Craniosynostosis in patients with RASopathies: Accumulating clinical evidence for expanding the phenotype

Ueda, Kimiko; Yaoita, Masako; Niihori, Tetsuya; Aoki, Yoko; Okamoto, Nobuhiko

doi:10.1002/ajmg.a.38337

Cited by 39 publications

(37 citation statements)

References 19 publications

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“…Craniosynostosis has been recently implicated as a comorbidity of NS [23], and 5 patients (3 with PTPN11, 1 with KRAS, and 1 with SOS1 mutations) were diagnosed as having craniosynostosis (Tables 1 and 3). Twelve of 35 patients (34.3%) exhibited otolaryngeal diseases including hearing disorders, otitis media, enlarged tonsil, and adenotrophy (Tables 1 and 3).…”

Section: Clinical Characteristics Of Genetically Diagnosed Ns Patientsmentioning

confidence: 99%

Genotype-phenotype correlation analysis in Japanese patients with Noonan syndrome

et al. 2019

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Noonan syndrome (NS) is a heterogeneous disorder with multiple congenital malformations. Recent advances in molecular and genetic approaches have identified a number of responsible genes for NS, most of which are components of the RAS/MAPK signaling pathway, and genotype-phenotype correlation analyses have been extensively performed; however, analysis of Japanese NS patients is limited. Here, we evaluated clinical characteristics in genetically diagnosed NS patients and their relationships to genotypes. A total of 48 clinically diagnosed NS were included, and responsible mutations were identified in 39 patients (81.3%) with PTPN11 mutations being the most prevalent followed by SOS1 mutations. Cardiac anomalies including pulmonary stenosis and hypertrophic cardiomyopathy were most prevalent (87.2%), and the prevalence of hypertrophic cardiomyopathy was greater in patients without PTPN11 mutations than in those with PTPN11 mutations. Short stature was the second-most prevalent (69.2%) characteristic, and present height SD score was significantly associated with height SD score at 1 year old. Patients with SOS1 mutations had greater present height SD score and better growth during infancy. These findings suggest the presence of a genotype-phenotype correlation in Japanese patients with NS, which enables us to use genetic information to predict the clinical course and may allow for genotype-based medical interventions.

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Section: Clinical Characteristics Of Genetically Diagnosed Ns Patientsmentioning

confidence: 99%

Genotype-phenotype correlation analysis in Japanese patients with Noonan syndrome

et al. 2019

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“…Among RASopathies, craniosynostosis appears to be consistently associated with NS and CFC syndrome only, and with mutations limited to PTPN11, SHOC2, KRAS , and BRAF (Takenouchi et al, 2014 ; Addissie et al, 2015 ; Ueda et al, 2017 ). In the Ueda et al report ( 2017 ), 3 out of 34 NS patients (9%) and 6 out of 18 CFC patients (33%) had craniosynostosis, and craniosynostosis affected all patients with mutations in KRAS . This strong genotype-phenotype association suggests specific mechanisms of pathology, worthy of investigation.…”

Section: Gene-related Syndromic Craniosynostosismentioning

confidence: 99%

Syndromic Craniosynostosis Can Define New Candidate Genes for Suture Development or Result from the Non-specifc Effects of Pleiotropic Genes: Rasopathies and Chromatinopathies as Examples

et al. 2017

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Craniosynostosis is a heterogeneous condition caused by the premature fusion of cranial sutures, occurring mostly as an isolated anomaly. Pathogenesis of non-syndromic forms of craniosynostosis is largely unknown. In about 15–30% of cases craniosynostosis occurs in association with other physical anomalies and it is referred to as syndromic craniosynostosis. Syndromic forms of craniosynostosis arise from mutations in genes belonging to the Fibroblast Growth Factor Receptor (FGFR) family and the interconnected molecular pathways in most cases. However it can occur in association with other gene variants and with a variety of chromosome abnormalities as well, usually in association with intellectual disability (ID) and additional physical anomalies. Evaluating the molecular properties of the genes undergoing intragenic mutations or copy number variations (CNVs) along with prevalence of craniosynostosis in different conditions and animal models if available, we made an attempt to define two distinct groups of unusual syndromic craniosynostosis, which can reflect direct effects of emerging new candidate genes with roles in suture homeostasis or a non-specific phenotypic manifestation of pleiotropic genes, respectively. RASopathies and 9p23p22.3 deletions are reviewed as examples of conditions in the first group. In particular, we found that craniosynostosis is a relatively common component manifestation of cardio-facio-cutaneous (CFC) syndrome. Chromatinopathies and neurocristopathies are presented as examples of conditions in the second group. We observed that craniosynostosis is uncommon on average in these conditions. It was randomly associated with Kabuki, Koolen-de Vries/KANSL1 haploinsufficiency and Mowat–Wilson syndromes and in KAT6B-related disorders. As an exception, trigonocephaly in Bohring-Opitz syndrome reflects specific molecular properties of the chromatin modifier ASXL1 gene. Surveillance for craniosynostosis in syndromic forms of intellectual disability, as well as ascertainment of genomic CNVs by array-CGH in apparently non-syndromic craniosynostosis is recommended, to allow for improvement of both the clinical outcome of patients and the accurate individual diagnosis.

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“…It had been shown by Shukla that some components of the RAS/MAPK signaling pathway mediate dysregulated cranial development caused by pathogenic variants in fibroblast growth factor receptor (FGFR) genes (Shukla, Coumoul, Wang, Kim, & Deng, ). 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: 89%

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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Craniosynostosis in patients with RASopathies: Accumulating clinical evidence for expanding the phenotype

Cited by 39 publications

References 19 publications

Genotype-phenotype correlation analysis in Japanese patients with Noonan syndrome

Genotype-phenotype correlation analysis in Japanese patients with Noonan syndrome

Syndromic Craniosynostosis Can Define New Candidate Genes for Suture Development or Result from the Non-specifc Effects of Pleiotropic Genes: Rasopathies and Chromatinopathies as Examples

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

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