Noonan syndrome with multiple lentigines and associated craniosynostosis

McDonald, Bryan; Pigors, Manuela; Kelsell, David P.; O’Toole, Edel A.; Burkitt-Wright, Emma; Kerr, Bronwyn; Batta, K.

doi:10.1111/ced.13329

Cited by 11 publications

(7 citation statements)

References 5 publications

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“…Pathogenic, activating variants in genes of the fibroblast growth receptor (FGFR) pathway are the major cause of syndromic craniosynostoses, with variants in FGFR2 and FGFR3 causing almost half of these cases (Cunningham et al, 2007;Wilkie et al, 2017). However, craniosynostosis has recently been recognized to be associated with multiple RASopathies including CFCS, NS, NSML, and Noonan-like with loose anagen hair (Bertola et al, 2017;McDonald et al, 2018;Takenouchi et al, 2014;Ueda et al, 2017). The etiology of RASopathyassociated craniosynostosis is hypothesized to be related to the intersection of the RAS/MAPK and FGFR signaling pathways (Addissie et al, 2015;Takenouchi et al, 2014).…”

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confidence: 99%

Craniosynostosis is a feature of Costello syndrome

Weaver

Caré

Wakefield

et al. 2021

American J of Med Genetics Pt A

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confidence: 99%

Craniosynostosis is a feature of Costello syndrome

Weaver

Caré

Wakefield

et al. 2021

American J of Med Genetics Pt A

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“…Half of them correspond to NS, seven to CFCS, and only two fit with NSML diagnosis (including present case). The other patient with NSML and craniosynostosis was described recently by McDonald et al (). Exome sequencing analysis of that patient revealed a heterozygous pathogenic variant in PTPN11 (p.R498W), previously reported in association with NSML (Digilio et al, ; Sarkozy, Conti, et al, ; Sarkozy, Obregon, et al, ).…”

Section: Discussionmentioning

confidence: 89%

“…In addition, different studies have shown consistent association between craniosynostosis and NS patients with SHOC2 , KRAS , and PTPN11 pathogenic variants (Addissie et al, ; Takenouchi et al, ; Ueda, Yaoita, Niihori, Aoki, & Okamoto, ), and CFCS patients with KRAS and BRAF pathogenic variants (Ueda et al, ). Recently, the first patient with NSML ( PTPN11 pathogenic variant) and craniosynostosis was reported (McDonald et al, ).…”

Section: Introductionmentioning

confidence: 99%

RAF1 variant in a patient with Noonan syndrome with multiple lentigines and craniosynostosis

Rodrı́guez

Ponce

Berward

et al. 2019

American J of Med Genetics Pt A

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We report the case of a 14 years and 8 months girl, who is the first child of nonconsanguineous parents, with short stature, obstructive hypertrophic cardiomyopathy, multiple facial lentigines, high and wide forehead, downslanting palpebral fissures, lowset ears, short neck, and pectus excavatum; all features suggestive of Noonan syndrome with multiple lentigines (NSML). In addition, the patient exhibited craniosynostosis. Molecular analysis of rats sarcoma (RAS)/mitogen-activated protein kinase (MAPK) pathway genes with high-resolution melting curve analysis followed by sequencing showed a RAF1 amino acid substitution of valine to glycine at position 263 (p.V263G). The present report provides clinical data regarding the first association of a RAF1 variant and craniosynostosis in a patient with clinical diagnosis of NSML.

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“…Sagittal craniosynostosis was observed in NS1096. Craniosynostosis has been reported in patients with Noonan syndrome ( PTPN11 and KRAS ), Noonan syndrome with multiple lentigines ( PTPN11 and RAF1 ), Noonan syndrome‐like disorder with loose anagen hair ( SHOC2 and PPP1CB ), and CFC syndrome ( BRAF and KRAS ) (Addissie et al, 2015; Bertola et al, 2017; Kratz et al, 2009; McDonald et al, 2018; Rodriguez et al, 2019; Takenouchi et al, 2014; Ueda et al, 2017). To our best knowledge, craniosynostosis has not been reported in CS patients with HRAS variants.…”

Section: Discussionmentioning

confidence: 99%

Duplications in the G3 domain or switch II region in HRAS identified in patients with Costello syndrome

et al. 2021

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Costello syndrome (CS) is an autosomal-dominant disorder characterized by distinctive facial features, hypertrophic cardiomyopathy, skeletal abnormalities, intellectual disability, and predisposition to cancers. Germline variants in HRAS have been identified in patients with CS. Intragenic HRAS duplications have been reported in three patients with a milder phenotype of CS. In this study, we identified two known HRAS variants, p.(Glu63_Asp69dup), p.(Glu62_Arg68dup), and one novel HRAS variant, p.(Ile55_Asp57dup), in patients with CS, including a patient with craniosynostosis. These intragenic duplications are located in the G3 domain and the switch II region. Cells expressing cDNA with these three intragenic duplications showed an increase in ELK-1 transactivation. Injection of wild-type or mutant HRAS mRNAs with intragenic duplications in zebrafish embryos showed significant elongation of the yolk at 11 h postfertilization, which was improved by MEK inhibitor treatment, and a variety of developmental abnormalities at 3 days post fertilization was observed. These results indicate that small in-frame duplications affecting the G3 domain and switch II region of HRAS increase the activation of the ERK pathway, resulting in developmental abnormalities in zebrafish or patients with CS.

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Noonan syndrome with multiple lentigines and associated craniosynostosis

Abstract: Click https://www.wileyhealthlearning.com/ced.aspx for the corresponding questions to this CME article.

Cited by 11 publications

References 5 publications

Craniosynostosis is a feature of Costello syndrome

Craniosynostosis is a feature of Costello syndrome

RAF1 variant in a patient with Noonan syndrome with multiple lentigines and craniosynostosis

Duplications in the G3 domain or switch II region in HRAS identified in patients with Costello syndrome

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