Genotype-phenotype correlations in Noonan syndrome

Zenker, Martin; Buheitel, G.; Rauch, Ralf; Koenig, Rainer; Bosse, Kirstin; Kreß, Wolfram; Tietze, H. U.; Doerr, Helmuth-Guenther; Hofbeck, Michael; Singer, H.; Reis, André; Rauch, Anita

doi:10.1016/j.jpeds.2003.11.032

Cited by 224 publications

(228 citation statements)

References 22 publications

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“…In some studies, there were no differences in growth parameters between 51 PTPN11 mutation-positive and 64 mutation-negative subjects (29), as was the case in an analysis of adult height in 56 patients (30). In another study, 82% of 34 PTPN11 mutation-positive cases and 57% of the 23 PTPN11 mutation-negative subjects had a height of less than −2 SDS (mean −3.1 SDS and −2.4 SDS, respectively) (31). There are similar reports that PTPN11 mutation-positive subjects are shorter than PTPN11 mutation-negative subjects (32,33).…”

Section: Articles Isojima Et Almentioning

confidence: 92%

Growth references for Japanese individuals with Noonan syndrome

et al. 2015

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Background: Noonan syndrome (NS) is a clinically and genetically heterogeneous syndrome characterized by distinctive facial features, short stature, congenital heart diseases, and other comorbidities. NS-specific growth charts are essential for NS care, but currently no such charts are available for Asian populations. Methods:We conducted a nationwide survey by collaborating with three academic societies in Japan. We obtained the data of 356 clinically diagnosed NS subjects from 20 hospitals. The Lambda-Mu-Sigma method was used for establishing growth charts. results: A total of 308 subjects (males: 159 and females: 149) were analyzed after excluding 48 subjects because of missing auxological data (26 subjects), presence of complications affecting growth (5 subjects), and extreme longitudinal growth aberrations which lay more than three standard deviation scores from the mean in this population (17 subjects). Genetic analyses were performed in 150 patients (48.7%); 103 (68.7%) were reported to have some abnormalities in the known causative genes. Cardiovascular diseases were found in 256 patients (83.1%). The NS-specific height, weight, and BMI charts were constructed with 3,249 mixed longitudinal and cross-sectional measurements. conclusion: Growth standards for Japanese individuals with NS were established. These charts are expected to be used in various clinical settings.

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Section: Articles Isojima Et Almentioning

confidence: 92%

Growth references for Japanese individuals with Noonan syndrome

et al. 2015

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“…Indeed, the most frequent mutation found in NS is p .N308D (10,19). Mutation p.N308S has also been found in several studied patients (10,(19)(20)(21)(22)(23).…”

Section: Discussionmentioning

confidence: 85%

“…Although a clear genotype-phenotype correlation in NS has not been established, patients presenting mutations in PTPN11 tend to show a higher prevalence of pulmonary stenosis, short stature, sternal deformity and bleeding diathesis (10,19). Specifically for the mutation p.N308D, Tartaglia and cols.…”

Section: Discussionmentioning

confidence: 99%

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Co-occurring PTPN11 and SOS1 gene mutations in Noonan syndrome: does this predict a more severe phenotype?

Brasil

Malaquias²,

Wanderley

et al. 2010

Arq Bras Endocrinol Metab

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Noonan syndrome (NS) is an autosomal dominant disorder, with variable phenotypic expression, characterized by short stature, facial dysmorphisms and heart disease. Different genes of the RAS/MAPK signaling pathway are responsible for the syndrome, the most common are: PTPN11, SOS1, RAF1, and KRAS. The objective of this study was to report a patient with Noonan syndrome presenting mutations in two genes of RAS/MAPK pathway in order to establish whether these mutations lead to a more severe expression of the phenotype. We used direct sequencing of the PTPN11, SOS1, RAF1, and KRAS genes. We have identified two described mutations in heterozygosity: p.N308D and p.R552G in the genes PTPN11 and SOS1, respectively. The patient has typical clinical features similar to the ones with NS and mutation in only one gene, even those with the same mutation identified in this patient. A more severe or atypical phenotype was not observed, suggesting that these mutations do not exhibit an additive effect.

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“…Differential SHP2 activation by different alleles might help explain the variable phenotypic spectrum in NS, yet patient surveys have failed to identify strong PTPN11 genotype/ phenotype correlations (22,23). Notably, family members with the same PTPN11 mutation can have significantly different presentations (24), indicating that modifier alleles may have a strong effect on phenotype.…”

Section: Discussionmentioning

confidence: 99%

Noonan syndrome cardiac defects are caused by PTPN11 acting in endocardium to enhance endocardial-mesenchymal transformation

Araki

Chan

Newbigging

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

112

113

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Noonan syndrome (NS), the most common single-gene cause of congenital heart disease, is an autosomal dominant disorder that also features proportionate short stature, facial abnormalities, and an increased risk of myeloproliferative disease. Germline-activating mutations in PTPN11, which encodes the protein tyrosine phosphatase SHP2, cause about half of NS cases; other causative alleles include KRAS, SOS1, and RAF1 mutants. We showed previously that knock-in mice bearing the NS mutant Ptpn11 D61G on a mixed 129S4/SvJae X C57BL6/J background exhibit all major NS features, including a variety of cardiac defects, with variable penetrance. However, the cellular and molecular mechanisms underlying NS cardiac defects and whether genetic background and/or the specific NS mutation contribute to the NS phenotype remained unclear. Here, using an inducible knock-in approach, we show that all cardiac defects in NS result from mutant Shp2 expression in the endocardium, not in the myocardium or neural crest. Furthermore, the penetrance of NS defects is affected by genetic background and the specific Ptpn11 allele. Finally, ex vivo assays and pharmacological approaches show that NS mutants cause cardiac valve defects by increasing Erk MAPK activation, probably downstream of ErbB family receptor tyrosine kinases, extending the interval during which cardiac endocardial cells undergo endocardial-mesenchymal transformation. Our data provide a mechanistic underpinning for the cardiac defects in this disorder.cardiac development ͉ human disease ͉ signal transduction ͉ protein tyrosine phosphatase ͉ cardiac valves

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Genotype-phenotype correlations in Noonan syndrome

Cited by 224 publications

References 22 publications

Growth references for Japanese individuals with Noonan syndrome

Growth references for Japanese individuals with Noonan syndrome

Co-occurring PTPN11 and SOS1 gene mutations in Noonan syndrome: does this predict a more severe phenotype?

Noonan syndrome cardiac defects are caused by PTPN11 acting in endocardium to enhance endocardial-mesenchymal transformation

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