<i>KRAS</i> gene mutations in Noonan syndrome familial cases cluster in the vicinity of the switch II region of the G‐domain: Report of another family with metopic craniosynostosis

RASopathies are phenotypically overlapping genetic disorders caused by dysregulation of the RAS/mitogen-activated protein kinase (MAPK) signaling pathway. RASopathies include Noonan syndrome, cardio-facio-cutaneous (CFC) syndrome, Costello syndrome, Neurofibromatosis type 1, Legius syndrome, Noonan syndrome with multiple lentigines, Noonan-like syndrome, hereditary gingival fibromatosis, and capillary malformation/arteriovenous malformation syndrome. Recently, six patients with craniosynostosis and Noonan syndrome involving KRAS mutations were described in a review, and a patient with craniosynostosis and Noonan syndrome involving a SHOC2 mutation has also been reported. Here, we describe patients with craniosynostosis and Noonan syndrome due to de novo mutations in PTPN11 and patients with craniosynostosis and CFC syndrome due to de novo mutations in BRAF or KRAS. All of these patients had cranial deformities in addition to the typical phenotypes of CFC syndrome and Noonan syndrome. In RASopathy, patients with cranial deformities, further assessments may be necessary to look for craniosynostosis. Future studies should attempt to elucidate the pathogenic mechanism responsible for craniosynostosis mediated by the RAS/MAPK signaling pathway.

Section: Discussionmentioning

confidence: 97%

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

Ueda

Yaoita

Niihori

et al. 2017

“…We report a child with Noonan syndrome due to a KRAS mutation (p.P34Q) and sagittal craniosynostosis and review all reported cases of RASopathies to identify similar patients with craniosynostosis. Including the present report, from a total of 62 cases of RASopathies with KRAS mutations, six patients had NS and craniosynostosis [Schubbert et al, ; Kratz et al, ; Lo et al, ; Brasil et al, ]. This suggests that individuals with Noonan syndrome associated with KRAS mutations have an increased risk for craniosynostosis with 1 of every 10 published cases of KRAS mutations having craniosynostosis; this is greater than 300 times the prevalence in the general population.…”

Section: Discussionmentioning

confidence: 68%

“…The p.P34Q KRAS mutation in the present patient has been reported in another individual affected with NS without craniosynostosis [Zenker et al, ], demonstrating variable expressivity of the p.P34Q mutation. With the exception of patient two in Kratz et al [], the previously reported mutations in patients with NS and craniosynostosis had also been reported in NS patients without craniosynostosis [Schubbert et al, ; Nava et al, ; Brasil et al, ]. These reports indicate that there are other genetic or environmental modifiers that influence the described abnormal cranial development.…”

Section: Discussionmentioning

confidence: 92%

“…A total of 61 reported cases of RASopathies with KRAS mutations were identified in the literature (See Supplementary Table S1) [Carta et al, ; Niihori et al, ; Schubbert et al, ; Bertola et al, ; Nava et al, ; Sovik et al, ; Zenker et al, ; Ko et al, ; Lo et al, 2008; Nystrom et al, 2008; Kratz et al, ; Leventopoulos et al, ; Adaci et al, 2012; Brasil et al, ; Choi et al, ; Malaquias et al, ; Ortiz et al, ; Stark et al, ; Cronnen et al, 2013; Nosun et al, 2013; Quaio et al, ; Fujimoto et al, ; Seemanova et al, 2014]. A review of these reports yielded five patients with NS and craniosynostosis (See Table ).…”

Section: Resultsmentioning

confidence: 99%

“…This clinically defined group of medical genetic syndromes is known as the RASopathies. Mutations in KRAS , another RAS‐MAPK gene, account for approximately 3% of NS cases and 7% of all RASopathies including cardio‐facio‐cutaneous syndrome (CFC) and a few individuals with a phenotype suggesting Costello syndrome (CS) [Brasil et al, ]. Due to variable expressivity and ascertainment bias, the penetrance of NS is unknown and many adults are only diagnosed after having an affected child [Allanson et al, 2001].…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Craniosynostosis and Noonan syndrome withKRASmutations: Expanding the phenotype with a case report and review of the literature

Addissie

Kotecha

Hart

et al. 2015

Noonan syndrome (NS) is a multiple congenital anomaly syndrome caused by germline mutations in genes coding for components of the Ras-mitogen-activated protein kinase (RAS-MAPK) pathway. Features include short stature, characteristic facies, congenital heart anomalies, and developmental delay. While there is considerable clinical heterogeneity in NS, craniosynostosis is not a common feature of the condition. Here, we report on a 2 month-old girl with Noonan syndrome associated with a de novo mutation in KRAS (p.P34Q) and premature closure of the sagittal suture. We provide a review of the literature of germline KRAS mutations and find that approximately 10% of published cases have craniosynostosis. Our findings expand on the NS phenotype and suggest that germline mutations in the KRAS gene are causally involved in craniosynostosis, supporting the role of the RAS-MAPK pathway as a mediator of aberrant bone growth in cranial sutures. The inclusion of craniosynostosis as a possible phenotype in KRAS-associated Noonan Syndrome has implications in the differential diagnosis and surgical management of individuals with craniosynostosis.

Severe craniosynostosis with Noonan syndrome phenotype associated with SHOC2 mutation: Clinical evidence of crosslink between FGFR and RAS signaling pathways

Tamura

Sakamoto

Miwa

et al. 2014

Dysregulation in the RAS signaling cascade results in a family of malformation syndromes called RASopathies. Meanwhile, alterations in FGFR signaling cascade are responsible for various syndromic forms of craniosynostosis. In general, the phenotypic spectra of RASopathies and craniosynostosis syndromes do not overlap. Recently, however, mutations in ERF, a downstream molecule of the RAS signaling cascade, have been identified as a cause of complex craniosynostosis, suggesting that the RAS and FGFR signaling pathways can interact in the pathogenesis of malformation syndromes. Here, we document a boy with short stature, developmental delay, and severe craniosynostosis involving right coronal, bilateral lambdoid, and sagittal sutures with a de novo mutation in exon1 of SHOC2 (c.4A>G p.Ser2Gly). This observation further supports the existence of a crosslink between the RAS signaling cascade and craniosynostosis. In retrospect, the propositus had physical features suggestive of a dysregulated RAS signaling cascade, such as fetal pleural effusion, fetal hydrops, and atrial tachycardia. In addition to an abnormal cranial shape, which has been reported for this specific mutation, craniosynostosis might be a novel associated phenotype. In conclusion, the phenotypic combination of severe craniosynostosis and RASopathy features observed in the propositus suggests an interaction between the RAS and FGFR signaling cascades. Patients with craniosynostosis in combination with any RASopathy feature may require mutation screening for molecules in the FGFR-RAS signaling cascade.