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At least 19 recordsLinked to original sources
PubMed1991

Hypertrophic obstructive cardiomyopathy as a manifestation of a cardiocutaneous syndrome (Noonan syndrome).

The case of a 50-year-old patient with hypertrophic obstructive cardiomyopathy is reported. The patient demonstrated somatic signs of the Turner phenotype, but a cytogenetically normal karyotype was shown. These findings were compatible with the diagnosis of Noonan syndrome. The most commonly diagnosed cardiac disease in this syndrome is pulmonary stenosis, followed by hypertrophic cardiomyopathy. The patient's prognosis is limited by the natural history or the typical complications of the underlying cardiac lesion.

Cardiomyopathy, Hypertrophic↗
PubMed1996

Are cardio-facio-cutaneous syndrome and Noonan syndrome distinct? A case of CFC offspring of a mother with Noonan syndrome.

Cardio-facio-cutaneous syndrome is characterized by complex congenital heart disease, characteristic facies, ectodermal abnormalities, growth failure, and mental retardation. It has been described as a distinctive entity from Noonan syndrome. This paper presents a child with cardio-facio-cutaneous syndrome born to a mother with Noonan syndrome. This is suggestive of cardio-facio-cutaneous syndrome being a variable expression of Noonan syndrome.

Adult↗
PubMed2025

Genotype-phenotype correlations with autism spectrum disorder-related traits in noonan syndrome and noonan syndrome with multiple lentigines: a cross-sectional study.

BACKGROUND: Noonan syndrome (NS) and Noonan syndrome with multiple lentigines (NSML) are neurodevelopmental conditions caused by genetic variants leading to upregulated signaling in the RAS-MAPK pathway. While previous research has focused on genetic variability in cognitive and cardiac phenotypes, behavioral phenotypes, and their correlations across genetic variants and within the PTPN11 gene remain poorly characterized. METHODS: This study included 121 individuals with NS (PTPN11: 88, SOS1: 18, RAF1: 6, KRAS: 2, RIT1: 3, NRAS: 2, LZTR1: 2, SOS2: 1) and seven individuals with NSML (PTPN11), compared to age- and sex-matched typically developing (TD) (N = 71). Behavioral questionnaires assessed social responsiveness and ASD-related traits (using SRS-2), and emotional problems (using CBCL) to identify genetic variant-specific behavioral profiles. Biochemical profiling of SHP2 activity in PTPN11-associated NS variants examined genotype-phenotype relationships. RESULTS: Compared to TD individuals, those with PTPN11-associated NS, NSML, and SOS1-associated NS exhibited clinically elevated scores, indicating increased ASD-related behaviors, poorer social functioning, and heightened emotional problems. Genetic variant comparisons revealed that individuals with PTPN11-associated NS and NSML exhibited greater ASD-related challenges than those with RAF1. Individuals with NSML exhibit elevated attention problems compared to all other genetic groups. Logistic regression results suggested each one-unit increase in SHP2 fold activation for PTPN11-associated NS corresponded to a 64% higher likelihood of markedly elevated restricted and repetitive behaviors, suggesting genotype-phenotype links. LIMITATIONS: Small sample sizes for rarer variants, leading to unequal group sizes across subgroups, with PTPN11 variants comprising most of the NS group. Future research should address these sampling constraints and conduct functional studies to clarify variant impacts. Longitudinal assessments could elucidate behavioral phenotype trajectories. CONCLUSIONS: This study underscores the importance of genetic variant-specific research to understand unique behavioral phenotypes in NS and NSML. Our findings indicate a higher risk for ASD-related symptoms in PTPN11-associated NS and NSML compared to other variants. Additionally, individuals with PTPN11-associated NS and higher SHP2 fold activation exhibited greater impairments in restricted and repetitive behaviors, suggesting SHP2 activation variations may contribute to phenotypic variability. By linking ASD-related symptoms to biochemical predictors in PTPN11-associated NS, this study may inform future targeted treatment approaches.

Humans↗
PubMed2006

Germline gain-of-function mutations in SOS1 cause Noonan syndrome.

Noonan syndrome, the most common single-gene cause of congenital heart disease, is characterized by short stature, characteristic facies, learning problems and leukemia predisposition. Gain-of-function mutations in PTPN11, encoding the tyrosine phosphatase SHP2, cause approximately 50% of Noonan syndrome cases. SHP2 is required for RAS-ERK MAP kinase (MAPK) cascade activation, and Noonan syndrome mutants enhance ERK activation ex vivo and in mice. KRAS mutations account for <5% of cases of Noonan syndrome, but the gene(s) responsible for the remainder are unknown. We identified missense mutations in SOS1, which encodes an essential RAS guanine nucleotide-exchange factor (RAS-GEF), in approximately 20% of cases of Noonan syndrome without PTPN11 mutation. The prevalence of specific cardiac defects differs in SOS1 mutation-associated Noonan syndrome. Noonan syndrome-associated SOS1 mutations are hypermorphs encoding products that enhance RAS and ERK activation. Our results identify SOS1 mutants as a major cause of Noonan syndrome, representing the first example of activating GEF mutations associated with human disease and providing new insights into RAS-GEF regulation.

Adolescent↗
PubMed1996

Hypertrophic cardiomyopathy in Noonan syndrome.

Noonan syndrome, a well-known multiple congenital anomalies syndrome, is frequently accompanied by cardiovascular diseases including hypertrophic cardiomyopathy (HCM). The incidence of HCM in Noonan syndrome is approximately 20-30% and one-third of cases reveal ventricular outflow obstruction. HCM in Noonan syndrome is occasionally associated with a congenital heart defect, whereas classic HCM seldom accompanies cardiac malformations. Asymmetric septal hypertrophy and symmetric septal hypertrophy (concentric hypertrophy) can be observed both in HCM with Noonan syndrome and in classic HCM, but apical hypertrophy has not been reported in Noonan syndrome yet, although it appears in classic HCM. Congestive heart failure is the major cause of death in patients with HCM in Noonan syndrome, but cases of sudden death have also been reported. The histopathologic findings of ventricular myocardial tissue in HCM with Noonan syndrome are similar to those in classic HCM.

Adolescent↗
PubMed2001

Systemic lupus erythematosus in a man with Noonan syndrome.

Noonan syndrome is a multiple congenital anomaly condition characterized by craniofacial anomalies, short stature, cardiac malformations, and normal peripheral blood karyotype analysis. Prior reports of individuals with Noonan syndrome have revealed an association with several autoimmune diseases, including vasculitis and anterior uveitis, but no reports of systemic lupus erythematosus (SLE). Here we present the first case report of a 21-year-old man with a clinical diagnosis of Noonan syndrome and a recent history of mitral valve dysfunction and systemic lupus erythematosus. We discuss his findings in the context of known features of Noonan syndrome and propose that individuals with Noonan syndrome be regularly monitored for associated autoimmune phenomena.

Adult↗
PubMed2006

Germline KRAS mutations cause Noonan syndrome.

Noonan syndrome (MIM 163950) is characterized by short stature, facial dysmorphism and cardiac defects. Heterozygous mutations in PTPN11, which encodes SHP-2, cause approximately 50% of cases of Noonan syndrome. The SHP-2 phosphatase relays signals from activated receptor complexes to downstream effectors, including Ras. We discovered de novo germline KRAS mutations that introduce V14I, T58I or D153V amino acid substitutions in five individuals with Noonan syndrome and a P34R alteration in a individual with cardio-facio-cutaneous syndrome (MIM 115150), which has overlapping features with Noonan syndrome. Recombinant V14I and T58I K-Ras proteins show defective intrinsic GTP hydrolysis and impaired responsiveness to GTPase activating proteins, render primary hematopoietic progenitors hypersensitive to growth factors and deregulate signal transduction in a cell lineage-specific manner. These studies establish germline KRAS mutations as a cause of human disease and infer that the constellation of developmental abnormalities seen in Noonan syndrome spectrum is, in large part, due to hyperactive Ras.

Adolescent↗
PubMed2002

PTPN11 (protein-tyrosine phosphatase, nonreceptor-type 11) mutations in seven Japanese patients with Noonan syndrome.

Noonan syndrome is an autosomal dominant disorder defined by short stature, delayed puberty, and characteristic dysmorphic features. Tartaglia et al. (Nature Genetics, 29:465-468) have recently shown that gain-of-function mutations in the gene PTPN11 (protein-tyrosine phosphatase, nonreceptor-type 11) cause Noonan syndrome in roughly half of patients that they examined. To further explore the relevance of PTPN11 mutations to the pathogenesis of Noonan syndrome, we analyzed the PTPN11 gene in 21 Japanese patients. Mutation analysis of the 15 coding exons and their flanking introns by denaturing HPLC and direct sequencing revealed six different heterozygous missense mutations (Asp61Gly, Tyr63Cys, Ala72Ser, Thr73Ile, Phe285Ser, and Asn308Asp) in seven cases (six sporadic and one familial). The mutations clustered either in the N-Src homology 2 domain or in the protein-tyrosine phosphatase domain. The clinical features of the mutation-positive and mutation-negative patients were comparable. The results provide further support to the notion that PTPN11 mutations are responsible for the development of Noonan syndrome in a substantial fraction of patients and that relatively infrequent features of Noonan syndrome, such as sensory deafness and bleeding diathesis, can also result from mutations of PTPN11.

Adolescent↗
PubMedDate not supplied

Bilateral coronary artery dilatation and supravalvular pulmonary stenosis in a child with noonan syndrome.

Noonan syndrome is the second most frequent congenital malformation syndrome, after Down syndrome, associated with cardiovascular abnormalities. The most prevalent cardiovascular abnormalities in Noonan syndrome are pulmonary stenosis and hypertrophic cardiomyopathy. We report the case of a 12-year-old girl with Noonan syndrome who had multiple cardiovascular abnormalities, including extensive bilateral coronary artery dilatation, valvular and supravalvular pulmonary stenosis, atrial septal defect, and mitral valve prolapse. Both coronary artery dilatation and supravalvular pulmonary stenosis, although rarely reported, are abnormalities of the cardiovascular system that may occur in Noonan syndrome.

Cardiomyopathy, Hypertrophic↗
PubMed2006

Gain-of-function SOS1 mutations cause a distinctive form of Noonan syndrome.

Noonan syndrome is a developmental disorder characterized by short stature, facial dysmorphia, congenital heart defects and skeletal anomalies. Increased RAS-mitogen-activated protein kinase (MAPK) signaling due to PTPN11 and KRAS mutations causes 50% of cases of Noonan syndrome. Here, we report that 22 of 129 individuals with Noonan syndrome without PTPN11 or KRAS mutation have missense mutations in SOS1, which encodes a RAS-specific guanine nucleotide exchange factor. SOS1 mutations cluster at codons encoding residues implicated in the maintenance of SOS1 in its autoinhibited form. In addition, ectopic expression of two Noonan syndrome-associated mutants induces enhanced RAS and ERK activation. The phenotype associated with SOS1 defects lies within the Noonan syndrome spectrum but is distinctive, with a high prevalence of ectodermal abnormalities but generally normal development and linear growth. Our findings implicate gain-of-function mutations in a RAS guanine nucleotide exchange factor in disease for the first time and define a new mechanism by which upregulation of the RAS pathway can profoundly change human development.

Animals↗
PubMed2004

Genetics and variation in phenotype in Noonan syndrome.

Noonan syndrome is a well-known clinical entity comprising multiple congenital anomalies characterized by typical facial features, short stature and congenital heart defect. Approximately 50% of cases are sporadic. Familial cases are generally autosomal dominant. In 2001 a gene responsible for Noonan syndrome, PTPN11, encoding for the non-receptor protein tyrosine phosphatase SHP-2, was identified. Mutation analysis of the PTPN11 gene was carried out in Nijmegen in 150 patients with Noonan syndrome. Mutations were found in 68 patients (45%), the most common being A922G in exon 8. In exon 4 a mutation was found that encoded the C-SH2 domain of the PTPN11 gene in two unique patients who shared some uncommon features. A 218C-->T mutation was found in exon 3 in one patient with Noonan syndrome and mild juvenile myelomonocytic leukaemia.

Adenine↗
PubMed2002

Cerebral occlusive artery disease in Noonan syndrome.

Noonan syndrome is an autosomal-dominant inherited syndrome with variable expression of multiple malformations including cardiovascular and craniofacial anomalies. While cerebrovascular insults due to cardiogenic emboli, coagulation abnormalities or cerebrovascular malformations have been documented before, intracerebral occlusive artery disease is not well recognized as a cause of stroke in this syndrome. A 6-year-old girl with Noonan syndrome presented with repetitive transient ischemic attacks consisting of dysphasia and right-sided central facial and arm weakness. Neuroimaging showed acute ischemic lesions in the left putamen and caudate nucleus. Multiple intracranial stenoses were found during transcranial Doppler examination and MR angiography. Although hypertrophic cardiomyopathy was documented by transesophageal echocardiography, a cardioembolic origin of the ischemic attacks was unlikely in this case. The symptoms resolved and did not recur after antiplatelet and anticoagulant therapy was initiated. Stenoses of intracranial cerebral arteries should be considered among the causes of stroke in young patients with Noonan syndrome.

Arterial Occlusive Diseases↗
PubMed1992

Ocular manifestations of Noonan syndrome.

Noonan syndrome is a genetic condition inherited in an autosomally dominant manner, characterised by congenital heart disease, short stature, abnormal facies and the somatic features of Turner's syndrome, but a normal Karyotype. The ophthalmological and orthoptic findings on 58 patients with Noonan syndrome are reported. External features were hypertelorism (74%), downward sloping palpebral apertures (38%), epicanthic folds (39%) and ptosis (48%). The orthoptic examination revealed strabismus in 48%, refractive errors in 61%, amblyopia in 33%, and nystagmus in 9% of cases. Sixty-three per cent of cases had anterior segment changes consisting of: Prominent corneal nerves (46%), anterior stromal dystrophy (4%), cataracts (8%) and panuveitis (2%). Fundal changes occurred in 20% of the study group, including optic nerve head drusen, optic disc hypoplasia, colobomas and myelinated nerves. Forty-seven per cent required non surgical treatment and a further 16% had undergone surgery for strabismus or ptosis. Only three patients had no visual defects. With such a high incidence of ophthalmic abnormalities it is clearly important that children with Noonan syndrome are screened by an ophthalmologist at an early age.

Adolescent↗
PubMed2001

Mutations in PTPN11, encoding the protein tyrosine phosphatase SHP-2, cause Noonan syndrome.

Noonan syndrome (MIM 163950) is an autosomal dominant disorder characterized by dysmorphic facial features, proportionate short stature and heart disease (most commonly pulmonic stenosis and hypertrophic cardiomyopathy). Webbed neck, chest deformity, cryptorchidism, mental retardation and bleeding diatheses also are frequently associated with this disease. This syndrome is relatively common, with an estimated incidence of 1 in 1,000-2,500 live births. It has been mapped to a 5-cM region (NS1) [corrected] on chromosome 12q24.1, and genetic heterogeneity has also been documented. Here we show that missense mutations in PTPN11 (MIM 176876)-a gene encoding the nonreceptor protein tyrosine phosphatase SHP-2, which contains two Src homology 2 (SH2) domains-cause Noonan syndrome and account for more than 50% of the cases that we examined. All PTPN11 missense mutations cluster in interacting portions of the amino N-SH2 domain and the phosphotyrosine phosphatase domains, which are involved in switching the protein between its inactive and active conformations. An energetics-based structural analysis of two N-SH2 mutants indicates that in these mutants there may be a significant shift of the equilibrium favoring the active conformation. This implies that they are gain-of-function changes and that the pathogenesis of Noonan syndrome arises from excessive SHP-2 activity.

Chromosomes, Human, Pair 12↗
PubMed2000

Cardiopulmonary rehabilitation in a patient with Noonan syndrome.

Noonan syndrome, an autosomal dominant disease occurring with an incidence of 1 in 1,000 to 1 in 2,500 live births, is characterized by its particular cardiovascular abnormalities, including pulmonic valve stenosis, pulmonary artery stenosis, and, more rarely, septal defects and coarctation of the aorta. The case of a 20-year-old man admitted for inpatient cardiopulmonary rehabilitation after pulmonic valve repair, left pulmonary artery angioplasty, and pectus excavatum repair is presented. His endurance was markedly decreased, thus limiting his ability to perform activities of daily living and reducing his exercise tolerance. With participation in a comprehensive cardiopulmonary rehabilitation program, he experienced marked improvement with independence in his activities of daily living and an increase in his metabolic equivalent levels from to 2.8 to 5.4. After inpatient rehabilitation, he underwent left pulmonary stent placement before being discharged home. Subsequent outpatient cardiopulmonary rehabilitation has continued to improve significantly his overall exercise tolerance. Given that Noonan syndrome is viewed as the most common syndrome associated with congenital heart disease after Down syndrome, physiatrists must be familiar with its presentation, its associated abnormalities, and the treatment approach to optimize the patient's cardiopulmonary, musculoskeletal, and psychological status.

Adult↗
PubMed2003

Spectrum of mutations in PTPN11 and genotype-phenotype correlation in 96 patients with Noonan syndrome and five patients with cardio-facio-cutaneous syndrome.

Noonan syndrome (NS) is a relatively common, but genetically heterogeneous autosomal dominant malformation syndrome. Characteristic features are proportionate short stature, dysmorphic face, and congenital heart defects. Only recently, a gene involved in NS could be identified. It encodes the non-receptor protein tyrosine phosphatase SHP-2, which is an important molecule in several intracellular signal transduction pathways that control diverse developmental processes, most importantly cardiac semilunar valvulogenesis. We have screened this gene for mutations in 96 familial and sporadic, well-characterised NS patients and identified 15 different missense mutations in a total of 32 patients (33%), including 23 index patients. Most changes clustered in one exon which encodes parts of the N-SH2 domain. Five of the mutations were recurrent. Interestingly, no mutations in the PTPN11 gene were detected in five additional patients with cardio-facio-cutaneous (CFC) syndrome, which shows clinical similarities to NS.

DNA Mutational Analysis↗
PubMed2000

Growth hormone therapy in noonan syndrome.

Noonan syndrome (NS) is an autosomal dominant disorder that can be difficult to diagnose. Growth retardation is a consistent feature, however, and although children are not typically growth hormone (GH) deficient, a minority may have suboptimal GH levels. An ongoing multicentre study examining the safety and efficacy of GH therapy in NS showed increases in height standard deviation scores (SDS; p < 0. 0001) and height velocity (p < 0.0001) after 12 months of GH at pharmacological doses. There was no increase in mean maximal cardiac left ventricular wall thickness during the 12-month treatment period. Long-term follow-up data covering 3 years of GH therapy showed sustained increases in height SDS and height velocity compared with baseline (p < 0.02). Further large and appropriately controlled studies of high-quality design are essential to further our understanding of NS and to establish the long-term safety and efficacy of GH.

Adolescent↗