The RASopathies: Syndromes of Ras/MAPK Pathway Dysregulation

Tidyman, William E.

doi:10.1007/978-3-642-32864-0_32

Cited by 7 publications

(9 citation statements)

References 60 publications

(88 reference statements)

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“…Cardiofaciocutaneous (CFC) syndrome (OMIM # 115150, # 615278, # 615279, # 615280) is a rare and sporadic disease belonging to the group of conditions named RASopathies, that shares altered signal transduction of the RAS/MAPK (mitogen activated protein kinase) pathway (Tidyman & Rauen, ). CFC syndrome is clinically characterized by congenital heart defects, distinctive facial appearance, ectodermal abnormalities, failure to thrive with severe feeding problems, short stature with relative macrocephaly, moderate‐to‐severe intellectual disability, and possible association with seizures (Niihori et al, ; Pierpont et al, ; Raymond & Holmes, ).…”

Section: Introductionmentioning

confidence: 99%

Atypical presentation of pediatric BRAF RASopathy with acute encephalopathy

Pezzani

Marchetti

Cereda

et al. 2018

American J of Med Genetics Pt A

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We report a 9‐year‐old girl with hypotonia, severe motor delay, absent speech, and facial dysmorphism who developed acute encephalopathy with severe neurological outcome. Trio‐based whole exome sequencing (WES) analysis detected a de novo heterozygous mutation in the BRAF gene leading to the diagnosis of an atypical presentation of cardiofaciocutaneous (CFC) syndrome. This is the second case of CFC syndrome complicated with acute encephalopathy reported in the literature and supports the hypothesis that acute encephalopathy might be one of the complications of the syndrome due to an intrinsic susceptibility to this acute event. The report furthermore highlights the role of WES in providing a fast diagnosis in patients in critical conditions with atypical presentation of rare genetic syndromes.

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Section: Introductionmentioning

confidence: 99%

Atypical presentation of pediatric BRAF RASopathy with acute encephalopathy

Pezzani

Marchetti

Cereda

et al. 2018

American J of Med Genetics Pt A

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“…Dysregulation of the RAS‐MAPK signaling pathway, caused by germ line mutations in genes encoding regulators of activated RTKs ( CBL ), RAS proteins ( HRAS , KRAS , or NRAS ), modulators of RAS function ( PTPN11 , SOS1 , SHOC2 , NF1 , and SPRED1 ), or downstream signal transducers ( BRAF , RAF1 , MEK1 , and MEK2 ), has recently been recognized as the molecular cause underlying the RASopathies (Fig. 1A) [Schubbert et al, 2007; Denayer et al, 2008; Cordeddu et al, 2009; Tidyman and Rauen, 2009; Cirstea et al, 2010; Martinelli et al, 2010].…”

Section: Introductionmentioning

confidence: 99%

“…The other genes involved in NS or NS‐like conditions are RAF1 , SOS1 , KRAS , MEK1 , BRAF , SHOC2 , NRAS , and CBL , where SHOC2 and CBL are associated with the latter. These remaining eight genes are mutated in ∼20–35% of all patients with NS or NS‐like conditions [Nava et al, 2007; Razzaque et al, 2007; Nyström et al, 2008; Cordeddu et al, 2009; Sarkozy et al, 2009; Tidyman and Rauen, 2009; Cirstea et al, 2010; Martinelli et al, 2010].…”

Section: Introductionmentioning

confidence: 99%

Co‐occurring SHOC2 and PTPN11 mutations in a patient with severe/complex Noonan syndrome‐like phenotype

Ekvall

Hagenäs

Allanson

et al. 2011

American J of Med Genetics Pt A

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Noonan syndrome (NS) is a heterogeneous disorder caused by activating mutations in the RAS‐MAPK signaling pathway. It is associated with variable clinical expression including short stature, congenital heart defect, unusual pectus deformity, and typical facial features and the inheritance is autosomal dominant. Here, we present a clinical and molecular characterization of a patient with Noonan‐like syndrome with loose anagen hair phenotype and additional features including mild psychomotor developmental delay, osteoporosis, gingival hyperplasia, spinal neuroblastoma, intrathoracic extramedullary hematopoiesis, and liver hemangioma. Mutation analysis of PTPN11, SOS1, RAF1, KRAS, BRAF, MEK1, MEK2, NRAS, and SHOC2 was conducted, revealing a co‐occurrence of two heterozygous previously identified mutations in the index patient. The mutation SHOC2 c.4A > G; p.Ser2Gly represents a de novo mutation, whereas, PTPN11 c.1226G > C; p.Gly409Ala was inherited from the mother and also identified in the brother. The mother and the brother present with some NS manifestations, such as short stature, delayed puberty, keratosis pilaris, café‐au‐lait spots, refraction error (mother), and undescended testis (brother), but no NS facial features, supporting the notion that the PTPN11 p.Gly409Ala mutation leads to a relatively mild phenotype. We propose that, the atypical phenotype of the young woman with NS reported here is an additive effect, where the PTPN11 mutation acts as a modifier. Interestingly, co‐occurrence of RAS‐MAPK mutations has been previously identified in a few patients with variable NS or neurofibromatosis‐NS phenotypes. Taken together, the results suggest that co‐occurrence of mutations or modifying loci in the RAS‐MAPK pathway may contribute to the clinical variability observed among NS patients. © 2011 Wiley‐Liss, Inc.

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“…Unfortunately, Neurofibromin, encoded by the gene NF1 is a negative regulator of the Ras pathway by binding to activated Ras and catalyzing GTP hydrolysis, thereby returning Ras to the inactive GDP-bound state. Overall, 1 in 10,000 individuals are affected with an inherited syndrome that is caused by a mutation in the Ras pathway [Tidyman and Rauen, 2012]. Color coding indicates a specific association between a mutated gene and a syndrome that predisposes children to leukemia.…”

Section: Cbl Syndrome or Noonan Syndrome-like Disordermentioning

confidence: 99%

Genetic predispositions to childhood leukemia

Stieglitz

Loh

2013

Therapeutic Advances in Hematology

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While the majority of leukemia cases occur in the absence of any known predisposing factor, there are germline mutations that significantly increase the risk of developing hematopoietic malignancies in childhood. In this review article, we describe a number of these mutations and their clinical features. These predispositions can be broadly classified as those leading to bone marrow failure, those involving tumor suppressor genes, DNA repair defects, immunodeficiencies or other congenital syndromes associated with transient myeloid disorders. While leukemia can develop as a secondary event in the aforementioned syndromes, there are also several syndromes that specifically lead to the development of leukemia as their primary phenotype. Many of the genes discussed in this review can also be somatically mutated in other cancers, highlighting the importance of understanding shared alterations and mechanisms underpinning syndromic and sporadic leukemia.

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The RASopathies: Syndromes of Ras/MAPK Pathway Dysregulation

Cited by 7 publications

References 60 publications

Atypical presentation of pediatric BRAF RASopathy with acute encephalopathy

Atypical presentation of pediatric BRAF RASopathy with acute encephalopathy

Co‐occurring SHOC2 and PTPN11 mutations in a patient with severe/complex Noonan syndrome‐like phenotype

Genetic predispositions to childhood leukemia

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