonan syndrome. The mother had 5 miscarriages, 2 of them twinning pregnancies. Bertola et al. (2004) suggested that all first-degree relatives of patients with confirmed Noonan syndrome, even those with no signs of the disorder, be screened for PTPN11 mutations in order to provide accurate assessments of recurrence risk. Yoshida et al. (2004) reported PTPN11 mutation analysis and clinical assessment in 45 Japanese patients with Noonan syndrome. Sequence analysis of the coding exons 1 through 15 of PTPN11 revealed a novel 3-bp deletion (176876.0024) and 10 recurrent missense mutations in 18 patients. The authors estimated that PTPN11 mutations account for approximately 40% of Japanese Noonan syndrome patients. Jongmans et al. (2005) performed mutation analysis of the PTPN11 gene in 170 Noonan syndrome patients and identified a mutation in 76 (45%) of them. They described the distribution of these mutations, as well as genotype-phenotype relationships. The usefulness of the Noonan syndrome scoring system developed by van der Burgt et al. (1994) was demonstrated; when physicians based their diagnosis on the scoring system, the percentage of mutation-positive patients was higher. Mutations in the KRAS gene (190070) can also cause Noonan syndrome (NS3; 609942). One patient with a T58I mutation (190070.0011) also had a myeloproliferative disorder resembling juvenile myelomonocytic leukemia (JMML) (Schubbert et al., 2006). Tartaglia et al. (2006) proposed a model that splits NS- and leukemia-associated PTPN11 mutations in the 2 major classes of activating lesions with differential perturbing effects on development and hematopoiesis. The results documented a strict correlation between the identity of the lesion and disease, and demonstrated that NS-causative mutations have less potency for promoting SHP2 gain of function than do leukemia-associated ones. Roberts et al. (2007) and Tartaglia et al. (2007) investigated sizable groups of patients with Noonan syndrome but no mutation in PTPN11, which accounts for approximately 50% of such cases. They found that many had missense mutations in the SOS1 gene (182530) and that the SOS1-positive case patients represented approximately 20% of cases of Noonan syndrome. The phenotype of Noonan syndrome caused by SOS1 mutation, while within the Noonan syndrome spectrum, appears to be distinctive (see NS4, 610733). Kontaridis et al. (2006) examined the enzymatic properties of mutations in PTPN11 causing LEOPARD syndrome and found that, in contrast to the activating mutations that cause Noonan syndrome and neoplasia, LEOPARD syndrome mutants are catalytically defective and act as dominant-negative mutations that interfere with growth factor/ERK-MAPK (see 176948)-mediated signaling. Kontaridis et al. (2006) concluded that the pathogenesis of LEOPARD syndrome is distinct from that of Noonan syndrome and suggested that these disorders should be distinguished by mutation analysis rather than clinical presentation. In a prospective multicenter study in 35 Noonan syndrome patients with growth retardation, Limal et al. (2006) compared growth and hormonal growth factors before and during recombinant human GH therapy in patients with and without PTPN11 mutations. Sequencing of the PTPN11 coding sequence revealed 12 different heterozygous missense mutations in 20 of the 35 patients (57%). The results showed that among NS1 patients with short stature, some neonates had birth length less than -2 SDS. Growth of patients with mutations was reduced and responded less efficiently to GH than that of patients without mutations. Limal et al. (2006) concluded that the association of low IGF1 (147440) and insulin-like growth factor-binding protein, acid-labile subunit (IGFALS; 601489) with normal IGFBP3 (146732) levels could explain growth impairment of children with mutations and could suggest a GH resistance by a late postreceptor signaling defect. In a case of fetal demise at 12 weeks' gestation, Becker et al. (2007) identified compound heterozygosity for the N308S (176876.0004) and Y63C (176876.0008) mutations in the PTPN11 gene. The mother and father, who exhibited facial features of Noonan syndrome and had both undergone surgical correction of pulmonary valve stenosis, were heterozygous for N308S and Y63C, respectively. A second pregnancy resulted in the birth of a boy with Noonan syndrome carrying the paternal Y63C mutation. Ferrero et al. (2008) identified PTPN11 mutations in 31.5% of 37 sporadic patients and 1 family with a clinical diagnosis of Noonan syndrome. One of the remaining patients had a mutation in the SOS1 gene. - Cooccurrence of NF1 and PTPN11 Mutations Bertola et al. (2005) provided molecular evidence of the concurrence of neurofibromatosis and Noonan syndrome in a patient with a de novo missense mutation in the NF1 gene (613113.0043) and a mutation in the PTPN11 gene (176876.0023) inherited from her father. The proposita was noted to have cafe-au-lait spots at birth. Valvar and infundibular pulmonary stenosis and aortic coarctation were diagnosed at 20 months of age and surgically corrected at 3 years of age. As illustrated, the patient had marked hypertelorism and proptosis as well as freckling and cafe-au-lait spots. Lisch nodules were present. At the age of 8 years, a pilocytic astrocytoma in the suprasellar region involving the optic chiasm (first presenting symptomatically at 2 years of age), was partially resected. The father, who was diagnosed with Noonan syndrome, had downslanting palpebral fissures and prominent nasal labial folds. He was of short stature (159 cm) and had pectus excavatum. Electrocardiogram showed left-anterior hemiblock and complete right bundle branch block. Thiel et al. (2009) reported a patient with features of both neurofibromatosis I and Noonan syndrome who was compound heterozygous for mutations in both the NF1 (162200.0044) and PTPN11 (176876.0027) genes. The PTPN11 mutation occurred de novo, and the NF1 mutation was inherited from the patient's mother, who had mild features of neurofibromatosis I, including the absence of optic gliomas. The proband developed bilateral optic gliomas before age 2 years, suggesting an additive effect of the 2 mutations on the Ras pathway. The proband also had short stature, delayed development, sternal abnormalities, and valvular pulmonary stenosis. - Reviews Tartaglia et al. (2010) provided a detailed review of the clinical and molecular features of Noonan syndrome.
Diagnosis of Noonan syndrome (NS) is made clinically by observation of key features. Those cardinal features of NS are well delineated:...
Clinical DiagnosisDiagnosis of Noonan syndrome (NS) is made clinically by observation of key features. Those cardinal features of NS are well delineated:Short statureCongenital heart defectDevelopmental delay of variable degree Broad or webbed neckUnusual chest shape with superior pectus carinatum, inferior pectus excavatumApparently low-set nipplesCryptorchidism in malesCharacteristic facies. The facial appearance of NS shows considerable change with age, being most striking in the newborn period and middle childhood, and most subtle in the adult. Key features found irrespective of age include low-set, posteriorly rotated ears with fleshy helices; vivid blue or blue-green irises; and eyes that are often wide-spaced, with epicanthal folds and thick or droopy eyelids.Other:Coagulation defects. Coagulation screens such as prothrombin time, activated partial thromboplastin time, platelet count, and bleeding time may show abnormalities. Specific testing should identify the particular coagulation defect, such as von Willebrand disease, thrombocytopenia, varied coagulation factor defects (factors V, VIII, XI, XII, protein C), and platelet dysfunction.Lymphatic dysplasiasDiagnostic criteria developed by van der Burgt in 1997 were published in van der Burgt . While they have not been used extensively in North America, they are of particular value in the research domain, and are embedded in new management guidelines developed by Dyscerne in the United Kingdom [Noonan Syndrome Guideline Development Group 2010; click for full text (pdf)]. This clinical management guideline also provides details of recommended baseline investigations and age-specific management. Similar recommendations are provided in Romano et al . Click for full text (pdf).Molecular Genetic TestingGenes. The genes (PTPN11, SOS1, RAF1, KRAS, NRAS, BRAF, and MAP2K1) in which mutations are known to cause Noonan syndrome are included in Table 1 and Table A. Evidence for possible additional locus heterogeneity. It is presumed that additional loci causal for the NS phenotype may be identified. Evidence against linkage of the NS phenotype to 12q (the PTPN11 locus) in some families was suggested in the original report [Jamieson et al 1994]. It is unclear whether any of the families in this report may have had a mutation in any of the other genes in which mutation can cause Noonan syndrome. Testing by genePTPN11. Sequence analysis of all exons of PTPN11 detects missense mutations in about 50% of individuals tested [Tartaglia et al 2001, Tartaglia et al 2002, Jongmans et al 2004]. The small intragenic in-frame three-nucleotide deletion (p.Gly60del) in PTPN11 is also reliably detected by sequence analysis. Two chromosomal duplications involving PTPN11 as causative of Noonan syndrome have been reported [Shchelochkov et al 2008, Graham et al 2009]; however, the clinical utility of such testing is unknown. SOS1. Sequence analysis of exons 1-23 detects all reported missense mutations [Roberts et al 2007]. Because no deletions or duplications involving SOS1 as causative of Noonan syndrome have been reported [Nystrom et al 2010], the usefulness of such testing is unknown. RAF1. Sequence analysis of exons 1-17 detects all reported missense mutations [Pandit et al 2007, Razzaque et al 2007]. Because no deletions or duplications involving RAF1 as causative of Noonan syndrome have been reported [Nystrom et al 2010], the usefulness of such testing is unknown. KRAS. Sequence analysis of all exons of KRAS detects mutations in fewer than 5% of individuals with Noonan syndrome [Schubbert et al 2006]. Because no deletions or duplications involving KRAS as causative of Noonan syndrome have been reported [Nystrom et al 2010], the usefulness of such testing is unknown. NRAS. Sequence analysis of all exons of NRAS has detected a mutation in four individuals [Cirstea et al 2010]. BRAF and MAP2K1. Sequence analysis of these two genes detects a mutation in fewer than 2% of individuals with Noonan syndrome [Nava et al 2007, Nystrom et al 2008, Sarkozy et al 2009]. Because no deletions or duplications involving BRAF or MAP2K1 as causative of Noonan syndrome have been reported [Nystrom et al 2010], the usefulness of such testing is unknown. Testing by multigene panel. Multigene panels can be used for the simultaneous analysis of some or all of the genes in the RasMAPK pathway associated with Noonan syndrome. These panels vary by methods used and genes included; thus, the ability of a panel to detect a causative mutation or mutations in any given individual with the Noonan syndrome phenotype also varies.Table 1. Summary of Molecular Genetic Testing Used in Noonan Syndrome (NS)View in own windowGene SymbolProportion of NS Attributed to Mutations in This GeneTest Method Mutations Detected Test Availability PTPN1150%
Sequence analysis / mutation scanning 1, 2, 3Sequence variants 4Clinical Deletion / duplication analysis 5Partial-and whole-gene deletion 6SOS110%-13% 7Sequence analysis / mutation scanning 1, 2, 8Sequence variants 4ClinicalDeletion / duplication analysis 5Partial-and whole-gene deletion 6RAF13%-17%Sequence analysis 2, 9Sequence variants 4ClinicalDeletion / duplication analysis 5Partial- and whole-gene deletion 6KRAS<5%Sequence analysis Sequence variants 4ClinicalDeletion / duplication analysis 5Partial- and whole-gene deletion 6NRAS4 individuals to dateSequence analysisSequence variants 4Clinical BRAF<2% 10Sequence analysis / mutation scanning 1, 2Sequence variants 4ClinicalDeletion / duplication analysis 5Partial- and whole-gene deletion 6MAP2K1<2% 11Sequence analysis 2Sequence variants 4ClinicalDeletion / duplication analysis 5Partial- and whole-gene deletion 61. Sequence analysis and mutation scanning of the entire gene can have similar detection frequencies; however, detection rates for mutation scanning may vary considerably between laboratories based on specific protocol used. 2. Some laboratories offer sequencing of select exons. Note: The exons sequenced may vary by laboratory. Some laboratories offer a tiered approach to testing: if mutation is not identified in the selected exons, the remaining exons are sequenced.3. Some laboratories offer sequence analysis of exons 1-4, 7-9, and 11-14 before analysis of the entire coding region. 4. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations. 5. Testing that detects deletions/duplications not readily detectable by sequence analysis of genomic DNA; a variety of methods including quantitative PCR, real-time PCR, multiplex ligation-dependent probe amplification (MLPA), or array GH may be used. 6. No deletions or duplications involving PTPN11, KRAS, SOS1, RAF1, BRAF, or MAP2K1 as causative of Noonan syndrome have been reported. (Note: By definition, deletion/duplication analysis identifies rearrangements that are not identifiable by sequence analysis of genomic DNA.) 7. Approximately 16%-20% of individuals with a clinical diagnosis of Noonan syndrome who do not have an identified PTPN11 mutation are found to have an SOS1 mutation [Roberts et al 2007, Tartaglia et al 2007]. 8. Some laboratories offer sequence analysis of exons 7, 11, and 17 before analysis of the entire coding region.9. Some laboratories offer sequence analysis of exons 7, 14, and 17 before analysis of the entire coding region.10. Sarkozy et al 11. Nava et al Interpretation of test results. For issues to consider in interpretation of sequence analysis results, click here.Testing StrategyTo confirm/establish the diagnosis in a probandSequential molecular genetic testing. Based on the proportion of Noonan syndrome attributed to a mutation in each gene, the following order of testing may be considered: 1. Sequence analysis of PTPN11 2. If no mutation is identified, sequence analysis of SOS1 3. (etc.) RAF1 4. KRAS5. NRAS6. BRAF7. MAP2K1Note: (1) Information in Genotype-Phenotype Correlations may guide the selection of the second gene to be tested. (2) In some laboratories sequential testing may start with sequence analysis of select exons or ‘hotspots.’Multigene panel. An alternative to the sequential molecular genetic testing described above is a panel in which some or all of the genes in the RasMAPK pathway that cause Noonan syndrome, cardiofaciocutaneous syndrome, and Costello syndrome are sequenced simultaneously. Note: Often a mutation identified by such a panel is confirmed by sequence analysis of the involved gene. Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing mutation in the family. Genetically Related (Allelic) DisordersPTPN11LEOPARD syndrome (lentigines, ECG abnormalities, ocular hypertelorism, pulmonary stenosis, abnormalities of genitalia, retardation of growth, deafness) is an autosomal dominant condition with variable expression. It shows significant overlap with Noonan syndrome (NS), in which pigmentary findings such as nevi (25%), café au lait patches (10%), and lentigines (3%) are reported. In early childhood the phenotype of LEOPARD syndrome can be typical of Noonan syndrome; however, with age other characteristic features including lentigines and hearing loss develop. Inheritance is autosomal dominant. Mutations in PTPN11 and RAF1 are identified in about 93% of individuals LEOPARD syndrome. At least one individual with LEOPARD syndrome was found to have a BRAF mutation [Sarkozy et al 2009]. Leukemia and solid tumors. Juvenile myelomonocytic leukemia (JMML) accounts for one third of myelodysplastic syndrome (MDS) and about 2% of leukemia. Mutations in NRAS, KRAS2, and NF1 have been shown to deregulate the RAS/MAPK pathway leading to JMML in about 40% of affected individuals. Somatic mutations in exons 3 and 13 of PTPN11 have been demonstrated in 34% individuals with JMML in one cohort [Tartaglia et al 2003b]. Mutations in exon 3 were also found in 19% of children with MDS with an excess of blast cells, which often evolves into acute myeloid leukemia (AML) and is associated with poor prognosis. Nonsyndromic AML, especially the monocyte subtype FAB-MD, has been shown to be caused by PTPN11 mutations. All of these mutations cause gain of function in tyrosine-protein phosphatase non-receptor type II (SHP-2), likely leading to an early initiating lesion in JMML oncogenesis with increased cell proliferation attributable, in part, to prolonged activation of the RAS/MAPK pathway. More recently, the spectrum of leukemogenesis associated with PTPN11 mutations has been extended to include childhood acute lymphoblastic leukemia (ALL). Mutations were observed in 8% of individuals with B-cell precursor ALL, but not among children with T-lineage ALL [Tartaglia et al 2004b]. Additionally, Bentires-Alj et al  have described SHP-2-activating PTPN11 mutations in solid tumors including breast, lung, and gastric neoplasms and neuroblastoma.Noonan-like/multiple giant-cell lesion syndrome (see Clinical Description)A duplication of chromosome band 12q24.1-q24.23, the region that includes PTPN11, may cause a phenotype similar or identical to Noonan syndrome, presumably as a result of increased gene dosage [Shchelochkov et al 2008, Graham et al 2009].KRAS. In rare cases mutations in KRAS are associated with cardiofaciocutaneous syndrome (see Differential Diagnosis).SOS1. A frameshift mutation in SOS1 has been reported in a single four-generation family with hereditary gingival fibromatosis [Hart et al 2002]. This condition is a rare form of gingival overgrowth characterized by benign slowly progressive fibrous enlargement of the maxillary and mandibular keratinized gingiva. SOS1 mutations have not been reported in other families with this disorder. RAF1. LEOPARD syndrome is also caused by gain-of-function mutations in RAF1. About one third of affected families without PTPN11 mutations have a mutation in RAF1.In rare cases RAF1 missense mutations are observed in somatic cancer [see Pandit et al 2007, references].NRAS. NRAS mutations are commonly observed in somatic cancer.BRAF. Mutations in BRAF are usually found in cardiofaciocutaneous syndrome. Somatic mutations are a common cause of nevi.MEK1. Mutations in MEK1 are a common cause of cardiofaciocutaneous syndrome.
Females and males are equally likely to have Noonan syndrome (NS)....
Females and males are equally likely to have Noonan syndrome (NS).Growth. Birth weight is usually normal, although edema may cause a transient increase. Infants with NS frequently have feeding difficulties. This period of failure to thrive is self-limited, although poor weight gain may persist for up to 18 months.Length at birth is usually normal. Postnatal growth failure is often obvious from the first year of life [Otten & Noordam 2009]. Mean height then follows the third centile from ages two to four years until puberty, when below-average growth velocity and an attenuated adolescent growth spurt tend to occur. As bone maturity is usually delayed, prolonged growth into the 20s is possible. Final adult height approaches the lower limit of normal: 161-167 cm in males and 150-155 cm in females. Growth curves have been developed from these cross-sectional retrospective data. One study suggests that 30% of affected individuals have height within the normal adult range, while more than 50% of females and nearly 40% of males have an adult height below the third centile [Noonan et al 2003].Decreased IGF1 and IGF-binding protein 3, together with low responses to provocation, suggest impaired growth hormone release, or disturbance of the growth hormone/insulin-like growth factor I axis, in many affected persons. Mild growth hormone resistance related to a post-receptor signaling defect, which may be partially compensated for by elevated growth hormone secretion, is reported in individuals with NS and a PTPN11 mutation [Binder et al 2005]. See Management for discussion of growth hormone (GH) treatment.Cardiovascular. Significant bias in the frequency of congenital heart disease may exist because many clinicians have in the past required the presence of cardiac anomalies for diagnosis of NS. The frequency of congenital heart disease is estimated at between 50% and 80%. An electrocardiographic abnormality is documented in approximately 90% of individuals with NS and may be present without concomitant structural defects.Pulmonary valve stenosis, often with dysplasia, is the most common anomaly in NS, found in 20%-50% of affected individuals; it may be isolated or associated with other cardiovascular defects.Hypertrophic cardiomyopathy is found in 20% to 30% of affected individuals. It may present at birth, in infancy, or in childhood.Other structural defects frequently observed include atrial and ventricular septal defects, branch pulmonary artery stenosis, and tetralogy of Fallot. Coarctation of the aorta is more common than previously thought [Noonan 2005b].Psychomotor development. Early developmental milestones may be delayed, likely in part as a result of the combination of joint hyperextensibility and hypotonia.Most school-age children perform well in a normal educational setting, but 25% have learning disabilities [Lee et al 2005a] and 10% to 15% require special education [van der Burgt et al 1999]. Mild intellectual disability is observed in up to one third of affected individuals. Verbal performance is frequently lower than nonverbal performance. There may be a specific cognitive disability, either in verbal or praxic reasoning, requiring a special academic strategy and school placement. Articulation deficiency is common (72%) but usually responds well to speech therapy. Language delay may be related to hearing loss, perceptual motor disabilities, or articulation deficiencies.A study of the language phenotype of children and adults with NS showed that language impairments in general are more common in NS than in the general population and, when present, are associated with a higher risk for reading and spelling difficulties [Pierpont et al 2010]. Language is significantly correlated with nonverbal cognition, hearing ability, articulation, motor dexterity, and phonologic memory. No specific aspect of language was selectively affected in those with NS. Psychological health. Few details of psychological health in Noonan syndrome are reported. No particular syndrome of behavioral disability or psychopathology is observed, and self-esteem is comparable to age-related peers [Lee et al 2005a]. Noonan [2005a] has documented problems in a cohort of 51 adults: depression was found in 23%, and occasional substance abuse and bipolar disease was reported. Similar findings were not reported in a large UK cohort followed over many years [Shaw et al 2007]. Detailed psychological assessment of a small group of 11 affected individuals identified anxiety, panic attacks, social introversion, impoverished self-awareness, and marked difficulties in identifying and expressing feelings and emotions (alexithymia) [Verhoeven et al 2008]. This same research team suggests that in adulthood mild problems in attention, organizational skills, psychosocial immaturity, and alexithymia may be found, and thus assessment of social cognition and personality may be appropriate [Wingbermuehle et al 2009].Genitourinary. Renal abnormalities, generally mild, are present in 11% of individuals with NS. Dilatation of the renal pelvis is most common. Duplex collecting systems, minor rotational anomalies, distal ureteric stenosis, renal hypoplasia, unilateral renal agenesis, unilateral renal ectopia, and bilateral cysts with scarring are reported less commonly.Male pubertal development and subsequent fertility may be normal, delayed, or inadequate. Deficient spermatogenesis may be related to cryptorchidism, which is noted in 60% to 80% of males; however, a recent study of male gonadal function identified Sertoli cell dysfunction in males with cryptorchidism and those with normal testicular descent, suggesting an intrinsic defect leading to hypergonadotrophic hypogonadism [Marcus et al 2008]. Puberty may be delayed in females, with a mean age at menarche of 14.6±1.17 years. Normal fertility is the rule.Facial features. Differences in facial appearance, albeit subtle at certain ages, are a key clinical feature.In the neonate, tall forehead, hypertelorism with downslanting palpebral fissures, low-set, posteriorly rotated ears with a thickened helix, a deeply grooved philtrum with high, wide peaks to the vermillion border of the upper lip, and a short neck with excess nuchal skin and low posterior hairline are found.In infancy, eyes are prominent, with horizontal fissures, hypertelorism, and thickened or ptotic lids. The nose has a depressed root, wide base, and bulbous tip.In childhood, facial appearance is often lacking in affect or expression, as in an individual with a myopathy.By adolescence, facial shape is an inverted triangle, wide at the forehead and tapering to a pointed chin. Eyes are less prominent and features are sharper. The neck lengthens, accentuating skin webbing or prominence of the trapezius muscle.In the older adult, nasolabial folds are prominent, and the skin appears transparent and wrinkled.Bleeding diathesis. Most persons with NS have a history of abnormal bleeding or bruising. Early studies reported that about one third of all individuals with NS have one or more coagulation defects. More recently a lower rate of coagulopathy has been suggested [Derbent et al 2010]. That coagulopathy may manifest as severe surgical hemorrhage, clinically mild bruising, or laboratory abnormalities with no clinical consequences.Lymphatic. Varied lymphatic abnormalities are described in individuals with NS. They may be localized or widespread, prenatal, and/or postnatal. Dorsal limb (top of the foot and back of the hand) lymphedema is most common. Less common findings include: intestinal, pulmonary, or testicular lymphangiectasia; chylous effusions of the pleural space and/or peritoneum; and localized lymphedema of the scrotum or vulva.Prenatal features suggestive of Noonan syndrome, likely of a lymphatic nature, include: transient or persistent cystic hygroma, polyhydramnios, and (rarely) hydrops fetalis [Gandhi et al 2004, Yoshida et al 2004b, Joó et al 2005].Ocular. Ocular abnormalities including strabismus, refractive errors, amblyopia, and nystagmus occur in up to 95% of affected individuals. Anterior segment and fundus changes are less common.Dermatologic. Skin differences, particularly follicular keratosis over extensor surfaces and face, are relatively common and may occasionally be as severe as those found in cardiofaciocutaneous syndrome (see Differential Diagnosis). Café-au-lait spots and lentigines are described in NS more frequently than in the general population (see LEOPARD syndrome discussion in Genetically Related Disorders).OtherArnold-Chiari I malformation has been reported several times [Holder-Espinasse & Winter 2003], and the author is aware of at least three other individuals with this anomaly [Author, personal observation]. Hepatosplenomegaly is frequent; the cause is likely related to subclinical myelodysplasia.Juvenile myelomonocytic leukemia (JMML) is often caused by somatic mutations in PTPN11 (see Genetically Related Disorders) [Tartaglia et al 2003b, Tartaglia et al 2004b, Hasle 2009]. Additionally, individuals with Noonan syndrome and a germline mutation in PTPN11 have a predisposition to this unusual childhood leukemia. In general, JMML in Noonan syndrome runs a more benign course, a finding that may be related to the higher gain-of-function effect of somatic mutations leading to leukemogenesis [Tartaglia et al 2006]. Other malignancies. One recent study of individuals with Noonan syndrome caused by a mutation in PTPN11 supports a threefold increased risk of malignancy [Jongmans et al 2011].Acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML) are found at higher frequency in Noonan syndrome than in the general population [Hasle 2009, Jongmans et al 2011]. Solid tumors, such as rhabdomyosarcoma and neuroblastoma, are described [Denayer et al 2010, Jongmans et al 2010]. To date three embryonal rhabdomyosarcomas (ERMS) caused by a germline SOS1 mutation have been reported [Denayer et al 2010, Hastings et al 2010, Jongmans et al 2010]. One with obstructive jaundice involved the biliary ampulla/duodenum; one the bladder; and one the urachus. Three additional cases of ERMS and NS (of the orbit, vagina, and abdomen) were reported; genotype was not determined [Khan et al 1995, Jung et al 2003, Moschovi et al 2007]. Myeloproliferative disorders, either transient or more fulminant, can also occur in infants with Noonan syndrome [Kratz et al 2005].Noonan-like/multiple giant-cell lesion syndrome. The giant-cell granulomas and bone and joint anomalies in Noonan-like/multiple giant-cell lesion syndrome are recognized to be part of the Noonan syndrome spectrum. They can resemble cherubism, an autosomal dominant disorder caused by mutations in SH3BP2 (see Cherubism), lesions observed in neurofibromatosis (see Neurofibromatosis Type 1), or lesions observed in the Ramon syndrome with juvenile rheumatoid arthritis (polyarticular pigmented villonodular synovitis). Noonan-like/multiple giant-cell lesion syndrome is caused by mutations in PTPN11 [Jafarov et al 2005, Wolvius et al 2006] and SOS1 [Beneteau et al 2009, Neumann et al 2009]. One family with Noonan-like/multiple giant-cell lesion syndrome has a PTPN11 mutation reported in Noonan syndrome without giant cell lesions [Tartaglia et al 2002]; thus, additional genetic factors may be necessary for the giant cell proliferation to occur.These multiple giant cell lesions are also recently recognized in persons with cardiofaciocutaneous syndrome caused by BRAF and MEK1 [Neumann et al 2009]. Thus dysregulation of the Ras-MAPK pathway represents the common and basic molecular event predisposing to giant-cell lesion formation, arguing against the existence of Noonan-like/multiple giant-cell lesion syndrome as a separate entity.
PTPN11. Analysis of a large cohort of individuals with Noonan syndrome (NS) [Tartaglia et al 2001, Tartaglia et al 2002] has suggested that PTPN11 mutations are more likely to be found when pulmonary stenosis is present, whereas hypertrophic cardiomyopathy is less prevalent among individuals with NS caused by PTPN11 abnormalities. ...
PTPN11. Analysis of a large cohort of individuals with Noonan syndrome (NS) [Tartaglia et al 2001, Tartaglia et al 2002] has suggested that PTPN11 mutations are more likely to be found when pulmonary stenosis is present, whereas hypertrophic cardiomyopathy is less prevalent among individuals with NS caused by PTPN11 abnormalities. Additional cohort analyses have linked PTPN11 mutations to short stature, pectus deformity, easy bruising, characteristic facial appearance [Yoshida et al 2004a, Zenker et al 2004], and cryptorchidism [Jongmans et al 2004]. In contradistinction, the study of Allanson et al  failed to establish any facial phenotype-genotype correlation.The likelihood of developmental delay does not differ in mutation-positive and -negative groups, although individuals with the p.Asn308Asp mutation are said to be more likely to receive normal education [Jongmans et al 2004]. Mutations at codons 61, 71, 72, and 76 are significantly associated with leukemogenesis and identify a subgroup of individuals with NS at risk for JMML [Niihori et al 2005].The post-receptor signaling defect causing mild growth hormone resistance in individuals with NS and a PTPN11 mutation [Binder et al 2005] leads to reduced efficacy of short-term growth hormone (GH) treatment in mutation-positive individuals [Binder et al 2005, Ferreira et al 2005, Limal et al 2006]. However, careful review of height data reveals that individuals with a PTPN11 mutation presented with more severe short stature and, therefore, reached a lower final height despite a similar height gain [Noordam et al 2008].An in-frame three-nucleotide PTPN11 deletion (p.Gly60del) in a female infant with severe features of Noonan syndrome, including hydrops fetalis and juvenile myelomonocytic leukemia [Yoshida et al 2004a], has been reported. The D61del three nucleotide PTPN11 deletion has also been reported in a child with typical rather than severe NS [Lee et al 2005b]SOS1. Tartaglia et al  concluded that the phenotype in 22 individuals with NS who had an SOS1 mutation fell within the spectrum of NS, but emphasized the more frequent occurrence of ectodermal abnormalities and a greater likelihood of normal development and stature in these individuals compared to others with NS. In a companion paper, Roberts et al  reported that 14 individuals with NS who had a SOS1 mutation did not differ in development and stature from other individuals with NS. Cardiac septal defects were found more frequently than in individuals with NS and mutations in PTPN11. The study did not make specific mention of ectodermal findings. Pierpont et al  have studied intellectual abilities in Noonan syndrome and report that individuals with SOS1 mutations generally have average or higher-level skills. RAF1. The studies reported to date emphasize a striking correlation with hypertrophic cardiomyopathy, with 95% of affected individuals with a RAF1 mutation showing this feature, in comparison with the overall prevalence in NS of 18%. This suggests that pathologic cardiomyocyte hypertrophy occurs because of increased Ras signaling. Multiple nevi, lentigines, and/or café au lait spots were reported in one third of people with RAF1-associated NS.KRAS. The phenotype associated with mutations in KRAS tends to be atypical, with greater likelihood and severity of intellectual disability [Zenker et al 2007] in these individuals than in others with NS. Kratz et al  reported the somewhat unusual feature of craniosynostosis in two unrelated probands with NS and a missense KRAS mutation. NRAS. To date few individuals with an NRAS mutation have been reported. The clinical features appear to be typical with no particular or distinctive phenotype observed [Cirstea et al 2010]. The rare individuals with a mutation in BRAF or MEK1 also appear to have features of classic Noonan syndrome, albeit with florid ectodermal manifestations [Nava et al 2007, Nystrom et al 2008, Sarkozy et al 2009].
Turner syndrome, found only in females, is differentiated from Noonan syndrome (NS) by demonstration of a sex chromosome abnormality on cytogenetic studies in individuals with Turner syndrome. The phenotype of Turner syndrome is actually quite different from that of NS, when one considers face, heart, development, and kidneys. In Turner syndrome, renal anomalies are more common, developmental delay is much less frequently found, and left-sided heart defects are the rule....
Turner syndrome, found only in females, is differentiated from Noonan syndrome (NS) by demonstration of a sex chromosome abnormality on cytogenetic studies in individuals with Turner syndrome. The phenotype of Turner syndrome is actually quite different from that of NS, when one considers face, heart, development, and kidneys. In Turner syndrome, renal anomalies are more common, developmental delay is much less frequently found, and left-sided heart defects are the rule.Like NS, Watson syndrome is characterized by short stature, pulmonary valve stenosis, variable intellectual development, and skin pigment changes (e.g., café au lait patches). The Watson syndrome phenotype also overlaps with that of neurofibromatosis type 1; the two are now known to be allelic [Allanson et al 1991].Cardiofaciocutaneous (CFC) syndrome and NS have the greatest overlap in features. CFC syndrome has similar cardiac and lymphatic findings [Noonan 2001, Armour & Allanson 2008]. In CFC syndrome, intellectual disability is usually more severe, with a higher likelihood of structural central nervous system anomalies; skin pathology is more florid; gastrointestinal problems are more severe and long lasting; and bleeding diathesis is rare. Facial appearance tends to be coarser, dolichocephaly and absent eyebrows are more frequently seen, and blue eyes are less commonly seen. To date, the four genes in which mutation is known to cause CFC syndrome are BRAF (~75%-80%), MAP2K1 and MAP2K2 (~10%-15%), and KRAS (<5%). Rarely, individuals have a mutation in a gene usually associated with Noonan syndrome [Narumi et al 2008, Nystrom et al 2008].Costello syndrome shares features with both NS and CFC [Hennekam 2003, Gripp et al 2006, Kerr et al 2006]. Many individuals with Costello syndrome have been studied molecularly; no PTPN11 mutation has been identified [Tartaglia et al 2003a; Tröger et al 2003]. Germline mutations occurring most commonly in exon 2 of the HRAS proto-oncogene have been shown to cause Costello syndrome [Aoki et al 2005].Noonan-like syndrome with loose anagen hair. Germline mutations in SHOC2 usually lead to a phenotype of Noonan-like features; a small proportion of those affected have the classic Noonan syndrome phenotype [Kerr, personal experience]. The recurrent missense SHOC2 mutation, 4A>G, has been found in a subgroup with features of NS but also growth hormone deficiency; distinctive hyperactive behavior that improves with age in most; hair anomalies including easily pluckable, sparse, thin slow-growing hair (loose anagen hair); darkly pigmented skin with eczema or ichthyosis; hypernasal voice; and an over-representation of mitral valve dysplasia and septal defects in comparison with classic NS [Cordeddu et al 2009]. Sequence analysis of all exons detects a mutation in about 5% of individuals with Noonan syndrome. Most have the classic loose anagen hair [Cordeddu et al 2009].Other. NS should be distinguished from other syndromes/conditions with developmental delay, short stature, congenital heart defects, and distinctive facies, especially the following: Williams syndrome Aarskog syndrome In utero exposure to alcohol or primidoneNeurofibromatosis type 1 (NF1) shares some features with NS, including short stature, learning difficulties and café au lait patches. Infrequently, affected individuals also have a NS-like facial appearance. This could be caused by chance concurrence of Noonan syndrome and NF1 [Colley et al 1996, Bertola et al 2005]. However, most often it appears to be a Noonan-like face in an individual with mutation-proven NF1, sometimes in the presence of a variant NF1 phenotype [Stevenson et al 2006, Nystrom et al 2009].Note to clinicians: For a patient-specific ‘simultaneous consult’ related to this disorder, go to , an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).
To establish the extent of disease in an individual diagnosed with Noonan syndrome (NS), the following evaluations are recommended:...
Evaluations Following Initial DiagnosisTo establish the extent of disease in an individual diagnosed with Noonan syndrome (NS), the following evaluations are recommended:Complete physical and neurologic examinationPlotting of growth parameters on NS growth charts Cardiac evaluation with echocardiography and electrocardiographyOphthalmologic evaluationHearing evaluationCoagulation screenRenal ultrasound examination; urinalysis if the urinary tract is anomalousClinical and radiographic assessment of spine and rib cageBrain and cervical spine MRI if neurologic symptoms are presentMultidisciplinary developmental evaluationGenetics consultationTreatment of ManifestationsTreatment of the complications of Noonan syndrome is generally standard and does not differ from treatment in the general population. Management guidelines have been developed by Dyscerne, a European consortium [Noonan Syndrome Guideline Development Group 2010; click for full text (pdf)]; a separate set has been published by an American consortium working with the Noonan Syndrome Support Group [Romano et al 2010; click for full text (pdf)].Treatment of cardiovascular anomalies is generally the same as in the general population.Developmental disabilities should be addressed by early intervention programs and individualized education strategies.The bleeding diathesis in Noonan syndrome can have a variety of causes. Specific treatment for serious bleeding may be guided by knowledge of a factor deficiency or platelet aggregation anomaly. Factor VIIa has been successfully used to control bleeding caused by hemophilia, von Willebrand disease, thrombocytopenia, and thrombasthenia. It has also been used in an infant with Noonan syndrome whose platelet count and prothrombin and partial thromboplastin times were normal, to control severe postoperative blood loss resulting from gastritis [Tofil et al 2005].Studies of growth hormone (GH) treatment have been published from the UK, Japan [Ogawa et al 2004], the Netherlands [Noordam 2007, Noordam et al 2008], Sweden [Osio et al 2005], and the United States [Romano et al 2009]. The rationale for GH treatment of individuals with Noonan syndrome includes (1) significant short stature compared with normal peers; (2) possible impairment of the GH-insulin-like-growth-factor type I (GH-IGF-I) axis; and (3) documented response to GH treatment in recent studies. In the US, but not in Europe, short stature associated with Noonan syndrome may be an indication for treatment independent of the status of the GH-IGF-I axis. In Europe, GH treatment is the standard of care for children with abnormalities of the GH-IGF-I axis and could be used when GH physiology is normal. No standard dose has been established; no correlation between dosage used and final height is apparent. Short- and long-term studies have demonstrated a consistent and significant increase in height velocity in children with Noonan syndrome who have been treated. GH therapy appears to be effective in increasing short-term growth in children with Noonan syndrome and is well tolerated. Data on final height are encouraging. Substantial height gain during prepubertal years and puberty contributes to final height within the general population range in the majority of those treated, especially males [Osio et al 2005, Noordam et al 2008, Romano et al 2009]. The increase in height SD varies from 0.6 to 1.8 SD and may depend on age at start of treatment, duration of study, age at onset of puberty, and/or GH sensitivity [Osio et al 2005, Noordam et al 2008, Dahlgren 2009]. SurveillanceIf anomalies are found in any system (see Evaluations Following Initial Diagnosis), periodic follow-up should be planned and life-long monitoring may be necessary; for example, periodic echocardiography if cardiovascular abnormalities are present, periodic eye examination if a refraction error or strabismus is found, urinalysis if there are structural abnormalities of the collecting system. Agents/Circumstances to AvoidAspirin therapy should be avoided because it may exacerbate a bleeding diathesis.Evaluation of Relatives at RiskSee Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.Therapies Under InvestigationSearch ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.
Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED....
Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.Table A. Noonan Syndrome: Genes and DatabasesView in own windowGene SymbolChromosomal LocusProtein NameLocus SpecificHGMDPTPN1112q24.13
Tyrosine-protein phosphatase non-receptor type 11Catalogue of Somatic Mutations in Cancer (COSMIC) PTPN11base: Database for pathogenic mutations in the SHP-2 SH2 domain PTPN11 homepage - Mendelian genesPTPN11BRAF7q34B-Raf proto-oncogene serine/threonine-protein kinaseCatalogue of Somatic Mutations in Cancer (COSMIC) BRAF homepage - Mendelian genesBRAFKRAS12p12.1GTPase KRasCatalogue of Somatic Mutations in Cancer (COSMIC) KRAS homepage - Mendelian genesKRASMAP2K115q22.31Dual specificity mitogen-activated protein kinase kinase 1MAP2K1 @ LOVDMAP2K1SOS12p22.1Son of sevenless homolog 1SOS1 homepage - Mendelian genesSOS1RAF13p25.2RAF proto-oncogene serine/threonine-protein kinaseCatalogue of Somatic Mutations in Cancer (COSMIC)RAF1NRAS1p13.2GTPase NRasCatalogue of Somatic Mutations in Cancer (COSMIC) Resource of Asian Primary Immunodeficiency Diseases (RAPID) NRAS homepage - Mendelian genesNRASData are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.Table B. OMIM Entries for Noonan Syndrome (View All in OMIM) View in own window 163950NOONAN SYNDROME 1; NS1 164757V-RAF MURINE SARCOMA VIRAL ONCOGENE HOMOLOG B1; BRAF 164760V-RAF-1 MURINE LEUKEMIA VIRAL ONCOGENE HOMOLOG 1; RAF1 164790NEUROBLASTOMA RAS VIRAL ONCOGENE HOMOLOG; NRAS 176872MITOGEN-ACTIVATED PROTEIN KINASE KINASE 1; MAP2K1 176876PROTEIN-TYROSINE PHOSPHATASE, NONRECEPTOR-TYPE, 11; PTPN11 182530SON OF SEVENLESS, DROSOPHILA, HOMOLOG 1; SOS1 190070V-KI-RAS2 KIRSTEN RAT SARCOMA VIRAL ONCOGENE HOMOLOG; KRAS 609942NOONAN SYNDROME 3; NS3 610733NOONAN SYNDROME 4; NS4 611553NOONAN SYNDROME 5; NS5 613224NOONAN SYNDROME 6; NS6 613706NOONAN SYNDROME 7; NS7PTPN11Normal allelic variants. Tartaglia et al  identified mutation of PTPN11 as causative of Noonan syndrome. The gene comprises 15 exons.Pathologic allelic variants. Missense mutations in PTPN11 were identified in 50% of affected individuals examined. Ninety-five percent of these mutations alter residues at or close to the SH2-PTP interacting surfaces, which are involved in switching between active and inactive conformations of the protein and cause catalytic activation and gain of function. Five percent of the mutations alter sensitivity to activation from binding partners. One in-frame deletion, p.Gly60del, has been described [Yoshida et al 2004a]. See Table 2.Table 2. Selected PTPN11 Pathologic Allelic VariantsView in own windowDNA Nucleotide Change Protein Amino Acid ChangeReference Sequences c.922A>Gp.Asn308AspNM_002834.3 NP_002825.3c.179_181delGTG p.Gly60delSee Quick Reference for an explanation of nomenclature. GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www.hgvs.org).Normal gene product. PTPN11 encodes tyrosine-protein phosphatase non-receptor type 11 (SHP-2), a widely expressed extracellular protein that has two tandemly arranged SRC-2 homology 2 (SH2) domains at the N terminus (N-SH2 and C-SH2), a single catalytic protein tyrosine phosphatase (PTP) domain, and a carboxy tail with two TP sites and a proline-rich stretch. The SH2-PTP interaction maintains the protein in an inactive state. The protein is a key molecule in the cellular response to growth factors, hormones, cytokines, and cell adhesion molecules. It is required in several intracellular signal transduction pathways that control diverse developmental processes (including cardiac semilunar valvulogenesis and blood cell progenitor commitment and differentiation) and has a role in modulating cellular proliferation, differentiation, migration, and apoptosis [Tartaglia et al 2002, Fragale et al 2004].Abnormal gene product. Activation of tyrosine-protein phosphatase non-receptor type II stimulates epidermal growth factor-mediated RAS/ERK/MAPK activation, increasing cell proliferation [Tartaglia et al 2002, Fragale et al 2004].KRASNormal allelic variants. The gene comprises four exons spanning 45 kb. Alternative splicing produces two isoforms (4a and 4b) that differ at the C terminus. In 98% of transcripts, exon 4a is spliced out; and only exon 4b is available for translation into protein. The effector or switch domains are part of exons 1 and 2, while binding to guanine nucleotide exchange factors occurs in exon 3.Pathologic allelic variants. Somatic KRAS and NRAS mutations have been found in myeloid malignancies and other cancers. The association between abnormal Kras and Noonan syndrome is the first evidence of a role in embryonic development. These gain-of-function mutations confer biochemical and cellular phenotypes similar to Noonan syndrome-associated SHP-2 mutations.Normal gene product. Ras proteins regulate cell fates by cycling between active guanosine triphosphate (GTP)-bound and inactive guanosine diphosphate (GDP)-bound conformations. They are key regulators of the RAS-RAF-MEK-ERK pathway, which is important for proliferation, growth, and death of cells.Abnormal gene product. The abnormal K-Ras protein induces hypersensitivity of primary hematopoietic progenitor cells to growth factors and deregulates signal transduction in a cell lineage-specific manner. Strong gain-of-function KRAS mutations may be incompatible with life.SOS1Normal allelic variants. SOS1 comprises 23 exons and encodes a 150-kd multidomain protein. Pathologic allelic variants. Noonan syndrome-associated SOS1 missense mutations are hypermorphic; that is, they increase signaling through the RasMAPK pathway. The vast majority are located in highly conserved sites. They cluster at codons encoding residues implicated in the maintenance of SOS1 in its autoinhibited form. One such cluster is found in the codons encoding the PH domain and may disrupt the autoinhibited conformation by destabilizing the conformation of the DH domain. Another cluster resides in codons encoding the helical linker between the DH and REM domains. A third cluster affects codons of residues that mediate the interaction between the DH and REM domains.Normal gene product. SOS1 (son of sevenless homolog 1) protein comprises a RAS-GEF (guanine nucleotide exchange factor) domain, a conserved histone-like fold, Dbl homology (DH) and plekstrin homology (PH) domains, a helical linker, a RAS exchange motif (REM), and a proline-rich region. The Dbl homology domain may act as a guanine nucleotide exchange factor (GEF) for the RAC family small G proteins (RAC-GEF). SOS1 has two RAS binding sites: an effector site in the Cdc25 domain and an allosteric site formed by the REM and Cdc25 domains. RAS binding to the allosteric site enhances RAS-GEF activity. The DH-PH module controls RAS binding at this site and likely acts as an intramolecular inhibitor of RAS-GEF activity. The entire N terminus functions as an integrated unit to inhibit the REM-Cdc25 domain. SOS1 is a RAS-specific guanine nucleotide exchange factor (GEF). The protein is autoinhibited owing to complex regulatory intra- and intermolecular interactions. After receptor tyrosine kinase (RTK) stimulation, SOS1 is recruited to the plasma membrane, where it acquires a catalytically active conformation. It then, in turn, catalyzes activation of the RAS-MAPK pathway by conversion of RAS-GDP to RAS-GTP. Abnormal gene product. Noonan syndrome-associated SOS1 mutations abrogate autoinhibition, increasing and prolonging RAS activation and downstream signaling through enhanced RAS-GEF activity. Somatic SOS1 mutations have not been found in cancer.RAF1Normal allelic variants. RAF1 comprises 17 exons.Pathologic allelic variants. The consensus 14-3-3 recognition site includes amino acid residues Arg256, Ser257, Ser259, and Pro261 in exon 7. Many of the mutations identified in Noonan syndrome cluster in this CR2 domain, interfere with 14-3-3 binding, and cause greater kinase activity than wild-type protein, both basally and after EGF stimulation. Other mutations reside in the RAF activation segment in CR3 and show reduced or absent kinase activity. However, they still result in constitutive ERK activation. Somatic RAF1 mutations have only rarely been found in cancer. Most of these cancer-causing mutations do not cluster in the CR2 and CR3 hot spots.Normal gene product. RAF1 is ubiquitously expressed and encodes a protein of 648 amino acids with three domains. It has three conserved regions (CR). CR1 (exons 2-5) encode a RAS-binding domain (RBD) and a cysteine-rich domain (CRD). CR2 lies in exon 7, while CR3, which spans exons 10-17, encodes an activation segment. The gene is highly regulated with numerous serine and threonine residues that can be phosphorylated, resulting in activation or inactivation. The Ser259 residue in CR2 is particularly important. In the inactive state, the N terminus of RAF1 interacts with and inactivates the kinase domain at the C terminus. This conformation is stabilized by 14-3-3 protein dimers that bind to phosphorylated Ser259 and Ser261. Dephosphorylation of Ser259 facilitates binding of RAF1 to RAS-GTP and propagation of the signal through the RAS-MAPK cascade via RAF1 MEK kinase activity. CR1 and CR2 both have negative regulatory function, removal of which results in oncogenic activity. The kinase domain, CR3, also associates with 14-3-3.Abnormal gene product. Noonan syndrome-associated RAF1 mutations increase and prolong RAS activation and downstream signaling through enhanced RAS-GEF activity and reduced 14-3-3 binding and autoinhibition.NRASNormal allelic variants. NRAS comprises seven exons. There are two main NRAS transcripts of 4.3 kb and 2 kb.Pathologic allelic variants. The two pathologic variants reported in association with NS are Thr50Ile and Gly60Glu, both in exon 3. The Thr50-to-Ile substitution is located within a conserved residue located in the beta-2-beta-3 loop connecting the two switch regions. In vitro functional expression studies showed that the mutant protein resulted in enhanced downstream phosphorylation in the presence of serum. Protein modeling suggests that Thr50 interacts with the polar heads of membrane phospholipids and is an integral part of a region that controls RAS membrane orientation. In vitro functional expression studies showed that the Gly60Glu mutant protein resulted in enhanced downstream phosphorylation in the presence of serum and that mutant protein accumulated constitutively in the active GTP-bound form. Normal gene product. RAS proteins act as molecular switches through cycling between inactive GDP-bound and active GTP-bound states. In its active form, Ras can interact productively with over 20 effectors including Raf, phosphatidylinositol-3-kinase, and Ral-GDP dissociation simulator (GDS). This activates the Raf-MEK-MAPK cascade which promotes cell proliferation, differentiation, or survival. Abnormal gene product. Expression of the NS-associated NRAS substitutions Thr50Ile or Gly60Glu in model cells resulted in enhanced phosphorylation of MEK and ERK in the presence of serum or after epidermal growth factor (EGF) stimulation. Similar to germline KRAS mutations causing Noonan syndrome and cardiofaciocutaneous syndrome, germline NRAS alterations do not affect residues commonly mutated in human cancers and appear to be less activating in dysregulating intracellular signaling in vitro compared with cancer-associated somatic mutations. BRAF Normal allelic variants. BRAF encodes B-Raf, a member of the Raf family, which also includes C-Raf and A-Raf encoded by the X-linked gene ARAF. BRAF spans approximately 190 kb and comprises 18 exons. Pathologic allelic variants. The spectrum of BRAF mutations in individuals with Noonan syndrome is restricted to only two variants in three cases. These variants are novel, never having been identified in cancer. Two mutations were de novo and one was familial.Normal gene product. The protein product of BRAF is B-Raf, a serine/threonine protein kinase that is one of the many direct downstream effectors of Ras. The Raf/MEK/ERK module of kinases is critically involved in cell proliferation, differentiation, motility, apoptosis, and senescence. B-Raf has only two known downstream effectors, mitogen-activated protein kinase 1 and 2 (also known as MEK1 and MEK2). The three conserved regions (CR) in B-Raf: CR1 (conserved region 1), containing the Ras binding domain and the cysteine-rich domain, both of which are required for recruitment of B-Raf to the cell membrane CR2, the smallest of the conserved regions CR3, the kinase domain containing the glycine-rich loop (exon 11) and the activation segment (exon 15) of the catalytic domainExons 3-6 encode a RAS-binding domain (RBD) and a cysteine-rich domain (CRD), while the kinase domain is encoded by exons 11-17. BRAF is ubiquitously expressed and encodes a protein of 766 amino acids. It is activated following GTP-bound RAS binding, and phosphorylates and activates the dual specificity mitogen-activated protein kinase kinases (MEK1 and MEK2).Abnormal gene product. A 722C>T transition, exon 6, Thr241Met has been reported in association with NS; a closely related mutant protein, Thr241Pro, has been reported in one individual with LEOPARD syndrome. In vitro studies showed a slight increase in MEK phosphorylation. A 1789 C>T transversion, exon 15, Leu597Val, has been reported in a single case of NS.MAP2K1Normal allelic variants. MEK, like Raf, exists as a multigene family. MAP2K1 spans approximately 104 kb. Pathologic allelic variants. Missense mutations in MAP2K1 cause Noonan syndrome in fewer than 2% of clinically diagnosed individuals. Somatic mutations have been reported in ovarian cancer [Estep et al 2007] and lung cancer [Marks et al 2008]. Normal gene product. MAP2K1 encodes threonine/tyrosine kinases with the ability to activate ERK1 and ERK2. The normal protein encoded by MAPK21 is dual specificity mitogen-activated protein kinase kinase 1 (MEK1). The MEK1 and MEK2 proteins have approximately 85% amino acid identity. MEK1 and MEK2 proteins do not serve redundant purposes as determined in mouse development. Abnormal gene product. Three individuals with NS had a novel mutation in exon 2 of MAP2K1. These mutations were found in exons already identified as mutational hot spots in cardiofaciocutaneous syndrome.
Disclaimer: IBIS Databases and associated information are protected by copyright.
This server and its associated data and services are for academic, non-commercial use only.
The Helmholtz Zentrum München has no liability for the use of results, data or information which have been provided through this server.
Neither the use for commercial purposes, nor the redistribution of IBIS database files to third parties nor
the distribution of parts of files or derivative products to any third parties is permitted.
Commercial users shall contact the Helmholtz Zentrum München for a separate users license.